2384891 ACIDS INCLUDING OPEN READING FRAMES ENCODING POLYPEPTIDES; ORFX

ACIDES NUCLEIQUES COMPRENANT DES PHASES DE LECTURE OUVERTE CODANT DES POLYPEPTIDES; ORFX

English Abstract

The present invention provides open reading frames encoding isolated
polypeptides, as well as polynucleotides encoding ORFX and antibodies that
immunospecifically bind to ORFX or any derivative, variant, mutant, or
fragment of the ORFX polypeptides, polynucleotides or antibodies. The
invention additionally provides methods in which the ORFX polypeptide,
polynucleotide and antibody are used in detection and treatment of a broad
range of pathological states, as well as to other uses.

French Abstract

La présente invention concerne des phases de lecture ouverte ORFX, des polypeptides isolés, ainsi que des polynucléotides codant les ORFX et les anticorps qui lient les ORFX ou tout autre dérivé de manière immunospécifique, des variants, des mutants, ou des fragments de polypeptide, polynucléotide ou anticorps ORFX utilisés dans la détection et le traitement de plusieurs états pathologiques, comme dans d'autres domaines.

Claims

What is claimed is:
1. An isolated nucleic acid molecule encoding a polypeptide comprising an
amino
acid sequence that is at least 85% identical to a polypeptide including an
amino acid sequence
selected from the group consisting of SEQ ID NO:2n, wherein n is any integer 1-
3161, or the
complement thereof.
2. The isolated nucleic acid molecule of claim 1, said molecule hybridizing
under
stringent conditions to a nucleic acid sequence complementary to a nucleic
acid molecule
comprising the sequence of nucleotides selected from the group consisting of
SEQ ID NO:2n-
wherein n is any integer 1-3161, or the complement thereof.
3. The isolated nucleic acid molecule of claim 1, said molecule encoding a
polypeptide comprising the amino acid sequence selected from the group
consisting of SEQ ID
NO: 2n, wherein n is any integer 1-3161, or an amino acid sequence comprising
one or more
conservative substitutions in the amino acid sequence selected from the group
consisting of SEQ
ID NO: 2n.
4. The isolated nucleic acid molecule of claim 1, wherein said molecule
encodes
polypeptide comprising the amino acid sequence selected from the group
consisting of SEQ ID
NO: 2n, wherein n is any integer 1-3161.
5. The isolated nucleic acid molecule of claim l, wherein said molecule
comprise
the sequence of nucleotides selected from the group consisting of SEQ ID NO:2n-
1, wherein
any integer 1-3161, or the complement thereof.
6. An oligonucleotide less than 100 nucleotides in length and comprising at
least
contiguous nucleotides selected from the group consisting of SEQ ID NO:2n-1,
wherein n is a
integer 1-3161, or the complement thereof.
7. A vector comprising the nucleic acid molecule of claim 1.
5503

8. ~The vector of claim 7, wherein said vector is an expression vector.
9 ~A host cell comprising the isolated nucleic acid molecule of claim 1.
10. ~A substantially purified polypeptide comprising an amino acid sequence at
least
80% identical to a polypeptide comprising the amino acid sequence selected
from the group
consisting of SEQ ID NO: 2n, wherein n is any integer 1-3161.
11. ~The polypeptide of claim 10, wherein said polypeptide comprises the amino
acid
sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is any
integer 1-3161.
12. ~An antibody that selectively binds to the polypeptide of claim 10.
13. ~A pharmaceutical composition comprising a therapeutically or
prophylactically
effective amount of a therapeutic selected from the group consisting of:
a) the nucleic acid of claim 1;
b) the polypeptide of claim 10; and
c) the antibody of claim 12;
and a pharmaceutically acceptable carrier.
14. ~A kit comprising in one or more containers, a therapeutically or
prophylactically
effective amount of the pharmaceutical composition of claim 13.
15. ~A method of producing the polypeptide of claim 10, said method comprising
culturing the host cell of claim 9 under conditions in which the nucleic acid
molecule is
expressed.
16. ~A method of detecting the presence of the polypeptide of claim 10 in a
sample,
comprising contacting the sample with a compound that selectively binds to
said polypeptide
under conditions allowing the formation of a complex between said polypeptide
and said
5504

compound, and detecting said complex, if present, thereby identifying said
polypeptide in said
sample.
17. A method of detecting the presence of a nucleic acid molecule of claim 1
in a
sample, the method comprising contacting the sample with a nucleic acid probe
or primer that
selectively binds to the nucleic acid molecule and determining whether the
nucleic acid probe ~
primer bound to the nucleic acid molecule of claim 1 is present in the sample.
18. A method for modulating the activity of the polypeptide of claim 10, the
method
comprising contacting a cell sample comprising the polypeptide of claim 10
with a compound
that binds to said polypeptide in an amount sufficient to modulate the
activity of the polypeptide
19. The use of a therapeutic in the manufacture of a medicament for treating a
syndrome associated with a ORFX-associated disorder, wherein said therapeutic
is selected from
the group consisting of:
a) the nucleic acid of claim 1;
b) the polypeptide of claim 10; and
c) the antibody of claim 12.
20. A method for screening for a modulator of activity or of latency or
predisposition
to an ORFX-associated disorder, said method comprising:
a) contacting a test compound with the polypeptide of claim 10; and
b) determining if said test compound binds to said polypeptide,
wherein binding of said test compound to said polypeptide indicates the test
compound is a
modulator of activity or of latency or predisposition to an ORFX-associated
disorder.
21. A method for screening for a modulator of activity or of latency or
predisposition
to an ORFX-associated disorder, said method comprising:
a) administering a test compound to a test subject at an increased risk ORFX-
associated disorder, wherein said test subject recombinantly expresses a
polypeptide encoded by the nucleotide of claim 1;
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b) measuring expression the activity of said protein in said test subject;
c) measuring the activity of said protein in a control subject that
recombinantly
expresses said protein and is not at increased risk for an ORFX-associated
disorder; and
d) comparing expression of said protein in said test subject and said control
subject,
wherein a change in the activity of said protein in said test subject relative
to said
control subject indicates the test compound is a modulator or of latency of
predispostition to an ORFX-associated disorder.
22. The method of claim 20, wherein said test animal is a recombinant test
animal
that expresses a test protein transgene or expresses said transgene under the
control of a promoter
at an increased level relative to a wild-type test animal, and wherein said
promoter is not the
native gene promoter of said transgene.
23. A method for determining the presence of or predisposition to a disease
associated
with altered levels of a polypeptide of claim 11 in a subject, the method
comprising:
a) measuring the amount of the polypeptide in a sample from said subject; and
b) comparing the amount of said polypeptide in step (a) to the amount of the
polypeptide present in a control sample,
wherein an alteration in the level of the polypeptide in step (a) as compared
to the control
sample indicates the presence of or predisposition to a disease in said
subject.
24. The method of claim 23, wherein said subject is a human.
25. A method for determining the presence of or predisposition to a disease
associated
with altered levels the nucleic acid molecule of claim 1 in a subject, the
method comprising:
a) measuring the amount of the nucleic acid in a sample from the mammalian
subject; and
b) comparing the amount of said nucleic acid in step (a) to the amount of the
nucleic
acid present in a control sample,
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wherein an alteration in the level of the nucleic acid in step (a) as compared
to the coy
sample indicates the presence of or predisposition to said disease in said
subject.
26. The method of claim 25, wherein said subject is a human.
27. A method of treating or preventing a pathological condition associated
with ai
ORFX-associated disorder in a subject, the method comprising administering to
said subject
polypeptide of claim 10 in an amount sufficient to alleviate or prevent said
pathological
condition.
28. The method of claim 27, wherein said subject is a human.
29. A method of treating or preventing a pathological condition associated
with at
ORFX-associated disorder in a subject, the method comprising administering to
said subject
nucleic acid molecule of claim 1 in an amount sufficient to alleviate or
prevent said pathology
condition.
30. The method of claim 29, wherein said subject is a human.
31. A method of treating or preventing a pathological condition associated
with an
ORFX-associated disorder in a subject, the method comprising administering to
said subject
antibody of claim 12 in an amount sufficient to alleviate or prevent said
pathological condition
32. The method of claim 31, wherein said subject is a human.
5507

Description

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CA 02383592 2001-09-26
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NOVEL POLYNUCLEOTIDES AND POLYPEPTIDES ENCODED THEREBY
BACKGROUND OF THE INVENTION
The invention relates generally to nucleic acids and polypeptides encoded
thereby, and
methods of using these nucleic acids and polypeptides.
SUMMARY OF THE INVENTION
The invention is based in part on the discovery of nucleic acids that include
open reading
frames encoding novel polypeptides, and on the polypeptides encoded thereby.
The nucleic
acids and polypeptides are collectively referred to herein as "ORFX".
Accordingly, in one aspect, the invention provides an isolated nucleic acid
molecule
(SEQ ID N0:2n-1, wherein n is an integer between 1-3161), that encodes novel
polypeptide, or a
fragment, homolog, analog or derivative thereof. The nucleic acid can include,
e.g., a nucleic
acid sequence encoding a polypeptide at least 85% identical to a polypeptide
comprising the
amino acid sequences of SEQ ID N0:2n, wherein n is an integer between 1-3161.
The nucleic
acid can be, e.g., a genomic DNA fragment, or a cDNA molecule.
Also included in the invention is a vector containing one or more of the
nucleic acids
described herein, and a cell containing the vectors or nucleic acids described
herein.
The invention is also directed to host cells transformed with a recombinant
expression
vector comprising any of the nucleic acid molecules described above.
In another aspect, the invention includes a pharmaceutical composition that
includes an
ORFX nucleic acid and a pharmaceutically acceptable carrier or diluent.

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In a further aspect, the invention includes a substantially purified ORF
polypeptide, e.g.,
any of the ORFX polypeptides encoded by an ORFX nucleic acid, and fragments,
homologs,
analogs, and derivatives thereof. The invention also includes a pharmaceutical
composition that
includes a ORFX polypeptide and a pharmaceutically acceptable carrier or
diluent.
S In a still a further aspect, the invention provides an antibody that binds
specifically to an
ORFX polypeptide. The antibody can be, e.g., a monoclonal or polyclonal
antibody, and
fragments, homologs, analogs, and derivatives thereof. The invention also
includes a
pharmaceutical composition including ORFX antibody and a pharmaceutically
acceptable carrier
or diluent. The invention is also directed to isolated antibodies that bind to
an epitope on a
polypeptide encoded by any of the nucleic acid molecules described above.
The invention also includes kits comprising any of the pharmaceutical
compositions
described above.
The invention fiu~ther provides a method for producing an ORFX polypeptide by
providing a cell containing a ORFX nucleic acid, e.g., a vector that includes
a ORFX nucleic
1 S acid, and culturing the cell under conditions sufficient to express the
ORFX polypeptide encoded
by the nucleic acid. The expressed ORFX polypeptide is then recovered from the
cell.
Preferably, the cell produces little or no endogenous ORFX polypeptide. The
cell can be, e.g., a
prokaryotic cell or eukaryotic cell.
The invention is also directed to methods of identifying an ORFX polypeptide
or nucleic
acids in a sample by contacting the sample with a compound that specifically
binds to the
polypeptide or nucleic acid, and detecting complex formation, if present.
The invention further provides methods of identifying a compound that
modulates the
activity of a ORFX polypeptide by contacting ORFX polypeptide with a compound
and
determining whether the ORFX polypeptide activity is modified.
The invention is also directed to compounds that modulate ORFX polypeptide
activity
identified by contacting a ORFX polypeptide with the compound and determining
whether the
compound modifies activity of the ORFX polypeptide, binds to the ORFX
polypeptide, or binds
to a nucleic acid molecule encoding a ORFX polypeptide.
In a another aspect, the invention provides a method of determining the
presence of or
predisposition of an ORFX-associated disorder in a subject. The method
includes providing a
sample from the subject and measuring the amount of ORFX polypeptide in the
subject sample.
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The amount of ORFX polypeptide in the subject sample is then compared to the
amount of
ORFX polypeptide in a control sample. An alteration in the amount of ORFX
polypeptide in the
subject protein sample relative to the amount of ORFX polypeptide in the
control protein sample
indicates the subject has a tissue proliferation-associated condition. A
control sample is
preferably taken from a matched individual, i.e., an individual of similar
age, sex, or other
general condition but who is not suspected of having a tissue proliferation-
associated condition.
Alternatively, the control sample may be taken from the subject at a time when
the subject is not
suspected of having a tissue proliferation-associated disorder. In some
embodiments, the ORFX
is detected using a ORFX antibody.
In a further aspect, the invention provides a method of determining the
presence of or
predisposition of an ORFX-associated disorder in a subject. The method
includes providing a
nucleic acid sample, e.g., RNA or DNA, or both, from the subject and measuring
the amount of
the ORFX nucleic acid in the subject nucleic acid sample. The amount of ORFX
nucleic acid
sample in the subject nucleic acid is then compared to the amount of an ORFX
nucleic acid in a
control sample. An alteration in the amount of ORFX nucleic acid in the sample
relative to the
amount of ORFX in the control sample indicates the subject has a tissue
proliferation-associated
disorder.
In a still further aspect, the invention provides method of treating or
preventing or
delaying a ORFX-associated disorder. The method includes administering to a
subject in which
such treatment or prevention or delay is desired a ORFX nucleic acid, a ORFX
polypeptide, or
an ORFX antibody in an amount sufficient to treat, prevent, or delay a tissue
proliferation-
associated disorder in the subject.
Unless otherwise defined, all technical and scientific terms used herein have
the same
meaning as commonly understood by one of ordinary skill in the art to which
this invention
belongs. Although methods and materials similar or equivalent to those
described herein can be
used in the practice or testing of the present invention, suitable methods and
materials are
described below. All publications, patent applications, patents, and other
references mentioned
herein are incorporated by reference in their entirety. In the case of
conflict, the present
specification, including definitions, will control. In addition, the
materials, methods, and
examples are illustrative only and not intended to be limiting.
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Other features and advantages of the invention will be apparent from the
following
detailed description and claims.
DETAILED DESCRIPTION OF THE INVENTION
The invention provides novel polypeptides and nucleotides encoded thereby. The
polynucleotides and their encoded polypeptides can be grouped according to the
functions played
by their gene products. Such functions include, structural proteins, proteins
from which
associated with metabolic pathways fatty acid metabolism, glycolysis,
intermediary metabolism,
calcium metabolism, proteases, and amino acid metabolism, etc.
Included in the invention are 3161 novel nucleic acid sequences and their
encoded
polypeptides. The sequences are collectively referred to as "ORFX nucleic
acids" or ORFX
polynucleotides" and the corresponding encoded polypeptide is referred to as a
"ORFX
polypeptide" or ORFX protein". For example, an ORFX nucleic acid according to
the invention
is a nucleic acid including an ORF 1 nucleic acid, and an ORF polypeptide
according to the
invention is a polypeptide that includes the amino acid sequence of an ORF1
polypeptide.
Unless indicated otherwise, "ORFX" is meant to refer to any of the ORF1-3161
sequences
disclosed herein.
Table 1 provides a summary of the ORFX nucleic acids and their encoded
polypeptides
are summarized in Table 1. Nucleic acid sequences and polypeptide sequences
for ORFX
nucleic acids according to the invention is provided in the section of the
specification entitled
"Disclosed Sequences of ORFX Nucleic Acid and Polypeptide Sequences."
Column 1 of Table 1, entitled "ORF #", denotes an ORF number assigned to a
nucleic
acid containing an open reading frame according to the invention.
Column 2 of Table 1, entitled "Internal Identification number (Nucleic Acid
Sequence
Identification Number, Polypeptide Sequence Identification Number), provides
an internal
identification number for the indicated ORF, along with sequence
identification numbers (SEQ
ID NOs.) corresponding to the indicated ORF. In general, for an ORFn according
to the
invention (wherein n is any integer from 1 to 3161 ), a nucleic acid
corresponding to the ORF is
SEQ ID N0:2n-1, and an amino acid sequence encoded by the ORF is SEQ ID N0:2n.
For
example, a nucleic acid sequence corresponding to an ORF1 nucleic acid is SEQ
ID NO:1, and a
polypeptide sequence corresponding to an ORF 1 polypeptide is SEQ ID N0:2.
Similarly, a
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nucleic acid sequence corresponding to an ORF4 nucleic acid is SEQ ID N0:7,
and a
polypeptide sequence corresponding to an ORF4 polypeptide is SEQ ID N0:8; a
nucleic acid
sequence corresponding to an ORF198 nucleic acid sequence is SEQ ID N0:395,
and a
polypeptide sequence corresponding to an ORF198 polypeptide is SEQ ID N0:396.
Nucleic acid
sequences and polypeptide sequences for ORFX nucleic acids according to the
invention are
provided in the section of the specification entitled "Disclosed Sequences of
ORFX Nucleic Acid
and Polypeptide Sequences."
Column 2 of Table 1, entitled "Protein Similarity", lists previously described
proteins
that are related to polypeptides encoded by the ORFs. Genbank identifiers for
the previously
described proteins are provided. These can be retrieved from
http://www.ncbi.nlm.nih.gov/.
To determine similarity to previously described proteins, polypeptides encoded
by ORFX
DNA sequences were tested using the Framesearch Algorithm against a
nonredundant version of
the GenPept Database from NCBI/Genbank. DNA sequences that had a score of'90'
or above
(Framesearch algorithm score, Edelman et. al. GCG Genetics) to a known protein
were selected.
Open reading frames were extended beyond the region of the protein matched
using standard
DNA translation and codon tables. Novel proteins that lacked a protein match
were translated
against the standard genetic codons and proteins with an ORF at least 80 amino
acids and
containing a Methionine start are included in the Table.
Column 3 of Table 3, entitled "Protein Domains", lists previously described
protein
domains, designated by pfam entries, that are present in polypeptides encoded
by the ORFs,
Also included in column 3 are proteins in which these domains are present. The
pfam entries can
be retrieved from http://pfam.wustl.edu/. DNA sequences were translated in all
six frames and
tested using the Hmmer Algorithm against the Pfam Database (References to the
algorithm and
Pfam database can be found at http://pfam.wustl.edu). Translated DNA sequences
that
matched a protein domain entry in the Pfam database AND had a score of 7.5'
were selected.
Column 4 of Table 3, entitled "Protein Classification", lists the type of
classification
assigned for the protein, based on its homology. Examples of proteins in the
classification
include the following proteins:

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Amylases
Amylase is responsible for endohydrolysis of 1,4-alpha-glucosidic linkages in
oligosaccharides and polysaccharides. Variations in amylase gene may be
indicative of delayed
maturation and of various amylase producing neoplasms and carcinomas.
Amyloid
The serum amyloid A (SAA) proteins comprise a family of vertebrate proteins
that
associate predominantly with high density lipoproteins (HDL). The synthesis of
certain members
of the family is greatly increased in inflammation. Prolonged elevation of
plasma SAA levels, as
in chronic inflammation, 15 results in a pathological condition, called
amyloidosis, which affects
the liver, kidney and spleen and which is characterized by the highly
insoluble accumulation of
SAA in these tissues. Amyloid selectively inhibits insulin-stimulated glucose
utilization and
glycogen deposition in muscle, while not affecting adipocyte glucose
metabolism. Deposition of
fibrillar amyloid proteins intraneuronally, as neurofibrillary tangles,
extracellularly, as plaques
and in blood vessels, is characteristic of both Alzheimer's disease and aged
Down's syndrome.
Amyloid deposition is also associated with type II diabetes mellitus.
Angiopoeitin
Members of the angiopoeitin/fibrinogen family have been shown to stimulate the
generation of new blood vessels, inhibit the generation of new blood vessels,
and perform several
roles in blood clotting. This generation of new blood vessels, called
angiogenesis, is also an
essential step in tumor growth in order for the tumor to get the blood supply
it needs to expand.
Variation in these genes may be predictive of any form of heart disease,
numerous blood clotting
disorders, stroke, hypertension and predisposition to tumor formation and
metastasis. In
particular, these variants may be predictive of the response to various
antihypertensive drugs and
chemotherapeutic and anti-tumor agents.
Apoptosis-related proteins
Active cell suicide (apoptosis) is induced by events such as growth factor
withdrawal and
toxins. It is controlled by regulators, which have either an inhibitory effect
on programmed cell
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death (anti-apoptotic) or block the protective effect of inhibitors (pro-
apoptotic). Many viruses
have found a way of countering defensive apoptosis by encoding their own anti-
apoptosis genes
preventing their target-cells from dying too soon. Variants of apoptosis
related genes may be
useful in formulation of anti-aging drugs.
Cadherin, Cyclin, Polymerase, Oncogenes, Histones, Kinases
Members of the cell division/cell cycle pathways such as cyclins, many
transcription
factors and kinases, DNA polymerases, histones, helicases and other oncogenes
play a critical
role in carcinogenesis where the uncontrolled proliferation of cells leads to
tumor formation and
eventually metastasis. Variation in these genes may be predictive of
predisposition to any form
of cancer, from increased risk of tumor formation to increased rate of
metastasis. In particular,
these variants may be predictive of the response to various chemotherapeutic
and anti-tumor
agents.
Colony-stimulating factor-related proteins
Granulocyte/macrophage colony-stimulating factors are cytokines that act in
1 S hematopoiesis by controlling the production, differentiation, and function
of 2 related white cell
populations of the blood, the granulocytes and the monocytes-macrophages.
Complement-related proteins
Complement proteins are immune associated cytotoxic agents, acting in a chain
reaction
to exterminate target cells to that were opsonized (primed) with antibodies,
by forming a
membrane attack complex (MAC). The mechanism of killing is by opening pores in
the target
cell membrane. Variations in 20 complement genes or their inhibitors are
associated with many
autoimmune disorders. Modified serum levels of complement products cause
edemas of various
tissues, lupus (SLE), vasculitis, glomerulonephritis, renal failure, hemolytic
anemia,
thrombocytopenia, and arthritis. They interfere with mechanisms of ADCC
(antibody dependent
cell cytotoxicity), severely impair immune competence and reduce phagocytic
ability. Variants
of complement genes may also be indicative of type I diabetes mellitus,
meningitis neurological
disorders such as nemaline myopathy, neonatal hypotonia, muscular disorders
such as congenital
myopathy and other diseases.
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Cytochrome
The respiratory chain is a key biochemical pathway which is essential to all
aerobic cells.
There are five different cytochromes involved in the chain. These are heme
bound proteins
which serve as electron carriers. Modifications in these genes may be
predictive of ataxia
areflexia, dementia and myopathic and neuropathic changes in muscles. Also,
association with
various types of solid tumors.
Kinesins
Kinesins are tubulin molecular motors that function to transport organelles
within cells
and to move chromosomes along microtubules during cell division. Modifications
of these genes
may be indicative of neurological disorders such as Pick disease of the brain,
tuberous sclerosis.
Cytokines, Interferon, Interleukin
Members of the cytokine families are known for their potent ability to
stimulate cell
growth and division even at low concentrations. Cytokines such as
erythropoietin are
cell-specific in their growth stimulation; erythropoietin is useful for the
stimulation of the
proliferation of erythroblasts. Variants in cytokines may be predictive for a
wide variety of
diseases, including cancer predisposition.
G-protein coupled receptors
G-protein coupled receptors (also called R7G) are an extensive group of
hormones,
neurotransmitters, odorants and light receptors which transduce extracellular
signals by
interaction with guanine nucleotide-binding (G) proteins. Alterations in genes
coding for
G-coupled proteins may be involved in and indicative of a vast number of
physiological
conditions. These include blood pressure regulation, renal dysfunctions, male
infertility,
dopamine associated cognitive, emotional, and endocrine functions,
hypercalcemia,
chondrodysplasia and osteoporosis, pseudohypoparathyroidism, -growth
retardation and
dwarfism.

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Thioesterases
Eukaryotic thiol proteases are a family of proteolytic enzymes which contain
an active
site cysteine. Catalysis proceeds through a thioester intermediate and is
facilitated by a nearby
histidine side chain; an asparagine completes the essential catalytic triad.
Variants of thioester
associated genes may be predictive of neuronal disorders and mental illnesses
such as Ceroid
Lipoffiscinosis, Neuronal 1, Infantile, Santavuori disease and more.
The key to the molecule type is as follows:
Abbrev: Title:
amylase amylase protein
amylaseinhib amylase inhibitor
amyloid amyloid protein
apoptosis apoptosis associated protein
apoptosisinhib apoptosis inhibitors
apoptosisrecep apoptosis receptors
ATPase_associated ATPase associated protein
biotindep biotin dependent enzyme/protein
cadherin cadherin protein
calcium_channel calcium channel protein
carboxylase carboxylase protein
cathepsin cathepsin/carboxypeptidases
cathepsininhib cathepsin/carboxypeptidase inhibitor
chloride_channel chloride channel protein
collagen collagen
complement complement protein
complementrecept complement receptor protein
complementinhib complement inhibitor
csf colony stimulating factor
csfrecept colony stimulating factor receptor
cyclin cyclin protein
cyto450 cytochrome p450 protein
cytochrome cytochrome related protein
deaminase deaminase
dehydrogenase dehydrogenase
desaturase desaturase
dna_rna_bind DNA/RNA binding protein/factor
dna_rna_inhib DNA/RNA binding protein/factor inhibitor
dynein dynein
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elastase elastase
elastaseinhib elastase inhibitor
eph EPH family of tyrosine kinases
esterase esterase
esteraseinhib esterase inhibitor
fgf fibroblast growth factor
fgfreceptor fibroblast growth factor receptor
gaba GABA receptor
glucoamylase glucoamylase
glucoronidase glucoronidase
glycoprotein glycoprotein
Guanylyl guanylylate cyclase
helicase helicase
histone histone
HOM homologous
homeobox homeobox protein
hydrolase hydrolase
hydroxysteroid hydroxysteroid associated protein
hypoxanthine hypoxanthine associated protein
immunoglob immunoglobulin
immunoglobrecept immunoglobulin receptor
interferon interferon
interleukin interleukin
interleukinrecept interleukin receptor
isomerase isomerase
isomeraseinhibitor isomerase inhibitor
isomerasereceptor isomerase receptor
kinase kinase
kinaseinhibitor kinase inhibitor
kinasereceptor kinase receptor
kinesin kinesin
laminin laminin associated protein
lipase lipase
metallothionein metallothionein
MHC major histocompatability complex
misc_channel miscellaneous channel
ngf nerve growth factor
nuci_recpt nuclear receptor
nuclease nuclease
oncogene oncogene associated protein
oxidase oxidase
oxygenase oxygenase
peptidase peptidase
peroxidase peroxidase
phosphatase phosphatase
phosphataseinhib phosphatase inhibitor

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phosphorylase phosphorylase
PIR PIR DATABASE (release 56, 29-OCT-
1998)
polymerase polymerase
potassium_channel potassium channel protein
prostaglandin prostaglandin
protease protease
proteaseinhib protease inhibitor
reductase reductase
ribosomalprot ribosomal associated protein
RTR EMBLDATABASE translated entries not
to
be incorporated into SWISS-PROT (20-
JUL-1998)
SIM similar
1 S SPTR EMBL DATABASE translated entries to
be
incorporated into SWISS-PROT (20-JLJL-
1998)
struct structural associated protein
sulfotransferase sulfotransferase
SWP SWISS-PROT DATABASE (release 18-
OCT-1998)
SWPN SWISS-PROT Update (release 11-NOV-98)
synthase synthase
tgf transforming growth factor
tgfreceptor transforming growth factor receptor
thioesterase thioesterase
thiolase thiolase
tm7 seven transmembrane domain G-protein
coupled receptor
tnf necrosis factor receptor
traffic tumor necrosis factor
tnfreceptor tumor trafficking associated protein
TRN EMBL DATABASE translated entries
update (20-JLJL-1998)
transcriptfactor transcription factor
transferase transferase
transport transport protein
tubulin tubulin
ubiquitin ubiquitin
unclassified Protein not categorized into one of
the
aforementioned protein families
water channel water channel protein
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Column S of Table 1, entitled, "Cells or Tissues in Which Gene is Expressed",
denotes tissues,
represented by five digit numbers, in which RNA homologous to the ORF nucleic
acid
sequences is present. Tissues or cells corresponding to the numbers are
provided in Table 2.
ORFX nucleic acids, and their encoded polypeptides, according to the invention
are
useful in a variety of applications and contexts. For example, various ORFX
nucleic acids and
polypeptides according to the invention are useful, inter alia, as novel
members of the protein
families indicated in Table 1, and/or according to the presence of domains and
sequence
relatedness to previously described proteins as summarized in Table 1.
ORFX nucleic acids and polypeptides according to the invention can also be
used to
identify cell types listed in Table 1 for an indicated ORFX according to the
invention.
Additional utilities for ORFX nucleic acids and polypeptides according to the
invention are
disclosed herein.
ORFX Nucleic Acids
The novel nucleic acids of the invention include those that encode an ORFX or
ORFX-
like protein, or biologically active portions thereof. The nucleic acids
include nucleic acids
encoding polypeptides that include the amino acid sequence of one or more of
SEQ ID N0:2n,
wherein n = 1 to 3161. The encoded polypeptides can thus include, e.g., the
amino acid
sequences of SEQ ID NO: 2, 4, 6, 8, 10, . . ., 6310, 6312, 6314, 6316, 6318,
6320, and/or 6322.
In some embodiments, a nucleic acid encoding a polypeptide having the amino
acid
sequence of one or more of SEQ ID N0:2n (wherein n = 1 to 3161 ) includes the
nucleic acid
sequence of any of SEQ ID N0:2n-1 (wherein n = 1 to 3161 ), or a fragment
thereof.
Additionally, the invention includes mutant or variant nucleic acids of any of
SEQ ID N0:2n-1
(wherein n = 1 to 3161 ), or a fragment thereof, any of whose bases may be
changed from the
disclosed sequence while still encoding a protein that maintains its ORFX -
like activities and
physiological functions. The invention further includes the complement of the
nucleic acid
sequence of any of SEQ ID N0:2n-1 (wherein n = 1 to 3161 ), including
fragments, derivatives,
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analogs and homolog thereof. The invention additionally includes nucleic acids
or nucleic acid
fragments, or complements thereto, whose structures include chemical
modifications.
Also included are nucleic acid fragments sufficient for use as hybridization
probes to
identify ORFX-encoding nucleic acids (e.g., ORFX mRNA) and fragments for use
as
polymerase chain reaction (PCR) primers for the amplification or mutation of
ORFX nucleic
acid molecules. As used herein, the term "nucleic acid molecule" is intended
to include DNA
molecules (e.g., cDNA or genomic DNA), RNA molecules (e.g., mRNA), analogs of
the DNA or
RNA generated using nucleotide analogs, and derivatives, fragments and
homologs thereof. The
nucleic acid molecule can be single-stranded or double-stranded, but
preferably is
double-stranded DNA.
"Probes" refer to nucleic acid sequences of variable length, preferably
between at least
about 10 nucleotides (nt), 100 nt, or as many as about, e.g., 6,000 nt,
depending on use. Probes
are used in the detection of identical, similar, or complementary nucleic acid
sequences. Longer
length probes are usually obtained from a natural or recombinant source, are
highly specific and
much slower to hybridize than oligomers. Probes may be single- or double-
stranded and
designed to have specificity in PCR, membrane-based hybridization
technologies, or ELISA-like
technologies.
An "isolated" nucleic acid molecule is one that is separated from other
nucleic acid
molecules that are present in the natural source of the nucleic acid. Examples
of isolated nucleic
acid molecules include, but are not limited to, recombinant DNA molecules
contained in a
vector, recombinant DNA molecules maintained in a heterologous host cell,
partially or
substantially purified nucleic acid molecules, and synthetic DNA or RNA
molecules. Preferably,
an "isolated" nucleic acid is free of sequences which naturally flank the
nucleic acid (i.e.,
sequences located at the 5' and 3' ends of the nucleic acid) in the genomic
DNA of the organism
from which the nucleic acid is derived. For example, in various embodiments,
the isolated
ORFX nucleic acid molecule can contain less than about 50 kb, 25 kb, 5 kb, 4
kb, 3 kb, 2 kb, 1
kb, 0.5 kb or 0.1 kb of nucleotide sequences which naturally flank the nucleic
acid molecule in
genomic DNA of the cell from which the nucleic acid is derived: Moreover, an
"isolated"
nucleic acid molecule, such as a cDNA molecule, can be substantially free of
other cellular
material or culture medium when produced by recombinant techniques, or of
chemical
precursors or other chemicals when chemically synthesized.
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A nucleic acid molecule of the present invention, e.g., a nucleic acid
molecule having the
nucleotide sequence of SEQ ID N0:2n-1 (wherein n = 1 to 3161), or a complement
of any of this
nucleotide sequence, can be isolated using standard molecular biology
techniques and the
sequence information provided herein. Using all or a portion of the nucleic
acid sequence of any
S of SEQ ID N0:2n-1 (wherein n=1 to 3161) as a hybridization probe, ORFX
nucleic acid
sequences can be isolated using standard hybridization and cloning techniques
(e.g., as described
in Sambrook et al., eds., MOLECULAR CLONING: A LABORATORY MANUAL 2°d
Ed., Cold Spring
Harbor Laboratory Press, Cold Spring Harbor, NY, 1989; and Ausubel, et al.,
eds., CURRENT
PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, NY, 1993.)
A nucleic acid of the invention can be amplified using cDNA, mRNA or
alternatively,
genomic DNA, as a template and appropriate oligonucleotide primers according
to standard PCR
amplification techniques. The nucleic acid so amplified can be cloned into an
appropriate vector
and characterized by DNA sequence analysis. Furthermore, oligonucleotides
corresponding to
ORFX nucleotide sequences can be prepared by standard synthetic techniques,
e.g., using an
automated DNA synthesizer.
As used herein, the term "oligonucleotide" refers to a series of linked
nucleotide residues,
which oligonucleotide has a sufficient number of nucleotide bases to be used
in a PCR reaction.
A short oligonucleotide sequence may be based on, or designed from, a genomic
or cDNA
sequence and is used to amplify, confirm, or reveal the presence of an
identical, similar or
complementary DNA or RNA in a particular cell or tissue. Oligonucleotides
comprise portions
of a nucleic acid sequence having about 10 nt, 50 nt, or 100 nt in length,
preferably about 15 nt
to 30 nt in length. In one embodiment, an oligonucleotide comprising a nucleic
acid molecule
less than 100 nt in length would further comprise at lease 6 contiguous
nucleotides of any of
SEQ ID N0:2n-1 (wherein n = 1 to 3161), or a complement thereof.
Oligonucleotides may be
chemically synthesized and may be used as probes.
In another embodiment, an isolated nucleic acid molecule of the invention
comprises a
nucleic acid molecule that is a complement of the nucleotide sequence shown in
any of SEQ ID
N0:2n-1 (wherein n = 1 to 3161). In another embodiment, an isolated nucleic
acid molecule of
the invention comprises a nucleic acid molecule that is a complement of the
nucleotide sequence
shown in any of SEQ ID N0:2n-1 (wherein n = 1 to 3161), or a portion of this
nucleotide
sequence. A nucleic acid molecule that is complementary to the nucleotide
sequence shown in
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is one that is sufficiently complementary to the nucleotide sequence shown in
of any of SEQ ID
N0:2n-1 (wherein n = 1 to 3161) that it can hydrogen bond with little or no
mismatches to the
nucleotide sequence shown in of any of SEQ ID N0:2n-1 (wherein n = 1 to 3161)"
thereby
forming a stable duplex.
As used herein, the term "complementary" refers to Watson-Crick or Hoogsteen
base
pairing between nucleotides units of a nucleic acid molecule, and the term
"binding" means the
physical or chemical interaction between two polypeptides or compounds or
associated
polypeptides or compounds or combinations thereof. Binding includes ionic, non-
ionic, Von der
Waals, hydrophobic interactions, etc. A physical interaction can be either
direct or indirect.
Indirect interactions may be through or due to the effects of another
polypeptide or compound.
Direct binding refers to interactions that do not take place through, or due
to, the effect of
another polypeptide or compound, but instead are without other substantial
chemical
intermediates.
Moreover, the nucleic acid molecule of the invention can comprise only a
portion of the
nucleic acid sequence of any of SEQ ID N0:2n-1 (wherein n = 1 to 3161), e.g.,
a fragment that
can be used as a probe or primer, or a fragment encoding a biologically active
portion of ORFX.
Fragments provided herein are defined as sequences of at least 6 (contiguous)
nucleic acids or at
least 4 (contiguous) amino acids, a length sufficient to allow for specific
hybridization in the case
of nucleic acids or for specific recognition of an epitope in the case of
amino acids, respectively,
and are at most some portion less than a full length sequence. Fragments may
be derived from
any contiguous portion of a nucleic acid or amino acid sequence of choice.
Derivatives are
nucleic acid sequences or amino acid sequences formed from the native
compounds either
directly or by modification or partial substitution. Analogs are nucleic acid
sequences or amino
acid sequences that have a structure similar to, but not identical to, the
native compound but
differs from it in respect to certain components or side chains. Analogs may
be synthetic or from
a different evolutionary origin and may have a similar or opposite metabolic
activity compared to
wild type.
Derivatives and analogs may be full length or other than full length, if the
derivative or
analog contains a modified nucleic acid or amino acid, as described below.
Derivatives or
analogs of the nucleic acids or proteins of the invention include, but are not
limited to, molecules
comprising regions that are substantially homologous to the nucleic acids or
proteins of the

CA 02383592 2001-09-26
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invention, in various embodiments, by at least about 70%, 80%, 85%, 90%, 95%,
98%, or even
99% identity (with a preferred identity of 80-99%) over a nucleic acid or
amino acid sequence of
identical size or when compared to an aligned sequence in which the alignment
is done by a
computer homology program known in the art, or whose encoding nucleic acid is
capable of
hybridizing to the complement of a sequence encoding the aforementioned
proteins under
stringent, moderately stringent, or low stringent conditions. See e.g.
Ausubel, et al., CURRENT
PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, NY, 1993, and
below.
An exemplary program is the Gap program (Wisconsin Sequence Analysis Package,
Version 8
for UNIX, Genetics Computer Group, University Research Park, Madison, WI)
using the default
settings, which uses the algorithm of Smith and Waterman (Adv. Appl. Math.,
1981, 2: 482-489,
which is incorporated herein by reference in its entirety).
A "homologous nucleic acid sequence" or "homologous amino acid sequence," or
variations thereof, refer to sequences characterized by a homology at the
nucleotide level or
amino acid level as discussed above. Homologous nucleotide sequences encode
those sequences
coding for isoforms of ORFX polypeptide. Isoforms can be expressed in
different tissues of the
same organism as a result of, for example, alternative splicing of RNA.
Alternatively, isoforms
can be encoded by different genes. In the present invention, homologous
nucleotide sequences
include nucleotide sequences encoding for a ORFX polypeptide of species other
than humans;
including, but not limited to, mammals, and thus can include, e.g., mouse,
rat, rabbit, dog, cat
cow, horse, and other organisms. Homologous nucleotide sequences also include,
but are not
limited to, naturally occurring allelic variations and mutations of the
nucleotide sequences set
forth herein. A homologous nucleotide sequence does not, however, include the
nucleotide
sequence encoding human ORFX protein. Homologous nucleic acid sequences
include those
nucleic acid sequences that encode conservative amino acid substitutions (see
below) in any of
SEQ ID N0:2n (wherein n = 1 to 3161 ) as well as a polypeptide having ORFX
activity.
Biological activities of the ORFX proteins are described below. A homologous
amino acid
sequence does not encode the amino acid sequence of a human ORFX polypeptide.
The nucleotide sequence determined from the cloning of the human ORFX gene
allows
for the generation of probes and primers designed for use in identifying the
cell types disclosed
and/or cloning ORFX homologues in other cell types, e.g., from other tissues,
as well as ORFX
homologues from other mammals. The probe/primer typically comprises a
substantially purified
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oligonucleotide. The oligonucleotide typically comprises a region of
nucleotide sequence that
hybridizes under stringent conditions to at least about 12, 25, 50, 100, 150,
200, 250, 300, 350 or
400 or more consecutive sense strand nucleotide sequence of SEQ ID N0:2n-1
(wherein n = 1 to
3161 ); or an anti-sense strand nucleotide sequence of SEQ ID N0:2n-1 (wherein
n = 1 to 3161 );
or of a naturally occurring mutant of SEQ ID N0:2n-1 (wherein n = 1 to 3161).
Probes based on the human ORFX nucleotide sequence can be used to detect
transcripts
or genomic sequences encoding the same or homologous proteins. In various
embodiments, the
probe further comprises a label group attached thereto, e.g., the label group
can be a
radioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor. Such
probes can be
used as a part of a diagnostic test kit for identifying cells or tissue which
misexpress a ORFX
protein, such as by measuring a level of a ORFX-encoding nucleic acid in a
sample of cells from
a subject e.g., detecting ORFX mRNA levels or determining whether a genomic
ORFX gene has
been mutated or deleted.
"A polypeptide having a biologically active portion of ORFX" refers to
polypeptides
exhibiting activity similar, but not necessarily identical to, an activity of
a polypeptide of the
present invention, including mature forms, as measured in a particular
biological assay, with or
without dose dependency. A nucleic acid fragment encoding a "biologically
active portion of
ORFX" can be prepared by isolating a portion of SEQ ID N0:2n-1 (wherein n = 1
to 3161), that
encodes a polypeptide having a ORFX biological activity (biological activities
of the ORFX
proteins are summarized in Table 1), expressing the encoded portion of ORFX
protein (e.g., by
recombinant expression in vitro) and assessing the activity of the encoded
portion of ORFX. For
example, a nucleic acid fragment encoding a biologically active portion of
ORFX can optionally
include a domain as shown in Table 1, column 4.
ORFX variants
The invention further encompasses nucleic acid molecules that differ from the
disclosed
ORFX nucleotide sequences due to degeneracy of the genetic code. These nucleic
acids thus
encode the same ORFX protein as that encoded by the nucleotide sequence shown
in SEQ ID
N0:2n-1 (wherein n = 1 to 3161). In another embodiment, an isolated nucleic
acid molecule of
the invention has a nucleotide sequence encoding a protein having an amino
acid sequence
shown in any of SEQ ID N0:2n (wherein n = 1 to 3161 ).
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In addition to the human ORFX nucleotide sequence shown in any of SEQ ID N0:2n-
1
(wherein n = 1 to 3161), it will be appreciated by those skilled in the art
that DNA sequence
polymorphisms that lead to changes in the amino acid sequences of ORFX may
exist within a
population (e.g., the human population). Such genetic polymorphism in the ORFX
gene may
S exist among individuals within a population due to natural allelic
variation. As used herein, the
terms "gene" and "recombinant gene" refer to nucleic acid molecules comprising
an open reading
frame encoding a ORFX protein, preferably a mammalian ORFX protein. Such
natural allelic
variations can typically result in 1-5% variance in the nucleotide sequence of
the ORFX gene.
Any and all such nucleotide variations and resulting amino acid polymorphisms
in ORFX that
are the result of natural allelic variation and that do not alter the
functional activity of ORFX are
intended to be within the scope of the invention.
Moreover, nucleic acid molecules encoding ORFX proteins from other species,
and thus
that have a nucleotide sequence that differs from the human sequence of any of
SEQ ID N0:2n-
1 (wherein n = 1 to 3161), are intended to be within the scope of the
invention. Nucleic acid
molecules corresponding to natural allelic variants and homologues of the ORFX
cDNAs of the
invention can be isolated based on their homology to the human ORFX nucleic
acids disclosed
herein using the human cDNAs, or a portion thereof, as a hybridization probe
according to
standard hybridization techniques under stringent hybridization conditions.
In another embodiment, an isolated nucleic acid molecule of the invention is
at least 6
nucleotides in length and hybridizes under stringent conditions to the nucleic
acid molecule
comprising the nucleotide sequence of any of SEQ ID N0:2n-1 (wherein n = 1 to
3161). In
another embodiment, the nucleic acid is at least 10, 25, 50, 100, 250, 500 or
750 nucleotides in
length. In another embodiment, an isolated nucleic acid molecule of the
invention hybridizes to
the coding region. As used herein, the term "hybridizes under stringent
conditions" is intended
to describe conditions for hybridization and washing under which nucleotide
sequences at least
60% homologous to each other typically remain hybridized to each other.
Homologs (i. e., nucleic acids encoding ORFX proteins derived from species
other than
human) or other related sequences (e.g., paralogs) can be obtained by low,
moderate or high
stringency hybridization with all or a portion of the particular human
sequence as a probe using
methods well known in the art for nucleic acid hybridization and cloning.
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As used herein, the phrase "stringent hybridization conditions" refers to
conditions under
which a probe, primer or oligonucleotide will hybridize to its target
sequence, but to no other
sequences. Stringent conditions are sequence-dependent and will be different
in different
circumstances. Longer sequences hybridize specifically at higher temperatures
than shorter
sequences. Generally, stringent conditions are selected to be about 5°C
lower than the thermal
melting point (Tm) for the specific sequence at a defined ionic strength and
pH. The Tm is the
temperature (under defined ionic strength, pH and nucleic acid concentration)
at which 50% of
the probes complementary to the target sequence hybridize to the target
sequence at equilibrium.
Since the target sequences are generally present at excess, at Tm, 50% of the
probes are occupied
at equilibrium. Typically, stringent conditions will be those in which the
salt concentration is
less than about 1.0 M sodium ion, typically about 0.01 to 1.0 M sodium ion (or
other salts) at pH
7.0 to 8.3 and the temperature is at least about 30°C for short probes,
primers or oligonucleotides
(e.g., 10 nt to SO nt) and at least about 60°C for longer probes,
primers and oligonucleotides.
Stringent conditions may also be achieved with the addition of destabilizing
agents, such as
formamide.
Stringent conditions are known to those skilled in the art and can be found in
CURRENT
PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6.
Preferably,
the conditions are such that sequences at least about 65%, 70%, 75%, 85%, 90%,
95%, 98%, or
99% homologous to each other typically remain hybridized to each other. A non-
limiting
example of stringent hybridization conditions is hybridization in a high salt
buffer comprising
6X SSC, 50 mM Tris-HCl (pH 7.5), 1 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.02%
BSA, and
500 mg/ml denatured salmon sperm DNA at 65°C. This hybridization is
followed by one or
more washes in 0.2X SSC, 0.01% BSA at 50°C. An isolated nucleic acid
molecule of the
invention that hybridizes under stringent conditions to the sequence of any of
SEQ ID N0:2n-1
(wherein n = 1 to 3161 ) corresponds to a naturally occurnng nucleic acid
molecule. As used
herein, a "naturally-occurring" nucleic acid molecule refers to an RNA or DNA
molecule having
a nucleotide sequence that occurs in nature (e.g., encodes a natural protein).
In a second embodiment, a nucleic acid sequence that is hybridizable to the
nucleic acid
molecule comprising the nucleotide sequence of any of SEQ ID N0:2n-1 (wherein
n = 1 to
3161), or fragments, analogs or derivatives thereof, under conditions of
moderate stringency is
provided. A non-limiting example of moderate stringency hybridization
conditions are
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hybridization in 6X SSC, SX Denhardt's solution, 0.5% SDS and 100 mg/ml
denatured salmon
sperm DNA at 55°C, followed by one or more washes in 1X SSC, 0.1% SDS
at 37°C. Other
conditions of moderate stringency that may be used are well known in the art.
See, e.g., Ausubel
et al. (eds.), 1993, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley &
Sons, NY, and
Kriegler, 1990, GENE TRANSFER AND EXPRESSION, A LABORATORY MANUAL, Stockton
Press,
NY.
In a third embodiment, a nucleic acid that is hybridizable to the nucleic acid
molecule
comprising the nucleotide sequence of any of SEQ ID N0:2n-1 (wherein n = 1 to
3161), or
fragments, analogs or derivatives thereof, under conditions of low stringency,
is provided. A
non-limiting example of low stringency hybridization conditions are
hybridization in 35%
formamide, SX SSC, 50 mM Tris-HCl (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02%
Ficoll, 0.2%
BSA, 100 mg/ml denatured salmon sperm DNA, 10% (wt/vol) dextran sulfate at
40°C, followed
by one or more washes in 2X SSC, 25 mM Tris-HCl (pH 7.4), 5 mM EDTA, and 0.1%
SDS at
50°C. Other conditions of low stringency that may be used are well
known in the art (e.g., as
employed for cross-species hybridizations). See, e.g., Ausubel et al. (eds.),
1993, CURRENT
PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, NY, and Kriegler, 1990,
GENE
TRANSFER AND EXPRESSION, A LABORATORY MANUAL, Stockton Press, NY; Shilo and
Weinberg, 1981, Proc Natl Acad Sci USA 78: 6789-6792.
Conservative mutations
In addition to naturally-occurring allelic variants of the ORFX sequence that
may exist in
the population, the skilled artisan will further appreciate that changes can
be introduced by
mutation into the nucleotide sequence of any of SEQ ID N0:2n-1 (wherein n = 1
to 3161),
thereby leading to changes in the amino acid sequence of the encoded ORFX
protein, without
altering the functional ability of the ORFX protein. For example, nucleotide
substitutions
leading to amino acid substitutions at "non-essential" amino acid residues can
be made in the
sequence of any of SEQ ID N0:2n-1 (wherein n = 1 to 3161). A "non-essential"
amino acid
residue is a residue that can be altered from the wild-type sequence of ORFX
without altering the
biological activity, whereas an "essential" amino acid residue is required for
biological activity.
For example, amino acid residues that are conserved among the ORFX proteins of
the present
invention, are predicted to be particularly unamenable to alteration.

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Amino acid residues that are conserved among members of an ORFX family members
are predicted to be less amenable to alteration. For example, an ORFX protein
according to the
present invention can contain at least one domain (e.g., as shown in Table 1 )
that is a typically
conserved region in an ORFX family member. As such, these conserved domains
are not likely
to be amenable to mutation. Other amino acid residues, however, (e.g., those
that are not
conserved or only semi-conserved among members of the ORFX family) may not be
as essential
for activity and thus are more likely to be amenable to alteration.
Another aspect of the invention pertains to nucleic acid molecules encoding
ORFX
proteins that contain changes in amino acid residues that are not essential
for activity. Such
ORFX proteins differ in amino acid sequence from any of any of SEQ ID N0:2n
(wherein n = 1
to 3161 ), yet retain biological activity. In one embodiment, the isolated
nucleic acid molecule
comprises a nucleotide sequence encoding a protein, wherein the protein
comprises an amino
acid sequence at least about 75% homologous to the amino acid sequence of any
of SEQ ID
N0:2n (wherein n = 1 to 3161 ). Preferably, the protein encoded by the nucleic
acid is at least
about 80% homologous to any of SEQ ID N0:2n (wherein n = 1 to 3161 ), more
preferably at
least about 90%, 95%, 98%, and most preferably at least about 99% homologous
to SEQ ID
N0:2.
An isolated nucleic acid molecule encoding a ORFX protein homologous to the
protein
of any of SEQ ID N0:2n (wherein n = 1 to 3161) can be created by introducing
one or more
nucleotide substitutions, additions or deletions into the corresponding
nucleotide sequence, i. e.
SEQ ID N0:2n-1 for the corresponding n, such that one or more amino acid
substitutions,
additions or deletions are introduced into the encoded protein.
Mutations can be introduced into SEQ ID N0:2n-1 (wherein n = 1 to 3161) by
standard
techniques, such as site-directed mutagenesis and PCR-mediated mutagenesis.
Preferably,
conservative amino acid substitutions are made at one or more predicted non-
essential amino
acid residues. A "conservative amino acid substitution" is one in which the
amino acid residue is
replaced with an amino acid residue having a similar side chain. Families of
amino acid residues
having similar side chains have been defined in the art. These families
include amino acids with
basic side chains (e.g., lysine, arginine, histidine), acidic side chains
(e.g., aspartic acid, glutamic
acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine,
serine, threonine,
tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine,
isoleucine, proline,
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phenylalanine, methionine, tryptophan), beta-branched side chains (e.g.,
threonine, valine,
isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine,
tryptophan, histidine). Thus,
a predicted nonessential amino acid residue in ORFX is replaced with another
amino acid residue
from the same side chain family. Alternatively, in another embodiment,
mutations can be
introduced randomly along all or part of a ORFX coding sequence, such as by
saturation
mutagenesis, and the resultant mutants can be screened for ORFX biological
activity to identify
mutants that retain activity. Following mutagenesis of SEQ ID N0:2n-1 (wherein
n = 1 to
3161 ), the encoded protein can be expressed by any recombinant technology
known in the art
and the activity of the protein can be determined.
In one embodiment, a mutant ORFX protein can be assayed for ( 1 ) the ability
to form
protein:protein interactions with other ORFX proteins, other cell-surface
proteins, or biologically
active portions thereof, (2) complex formation between a mutant ORFX protein
and a ORFX
receptor; (3) the ability of a mutant ORFX protein to bind to an intracellular
target protein or
biologically active portion thereof; (e.g., avidin proteins); (4) the ability
to bind BRA protein; or
(5) the ability to specifically bind an anti-ORFX protein antibody.
Antisense
Another aspect of the invention pertains to isolated antisense nucleic acid
molecules that
are hybridizable to or complementary to the nucleic acid molecule comprising
the nucleotide
sequence of SEQ ID N0:2n-1 (wherein n = 1 to 3161), or fragments, analogs or
derivatives
thereof. An "antisense" nucleic acid comprises a nucleotide sequence that is
complementary to a
"sense" nucleic acid encoding a protein, e.g., complementary to the coding
strand of a
double-stranded cDNA molecule or complementary to an mRNA sequence. In
specific aspects,
antisense nucleic acid molecules are provided that comprise a sequence
complementary to at
least about 10, 25, 50, 100, 250 or 500 nucleotides or an entire ORFX coding
strand, or to only a
portion thereof. Nucleic acid molecules encoding fragments, homologs,
derivatives and analogs
of a ORFX protein of any of SEQ ID N0:2n (wherein n = 1 to 3161) or antisense
nucleic acids
complementary to a ORFX nucleic acid sequence of SEQ ID N0:2n-1 (wherein n = 1
to 3161 )
are additionally provided.
In one embodiment, an antisense nucleic acid molecule is antisense to a
"coding region"
of the coding strand of a nucleotide sequence encoding ORFX. The term "coding
region" refers
to the region of the nucleotide sequence comprising codons which are
translated into amino acid
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residues (e.g., the protein coding region of a human ORFX that corresponds to
any of SEQ ID
N0:2n (wherein n = 1 to 3161 )). In another embodiment, the antisense nucleic
acid molecule is
antisense to a "noncoding region" of the coding strand of a nucleotide
sequence encoding ORFX.
The term "noncoding region" refers to 5' and 3' sequences which flank the
coding region that are
not translated into amino acids (i.e., also referred to as 5' and 3'
untranslated regions).
Given the coding strand sequences encoding ORFX disclosed herein (e.g., SEQ ID
N0:2n-1 (wherein n = 1 to 3161 ) ), antisense nucleic acids of the invention
can be designed
according to the rules of Watson and Crick or Hoogsteen base pairing. The
antisense nucleic
acid molecule can be complementary to the entire coding region of ORFX mRNA,
but more
preferably is an oligonucleotide that is antisense to only a portion of the
coding or noncoding
region of ORFX mRNA. For example, the antisense oligonucleotide can be
complementary to
the region surrounding the translation start site of ORFX mRNA. An antisense
oligonucleotide
can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 nucleotides
in length. An
antisense nucleic acid of the invention can be constructed using chemical
synthesis or enzymatic
ligation reactions using procedures known in the art. For example, an
antisense nucleic acid
(e.g., an antisense oligonucleotide) can be chemically synthesized using
naturally occurring
nucleotides or variously modified nucleotides designed to increase the
biological stability of the
molecules or to increase the physical stability of the duplex formed between
the antisense and
sense nucleic acids, e.g., phosphorothioate derivatives and acridine
substituted nucleotides can
be used.
Examples of modified nucleotides that can be used to generate the antisense
nucleic acid
include: 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil,
hypoxanthine, xanthine,
4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-
2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-
galactosylqueosine,
inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-
dimethylguanine,
2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-
adenine,
7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil,
beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil, S-methoxyuracil,
2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine,
pseudouracil,
queosine, 2-thiocytosine, S-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-
methyluracil,
uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), S-methyl-2-
thiouracil,
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3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine.
Alternatively, the
antisense nucleic acid can be produced biologically using an expression vector
into which a
nucleic acid has been subcloned in an antisense orientation (i.e., RNA
transcribed from the
inserted nucleic acid will be of an antisense orientation to a target nucleic
acid of interest,
described further in the following subsection).
The antisense nucleic acid molecules of the invention are typically
administered to a
subject or generated in situ such that they hybridize with or bind to cellular
mRNA and/or
genomic DNA encoding a ORFX protein to thereby inhibit expression of the
protein, e.g., by
inhibiting transcription and/or translation. The hybridization can be by
conventional nucleotide
complementarity to form a stable duplex, or, for example, in the case of an
antisense nucleic acid
molecule that binds to DNA duplexes, through specific interactions in the
major groove of the
double helix. An example of a route of administration of antisense nucleic
acid molecules of the
invention includes direct injection at a tissue site. Alternatively, antisense
nucleic acid
molecules can be modified to target selected cells and then administered
systemically. For
example, for systemic administration, antisense molecules can be modified such
that they
specifically bind to receptors or antigens expressed on a selected cell
surface, e.g., by linking the
antisense nucleic acid molecules to peptides or antibodies that bind to cell
surface receptors or
antigens. The antisense nucleic acid molecules can also be delivered to cells
using the vectors
described herein. To achieve sufficient intracellular concentrations of
antisense molecules,
vector constructs in which the antisense nucleic acid molecule is placed under
the control of a
strong pol II or pol III promoter are preferred.
In yet another embodiment, the antisense nucleic acid molecule of the
invention is an
oc-anomeric nucleic acid molecule. An a-anomeric nucleic acid molecule forms
specific
double-stranded hybrids with complementary RNA in which, contrary to the usual
(3-units, the
strands run parallel to each other (Gaultier et al. (1987) Nucleic Acids Res
15: 6625-6641). The
antisense nucleic acid molecule can also comprise a 2'-o-methylribonucleotide
(moue et al.
(1987) Nucleic Acids Res 1 S: 6131-6148) or a chimeric RNA -DNA analogue (moue
et al. (1987)
FEBS Lett 215: 327-330).
Ribozymes and PNA moieties
Such modifications include, by way of nonlimiting example, modified bases, and
nucleic
acids whose sugar phosphate backbones are modified or derivatized. These
modifications are
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carried out at least in part to enhance the chemical stability of the modified
nucleic acid, such
that they may be used, for example, as antisense binding nucleic acids in
therapeutic applications
in a subject.
In still another embodiment, an antisense nucleic acid of the invention is a
ribozyme.
Ribozymes are catalytic RNA molecules with ribonuclease activity that are
capable of cleaving a
single-stranded nucleic acid, such as an mRNA, to which they have a
complementary region.
Thus, ribozymes (e.g., hammerhead ribozymes (described in Haselhoff and
Gerlach (1988)
Nature 334:585-591)) can be used to catalytically cleave ORFX mRNA transcripts
to thereby
inhibit translation of ORFX mRNA. A ribozyme having specificity for a ORFX-
encoding
nucleic acid can be designed based upon the nucleotide sequence of a ORFX DNA
disclosed
herein (i.e., SEQ ID N0:2n-1 (wherein n = 1 to 3161)). For example, a
derivative of a
Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence
of the active
site is complementary to the nucleotide sequence to be cleaved in a ORFX-
encoding mRNA.
See, e.g., Cech et al. U.S. Pat. No. 4,987,071; and Cech et al. U.S. Pat. No.
5,116,742.
Alternatively, ORFX mRNA can be used to select a catalytic RNA having a
specific
ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel et al.,
(1993) Science
261:1411-1418.
Alternatively, ORFX gene expression can be inhibited by targeting nucleotide
sequences
complementary to the regulatory region of the ORFX (e.g., the ORFX promoter
and/or
enhancers) to form triple helical structures that prevent transcription of the
ORFX gene in target
cells. See generally, Helene. (1991) Anticancer Drug Des. 6: 569-84; Helene.
et al. (1992) Ann.
N. Y. Acad. Sci. 660:27-36; and Maher (1992) Bioassays 14: 807-15.
In various embodiments, the nucleic acids of ORFX can be modified at the base
moiety,
sugar moiety or phosphate backbone to improve, e.g., the stability,
hybridization, or solubility of
the molecule. For example, the deoxyribose phosphate backbone of the nucleic
acids can be
modified to generate peptide nucleic acids (see Hyrup et al. (1996) Bioorg Med
Chem 4: S-23).
As used herein, the terms "peptide nucleic acids" or "PNAs" refer to nucleic
acid mimics, e.g.,
DNA mimics, in which the deoxyribose phosphate backbone is replaced by a
pseudopeptide
backbone and only the four natural nucleobases are retained. The neutral
backbone of PNAs has
been shown to allow for specific hybridization to DNA and RNA under conditions
of low ionic
strength. The synthesis of PNA oligomers can be performed using standard solid
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CA 02383592 2001-09-26
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synthesis protocols as described in Hyrup et al. (1996) above; Perry-O'Keefe
et al. (1996) PNAS
93: 14670-675.
PNAs of ORFX can be used in therapeutic and diagnostic applications. For
example,
PNAs can be used as antisense or antigene agents for sequence-specific
modulation of gene
expression by, e.g., inducing transcription or translation arrest or
inhibiting replication. PNAs of
ORFX can also be used, e.g., in the analysis of single base pair mutations in
a gene by, e.g., PNA
directed PCR clamping; as artificial restriction enzymes when used in
combination with other
enzymes, e.g., S1 nucleases (Hyrup B. (1996) above); or as probes or primers
for DNA sequence
and hybridization (Hyrup et al. (1996), above; Perry-O'Keefe (1996), above).
In another embodiment, PNAs of ORFX can be modified, e.g., to enhance their
stability
or cellular uptake, by attaching lipophilic or other helper groups to PNA, by
the formation of
PNA-DNA chimeras, or by the use of liposomes or other techniques of drug
delivery known in
the art. For example, PNA-DNA chimeras of ORFX can be generated that may
combine the
advantageous properties of PNA and DNA. Such chimeras allow DNA recognition
enzymes,
e.g., RNase H and DNA polymerases, to interact with the DNA portion while the
PNA portion
would provide high binding affinity and specificity. PNA-DNA chimeras can be
linked using
linkers of appropriate lengths selected in terms of base stacking, number of
bonds between the
nucleobases, and orientation (Hyrup (1996) above). The synthesis of PNA-DNA
chimeras can
be performed as described in Hyrup (1996) above and Finn et al. (1996) Nucl
Acids Res 24:
3357-63. For example, a DNA chain can be synthesized on a solid support using
standard
phosphoramidite coupling chemistry, and modified nucleoside analogs, e.g.,
5'-(4-methoxytrityl)amino-5'-deoxy-thymidine phosphoramidite, can be used
between the PNA
and the 5' end of DNA (Mag et al. (1989) Nucl Acid Res 17: 5973-88). PNA
monomers are then
coupled in a stepwise manner to produce a chimeric molecule with a 5' PNA
segment and a 3'
DNA segment (Finn et al. ( 1996) above). Alternatively, chimeric molecules can
be synthesized
with a S' DNA segment and a 3' PNA segment. See, Petersen et al. (1975) Bioorg
Med Chem
Lett 5: 1119-11124.
In other embodiments, the oligonucleotide may include other appended groups
such as
peptides (e.g., for targeting host cell receptors in vivo), or agents
facilitating transport across the
cell membrane (see, e.g., Letsinger et al., 1989, Proc. Natl. Acad. Sci.
U.S.A. 86:6553-6556;
Lemaitre et al., 1987, Proc. Natl. Acad. Sci. 84:648-652; PCT Publication No.
W088/09810) or
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the blood-brain barrier (see, e.g., PCT Publication No. W089/10134). In
addition,
oligonucleotides can be modified with hybridization triggered cleavage agents
(See, e.g., Krol et
al., 1988, BioTechniques 6:958-976) or intercalating agents. (See, e.g., Zon,
1988, Pharm. Res.
S: 539-549). To this end, the oligonucleotide may be conjugated to another
molecule, e.g., a
peptide, a hybridization triggered cross-linking agent, a transport agent, a
hybridization-triggered
cleavage agent, etc.
ORFX polypeptides
The novel protein of the invention includes the ORFX-like protein whose
sequence is
provided in any of SEQ ID N0:2n (wherein n = 1 to 3161 ). The invention also
includes a
mutant or variant protein any of whose residues may be changed from the
corresponding residue
shown in FIG. 1 while still encoding a protein that maintains its ORFX-like
activities and
physiological functions, or a functional fragment thereof. For example, the
invention includes
the polypeptides encoded by the variant ORFX nucleic acids described above. In
the mutant or
variant protein, up to 20% or more of the residues may be so changed.
In general, an ORFX -like variant that preserves ORFX-like function includes
any variant
in which residues at a particular position in the sequence have been
substituted by other amino
acids, and further include the possibility of inserting an additional residue
or residues between
two residues of the parent protein as well as the possibility of deleting one
or more residues from
the parent sequence. Any amino acid substitution, insertion, or deletion is
encompassed by the
invention. In favorable circumstances, the substitution is a conservative
substitution as defined
above. Furthermore, without limiting the scope of the invention, positions of
any of SEQ ID
N0:2n (wherein n = 1 to 3161 ) may be substitute such that a mutant or variant
protein may
include one or more substitutions
The invention also includes isolated ORFX proteins, and biologically active
portions
thereof, or derivatives, fragments, analogs or homologs thereof. Also provided
are polypeptide
fragments suitable for use as immunogens to raise anti-ORFX antibodies. In one
embodiment,
native ORFX proteins can be isolated from cells or tissue sources by an
appropriate purification
scheme using standard protein purification techniques. In another embodiment,
ORFX proteins
are produced by recombinant DNA techniques. Alternative to recombinant
expression, a ORFX
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protein or polypeptide can be synthesized chemically using standard peptide
synthesis
techniques.
An "isolated" or "purified" protein or biologically active portion thereof is
substantially
free of cellular material or other contaminating proteins from the cell or
tissue source from which
the ORFX protein is derived, or substantially free from chemical precursors or
other chemicals
when chemically synthesized. The language "substantially free of cellular
material" includes
preparations of ORFX protein in which the protein is separated from cellular
components of the
cells from which it is isolated or recombinantly produced. In one embodiment,
the language
"substantially free of cellular material" includes preparations of ORFX
protein having less than
about 30% (by dry weight) of non-ORFX protein (also referred to herein as a
"contaminating
protein"), more preferably less than about 20% of non-ORFX protein, still more
preferably less
than about 10% of non-ORFX protein, and most preferably less than about 5% non-
ORFX
protein. When the ORFX protein or biologically active portion thereof is
recombinantly
produced, it is also preferably substantially free of culture medium, i.e.,
culture medium
1 S represents less than about 20%, more preferably less than about 10%, and
most preferably less
than about 5% of the volume of the protein preparation.
The language "substantially free of chemical precursors or other chemicals"
includes
preparations of ORFX protein in which the protein is separated from chemical
precursors or
other chemicals that are involved in the synthesis of the protein. In one
embodiment, the
language "substantially free of chemical precursors or other chemicals"
includes preparations of
ORFX protein having less than about 30% (by dry weight) of chemical precursors
or non-ORFX
chemicals, more preferably less than about 20% chemical precursors or non-ORFX
chemicals,
still more preferably less than about 10% chemical precursors or non-ORFX
chemicals, and most
preferably less than about 5% chemical precursors or non-ORFX chemicals.
Biologically active portions of a ORFX protein include peptides comprising
amino acid
sequences sufficiently homologous to or derived from the amino acid sequence
of the ORFX
protein, e.g., the amino acid sequence shown in SEQ ID N0:2 that include fewer
amino acids
than the full length ORFX proteins, and exhibit at least one activity of a
ORFX protein.
Typically, biologically active portions comprise a domain or motif with at
least one activity of
the ORFX protein. A biologically active portion of a ORFX protein can be a
polypeptide which
is, for example, 10, 25, 50, 100 or more amino acids in length.
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A biologically active portion of a ORFX protein of the present invention may
contain at
least one of the above-identified domains conserved between the FGF family of
proteins.
Moreover, other biologically active portions, in which other regions of the
protein are deleted,
can be prepared by recombinant techniques and evaluated for one or more of the
functional
activities of a native ORFX protein.
In an embodiment, the ORFX protein has an amino acid sequence shown in any of
SEQ
ID N0:2n (wherein n = 1 to 3161 ). In other embodiments, the ORFX protein is
substantially
homologous to any of SEQ ID N0:2n (wherein n = 1 to 3161) and retains the
functional activity
of the protein of any of SEQ ID N0:2n (wherein n = 1 to 3161), yet differs in
amino acid
sequence due to natural allelic variation or mutagenesis, as described in
detail below.
Accordingly, in another embodiment, the ORFX protein is a protein that
comprises an amino
acid sequence at least about 45% homologous, and more preferably about 55, 65,
70, 75, 80, 85,
90, 95, 98 or even 99% homologous to the amino acid sequence of any of SEQ ID
N0:2n
(wherein n = 1 to 3161 ) and retains the functional activity of the ORFX
proteins of the
1 S corresponding polypeptide having the sequence of SEQ ID N0:2n (wherein n =
1 to 3161 ).
Determining homology between two or more sequences
To determine the percent homology of two amino acid sequences or of two
nucleic acids,
the sequences are aligned for optimal comparison purposes (e.g., gaps can be
introduced in either
of the sequences being compared for optimal alignment between the sequences).
The amino acid
residues or nucleotides at corresponding amino acid positions or nucleotide
positions are then
compared. When a position in the first sequence is occupied by the same amino
acid residue or
nucleotide as the corresponding position in the second sequence, then the
molecules are
homologous at that position (i.e., as used herein amino acid or nucleic acid
"homology" is
equivalent to amino acid or nucleic acid "identity").
The nucleic acid sequence homology may be determined as the degree of identity
between two sequences. The homology may be determined using computer programs
known in
the art, such as GAP software provided in the GCG program package. See,
Needleman and
Wunsch 1970 JMol Biol 48: 443-453. Using GCG GAP software with the following
settings for
nucleic acid sequence comparison: GAP creation penalty of 5.0 and GAP
extension penalty of
0.3, the coding region of the analogous nucleic acid sequences referred to
above exhibits a
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degree of identity preferably of at least 70%, 75%, 80%, 85%, 90%, 95%, 98%,
or 99%, with the
CDS (encoding) part of the DNA sequence shown in SEQ ID N0:2n-1 (wherein n = 1
to 3161).
The term "sequence identity" refers to the degree to which two polynucleotide
or
polypeptide sequences are identical on a residue-by-residue basis over a
particular region of
comparison. The term "percentage of sequence identity" is calculated by
comparing two
optimally aligned sequences over that region of comparison, determining the
number of positions
at which the identical nucleic acid base (e.g., A, T, C, G, U, or I, in the
case of nucleic acids)
occurs in both sequences to yield the number of matched positions, dividing
the number of
matched positions by the total number of positions in the region of comparison
(i.e., the window
size), and multiplying the result by 100 to yield the percentage of sequence
identity. The term
"substantial identity" as used herein denotes a characteristic of a
polynucleotide sequence,
wherein the polynucleotide comprises a sequence that has at least 80 percent
sequence identity,
preferably at least 85 percent identity and often 90 to 95 percent sequence
identity, more usually
at least 99 percent sequence identity as compared to a reference sequence over
a comparison
region. The term "percentage of positive residues" is calculated by comparing
two optimally
aligned sequences over that region of comparison, determining the number of
positions at which
the identical and conservative amino acid substitutions, as defined above,
occur in both
sequences to yield the number of matched positions, dividing the number of
matched positions
by the total number of positions in the region of comparison (i. e., the
window size), and
multiplying the result by 100 to yield the percentage of positive residues.
Chimeric and fusion proteins
The invention also provides ORFX chimeric or fusion proteins. As used herein,
a ORFX
"chimeric protein" or "fusion protein" includes a ORFX polypeptide operatively
linked to a
non-ORFX polypeptide. A "ORFX polypeptide" refers to a polypeptide having an
amino acid
sequence corresponding to ORFX, whereas a "non-ORFX polypeptide" refers to a
polypeptide
having an amino acid sequence corresponding to a protein that is not
substantially homologous to
the ORFX protein, e.g., a protein that is different from the ORFX protein and
that is derived
from the same or a different organism. Within a ORFX fusion protein the ORFX
polypeptide
can correspond to all or a portion of a ORFX protein. In one embodiment, a
ORFX fusion
protein comprises at least one biologically active portion of a ORFX protein.
In another
embodiment, a ORFX fusion protein comprises at least two biologically active
portions of a

CA 02383592 2001-09-26
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ORFX protein. Within the fusion protein, the term "operatively linked" is
intended to indicate
that the ORFX polypeptide and the non-ORFX polypeptide are fused in-frame to
each other.
The non-ORFX polypeptide can be fused to the N-terminus or C-terminus of the
ORFX
polypeptide.
For example, in one embodiment a ORFX fusion protein comprises a ORFX
polypeptide
operably linked to the extracellular domain of a second protein. Such fusion
proteins can be
further utilized in screening assays for compounds that modulate ORFX activity
(such assays are
described in detail below).
In another embodiment, the fusion protein is a GST-ORFX fusion protein in
which the
ORFX sequences are fused to the C-terminus of the GST (i.e., glutathione S-
transferase)
sequences. Such fusion proteins can facilitate the purification of recombinant
ORFX.
In yet another embodiment, the fusion protein is a ORFX protein containing a
heterologous signal sequence at its N-terminus. For example, the native ORFX
signal sequence
can be removed and replaced with a signal sequence from another protein. In
certain host cells
(e.g., mammalian host cells), expression and/or secretion of ORFX can be
increased through use
of a heterologous signal sequence.
In another embodiment, the fusion protein is a ORFX-immunoglobulin fusion
protein in
which the ORFX sequences comprising one or more domains are fused to sequences
derived
from a member of the immunoglobulin protein family. The ORFX-immunoglobulin
fusion
proteins of the invention can be incorporated into pharmaceutical compositions
and administered
to a subject to inhibit an interaction between a ORFX ligand and a ORFX
protein on the surface
of a cell, to thereby suppress ORFX-mediated signal transduction in vivo. In
one nonlimiting
example, a contemplated ORFX ligand of the invention is an ORFX receptor. The
ORFX-immunoglobulin fusion proteins can be used to modulate the
bioavailability of a ORFX
cognate ligand. Inhibition of the ORFX ligand/ORFX interaction may be useful
therapeutically
for both the treatment of proliferative and differentiative disorders, as well
as modulating (e.g.,
promoting or inhibiting) cell survival. Moreover, the ORFX-immunoglobulin
fusion proteins of
the invention can be used as immunogens to produce anti-ORFX antibodies in a
subject, to
purify ORFX ligands, and in screening assays to identify molecules that
inhibit the interaction of
ORFX with a ORFX ligand.
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A ORFX chimeric or fusion protein of the invention can be produced by standard
recombinant DNA techniques. For example, DNA fragments coding for the
different
polypeptide sequences are ligated together in-frame in accordance with
conventional techniques,
e.g., by employing blunt-ended or stagger-ended termini for ligation,
restriction enzyme
digestion to provide for appropriate termini, filling-in of cohesive ends as
appropriate, alkaline
phosphatase treatment to avoid undesirable joining, and enzymatic ligation. In
another
embodiment, the fusion gene can be synthesized by conventional techniques
including automated
DNA synthesizers. Alternatively, PCR amplification of gene fragments can be
carried out using
anchor primers that give rise to complementary overhangs between two
consecutive gene
fragments that can subsequently be annealed and reamplified to generate a
chimeric gene
sequence (see, for example, Ausubel et al. (eds.) CURRENT PROTOCOLS IN
MOLECULAR BIOLOGY,
John Wiley & Sons, 1992). Moreover, many expression vectors are commercially
available that
already encode a fusion moiety (e.g., a GST polypeptide). A ORFX-encoding
nucleic acid can
be cloned into such an expression vector such that the fusion moiety is linked
in-frame to the
ORFX protein.
ORFX agonists and antagonists
The present invention also pertains to variants of the ORFX proteins that
function as
either ORFX agonists (mimetics) or as ORFX antagonists. Variants of the ORFX
protein can be
generated by mutagenesis, e.g., discrete point mutation or truncation of the
ORFX protein. An
agonist of the ORFX protein can retain substantially the same, or a subset of,
the biological
activities of the naturally occurring form of the ORFX protein. An antagonist
of the ORFX
protein can inhibit one or more of the activities of the naturally occurnng
form of the ORFX
protein by, for example, competitively binding to a downstream or upstream
member of a
cellular signaling cascade which includes the ORFX protein. Thus, specific
biological effects
can be elicited by treatment with a variant of limited function. In one
embodiment, treatment of
a subject with a variant having a subset of the biological activities of the
naturally occurring form
of the protein has fewer side effects in a subject relative to treatment with
the naturally occurring
form of the ORFX proteins.
Variants of the ORFX protein that function as either ORFX agonists (mimetics)
or as
ORFX antagonists can be identified by screening combinatorial libraries of
mutants, e.g.,
truncation mutants, of the ORFX protein for ORFX protein agonist or antagonist
activity. In one
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embodiment, a variegated library of ORFX variants is generated by
combinatorial mutagenesis at
the nucleic acid level and is encoded by a variegated gene library. A
variegated library of ORFX
variants can be produced by, for example, enzymatically ligating a mixture of
synthetic
oligonucleotides into gene sequences such that a degenerate set of potential
ORFX sequences is
expressible as individual polypeptides, or alternatively, as a set of larger
fusion proteins (e.g., for
phage display) containing the set of ORFX sequences therein. There are a
variety of methods
which can be used to produce libraries of potential ORFX variants from a
degenerate
oligonucleotide sequence. Chemical synthesis of a degenerate gene sequence can
be performed
in an automatic DNA synthesizer, and the synthetic gene then ligated into an
appropriate
expression vector. Use of a degenerate set of genes allows for the provision,
in one mixture, of
all of the sequences encoding the desired set of potential ORFX sequences.
Methods for
synthesizing degenerate oligonucleotides are known in the art (see, e.g.,
Narang (1983)
Tetrahedron 39:3; Itakura et al. (1984) Annu Rev Biochem 53:323; Itakura et
al. (1984) Science
198:1056; Ike et al. (1983) Nucl Acid Res 11:477.
Polypeptide libraries
In addition, libraries of fragments of the ORFX protein coding sequence can be
used to'
generate a variegated population of ORFX fragments for screening and
subsequent selection of
variants of a ORFX protein. In one embodiment, a library of coding sequence
fragments can be
generated by treating a double stranded PCR fragment of a ORFX coding sequence
with a
nuclease under conditions wherein nicking occurs only about once per molecule,
denaturing the
double stranded DNA, renaturing the DNA to form double stranded DNA that can
include
sense/antisense pairs from different nicked products, removing single stranded
portions from
reformed duplexes by treatment with S 1 nuclease, and ligating the resulting
fragment library into
an expression vector. By this method, an expression library can be derived
which encodes
N-terminal and internal fragments of various sizes of the ORFX protein.
Several techniques are known in the art for screening gene products of
combinatorial
libraries made by point mutations or truncation, and for screening cDNA
libraries for gene
products having a selected property. Such techniques are adaptable for rapid
screening of the
gene libraries generated by the combinatorial mutagenesis of ORFX proteins.
The most widely
used techniques, which are amenable to high throughput analysis, for screening
large gene
libraries typically include cloning the gene library into replicable
expression vectors,
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transforming appropriate cells with the resulting library of vectors, and
expressing the
combinatorial genes under conditions in which detection of a desired activity
facilitates isolation
of the vector encoding the gene whose product was detected. Recrusive ensemble
mutagenesis
(REM), a new technique that enhances the frequency of functional mutants in
the libraries, can
be used in combination with the screening assays to identify ORFX variants
(Arkin and Yourvan
(1992) PNAS 89:7811-7815; Delgrave et al. (1993) Protein Engineering 6:327-
331).
Anti-ORFX Antibodies
The invention further encompasses antibodies and antibody fragments, such as
Fab or
(Fab)2, that bind immunospecifically to any of the proteins of the invention.
An isolated ORFX protein, or a portion or fragment thereof, can be used as an
immunogen to generate antibodies that bind ORFX using standard techniques for
polyclonal and
monoclonal antibody preparation. Full-length ORFX protein can be used.
Alternatively, the
invention provides antigenic peptide fragments of ORFX for use as immunogens.
The antigenic
peptide of ORFX comprises at least 4 amino acid residues of the amino acid
sequence shown in
any of SEQ ID N0:2n (wherein n = 1 to 3161). The antigenic peptide encompasses
an epitope
of ORFX such that an antibody raised against the peptide forms a specific
immune complex with
ORFX. The antigenic peptide may comprise at least 6 as residues, at least 8 as
residues, at least
10 as residues, at least 15 as residues, at least 20 as residues, or at least
30 as residues. In one
embodiment of the invention, the antigenic peptide comprises a polypeptide
comprising at least 6
contiguous amino acids of any of SEQ ID N0:2n (wherein n = 1 to 3161 ).
In an embodiment of the invention, epitopes encompassed by the antigenic
peptide are
regions of ORFX that are located on the surface of the protein, e.g.,
hydrophilic regions. As a
means for targeting antibody production, hydropathy plots showing regions of
hydrophilicity and
hydrophobicity may be generated by any method well known in the art,
including, for example,
the Kyte Doolittle or the Hopp Woods methods, either with or without Fourier
transformation.
See, e.g., Hopp and Woods, 1981, Proc. Nat. Acad. Sci. USA 78: 3824-3828; Kyte
and Doolittle
1982, J. Mol. Biol. 157: 105-142, each incorporated herein by reference in
their entirety.
As disclosed herein, an ORFX protein sequence of any of SEQ ID N0:2n (wherein
n = 1
to 3161 ) , or derivatives, fragments, analogs or homologs thereof, may be
utilized as
immunogens in the generation of antibodies that immunospecifically-bind these
protein
components. The term "antibody" as used herein refers to immunoglobulin
molecules and
34

CA 02383592 2001-09-26
WO 00/58473 PCT/US00/08621
immunologically active portions of immunoglobulin molecules, i.e., molecules
that contain an
antigen binding site that specifically binds (immunoreacts with) an antigen,
such as ORFX. Such
antibodies include, but are not limited to, polyclonal, monoclonal, chimeric,
single chain, Fab and
F(ab')2 fragments, and an Fab expression library. In a specific embodiment,
antibodies to human
ORFX proteins are disclosed. Various procedures known within the art may be
used for the
production of polyclonal or monoclonal antibodies to a ORFX protein sequence
of any of SEQ
ID N0:2n (wherein n = 1 to 3161 ) or derivative, fragment, analog or homolog
thereof. Some of
these proteins are discussed below.
For the production of polyclonal antibodies, various suitable host animals
(e.g., rabbit,
r
goat, mouse or other mammal) may be immunized by injection with the native
protein, or a
synthetic variant thereof, or a derivative of the foregoing. An appropriate
immunogenic
preparation can contain, for example, recombinantly expressed ORFX protein or
a chemically
synthesized ORFX polypeptide. The preparation can further include an adjuvant.
Various
adjuvants used to increase the immunological response include, but are not
limited to, Freund's
(complete and incomplete), mineral gels (e.g., aluminum hydroxide), surface
active substances
(e.g., lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions,
dinitrophenol, etc.),
human adjuvants such as Bacille Calmette-Guerin and Corynebacterium parvum, or
similar
immunostimulatory agents. If desired, the antibody molecules directed against
ORFX can be
isolated from the mammal (e.g., from the blood) and further purified by well
known techniques,
such as protein A chromatography to obtain the IgG fraction.
The term "monoclonal antibody" or "monoclonal antibody composition", as used
herein,
refers to a population of antibody molecules that contain only one species of
an antigen binding
site capable of immunoreacting with a particular epitope of ORFX. A monoclonal
antibody
composition thus typically displays a single binding affinity for a particular
ORFX protein with
which it immunoreacts. For preparation of monoclonal antibodies directed
towards a particular
ORFX protein, or derivatives, fragments, analogs or homologs thereof, any
technique that
provides for the production of antibody molecules by continuous cell line
culture may be
utilized. Such techniques include, but are not limited to, the hybridoma
technique (see Kohler &
Milstein, 1975 Nature 256: 495-497); the trioma technique; the human B-cell
hybridoma
technique (see Kozbor, et al., 1983 Immunol Today 4: 72) and the EBV hybridoma
technique to
produce human monoclonal antibodies (see Cole, et al., 1985 In: MONOCLONAL
ANTIBODIES AND

CA 02383592 2001-09-26
WO 00/58473 PCT/US00/08621
CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96). Human monoclonal antibodies
may be utilized
in the practice of the present invention and may be produced by using human
hybridomas (see
Cote, et al., 1983. Proc Natl Acad Sci USA 80: 2026-2030) or by transforming
human B-cells
with Epstein Barr Virus in vitro (see Cole, et al., 1985 In: MONOCLONAL
ANTIBODIES AND
S CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96). Each of the above citations
are incorporated
herein by reference in their entirety
According to the invention, techniques can be adapted for the production of
single-chain
antibodies specific to a ORFX protein (see e.g., U.S. Patent No. 4,946,778).
In addition,
methods can be adapted for the construction of Fab expression libraries (see
e.g., Huse, et al.,
1989 Science 246: 1275-1281 ) to allow rapid and effective identification of
monoclonal Fab
fragments with the desired specificity for a ORFX protein or derivatives,
fragments, analogs or
homologs thereof. Non-human antibodies can be "humanized" by techniques well
known in the
art. See e.g., U.S. Patent No. 5,225,539. Each of the above citations are
incorporated herein by
reference. Antibody fragments that contain the idiotypes to a ORFX protein may
be produced by
techniques known in the art including, but not limited to: (i) an F~ab~~2
fragment produced by
pepsin digestion of an antibody molecule; (ii) an Fab fragment generated by
reducing the
disulfide bridges of an F~ab')2 fragment; (iii) an Fab fragment generated by
the treatment of the
antibody molecule with papain and a reducing agent and (iv) F,, fragments.
Additionally, recombinant anti-ORFX antibodies, such as chimeric and humanized
monoclonal antibodies, comprising both human and non-human portions, which can
be made
using standard recombinant DNA techniques, are within the scope of the
invention. Such
chimeric and humanized monoclonal antibodies can be produced by recombinant
DNA
techniques known in the art, for example using methods described in PCT
International
Application No. PCT/US86/02269; European Patent Application No. 184,187;
European Patent
Application No. 171,496; European Patent Application No. 173,494; PCT
International
Publication No. WO 86/01533; U.S. Pat. No. 4,816,567; European Patent
Application No.
125,023; Better et a1.(1988) Science 240:1041-1043; Liu et al. (1987) PNAS
84:3439-3443; Liu
et al. (1987) Jlmmunol. 139:3521-3526; Sun et al. (1987) PNAS 84:214-218;
Nishimura et al.
(1987) Cancer Res 47:999-1005; Wood et al. (1985) Nature 314:446-449; Shaw et
al. (1988), J.
Natl Cancer Inst 80:1553-1559); Morrison(1985) Science 229:1202-1207; Oi et
al. (1986)
BioTechniques 4:214; U.S. Pat. No. 5,225,539; Jones et al. (1986) Nature
321:552-525;
36

CA 02383592 2001-09-26
WO 00/58473 PCT/US00/08621
Verhoeyan et al. (1988) Science 239:1534; and Beidler et al. (1988) Jlmmunol
141:4053-4060.
Each of the above citations are incorporated herein by reference.
In one embodiment, methods for the screening of antibodies that possess the
desired
specificity include, but are not limited to, enzyme-linked immunosorbent assay
(ELISA) and
other immunologically-mediated techniques known within the art. In a
specific.embodiment,
selection of antibodies that are specific to a particular domain of a ORFX
protein is facilitated by
generation of hybridomas that bind to the fragment of a ORFX protein
possessing such a domain.
Antibodies that are specific for one or more domains within a ORFX protein,
e.g., the domain
spanning the first fifty amino-terminal residues specific to ORFX when
compared to FGF-9, or
derivatives, fragments, analogs or homologs thereof, are also provided herein.
Anti-ORFX antibodies may be used in methods known within the art relating to
the
localization and/or quantitation of a ORFX protein (e.g., for use in measuring
levels of the
ORFX protein within appropriate physiological samples, for use in diagnostic
methods, for use
in imaging the protein, and the like). In a given embodiment, antibodies for
ORFX proteins, or
1 S derivatives, fragments, analogs or homologs thereof, that contain the
antibody derived binding
domain, are utilized as pharmacologically-active compounds [hereinafter
"Therapeutics"J.
An anti-ORFX antibody (e.g., monoclonal antibody) can be used to isolate ORFX
by
standard techniques, such as affinity chromatography or immunoprecipitation.
An anti-ORFX
antibody can facilitate the purification of natural ORFX from cells and of
recombinantly
produced ORFX expressed in host cells. Moreover, an anti-ORFX antibody can be
used to
detect ORFX protein (e.g., in a cellular lysate or cell supernatant) in order
to evaluate the
abundance and pattern of expression of the ORFX protein. Anti-ORFX antibodies
can be used
diagnostically to monitor protein levels in tissue as part of a clinical
testing procedure, e.g., to,
for example, determine the efficacy of a given treatment regimen. Detection
can be facilitated
by coupling (i.e., physically linking) the antibody to a detectable substance.
Examples of
detectable substances include various enzymes, prosthetic groups, fluorescent
materials,
luminescent materials, bioluminescent materials, and radioactive materials.
Examples of suitable
enzymes include horseradish peroxidase, alkaline phosphatase, ~i-
galactosidase, or
acetylcholinesterase; examples of suitable prosthetic group complexes include
streptavidin/biotin
and avidin/biotin; examples of suitable fluorescent materials include
umbelliferone, fluorescein,
fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein,
dansyl chloride or
37

CA 02383592 2001-09-26
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phycoerythrin; an example of a luminescent material includes luminol; examples
of
bioluminescent materials include luciferase, luciferin, and aequorin, and
examples of suitable
radioactive material include l2sh ~3~I, 3sS or 3H.
ORFX Recombinant Vectors and Host Cells
Another aspect of the invention pertains to vectors, preferably expression
vectors,
containing a nucleic acid encoding ORFX protein, or derivatives, fragments,
analogs or
homologs thereof. As used herein, the term "vector" refers to a nucleic acid
molecule capable of
transporting another nucleic acid to which it has been linked. One type of
vector is a "plasmid",
which refers to a circular double stranded DNA loop into which additional DNA
segments can
be ligated. Another type of vector is a viral vector, wherein additional DNA
segments can be
ligated into the viral genome. Certain vectors are capable of autonomous
replication in a host
cell into which they are introduced (e.g., bacterial vectors having a
bacterial origin of replication
and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian
vectors) are
integrated into the genome of a host cell upon introduction into the host
cell, and thereby are
1 S replicated along with the host genome. Moreover, certain vectors are
capable of directing the
expression of genes to which they are operatively linked. Such vectors are
referred to herein as
"expression vectors". In general, expression vectors of utility in recombinant
DNA techniques
are often in the form of plasmids. In the present specification, "plasmid" and
"vector" can be
used interchangeably as the plasmid is the most commonly used form of vector.
However, the
invention is intended to include such other forms of expression vectors, such
as viral vectors
(e.g., replication defective retroviruses, adenoviruses and adeno-associated
viruses), which serve
equivalent functions.
The recombinant expression vectors of the invention comprise a nucleic acid of
the
invention in a form suitable for expression of the nucleic acid in a host
cell, which means that the
recombinant expression vectors include one or more regulatory sequences,
selected on the basis
of the host cells to be used for expression, that is operatively linked to the
nucleic acid sequence
to be expressed. Within a recombinant expression vector, "operably linked" is
intended to mean
that the nucleotide sequence of interest is linked to the regulatory
sequences) in a manner that
allows for expression of the nucleotide sequence (e.g., in an in vitro
transcription/translation
system or in a host cell when the vector is introduced into the host cell).
The term "regulatory
sequence" is intended to includes promoters, enhancers and other expression
control elements
38

CA 02383592 2001-09-26
WO 00/58473 PCT/US00/08621
(e.g., polyadenylation signals). Such regulatory sequences are described, for
example, in
Goeddel; GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic
Press,
San Diego, Calif. (1990). Regulatory sequences include those that direct
constitutive expression
of a nucleotide sequence in many types of host cell and those that direct
expression of the
nucleotide sequence only in certain host cells (e.g., tissue-specific
regulatory sequences). It will
be appreciated by those skilled in the art that the design of the expression
vector can depend on
such factors as the choice of the host cell to be transformed, the level of
expression of protein
desired, etc. The expression vectors of the invention can be introduced into
host cells to thereby
produce proteins or peptides, including fusion proteins or peptides, encoded
by nucleic acids as
described herein (e.g., ORFX proteins, mutant forms of ORFX, fusion proteins,
etc.).
The recombinant expression vectors of the invention can be designed for
expression of
ORFX in prokaryotic or eukaryotic cells. For example, ORFX can be expressed in
bacterial cells
such as E. coli, insect cells (using baculovirus expression vectors) yeast
cells or mammalian
cells. Suitable host cells are discussed further in Goeddel, GENE EXPRESSION
TECHNOLOGY:
METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990).
Alternatively, the
recombinant expression vector can be transcribed and translated in vitro, for
example using T7
promoter regulatory sequences and T7 polymerase.
Expression of proteins in prokaryotes is most often carried out in E. coli
with vectors
containing constitutive or inducible promoters directing the expression of
either fusion or
non-fusion proteins. Fusion vectors add a number of amino acids to a protein
encoded therein,
usually to the amino terminus of the recombinant protein. Such fusion vectors
typically serve
three purposes: (1) to increase expression of recombinant protein; (2) to
increase the solubility of
the recombinant protein; and (3) to aid in the purification of the recombinant
protein by acting as
a ligand in affinity purification. Often, in fusion expression vectors, a
proteolytic cleavage site is
introduced at the junction of the fusion moiety and the recombinant protein to
enable separation
of the recombinant protein from the fusion moiety subsequent to purification
of the fusion
protein. Such enzymes, and their cognate recognition sequences, include Factor
Xa, thrombin
and enterokinase. Typical fusion expression vectors include pGEX (Pharmacia
Biotech Inc;
Smith and Johnson (1988) Gene 67:31-40), pMAL (New England Biolabs, Beverly,
Mass.) and
pRITS (Pharmacia, Piscataway, N.J.) that fuse glutathione S-transferase (GST),
maltose E
binding protein, or protein A, respectively, to the target recombinant
protein.
39

CA 02383592 2001-09-26
WO 00/58473 PCT/US00/08621
Examples of suitable inducible non-fusion E. coli expression vectors include
pTrc
(Amrann et al., (1988) Gene 69:301-315) and pET 1 1d (Studier et al., GENE
EXPRESSION
TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif.
(1990)
60-89).
One strategy to maximize recombinant protein expression in E. coli is to
express the
protein in a host bacteria with an impaired capacity to proteolytically cleave
the recombinant
protein. See, Gottesman, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY
185,
Academic Press, San Diego, Calif. (1990) 119-128. Another strategy is to alter
the nucleic acid
sequence of the nucleic acid to be inserted into an expression vector so that
the individual codons
for each amino acid are those preferentially utilized in E. coli (Wada et al.,
(1992) Nucleic Acids
Res. 20:2111-2118). Such alteration of nucleic acid sequences of the invention
can be carried
out by standard DNA synthesis techniques.
In another embodiment, the ORFX expression vector is a yeast expression
vector.
Examples of vectors for expression in yeast S. cerivisae include pYepSecl
(Baldari, et al.,
(1987) EMBOJ6:229-234), pMFa (Kurjan and Herskowitz, (1982) Cell 30:933-943),
pJRY88
(Schultz et al., (1987) Gene 54:113-123), pYES2 (Invitrogen Corporation, San
Diego, Calif.),
and picZ (InVitrogen Corp, San Diego, Calif.).
Alternatively, ORFX can be expressed in insect cells using baculovirus
expression
vectors. Baculovirus vectors available for expression of proteins in cultured
insect cells (e.g.,
SF9 cells) include the pAc series (Smith et al. (1983) Mol Cell Biol 3:2156-
2165) and the pVL
series (Lucklow and Summers (1989) Virology 170:31-39).
In yet another embodiment, a nucleic acid of the invention is expressed in
mammalian
cells using a mammalian expression vector. Examples of mammalian expression
vectors include
pCDM8 (Seed (1987) Nature 329:840) and pMT2PC (Kaufinan et al. (1987) EMBO J
6: 187-195). When used in mammalian cells, the expression vector's control
functions are often
provided by viral regulatory elements. For example, commonly used promoters
are derived from
polyoma, Adenovirus 2, cytomegalovirus and Simian Virus 40. For other suitable
expression
systems for both prokaryotic and eukaryotic cells. See, e.g., Chapters 16 and
17 of Sambrook et
al., MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor
Laboratory,
Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989.

CA 02383592 2001-09-26
WO 00/58473 PCT/US00/08621
In another embodiment, the recombinant mammalian expression vector is capable
of
directing expression of the nucleic acid preferentially in a particular cell
type (e.g.,
tissue-specific regulatory elements are used to express the nucleic acid).
Tissue-specific
regulatory elements are known in the art. Non-limiting examples of suitable
tissue-specific
S promoters include the albumin promoter (liver-specific; Pinkert et al.
(1987) Genes Dev
1:268-277), lymphoid-specific promoters (Calame and Eaton (1988) Adv Immunol
43:235-275),
in particular promoters of T cell receptors (Winoto and Baltimore (1989) EMBO
J 8:729-733)
and immunoglobulins (Banerji et al. (1983) Cell 33:729-740; Queen and
Baltimore (1983) Cell
33:741-748), neuron-specific promoters (e.g., the neurofilament promoter;
Byrne and Ruddle
(1989) PNAS 86:5473-5477), pancreas-specific promoters (Edlund et al. (1985)
Science
230:912-916), and mammary gland-specific promoters (e.g., milk whey promoter;
U.S. Pat. No.
4,873,316 and European Application Publication No. 264,166). Developmentally-
regulated
promoters are also encompassed, e.g., the marine hox promoters (Kessel and
Grass (1990)
Science 249:374-379) and the a-fetoprotein promoter (Campes and Tilghman
(1989) Genes Dev
3:537-546).
The invention further provides a recombinant expression vector comprising a
DNA
molecule of the invention cloned into the expression vector in an antisense
orientation. That is,
the DNA molecule is operatively linked to a regulatory sequence in a manner
that allows for
expression (by transcription of the DNA molecule) of an RNA molecule that is
antisense to
ORFX mRNA. Regulatory sequences operatively linked to a nucleic acid cloned in
the antisense
orientation can be chosen that direct the continuous expression of the
antisense RNA molecule in
a variety of cell types, for instance viral promoters and/or enhancers, or
regulatory sequences can
be chosen that direct constitutive, tissue specific or cell type specific
expression of antisense
RNA. The antisense expression vector can be in the form of a recombinant
plasmid, phagemid
or attenuated virus in which antisense nucleic acids are produced under the
control of a high
efficiency regulatory region, the activity of which can be determined by the
cell type into which
the vector is introduced. For a discussion of the regulation of gene
expression using antisense
genes see Weintraub et al., "Antisense RNA as a molecular tool for genetic
analysis,"
Reviews--Trends in Genetics, V o1. 1 ( 1 ) 1986.
Another aspect of the invention pertains to host cells into which a
recombinant
expression vector of the invention has been introduced. The terms "host cell"
and "recombinant
41

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host cell" are used interchangeably herein. It is understood that such terms
refer not only to the
particular subject cell but to the progeny or potential progeny of such a
cell. Because certain
modifications may occur in succeeding generations due to either mutation or
environmental
influences, such progeny may not, in fact, be identical to the parent cell,
but are still included
within the scope of the term as used herein.
A host cell can be any prokaryotic or eukaryotic cell. For example, ORFX
protein can be
expressed in bacterial cells such as E. coli, insect cells, yeast or mammalian
cells (such as
Chinese hamster ovary cells (CHO) or COS cells). Other suitable host cells are
known to those
skilled in the art.
Vector DNA can be introduced into prokaryotic or eukaryotic cells via
conventional
transformation or transfection techniques. As used herein, the terms
"transformation" and
"transfection" are intended to refer to a variety of art-recognized techniques
for introducing
foreign nucleic acid (e.g., DNA) into a host cell, including calcium phosphate
or calcium
chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection, or
electroporation.
Suitable methods for transforming or transfecting host cells can be found in
Sambrook, et al.
(MOLECULAR CLONING: A LABORATORY MANUAL. Zrid ed., COId Spring Harbor
Laboratory,
Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989), and
other laboratory
manuals.
For stable transfection of mammalian cells, it is known that, depending upon
the
expression vector and transfection technique used, only a small fraction of
cells may integrate
the foreign DNA into their genome. In order to identify and select these
integrants, a gene that
encodes a selectable marker (e.g., resistance to antibiotics) is generally
introduced into the host
cells along with the gene of interest. Various selectable markers include
those that confer
resistance to drugs, such as 6418, hygromycin and methotrexate. Nucleic acid
encoding a
selectable marker can be introduced into a host cell on the same vector as
that encoding ORFX
or can be introduced on a separate vector. Cells stably transfected with the
introduced nucleic
acid can be identified by drug selection (e.g., cells that have incorporated
the selectable marker
gene will survive, while the other cells die).
A host cell of the invention, such as a prokaryotic or eukaryotic host cell in
culture, can
be used to produce (i.e., express) ORFX protein. Accordingly, the invention
further provides
methods for producing ORFX protein using the host cells of the invention. In
one embodiment,
42

CA 02383592 2001-09-26
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the method comprises culturing the host cell of invention (into which a
recombinant expression
vector encoding ORFX has been introduced) in a suitable medium such that ORFX
protein is
produced. In another embodiment, the method further comprises isolating ORFX
from the
medium or the host cell.
Transgenic animals
The host cells of the invention can also be used to produce nonhuman
transgenic animals.
For example, in one embodiment, a host cell of the invention is a fertilized
oocyte or an
embryonic stem cell into which ORFX-coding sequences have been introduced.
Such host cells
can then be used to create non-human transgenic animals in which exogenous
ORFX sequences
have been introduced into their genome or homologous recombinant animals in
which
endogenous ORFX sequences have been altered. Such animals are useful for
studying the
function and/or activity of ORFX and for identifying and/or evaluating
modulators of ORFX
activity. As used herein, a "transgenic animal" is a non-human animal,
preferably a mammal,
more preferably a rodent such as a rat or mouse, in which one or more of the
cells of the animal
1 S includes a transgene. Other examples of transgenic animals include non-
human primates, sheep,
dogs, cows, goats, chickens, amphibians, etc. A transgene is exogenous DNA
that is integrated
into the genome of a cell from which a transgenic animal develops and that
remains in the
genome of the mature animal, thereby directing the expression of an encoded
gene product in
one or more cell types or tissues of the transgenic animal. As used herein, a
"homologous
recombinant animal" is a non-human animal, preferably a mammal, more
preferably a mouse, in
which an endogenous ORFX gene has been altered by homologous recombination
between the
endogenous gene and an exogenous DNA molecule introduced into a cell of the
animal, e.g., an
embryonic cell of the animal, prior to development of the animal.
A transgenic animal of the invention can be created by introducing ORFX-
encoding
nucleic acid into the male pronuclei of a fertilized oocyte, e.g., by
microinjection, retroviral
infection, and allowing the oocyte to develop in a pseudopregnant female
foster animal. The
human ORFX DNA sequence of SEQ ID N0:2n-1 (wherein n = 1 to 3161) can be
introduced as
a transgene into the genome of a non-human animal. Alternatively, a nonhuman
homologue of
the human ORFX gene, such as a mouse ORFX gene, can be isolated based on
hybridization to
the human ORFX cDNA (described further above) and used as a transgene.
Intronic sequences
and polyadenylation signals can also be included in the transgene to increase
the efficiency of
43

CA 02383592 2001-09-26
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expression of the transgene. A tissue-specific regulatory sequences) can be
operably linked to
the ORFX transgene to direct expression of ORFX protein to particular cells.
Methods for
generating transgenic animals via embryo manipulation and microinjection,
particularly animals
such as mice, have become conventional in the art and are described, for
example, in U.S. Pat.
Nos. 4,736,866; 4,870,009; and 4,873,191; and Hogan 1986, In: MANIPULATING THE
MousE
EMBRYO, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. Similar
methods are
used for production of other transgenic animals. A transgenic founder animal
can be identified
based upon the presence of the ORFX transgene in its genome and/or expression
of ORFX
mRNA in tissues or cells of the animals. A transgenic founder animal can then
be used to breed
additional animals carrying the transgene. Moreover, transgenic animals
carrying a transgene
encoding ORFX can further be bred to other transgenic animals carrying other
transgenes.
To create a homologous recombinant animal, a vector is prepared which contains
at least
a portion of a ORFX gene into which a deletion, addition or substitution has
been introduced to
thereby alter, e.g., functionally disrupt, the ORFX gene. The ORFX gene can be
a human gene
(e.g., SEQ ID N0:2n-1 (wherein n = 1 to 3161)), but more preferably, is a non-
human
homologue of a human ORFX gene. For example, a mouse homologue of human ORFX
gene of
SEQ ID N0:2n-1 (wherein n = 1 to 3161) can be used to construct a homologous
recombination
vector suitable for altering an endogenous ORFX gene in the mouse genome. In
one
embodiment, the vector is designed such that, upon homologous recombination,
the endogenous
ORFX gene is functionally disrupted (i.e., no longer encodes a functional
protein; also referred
to as a "knock out" vector).
Alternatively, the vector can be designed such that, upon homologous
recombination, the
endogenous ORFX gene is mutated or otherwise altered but still encodes
functional protein (e.g.,
the upstream regulatory region can be altered to thereby alter the expression
of the endogenous
ORFX protein). In the homologous recombination vector, the altered portion of
the ORFX gene
is flanked at its 5' and 3' ends by additional nucleic acid of the ORFX gene
to allow for
homologous recombination to occur between the exogenous ORFX gene carried by
the vector
and an endogenous ORFX gene in an embryonic stem cell. The. additional
flanking ORFX
nucleic acid is of sufficient length for successful homologous recombination
with the
endogenous gene. Typically, several kilobases of flanking DNA (both at the 5'
and 3' ends) are
included in the vector. See e.g., Thomas et al. (1987) Cell 51:503 for a
description of
44

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homologous recombination vectors. The vector is introduced into an embryonic
stem cell line
(e.g., by electroporation) and cells in which the introduced ORFX gene has
homologously
recombined with the endogenous ORFX gene are selected (see e.g., Li et al.
(1992) Cell 69:915).
The selected cells are then injected into a blastocyst of an animal (e.g., a
mouse) to form
aggregation chimeras. See e. g., Bradley 1987, In: TERATOCARCINOMAS AND
EMBRYONIC STEM
CELLS: A PRACTICAL APPROACH, Robertson, ed. IRL, Oxford, pp. 113-152. A
chimeric embryo
can then be implanted into a suitable pseudopregnant female foster animal and
the embryo
brought to term. Progeny harboring the homologously recombined DNA in their
germ cells can
be used to breed animals in which all cells of the animal contain the
homologously recombined
DNA by germline transmission of the transgene. Methods for constructing
homologous
recombination vectors and homologous recombinant animals are described further
in Bradley
(1991) Curr Opin Biotechnol 2:823-829; PCT International Publication Nos.: WO
90/11354;
WO 91/01140; WO 92/0968; and WO 93/04169.
In another embodiment, transgenic non-humans animals can be produced that
contain
selected systems that allow for regulated expression of the transgene. One
example of such a
system is the cre/loxP recombinase system of bacteriophage P 1. For a
description of the cre/loxP
recombinase system, see, e.g., Lakso et al. (1992) PNAS 89:6232-6236. Another
example of a
recombinase system is the FLP recombinase system of Saccharomyces cerevisiae
(O'Gorman et
al. (1991) Science 251:1351-1355. If a cre/loxP recombinase system is used to
regulate
expression of the transgene, animals containing transgenes encoding both the
Cre recombinase
and a selected protein are required. Such animals can be provided through the
construction of
"double" transgenic animals, e.g., by mating two transgenic animals, one
containing a transgene
encoding a selected protein and the other containing a transgene encoding a
recombinase.
Clones of the non-human transgenic animals described herein can also be
produced
according to the methods described in Wilmut et al. (1997) Nature 385:810-813.
In brief, a cell,
e.g., a somatic cell, from the transgenic animal can be isolated and induced
to exit the growth
cycle and enter Go phase. The quiescent cell can then be fused, e.g., through
the use of electrical
pulses, to an enucleated oocyte from an animal of the same species from which
the quiescent cell
is isolated. The reconstructed oocyte is then cultured such that it develops
to morula or
blastocyte and then transferred to pseudopregnant female foster animal. The
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CA 02383592 2001-09-26
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this female foster animal will be a clone of the animal from which the cell,
e.g., the somatic cell,
is isolated.
Pharmaceutical Compositions
The ORFX nucleic acid molecules, ORFX proteins, and anti-ORFX antibodies (also
S referred to herein as "active compounds") of the invention, and derivatives,
fragments, analogs
and homologs thereof, can be incorporated into pharmaceutical compositions
suitable for
administration. Such compositions typically comprise the nucleic acid
molecule, protein, or
antibody and a pharmaceutically acceptable carrier. As used herein,
"pharmaceutically
acceptable carrier" is intended to include any and all solvents, dispersion
media, coatings,
antibacterial and antifungal agents, isotonic and absorption delaying agents,
and the like,
compatible with pharmaceutical administration. Suitable carriers are described
in the most
recent edition of Remington's Pharmaceutical Sciences, a standard reference
text in the field,
which is incorporated herein by reference. Preferred examples of such carriers
or diluents
include, but are not limited to, water, saline, finger's solutions, dextrose
solution, and 5% human
serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also
be used. The
use of such media and agents for pharmaceutically active substances is well
known in the art.
Except insofar as any conventional media or agent is incompatible with the
active compound,
use thereof in the compositions is contemplated. Supplementary active
compounds can also be
incorporated into the compositions.
A pharmaceutical composition of the invention is formulated to be compatible
with its
intended route of administration. Examples of routes of administration include
parenteral, e.g.,
intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal
(topical),
transmucosal, and rectal administration. Solutions or suspensions used for
parenteral,
intradermal, or subcutaneous application can include the following components:
a sterile diluent
such as water for injection, saline solution, fixed oils, polyethylene
glycols, glycerine, propylene
glycol or other synthetic solvents; antibacterial agents such as benzyl
alcohol or methyl
parabens; antioxidants such as ascorbic acid or sodium bisulfate; chelating
agents such as
ethylenediam'inetetraacetic acid; buffers such as acetates, citrates or
phosphates, and agents for
the adjustment of tonicity such as sodium chloride or dextrose. The pH can be
adjusted with
acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral
preparation can
be enclosed in ampoules, disposable syringes or multiple dose vials made of
glass or plastic.
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Pharmaceutical compositions suitable for injectable use include sterile
aqueous solutions
(where water soluble) or dispersions and sterile powders for the
extemporaneous preparation of
sterile injectable solutions or dispersion. For intravenous administration,
suitable carriers
include physiological saline, bacteriostatic water, Cremophor ELTM (BASF,
Parsippany, N.J.) or
phosphate buffered saline (PBS). In all cases, the composition must be sterile
and should be
fluid to the extent that easy syringeability exists. It must be stable under
the conditions of
manufacture and storage and must be preserved against the contaminating action
of
microorganisms such as bacteria and fungi. The Garner can be a solvent or
dispersion medium
containing, for example, water, ethanol, polyol (for example, glycerol,
propylene glycol, and
liquid polyethylene glycol, and the like), and suitable mixtures thereof. The
proper fluidity can
be maintained, for example, by the use of a coating such as lecithin, by the
maintenance of the
required particle size in the case of dispersion and by the use of
surfactants. Prevention of the
action of microorganisms can be achieved by various antibacterial and
antifungal agents, for
example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the
like. In many
cases, it will be preferable to include isotonic agents, for example, sugars,
polyalcohols such as
manitol, sorbitol, sodium chloride in the composition. Prolonged absorption of
the injectable
compositions can be brought about by including in the composition an agent
which delays
absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions can be prepared by incorporating the active
compound (e.g., a
ORFX protein or anti-ORFX antibody) in the required amount in an appropriate
solvent with one
or a combination of ingredients enumerated above, as required, followed by
filtered sterilization.
Generally, dispersions are prepared by incorporating the active compound into
a sterile vehicle
that contains a basic dispersion medium and the required other ingredients
from those
enumerated above. In the case of sterile powders for the preparation of
sterile injectable
solutions, methods of preparation are vacuum drying and freeze-drying that
yields a powder of
the active ingredient plus any additional desired ingredient from a previously
sterile-filtered
solution thereof.
Oral compositions generally include an inert diluent or an edible carrier.
They can be
enclosed in gelatin capsules or compressed into tablets. _For the purpose of
oral therapeutic
administration, the active compound can be incorporated with excipients and
used in the form of
tablets, troches, or capsules. Oral compositions can also be prepared using a
fluid Garner for use
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as a mouthwash, wherein the compound in the fluid Garner is applied orally and
swished and
expectorated or swallowed. Pharmaceutically compatible binding agents, and/or
adjuvant
materials can be included as part of the composition. The tablets, pills,
capsules, troches and the
like can contain any of the following ingredients, or compounds of a similar
nature: a binder
such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient
such as starch or
lactose, a disintegrating agent such as alginic acid, Primogel, or corn
starch; a lubricant such as
magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a
sweetening agent
such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl
salicylate, or
orange flavoring.
For administration by inhalation, the compounds are delivered in the form of
an aerosol
spray from pressured container or dispenser which contains a suitable
propellant, e.g., a gas such
as carbon dioxide, or a nebulizer.
Systemic administration can also be by transmucosal or transdermal means. For
transmucosal or transdermal administration, penetrants appropriate to the
barner to be permeated
are used in the formulation. Such penetrants are generally known in the art,
and include, for
example, for transmucosal administration, detergents, bile salts, and fusidic
acid derivatives.
Transmucosal administration can be accomplished through the use of nasal
sprays or
suppositories. For transdermal administration, the active compounds are
formulated into
ointments, salves, gels, or creams as generally known in the art.
The compounds can also be prepared in the form of suppositories (e.g., with
conventional
suppository bases such as cocoa butter and other glycerides) or retention
enemas for rectal delivery.
In one embodiment, the active compounds are prepared with carriers that will
protect the
compound against rapid elimination from the body, such as a controlled release
formulation,
including implants and microencapsulated delivery systems. Biodegradable,
biocompatible
polymers can be used, such as ethylene vinyl acetate, polyanhydrides,
polyglycolic acid,
collagen, polyorthoesters, and polylactic acid. Methods for preparation of
such formulations will
be apparent to those skilled in the art. The materials can also be obtained
commercially from
Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions
(including liposomes
targeted to infected cells with monoclonal antibodies to viral antigens) can
also be used as
pharmaceutically acceptable carriers. These can be prepared according to
methods known to
those skilled in the art, for example, as described in U.S. Pat. No.
4,522,811.
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It is especially advantageous to formulate oral or parenteral compositions in
dosage unit
form for ease of administration and uniformity of dosage. Dosage unit form as
used herein refers
to physically discrete units suited as unitary dosages for the subject to be
treated; each unit
containing a predetermined quantity of active compound calculated to produce
the desired
therapeutic effect in association with the required pharmaceutical Garner. The
specification for
the dosage unit forms of the invention are dictated by and directly dependent
on the unique
characteristics of the active compound and the particular therapeutic effect
to be achieved.
The nucleic acid molecules of the invention can be inserted into vectors and
used as gene
therapy vectors. Gene therapy vectors can be delivered to a subject by any of
a number of
routes, e.g., as described in U.S. Patent Nos. 5,703,055. Delivery can thus
also include, e.g.,
intravenous injection, local administration (see U.S. Pat. No. 5,328,470) or
stereotactic injection
(see e.g., Chen et al. (1994) PNAS 91:3054-3057). The pharmaceutical
preparation of the gene
therapy vector can include the gene therapy vector in an acceptable diluent,
or can comprise a
slow release matrix in which the gene delivery vehicle is imbedded.
Alternatively, where the
complete gene delivery vector can be produced intact from recombinant cells,
e.g., retroviral
vectors, the pharmaceutical preparation can include one or more cells that
produce the gene
delivery system.
The pharmaceutical compositions can be included in a container, pack, or
dispenser
together with instructions for administration.
Additional Uses and Methods of the Invention
The nucleic acid molecules, proteins, protein homologues, and antibodies
described
herein can be used in one or more of the following methods: (a) screening
assays; (b) detection
assays (e.g., chromosomal mapping, cell and tissue typing, forensic biology),
(c) predictive
medicine (e.g., diagnostic assays, prognostic assays, monitoring clinical
trials, and
pharmacogenomics); and (d) methods of treatment (e.g., therapeutic and
prophylactic).
The isolated nucleic acid molecules of the invention can be used to express
ORFX
protein (e.g., via a recombinant expression vector in a host cell in gene
therapy applications), to
detect ORFX mRNA (e.g., in a biological sample) or a genetic lesion in a ORFX
gene, and to
modulate ORFX activity, as described further below. In addition, the ORFX
proteins can be
used to screen drugs or compounds that modulate the ORFX activity or
expression as well as to
treat disorders characterized by insufficient or excessive production of ORFX
protein, for
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CA 02383592 2001-09-26
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example proliferative or differentiative disorders, or production of ORFX
protein forms that have
decreased or aberrant activity compared to ORFX wild type protein. In
addition, the anti-ORFX
antibodies of the invention can be used to detect and isolate ORFX proteins
and modulate ORFX
activity.
This invention further pertains to novel agents identified by the above
described
screening assays and uses thereof for treatments as described herein.
Screening Assays
The invention provides a method (also referred to herein as a "screening
assay") for
identifying modulators, i.e., candidate or test compounds or agents (e.g.,
peptides,
peptidomimetics, small molecules or other drugs) that bind to ORFX proteins or
have a
stimulatory or inhibitory effect on, for example, ORFX expression or ORFX
activity.
In one embodiment, the invention provides assays for screening candidate or
test
compounds which bind to or modulate the activity of a ORFX protein or
polypeptide or
biologically active portion thereof. The test compounds of the present
invention can be obtained
using any of the numerous approaches in combinatorial library methods known in
the art,
including: biological libraries; spatially addressable parallel solid phase or
solution phase
libraries; synthetic library methods requiring deconvolution; the "one-bead
one-compound"
library method; and synthetic library methods using affinity chromatography
selection. The
biological library approach is limited to peptide libraries, while the other
four approaches are
applicable to peptide, non-peptide oligomer or small molecule libraries of
compounds (Lam
(1997) Anticancer Drug Des 12:145).
Examples of methods for the synthesis of molecular libraries can be found in
the art, for
example in: DeWitt et al. (1993) Proc Natl Acad Sci U.S.A. 90:6909; Erb et al.
(1994) Proc Natl
Acad Sci U.S.A. 91:11422; Zuckermann et al. (1994) JMed Chem 37:2678; Cho et
al. (1993)
Science 261:1303; Carrell et al. (1994) Angew Chem Int Ed Engl 33:2059; Carell
et al. (1994)
Angew Chem Int Ed Engl 33:2061; and Gallop et al. (1994) JMed Chem 37:1233.
Libraries of compounds may be presented in solution (e.g., Houghten (1992)
Biotechniques 13:412-421), or on beads (Lam (1991) Nature 354:82-84), on chips
(Fodor (1993)
Nature 364:555-556), bacteria (Ladner U.S. Pat. No. 5,223,409), spores (Ladner
USP'409),
plasmids (Cull et al. (1992) ProcNatl Acad Sci USA 89:1865-1869) or on phage
(Scott and

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Smith ( 1990) Science 249:3 86-390; Devlin ( 1990) Science 249:404-406; Cwirla
et al. ( 1990)
Proc Natl Acad Sci U.S.A. 87:6378-6382; Felici (1991) .l Mol Biol 222:301-310;
Ladner above.).
In one embodiment, an assay is a cell-based assay in which a cell which
expresses a
membrane-bound form of ORFX protein, or a biologically active portion thereof,
on the cell
surface is contacted with a test compound and the ability of the test compound
to bind to a
ORFX protein determined. The cell, for example, can of mammalian origin or a
yeast cell.
Determining the ability of the test compound to bind to the ORFX protein can
be accomplished,
for example, by coupling the test compound with a radioisotope or enzymatic
label such that
binding of the test compound to the ORFX protein or biologically active
portion thereof can be
determined by detecting the labeled compound in a complex. For example, test
compounds can
be labeled with 1251, 355, laC, or 3H, either directly or indirectly, and the
radioisotope detected by
direct counting of radioemission or by scintillation counting. Alternatively,
test compounds can
be enzymatically labeled with, for example, horseradish peroxidase, alkaline
phosphatase, or
luciferase, and the enzymatic label detected by determination of conversion of
an appropriate
substrate to product. In one embodiment, the assay comprises contacting a cell
which expresses
a membrane-bound form of ORFX protein, or a biologically active portion
thereof, on the cell
surface with a known compound which binds ORFX to form an assay mixture,
contacting the
assay mixture with a test compound, and determining the ability of the test
compound to interact
with a ORFX protein, wherein determining the ability of the test compound to
interact with a
ORFX protein comprises determining the ability of the test compound to
preferentially bind to
ORFX or a biologically active portion thereof as compared to the known
compound.
In another embodiment, an assay is a cell-based assay comprising contacting a
cell
expressing a membrane-bound form of ORFX protein, or a biologically active
portion thereof, on
the cell surface with a test compound and determining the ability of the test
compound to
modulate (e.g., stimulate or inhibit) the activity of the ORFX protein or
biologically active
portion thereof. Determining the ability of the test compound to modulate the
activity of ORFX
or a biologically active portion thereof can be accomplished, for example, by
determining the
ability of the ORFX protein to bind to or interact with a ORFX target
molecule. As used herein,
a "target molecule" is a molecule with which a ORFX protein binds or interacts
in nature, for
example, a molecule on the surface of a cell which expresses a ORFX
interacting protein, a
molecule on the surface of a second cell, a molecule in the extracellular
milieu, a molecule
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CA 02383592 2001-09-26
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associated with the internal surface of a cell membrane or a cytoplasmic
molecule. A ORFX
target molecule can be a non-ORFX molecule or a ORFX protein or polypeptide of
the present
invention. In one embodiment, a ORFX target molecule is a component of a
signal transduction
pathway that facilitates transduction of an extracellular signal (e.g., a
signal generated by binding
of a compound to a membrane-bound ORFX molecule) through the cell membrane and
into the
cell. The target, for example, can be a second intercellular protein that has
catalytic activity or a
protein that facilitates the association of downstream signaling molecules
with ORFX.
Determining the ability of the ORFX protein to bind to or interact with a ORFX
target
molecule can be accomplished by one of the methods described above for
determining direct
binding. In one embodiment, determining the ability of the ORFX protein to
bind to or interact
with a ORFX target molecule can be accomplished by determining the activity of
the target
molecule. For example, the activity of the target molecule can be determined
by detecting
induction of a cellular second messenger of the target (i. e. intracellular
Ca2+, diacylglycerol, IP3,
etc.), detecting catalytic/enzymatic activity of the target an appropriate
substrate, detecting the
induction of a reporter gene (comprising a ORFX-responsive regulatory element
operatively
linked to a nucleic acid encoding a detectable marker, e.g., luciferase), or
detecting a cellular
response, for example, cell survival, cellular differentiation, or cell
proliferation.
In yet another embodiment, an assay of the present invention is a cell-free
assay
comprising contacting a ORFX protein or biologically active portion thereof
with a test
compound and determining the ability of the test compound to bind to the ORFX
protein or
biologically active portion thereof. Binding of the test compound to the ORFX
protein can be
determined either directly or indirectly as described above. In one
embodiment, the assay
comprises contacting the ORFX protein or biologically active portion thereof
with a known
compound which binds ORFX to form an assay mixture, contacting the assay
mixture with a test
compound, and determining the ability of the test compound to interact with a
ORFX protein,
wherein determining the ability of the test compound to interact with a ORFX
protein comprises
determining the ability of the test compound to preferentially bind to ORFX or
biologically
active portion thereof as compared to the known compound.
In another embodiment, an assay is a cell-free assay comprising contacting
ORFX protein
or biologically active portion thereof with a test compound and determining
the ability of the test
compound to modulate (e.g., stimulate or inhibit) the activity of the ORFX
protein or
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biologically active portion thereof. Determining the ability of the test
compound to modulate the
activity of ORFX can be accomplished, for example, by determining the ability
of the ORFX
protein to bind to a ORFX target molecule by one of the methods described
above for
determining direct binding. In an alternative embodiment, determining the
ability of the test
compound to modulate the activity of ORFX can be accomplished by determining
the ability of
the ORFX protein further modulate a ORFX target molecule. For example, the
catalytic/enzymatic activity of the target molecule on an appropriate
substrate can be determined
as previously described.
In yet another embodiment, the cell-free assay comprises contacting the ORFX
protein or
biologically active portion thereof with a known compound which binds ORFX to
form an assay
mixture, contacting the assay mixture with a test compound, and determining
the ability of the
test compound to interact with a ORFX protein, wherein determining the ability
of the test
compound to interact with a ORFX protein comprises determining the ability of
the ORFX
protein to preferentially bind to or modulate the activity of a ORFX target
molecule.
The cell-free assays of the present invention are amenable to use of both the
soluble form
or the membrane-bound form of ORFX. In the case of cell-free assays comprising
the
membrane-bound form of ORFX, it may be desirable to utilize a solubilizing
agent such that the
membrane-bound form of ORFX is maintained in solution. Examples of such
solubilizing agents
include non-ionic detergents such as n-octylglucoside, n-dodecylglucoside, n-
dodecylmaltoside,
octanoyl-N-methylglucamide, decanoyl-N-methylglucamide, Triton X-100, Triton X-
114,
Thesit~, Isotridecypoly(ethylene glycol ether)", N-dodecyl--N,N-dimethyl-3-
ammonio-1-propane
sulfonate, 3-(3-cholamidopropyl)dimethylamminiol-1-propane sulfonate (CHAPS),
or
3-(3-cholamidopropyl)dimethylamminiol-2-hydroxy-1-propane sulfonate (CHAPSO).
In more than one embodiment of the above assay methods of the present
invention, it
may be desirable to immobilize either ORFX or its target molecule to
facilitate separation of
complexed from uncomplexed forms of one or both of the proteins, as well as to
accommodate
automation of the assay. Binding of a test compound to ORFX, or interaction of
ORFX with a
target molecule in the presence and absence of a candidate compound, can be
accomplished in
any vessel suitable for containing the reactants. Examples of such vessels
include microtiter
plates, test tubes, and micro-centrifuge tubes. In one embodiment, a fusion
protein can be
provided that adds a domain that allows one or both of the proteins to be
bound to a matrix. For
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example, GST-ORFX fusion proteins or GST-target fusion proteins can be
adsorbed onto
glutathione sepharose beads (Sigma Chemical, St. Louis, MO) or glutathione
derivatized
microtiter plates, that are then combined with the test compound or the test
compound and either
the non-adsorbed target protein or ORFX protein, and the mixture is incubated
under conditions
S conducive to complex formation (e.g., at physiological conditions for salt
and pH). Following
incubation, the beads or microtiter plate wells are washed to remove any
unbound components,
the matrix immobilized in the case of beads, complex determined either
directly or indirectly, for
example, as described above. Alternatively, the complexes can be dissociated
from the matrix,
and the level of ORFX binding or activity determined using standard
techniques.
Other techniques for immobilizing proteins on matrices can also be used in the
screening
assays of the invention. For example, either ORFX or its target molecule can
be immobilized
utilizing conjugation of biotin and streptavidin. Biotinylated ORFX or target
molecules can be
prepared from biotin-NHS (N-hydroxy-succinimide) using techniques well known
in the art
(e.g., biotinylation kit, Pierce Chemicals, Rockford, Ill.), and immobilized
in the wells of
1 S streptavidin-coated 96 well plates (Pierce Chemical). Alternatively,
antibodies reactive with
ORFX or target molecules, but which do not interfere with binding of the ORFX
protein to its
target molecule, can be derivatized to the wells of the plate, and unbound
target or ORFX
trapped in the wells by antibody conjugation. Methods for detecting such
complexes, in addition
to those described above for the GST-immobilized complexes, include
immunodetection of
complexes using antibodies reactive with the ORFX or target molecule, as well
as enzyme-linked
assays that rely on detecting an enzymatic activity associated with the ORFX
or target molecule.
In another embodiment, modulators of ORFX expression are identified in a
method
wherein a cell is contacted with a candidate compound and the expression of
ORFX mRNA or
protein in the cell is determined. The level of expression of ORFX mRNA or
protein in the
presence of the candidate compound is compared to the level of expression of
ORFX mRNA or
protein in the absence of the candidate compound. The candidate compound can
then be
identified as a modulator of ORFX expression based on this comparison. For
example, when
expression of ORFX mRNA or protein is greater (statistically significantly
greater) in the
presence of the candidate compound than in its absence, the candidate compound
is identified as
a stimulator of ORFX mRNA or protein expression. Alternatively, when
expression of ORFX
mRNA or protein is less (statistically significantly less) in the presence of
the candidate
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compound than in its absence, the candidate compound is identified as an
inhibitor of ORFX
mRNA or protein expression. The level of ORFX mRNA or protein expression in
the cells can
be determined by methods described herein for detecting ORFX mRNA or protein.
In yet another aspect of the invention, the ORFX proteins can be used as "bait
proteins"
in a two-hybrid assay or three hybrid assay (see, e.g., U.S. Pat. No.
5,283,317; Zervos et al.
(1993) Cell 72:223-232; Madura et al. (1993) J Biol Chem 268:12046-12054;
Bartel et al. (1993)
Biotechniques 14:920-924; Iwabuchi et al. (1993) Oncogene 8:1693-1696; and
Brent
W094/10300), to identify other proteins that bind to or interact with ORFX
("ORFX-binding
proteins" or "ORFX-by") and modulate ORFX activity. Such ORFX-binding proteins
are also
likely to be involved in the propagation of signals by the ORFX proteins as,
for example,
upstream or downstream elements of the ORFX pathway.
The two-hybrid system is based on the modular nature of most transcription
factors,
which consist of separable DNA-binding and activation domains. Briefly, the
assay utilizes two
different DNA constructs. In one construct, the gene that codes for ORFX is
fused to a gene
encoding the DNA binding domain of a known transcription factor (e.g., GAL-4).
In the other
construct, a DNA sequence, from a library of DNA sequences, that encodes an
unidentified
protein ("prey" or "sample") is fused to a gene that codes for the activation
domain of the known
transcription factor. If the "bait" and the "prey" proteins are able to
interact, in vivo, forming a
ORFX-dependent complex, the DNA-binding and activation domains of the
transcription factor
are brought into close proximity. This proximity allows transcription of a
reporter gene (e.g.,
LacZ) that is operably linked to a transcriptional regulatory site responsive
to the transcription
factor. Expression of the reporter gene can be detected and cell colonies
containing the
functional transcription factor can be isolated and used to obtain the cloned
gene that encodes the
protein which interacts with ORFX.
This invention further pertains to novel agents identified by the above-
described
screening assays and uses thereof for treatments as described herein.
Detection Assays
Portions or fragments of the cDNA sequences identified herein (and the
corresponding
complete gene sequences) can be used in numerous ways as polynucleotide
reagents. For
example, these sequences can be used to: (i) map their respective genes on a
chromosome; and,
thus, locate gene regions associated with genetic disease; (ii) identify an
individual from a
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minute biological sample (tissue typing); and (iii) aid in forensic
identification of a biological
sample.
The ORFX sequences of the present invention can also be used to identify
individuals
from minute biological samples. In this technique, an individual's genomic DNA
is digested
with one or more restriction enzymes, and probed on a Southern blot to yield
unique bands for
identification. The sequences of the present invention are useful as
additional DNA markers for
RFLP ("restriction fragment length polymorphisms," described in U.S. Pat. No.
5,272,057).
Furthermore, the sequences of the present invention can be used to provide an
alternative
technique that determines the actual base-by-base DNA sequence of selected
portions of an
individual's genome. Thus, the ORFX sequences described herein can be used to
prepare two
PCR primers from the 5' and 3' ends of the sequences. These primers can then
be used to
amplify an individual's DNA and subsequently sequence it.
Panels of corresponding DNA sequences from individuals, prepared in this
manner, can
provide unique individual identifications, as each individual will have a
unique set of such DNA
sequences due to allelic differences. The sequences of the present invention
can be used to
obtain such identification sequences from individuals and from tissue. The
ORFX sequences of
the invention uniquely represent portions of the human genome. Allelic
variation occurs to some
degree in the coding regions of these sequences, and to a greater degree in
the noncoding
regions. It is estimated that allelic variation between individual humans
occurs with a frequency
of about once per each 500 bases. Much of the allelic variation is due to
single nucleotide
polymorphisms (SNPs), which include restriction fragment length polymorphisms
(RFLPs).
Each of the sequences described herein can, to some degree, be used as a
standard against
which DNA from an individual can be compared for identification purposes.
Because greater
numbers of polymorphisms occur in the noncoding regions, fewer sequences are
necessary to
differentiate individuals. The noncoding sequences of SEQ ID N0:2n-1 (wherein
n = 1 to 3161),
as described above, can comfortably provide positive individual identification
with a panel of
perhaps 10 to 1,000 primers that each yield a noncoding amplified sequence of
100 bases. If
predicted coding sequences are used, a more appropriate number of primers for
positive
individual identification would be 500-2,000.
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Predictive Medicine
The present invention also pertains to the field of predictive medicine in
which diagnostic
assays, prognostic assays, pharmacogenomics, and monitoring clinical trials
are used for
prognostic (predictive) purposes to thereby treat an individual
prophylactically. Accordingly,
one aspect of the present invention relates to diagnostic assays for
determining ORFX protein
and/or nucleic acid expression as well as ORFX activity, in the context of a
biological sample
(e.g., blood, serum, cells, tissue) to thereby determine whether an individual
is afflicted with a
disease or disorder, or is at risk of developing a disorder, associated with
aberrant ORFX
expression or activity. The invention also provides for prognostic (or
predictive) assays for
determining whether an individual is at risk of developing a disorder
associated with ORFX
protein, nucleic acid expression or activity. For example, mutations in a ORFX
gene can be
assayed in a biological sample. Such assays can be used for prognostic or
predictive purpose to
thereby prophylactically treat an individual prior to the onset of a disorder
characterized by or
associated with ORFX protein, nucleic acid expression or activity.
Another aspect of the invention provides methods for determining ORFX protein,
nucleic
acid expression or ORFX activity in an individual to thereby select
appropriate therapeutic or
prophylactic agents for that individual (referred to herein as
"pharmacogenomics")
Pharmacogenomics allows for the selection of agents (e.g., drugs) for
therapeutic or prophylactic
treatment of an individual based on the genotype of the individual (e.g., the
genotype of the
individual examined to determine the ability of the individual to respond to a
particular agent.)
Yet another aspect of the invention pertains to monitoring the influence of
agents (e.g.,
drugs, compounds) on the expression or activity of ORFX in clinical trials.
Use of Partial ORFX Sequences in Forensic Biology
DNA-based identification techniques can also be used in forensic biology.
Forensic
biology is a scientific field employing genetic typing of biological evidence
found at a crime
scene as a means for positively identifying, for example, a perpetrator of a
crime. To make such
an identification, PCR technology can be used to amplify DNA sequences taken
from very small
biological samples such as tissues, e.g., hair or skin, or body fluids, e.g.,
blood, saliva, or semen
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found at a crime scene. The amplified sequence can then be compared to a
standard, thereby
allowing identification of the origin of the biological sample.
The sequences of the present invention can be used to provide polynucleotide
reagents,
e.g., PCR primers, targeted to specific loci in the human genome, that can
enhance the reliability
of DNA-based forensic identifications by, for example, providing another
"identification marker"
(i.e. another DNA sequence that is unique to a particular individual). As
mentioned above, actual
base sequence information can be used for identification as an accurate
alternative to patterns
formed by restriction enzyme generated fragments. Sequences targeted to
noncoding regions of
SEQ ID NOs:- are particularly appropriate for this use as greater numbers of
polymorphisms
occur in the noncoding regions, making it easier to differentiate individuals
using this technique.
Examples of polynucleotide reagents include the ORFX sequences or portions
thereof, e.g.,
fragments derived from the noncoding regions of one or more of SEQ ID N0:2n-1
(where n = 1
to 3161), having a length of at least 20 bases, preferably at least 30 bases.
The ORFX sequences described herein can further be used to provide
polynucleotide
reagents, e.g., labeled or label-able probes that can be used, for example, in
an in situ
hybridization technique, to identify a specific tissue, e.g., brain tissue,
etc. This can be very
useful in cases where a forensic pathologist is presented with a tissue of
unknown origin. Panels
of such ORFX probes can be used to identify tissue by species and/or by organ
type.
In a similar fashion, these reagents, e.g., ORFX primers or probes can be used
to screen
tissue culture for contamination (i. e. screen for the presence of a mixture
of different types of
cells in a culture).
Predictive Medicine
The present invention also pertains to the field of predictive medicine in
which diagnostic
assays, prognostic assays, pharmacogenomics, and monitoring clinical trials
are used for
prognostic (predictive) purposes to thereby treat an individual
prophylactically. Accordingly, one
aspect of the present invention relates to diagnostic assays for determining
ORFX protein and/or
nucleic acid expression as well as ORFX activity, in the context of a
biological sample (e.g.,
blood, serum, cells, tissue) to thereby determine whether an individual is
afflicted with a disease
or disorder, or is at risk of developing a disorder, associated with aberrant
ORFX expression or
activity. The invention also provides for prognostic (or predictive) assays
for determining
whether an individual is at risk of developing a disorder associated with ORFX
protein, nucleic
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acid expression or activity. For example, mutations in a ORFX gene can be
assayed in a
biological sample. Such assays can be used for prognostic or predictive
purpose to thereby
prophylactically treat an individual prior to the onset of a disorder
characterized by or associated
with ORFX protein, nucleic acid expression or activity.
Another aspect of the invention provides methods for determining ORFX protein,
nucleic
acid expression or ORFX activity in an individual to thereby select
appropriate therapeutic or
prophylactic agents for that individual (referred to herein as
"pharmacogenomics").
Pharmacogenomics allows for the selection of agents (e.g., drugs) for
therapeutic or prophylactic
treatment of an individual based on the genotype of the individual (e.g., the
genotype of the
individual examined to determine the ability of the individual to respond to a
particular agent.)
Yet another aspect of the invention pertains to monitoring the influence of
agents (e.g.,
drugs, compounds) on the expression or activity of ORFX in clinical trials.
These and other agents are described in further detail in the following
sections.
Diagnostic Assays
Other conditions in which proliferation of cells plays a role include tumors,
restenosis,
psoriasis, Dupuytren's contracture, diabetic complications, Kaposi's sarcoma
and rheumatoid
arthritis.
An ORFX polypeptide may be used to identify an interacting polypeptide a
sample or
tissue. The method comprises contacting the sample or tissue with ORFX,
allowing formation of
a complex between the ORFX polypeptide and the interacting polypeptide, and
detecting the
complex, if present.
The proteins of the invention may be used to stimulate production of
antibodies
specifically binding the proteins. Such antibodies may be used in
immunodiagnostic procedures
to detect the occurrence of the protein in a sample. The proteins of the
invention may be used to
stimulate cell growth and cell proliferation in conditions in which such
growth would be
favorable. An example would be to counteract toxic side effects of
chemotherapeutic agents on,
for example, hematopoiesis and platelet formation, linings of the
gastrointestinal tract, and hair
follicles. They may also be used to stimulate new cell growth in neurological
disorders
including, for example, Alzheimer's disease. Alternatively, antagonistic
treatments may be
administered in which an antibody specifically binding the ORFX -like proteins
of the invention
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would abrogate the specific growth-inducing effects of the proteins. Such
antibodies may be
useful, for example, in the treatment of proliferative disorders including
various tumors and
benign hyperplasias.
Polynucleotides or oligonucleotides corresponding to any one portion of the
ORFX
nucleic acids of SEQ ID N0:2n-1 (wherein n = 1 to 3161) may be used to detect
DNA
containing a corresponding ORF gene, or detect the expression of a
corresponding ORFX gene,
or ORFX-like gene. For example, an ORFX nucleic acid expressed in a particular
cell or tissue,
as noted in Table 2, can be used to identify the presence of that particular
cell type.
An exemplary method for detecting the presence or absence of ORFX in a
biological
sample involves obtaining a biological sample from a test subject and
contacting the biological
sample with a compound or an agent capable of detecting ORFX protein or
nucleic acid (e.g.,
mRNA, genomic DNA) that encodes ORFX protein such that the presence of ORFX is
detected
in the biological sample. An agent for detecting ORFX mRNA or genomic DNA is a
labeled
nucleic acid probe capable of hybridizing to ORFX mRNA or genomic DNA. The
nucleic acid
probe can be, for example, a full-length ORFX nucleic acid, such as the
nucleic acid of SEQ ID
N0:2n-1 (wherein n = 1 to 3161), or a portion thereof, such as an
oligonucleotide of at least 15,
30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically
hybridize under
stringent conditions to ORFX mRNA or genomic DNA, as described above. Other
suitable
probes for use in the diagnostic assays of the invention are described herein.
An agent for detecting ORFX protein is an antibody capable of binding to ORFX
protein,
preferably an antibody with a detectable label. Antibodies can be polyclonal,
or more preferably,
monoclonal. An intact antibody, or a fragment thereof (e.g., Fab or F(ab')z)
can be used. The
term "labeled", with regard to the probe or antibody, is intended to encompass
direct labeling of
the probe or antibody by coupling (i.e., physically linking) a detectable
substance to the probe or
antibody, as well as indirect labeling of the probe or antibody by reactivity
with another reagent
that is directly labeled. Examples of indirect labeling include detection of a
primary antibody
using a fluorescently labeled secondary antibody and end-labeling of a DNA
probe with biotin
such that it can be detected with fluorescently labeled streptavidin. The term
"biological sample"
is intended to include tissues, cells and biological fluids isolated from a
subject, as well as
tissues, cells and fluids present within a subject. That is, the detection
method of the invention
can be used to detect ORFX mRNA, protein, or genomic DNA in a biological
sample in vitro as

CA 02383592 2001-09-26
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well as in vivo. For example, in vitro techniques for detection of ORFX mRNA
include Northern
hybridizations and in situ hybridizations. In vitro techniques for detection
of ORFX protein
include enzyme linked immunosorbent assays (ELISAs), Western blots,
immunoprecipitations
and immunofluorescence. In vitro techniques for detection of ORFX genomic DNA
include
Southern hybridizations. Furthermore, in vivo techniques for detection of ORFX
protein include
introducing into a subject a labeled anti-ORFX antibody. For example, the
antibody can be
labeled with a radioactive marker whose presence and location in a subject can
be detected by
standard imaging techniques.
In one embodiment, the biological sample contains protein molecules from the
test
subject. Alternatively, the biological sample can contain mRNA molecules from
the test subject
or genomic DNA molecules from the test subject. A preferred biological sample
is a peripheral
blood leukocyte sample isolated by conventional means from a subject.
In another embodiment, the methods further involve obtaining a control
biological
sample from a control subject, contacting the control sample with a compound
or agent capable
of detecting ORFX protein, mRNA, or genomic DNA, such that the presence of
ORFX protein,
mRNA or genomic DNA is detected in the biological sample, and comparing the
presence of
ORFX protein, mRNA or genomic DNA in the control sample with the presence of
ORFX
protein, mItNA or genomic DNA in the test sample.
The invention also encompasses kits for detecting the presence of ORFX in a
biological
sample. For example, the kit can comprise: a labeled compound or agent capable
of detecting
ORFX protein or mIZNA in a biological sample; means for determining the amount
of ORFX in
the sample; and means for comparing the amount of ORFX in the sample with a
standard. The
compound or agent can be packaged in a suitable container. The kit can further
comprise
instructions for using the kit to detect ORFX protein or nucleic acid.
Prognostic Assays
The diagnostic methods described herein can furthermore be utilized to
identify subjects
having or at risk of developing a disease or disorder associated with aberrant
ORFX expression
or activity. For example, the assays described herein, such as the preceding
diagnostic assays or
the following assays, can be utilized to identify a subject having or at risk
of developing a
disorder associated with ORFX protein, nucleic acid expression or activity in,
e.g., proliferative
or differentiative disorders such as hyperplasias, tumors, restenosis,
psoriasis, Dupuytren's
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contracture, diabetic complications, or rheumatoid arthritis, etc.; and glia-
associated disorders
such as cerebral lesions, diabetic neuropathies, cerebral edema, senile
dementia, Alzheimer's
disease, etc. Alternatively, the prognostic assays can be utilized to identify
a subject having or at
risk for developing a disease or disorder. Thus, the present invention
provides a method for
identifying a disease or disorder associated with aberrant ORFX expression or
activity in which a
test sample is obtained from a subject and ORFX protein or nucleic acid (e.g.,
mRNA, genomic
DNA) is detected, wherein the presence of ORFX protein or nucleic acid is
diagnostic for a
subject having or at risk of developing a disease or disorder associated with
aberrant ORFX
expression or activity. As used herein, a "test sample" refers to a biological
sample obtained
from a subject of interest. For example, a test sample can be a biological
fluid (e.g., serum), cell
sample, or tissue.
Furthermore, the prognostic assays described herein can be used to determine
whether a
subject can be administered an agent (e.g., an agonist, antagonist,
peptidomimetic, protein,
peptide, nucleic acid, small molecule, or other drug candidate) to treat a
disease or disorder
associated with aberrant ORFX expression or activity. For example, such
methods can be used
to determine whether a subject can be effectively treated with an agent for a
disorder, such as a
proliferative disorder, differentiative disorder, glia-associated disorders,
etc. Thus, the present
invention provides methods for determining whether a subject can be
effectively treated with an
agent for a disorder associated with aberrant ORFX expression or activity in
which a test sample
is obtained and ORFX protein or nucleic acid is detected (e.g., wherein the
presence of ORFX
protein or nucleic acid is diagnostic for a subject that can be administered
the agent to treat a
disorder associated with aberrant ORFX expression or activity.)
The methods of the invention can also be used to detect genetic lesions in a
ORFX gene,
thereby determining if a subject with the lesioned gene is at risk for, or
suffers from, a
proliferative disorder, differentiative disorder, glia-associated disorder,
etc. In various
embodiments, the methods include detecting, in a sample of cells from the
subject, the presence
or absence of a genetic lesion characterized by at least one of an alteration
affecting the integrity
of a gene encoding a ORFX-protein, or the mis-expression of the ORFX gene. For
example,
such genetic lesions can be detected by ascertaining the existence of at least
one of (1) a deletion
of one or more nucleotides from a ORFX gene; (2) an addition of one or more
nucleotides to a
ORFX gene; (3) a substitution of one or more nucleotides of a ORFX gene, (4) a
chromosomal
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rearrangement of a ORFX gene; (5) an alteration in the level of a messenger
RNA transcript of a
ORFX gene, (6) aberrant modification of a ORFX gene, such as of the
methylation pattern of the
genomic DNA, (7) the presence of a non-wild type splicing pattern of a
messenger RNA
transcript of a ORFX gene, (8) a non-wild type level of a ORFX-Protein, (9)
allelic loss of a
ORFX gene, and (10) inappropriate post-translational modification of a ORFX-
protein. As
described herein, there are a large number of assay techniques known in the
art which can be
used for detecting lesions in a ORFX gene. A preferred biological sample is a
peripheral blood
leukocyte sample isolated by conventional means from a subject. However, any
biological
sample containing nucleated cells may be used, including, for example, buccal
mucosal cells.
In certain embodiments, detection of the lesion involves the use of a
probe/primer in a
polymerase chain reaction (PCR) (see, e.g., U.S. Pat. Nos. 4,683,195 and
4,683,202), such as
anchor PCR or RACE PCR, or, alternatively, in a ligation chain reaction (LCR)
(see, e.g.,
Landegran et al. (1988) Science 241:1077-1080; and Nakazawa et al. (1994) PNAS
91:360-364),
the latter of which can be particularly useful for detecting point mutations
in the ORFX-gene
(see Abravaya et al. (1995) Nucl Acids Res 23:675-682). This method can
include the steps of
collecting a sample of cells from a patient, isolating nucleic acid (e.g.,
genomic, mRNA or both)
from the cells of the sample, contacting the nucleic acid sample with one or
more primers that
specifically hybridize to a ORFX gene under conditions such that hybridization
and
amplification of the ORFX gene (if present) occurs, and detecting the presence
or absence of an
amplification product, or detecting the size of the amplification product and
comparing the
length to a control sample. It is anticipated that PCR and/or LCR may be
desirable to use as a
preliminary amplification step in conjunction with any of the techniques used
for detecting
mutations described herein.
Alternative amplification methods include: self sustained sequence replication
(Guatelli
et al., 1990, Proc Natl Acad Sci USA 87:1874-1878), transcriptional
amplification system
(Kwoh, et al., 1989, Proc Natl Acad Sci USA 86:1173-1177), Q-Bees Replicase
(Lizardi et al,
1988, BioTechnolo~ 6:1197), or any other nucleic acid amplification method,
followed by the
detection of the amplified molecules using techniques well known to those of
skill in the art.
These detection schemes are especially useful for the detection of nucleic
acid molecules if such
molecules are present in very low numbers.
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In an alternative embodiment, mutations in a ORFX gene from a sample cell can
be
identified by alterations in restriction enzyme cleavage patterns. For
example, sample and
control DNA is isolated, amplified (optionally), digested with one or more
restriction
endonucleases, and fragment length sizes are determined by gel electrophoresis
and compared.
Differences in fragment length sizes between sample and control DNA indicates
mutations in the
sample DNA. Moreover, the use of sequence specific ribozymes (see, for
example, U.S. Pat. No.
5,493,531) can be used to score for the presence of specific mutations by
development or loss of
a ribozyme cleavage site.
In other embodiments, genetic mutations in ORFX can be identified by
hybridizing a
sample and control nucleic acids, e.g., DNA or RNA, to high density arrays
containing hundreds
or thousands of oligonucleotides probes (Cronin et al. (1996) Human Mutation
7: 244-255;
Kozal et al. (1996) Nature Medicine 2: 753-759). For example, genetic
mutations in ORFX can
be identified in two dimensional arrays containing light-generated DNA probes
as described in
Cronin et al. above. Briefly, a first hybridization array of probes can be
used to scan through
long stretches of DNA in a sample and control to identify base changes between
the sequences
by making linear arrays of sequential overlapping probes. This step allows the
identification of
point mutations. This step is followed by a second hybridization array that
allows the
characterization of specific mutations by using smaller, specialized probe
arrays complementary
to all variants or mutations detected. Each mutation array is composed of
parallel probe sets, one
complementary to the wild-type gene and the other complementary to the mutant
gene.
In yet another embodiment, any of a variety of sequencing reactions known in
the art can
be used to directly sequence the ORFX gene and detect mutations by comparing
the sequence of
the sample ORFX with the corresponding wild-type (control) sequence. Examples
of sequencing
reactions include those based on techniques developed by Maxim and Gilbert
(1977) PNAS
74:560 or Sanger (1977) PNAS 74:5463. It is also contemplated that any of a
variety of
automated sequencing procedures can be utilized when performing the diagnostic
assays (Naeve
et al., (1995) Biotechniques 19:448), including sequencing by mass
spectrometry (see, e.g., PCT
International Publ. No. WO 94/16101; Cohen et al. (1996) Adv Chromatogr 36:127-
162; and
Griffin et al. (1993) Appl Biochem Biotechnol 38:147-159).
Other methods for detecting mutations in the ORFX gene include methods in
which
protection from cleavage agents is used to detect mismatched bases in RNA/RNA
or RNA/DNA
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heteroduplexes (Myers et al. (1985) Science 230:1242). In general, the art
technique of
"mismatch cleavage" starts by providing heteroduplexes of formed by
hybridizing (labeled) RNA
or DNA containing the wild-type ORFX sequence with potentially mutant RNA or
DNA
obtained from a tissue sample. The double-stranded duplexes are treated with
an agent that
cleaves single-stranded regions of the duplex such as which will exist due to
basepair
mismatches between the control and sample strands. For instance, RNA/DNA
duplexes can be
treated with RNase and DNA/DNA hybrids treated with S 1 nuclease to
enzymatically digesting
the mismatched regions. In other embodiments, either DNA/DNA or RNA/DNA
duplexes can
be treated with hydroxylamine or osmium tetroxide and with piperidine in order
to digest
mismatched regions. After digestion of the mismatched regions, the resulting
material is then
separated by size on denaturing polyacrylamide gels to determine the site of
mutation. See, for
example, Cotton et al (1988) Proc Natl Acad Sci USA 85:4397; Saleeba et al
(1992) Methods
Enrymol 217:286-295. In an embodiment, the control DNA or RNA can be labeled
for
detection.
1 S In still another embodiment, the mismatch cleavage reaction employs one or
more
proteins that recognize mismatched base pairs in double-stranded DNA (so
called "DNA
mismatch repair" enzymes) in defined systems for detecting and mapping point
mutations in
ORFX cDNAs obtained from samples of cells. For example, the mutt enzyme of E.
coli cleaves
A at G/A mismatches and the thymidine DNA glycosylase from HeLa cells cleaves
T at G/T
mismatches (Hsu et al. (1994) Carcinogenesis 15:1657-1662). According to an
exemplary
embodiment, a probe based on a ORFX sequence, e.g., a wild-type ORFX sequence,
is
hybridized to a cDNA or other DNA product from a test cell(s). The duplex is
treated with a
DNA mismatch repair enzyme, and the cleavage products, if any, can be detected
from
electrophoresis protocols or the like. See, for example, U.S. Pat. No.
5,459,039.
In other embodiments, alterations in electrophoretic mobility will be used to
identify
mutations in ORFX genes. For example, single strand conformation polymorphism
(SSCP) may
be used to detect differences in electrophoretic mobility between mutant and
wild type nucleic
acids (Orita et al. (1989) Proc Natl Acad Sci USA: 86:2766, see also Cotton
(1993) Mutat Res
285:125-144; Hayashi (1992) Genet Anal Tech Appl 9:73-79). Single-stranded DNA
fragments
of sample and control ORFX nucleic acids will be denatured and allowed to
renature. The
secondary structure of single-stranded nucleic acids varies according to
sequence, the resulting

CA 02383592 2001-09-26
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alteration in electrophoretic mobility enables the detection of even a single
base change. The
DNA fragments may be labeled or detected with labeled probes. The sensitivity
of the assay
may be enhanced by using RNA, rather than DNA, in which the secondary
structure is more
sensitive to a change in sequence. In one embodiment, the subject method
utilizes heteroduplex
analysis to separate double stranded heteroduplex molecules on the basis of
changes in
electrophoretic mobility. See, e.g., Keen et al. (1991) Trends Genet 7:5.
In yet another embodiment the movement of mutant or wild-type fragments in
polyacrylamide gels containing a gradient of denaturant is assayed using
denaturing gradient gel
electrophoresis (DGGE). See, e.g., Myers et al (1985) Nature 313:495. When
DGGE is used as
the method of analysis, DNA will be modified to insure that it does not
completely denature, for
example by adding a GC clamp of approximately 40 by of high-melting GC-rich
DNA by PCR.
In a further embodiment, a temperature gradient is used in place of a
denaturing gradient to
identify differences in the mobility of control and sample DNA. See, e.g.,
Rosenbaum and
Reissner ( 1987) Biophys Chem 265:12753.
Examples of other techniques for detecting point mutations include, but are
not limited
to, selective oligonucleotide hybridization, selective amplification, or
selective primer extension.
For example, oligonucleotide primers may be prepared in which the known
mutation is placed
centrally and then hybridized to target DNA under conditions that permit
hybridization only if a
perfect match is found. See, e.g., Saiki et al. (1986) Nature 324:163); Saiki
et al. (1989) Proc
Natl Acad. Sci USA 86:6230. Such allele specific oligonucleotides are
hybridized to PCR
amplified target DNA or a number of different mutations when the
oligonucleotides are attached
to the hybridizing membrane and hybridized with labeled target DNA.
Alternatively, allele specific amplification technology that depends on
selective PCR
amplification may be used in conjunction with the instant invention.
Oligonucleotides used as
primers for specific amplification may carry the mutation of interest in the
center of the molecule
(so that amplification depends on differential hybridization) (Gibbs et al.
(1989) Nucleic Acids
Res 17:2437-2448) or at the extreme 3' end of one primer where, under
appropriate conditions,
mismatch can prevent, or reduce polymerase extension (Prossner (1993) Tibtech
11:238). In
addition it may be desirable to introduce a novel restriction site in the
region of the mutation to
create cleavage-based detection. See, e.g., Gasparini et al (1992) Mol Cell
Probes 6:1. It is
anticipated that in certain embodiments amplification may also be performed
using Taq ligase
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for amplification. See, e.g., Barany (1991) Proc Natl Acad Sci USA 88:189. In
such cases,
ligation will occur only if there is a perfect match at the 3' end of the 5'
sequence, making it
possible to detect the presence of a known mutation at a specific site by
looking for the presence
or absence of amplification.
The methods described herein may be performed, for example, by utilizing pre-
packaged
diagnostic kits comprising at least one probe nucleic acid or antibody reagent
described herein,
which may be conveniently used, e.g., in clinical settings to diagnose
patients exhibiting
symptoms or family history of a disease or illness involving a ORFX gene.
Furthermore, any cell type or tissue, preferably peripheral blood leukocytes,
in which
ORFX is expressed may be utilized in the prognostic assays described herein.
However, any
biological sample containing nucleated cells may be used, including, for
example, buccal
mucosal cells.
Pharmacogenomics
Agents, or modulators that have a stimulatory or inhibitory effect on ORFX
activity (e.g.,
ORFX gene expression), as identified by a screening assay described herein can
be administered
to individuals to treat (prophylactically or therapeutically) disorders (e.g.,
neurological, cancer-
related or gestational disorders) associated with aberrant ORFX activity. In
conjunction with
such treatment, the pharmacogenomics (i.e., the study of the relationship
between an individual's
genotype and that individual's response to a foreign compound or drug) of the
individual may be
considered. Differences in metabolism of therapeutics can lead to severe
toxicity or therapeutic
failure by altering the relation between dose and blood concentration of the
pharmacologically
active drug. Thus, the pharmacogenomics of the individual permits the
selection of effective
agents (e.g., drugs) for prophylactic or therapeutic treatments based on a
consideration of the
individual's genotype. Such pharmacogenomics can further be used to determine
appropriate
dosages and therapeutic regimens. Accordingly, the activity of ORFX protein,
expression of
ORFX nucleic acid, or mutation content of ORFX genes in an individual can be
determined to
thereby select appropriate agents) for therapeutic or prophylactic treatment
of the individual.
Pharmacogenomics deals with clinically significant hereditary variations in
the response
to drugs due to altered drug disposition and abnormal action in affected
persons. See e.g.,
Eichelbaum, 1996, Clin Exp Pharmacol Physiol, 23:983-985 and Linder, 1997,
Clin Chem,
43:254-266. In general, two types of pharmacogenetic conditions can be
differentiated. Genetic
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conditions transmitted as a single factor altering the way drugs act on the
body (altered drug
action) or genetic conditions transmitted as single factors altering the way
the body acts on drugs
(altered drug metabolism). These pharmacogenetic conditions can occur either
as rare defects or
as polymorphisms. For example, glucose-6-phosphate dehydrogenase (G6PD)
deficiency is a
common inherited enzymopathy in which the main clinical complication is
haemolysis after
ingestion of oxidant drugs (anti-malarials, sulfonamides, analgesics,
nitrofurans) and
consumption of fava beans.
As an illustrative embodiment, the activity of drug metabolizing enzymes is a
major
determinant of both the intensity and duration of drug action. The discovery
of genetic
polymorphisms of drug metabolizing enzymes (e.g., N-acetyltransferase 2 (NAT
2) and
cytochrome P450 enzymes CYP2D6 and CYP2C 19) has provided an explanation as to
why
some patients do not obtain the expected drug effects or show exaggerated drug
response and
serious toxicity after taking the standard and safe dose of a drug. These
polymorphisms are
expressed in two phenotypes in the population, the extensive metabolizes (EM)
and poor
metabolizes (PM). The prevalence of PM is different among different
populations. For example,
the gene coding for CYP2D6 is highly polymorphic and several mutations have
been identified
in PM, which all lead to the absence of functional CYP2D6. Poor metabolizers
of CYP2D6 and
CYP2C 19 quite frequently experience exaggerated drug response and side
effects when they
receive standard doses. If a metabolite is the active therapeutic moiety, PM
show no therapeutic
response, as demonstrated for the analgesic effect of codeine mediated by its
CYP2D6-formed
metabolite morphine. The other extreme are the so called ultra-rapid
metabolizers who do not
respond to standard doses. Recently, the molecular basis of ultra-rapid
metabolism has been
identified to be due to CYP2D6 gene amplification.
Thus, the activity of ORFX protein, expression of ORFX nucleic acid, or
mutation
content of ORFX genes in an individual can be determined to thereby select
appropriate agents)
for therapeutic or prophylactic treatment of the individual. In addition,
pharmacogenetic studies
can be used to apply genotyping of polymorphic alleles encoding drug-
metabolizing enzymes to
the identification of an individual's drug responsiveness phenotype. This
knowledge, when
applied to dosing or drug selection, can avoid adverse reactions or
therapeutic failure and thus
enhance therapeutic or prophylactic efficiency when treating a subject with a
ORFX modulator,
such as a modulator identified by one of the exemplary screening assays
described herein.
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Monitoring Clinical Efficacy
Monitoring the influence of agents (e.g., drugs, compounds) on the expression
or activity
of ORFX (e.g., the ability to modulate aberrant cell proliferation and/or
differentiation) can be
applied in basic drug screening and in clinical trials. For example, the
effectiveness of an agent
determined by a screening assay as described herein to increase ORFX gene
expression, protein
levels, or upregulate ORFX activity, can be monitored in clinical trials of
subjects exhibiting
decreased ORFX gene expression, protein levels, or downregulated ORFX
activity.
Alternatively, the effectiveness of an agent determined by a screening assay
to decrease ORFX
gene expression, protein levels, or downregulate ORFX activity, can be
monitored in clinical
trials of subjects exhibiting increased ORFX gene expression, protein levels,
or upregulated
ORFX activity. In such clinical trials, the expression or activity of ORFX
and, preferably, other
genes that have been implicated in, for example, a proliferative or
neurological disorder, can be
used as a "read out" or marker of the responsiveness of a particular cell.
For example, genes, including ORFX, that are modulated in cells by treatment
with an
agent (e.g., compound, drug or small molecule) that modulates ORFX activity
(e.g., identified in
a screening assay as described herein) can be identified. Thus, to study the
effect of agents on
cellular proliferation disorders, for example, in a clinical trial, cells can
be isolated and RNA
prepared and analyzed for the levels of expression of ORFX and other genes
implicated in the
disorder. The levels of gene expression (i.e., a gene expression pattern) can
be quantified by
Northern blot analysis or RT-PCR, as described herein, or alternatively by
measuring the amount
of protein produced, by one of the methods as described herein, or by
measuring the levels of
activity of ORFX or other genes. In this way, the gene expression pattern can
serve as a marker,
indicative of the physiological response of the cells to the agent.
Accordingly, this response state
may be determined before, and at various points during, treatment of the
individual with the
agent.
In one embodiment, the invention provides a method for monitoring the
effectiveness of
treatment of a subject with an agent (e.g., an agonist, antagonist, protein,
peptide, nucleic acid,
peptidomimetic, small molecule, or other drug candidate identified by the
screening assays
described herein) comprising the steps of (i) obtaining a pre-administration
sample from a
subject prior to administration of the agent; (ii) detecting the level of
expression of a ORFX
protein, mRNA, or genomic DNA in the preadministration sample; (iii) obtaining
one or more
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post-administration samples from the subject; (iv) detecting the level of
expression or activity of
the ORFX protein, mRNA, or genomic DNA in the post-administration samples; (v)
comparing
the level of expression or activity of the ORFX protein, mRNA, or genomic DNA
in the
pre-administration sample with the ORFX protein, mRNA, or genomic DNA in the
post
administration sample or samples; and (vi) altering the administration of the
agent to the subject
accordingly. For example, increased administration of the agent may be
desirable to increase the
expression or activity of ORFX to higher levels than detected, i.e., to
increase the effectiveness
of the agent. Alternatively, decreased administration of the agent may be
desirable to decrease
expression or activity of ORFX to lower levels than detected, i.e., to
decrease the effectiveness
of the agent.
Methods of Treatment
The present invention provides for both prophylactic and therapeutic methods
of treating
a subject at risk of (or susceptible to) a disorder or having a disorder
associated with aberrant
ORFX expression or activity.
Diseases and disorders that are characterized by increased (relative to a
subject not
suffering from the disease or disorder) levels or biological activity may be
treated with
Therapeutics that antagonize (i.e., reduce or inhibit) activity. Therapeutics
that antagonize
activity may be administered in a therapeutic or prophylactic manner.
Therapeutics that may be
utilized include, but are not limited to, (i) a ORFX polypeptide, or analogs,
derivatives,
fragments or homologs thereof; (ii) antibodies to a ORFX peptide; (iii)
nucleic acids encoding a
ORFX peptide; (iv) administration of antisense nucleic acid and nucleic acids
that are
"dysfunctional" (i. e., due to a heterologous insertion within the coding
sequences of coding
sequences to a ORFX peptide) that are utilized to "knockout" endogenous
function of a ORFX
peptide by homologous recombination (see, e.g., Capecchi, 1989, Science 244:
1288-1292); or
(v) modulators (i.e., inhibitors, agonists and antagonists, including
additional peptide mimetic of
the invention or antibodies specific to a peptide of the invention) that alter
the interaction
between a ORFX peptide and its binding partner.
Diseases and disorders that are characterized by decreased (relative to a
subject not
suffering from the disease or disorder) levels or biological activity may be
treated with
Therapeutics that increase (i.e., are agonists to) activity. Therapeutics that
upregulate activity
may be administered in a therapeutic or prophylactic manner. Therapeutics that
may be utilized

CA 02383592 2001-09-26
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include, but are not limited to, a ORFX peptide, or analogs, derivatives,
fragments or homologs
thereof; or an agonist that increases bioavailability.
Increased or decreased levels can be readily detected by quantifying peptide
and/or RNA,
by obtaining a patient tissue sample (e.g., from biopsy tissue) and assaying
it in vitro for RNA or
peptide levels, structure and/or activity of the expressed peptides (or mRNAs
of a ORFX
peptide). Methods that are well-known within the art include, but are not
limited to,
immunoassays (e.g., by Western blot analysis, immunoprecipitation followed by
sodium dodecyl
sulfate (SDS) polyacrylamide gel electrophoresis, immunocytochemistry, etc.)
and/or
hybridization assays to detect expression of mRNAs (e.g., Northern assays, dot
blots, in situ
hybridization, etc.).
In one aspect, the invention provides a method for preventing, in a subject, a
disease or
condition associated with an aberrant ORFX expression or activity, by
administering to the
subject an agent that modulates ORFX expression or at least one ORFX activity.
Subjects at risk
for a disease that is caused or contributed to by aberrant ORFX expression or
activity can be
identified by, for example, any or a combination of diagnostic or prognostic
assays as described
herein. Administration of a prophylactic agent can occur prior to the
manifestation of symptoms
characteristic of the ORFX aberrancy, such that a disease or disorder is
prevented or,
alternatively, delayed in its progression. Depending on the type of ORFX
aberrancy, for
example, a ORFX agonist or ORFX antagonist agent can be used for treating the
subject. The
appropriate agent can be determined based on screening assays described
herein.
Another aspect of the invention pertains to methods of modulating ORFX
expression or
activity for therapeutic purposes. The modulatory method of the invention
involves contacting a
cell with an agent that modulates one or more of the activities of ORFX
protein activity
associated with the cell. An agent that modulates ORFX protein activity can be
an agent as
described herein, such as a nucleic acid or a protein, a naturally-occurring
cognate ligand of a
ORFX protein, a peptide, a ORFX peptidomimetic, or other small molecule. In
one
embodiment, the agent stimulates one or more ORFX protein activity. Examples
of such
stimulatory agents include active ORFX protein and a nucleic acid molecule
encoding ORFX
that has been introduced into the cell. In another embodiment, the agent
inhibits one or more
ORFX protein activity. Examples of such inhibitory agents include antisense
ORFX nucleic acid
molecules and anti-ORFX antibodies. These modulatory methods can be performed
in vitro
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(e.g., by culturing the cell with the agent) or, alternatively, in vivo (e.g.,
by administering the
agent to a subject). As such, the present invention provides methods of
treating an individual
afflicted with a disease or disorder characterized by aberrant expression or
activity of a ORFX
protein or nucleic acid molecule. In one embodiment, the method involves
administering an
agent (e.g., an agent identified by a screening assay described herein), or
combination of agents
that modulates (e.g., upregulates or downregulates) ORFX expression or
activity. In another
embodiment, the method involves administering a ORFX protein or nucleic acid
molecule as
therapy to compensate for reduced or aberrant ORFX expression or activity.
Determination of the Biological Effect of a Therapeutic
In various embodiments of the present invention, suitable in vitro or in vivo
assays are
utilized to determine the effect of a specific Therapeutic and whether its
administration is
indicated for treatment of the affected tissue.
In various specific embodiments, in vitro assays may be performed with
representative
cells of the types) involved in the patient's disorder, to determine if a
given Therapeutic exerts
the desired effect upon the cell type(s). Compounds for use in therapy may be
tested in suitable
animal model systems including, but not limited to rats, mice, chicken, cows,
monkeys, rabbits,
and the like, prior to testing in human subjects. Similarly, for in vivo
testing, any of the animal
model system known in the art may be used prior to administration to human
subjects.
Malignancies
Some ORFX polypeptides are expressed in cancerous cells (see, e.g., Tables 1
and 2).
Accordingly, the corresponding ORF protein is involved in the regulation of
cell proliferation.
Accordingly, Therapeutics of the present invention may be useful in the
therapeutic or
prophylactic treatment of diseases or disorders that are associated with cell
hyperproliferation
and/or loss of control of cell proliferation (e.g., cancers, malignancies and
tumors). For a review
of such hyperproliferation disorders, see e.g., Fishman, et al., 1985.
MEDICINE, 2nd ed., J.B.
Lippincott Co., Philadelphia, PA.
Therapeutics of the present invention may be assayed by any method known
within the
art for efficacy in treating or preventing malignancies and related disorders.
Such assays include,
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but are not limited to, in vitro assays utilizing transformed cells or cells
derived from the
patient's tumor, as well as in vivo assays using animal models of cancer or
malignancies.
Potentially effective Therapeutics are those that, for example, inhibit the
proliferation of
tumor-derived or transformed cells in culture or cause a regression of tumors
in animal models,
in comparison to the controls.
In the practice of the present invention, once a malignancy or cancer 'has
been shown to
be amenable to treatment by modulating (i.e., inhibiting, antagonizing or
agonizing) activity, that
cancer or malignancy may subsequently be treated or prevented by the
administration of a
Therapeutic that serves to modulate protein function.
Premalignant conditions
The Therapeutics of the present invention that are effective in the
therapeutic or
prophylactic treatment of cancer or malignancies may also be administered for
the treatment of
pre-malignant conditions and/or to prevent the progression of a pre-malignancy
to a neoplastic or
malignant state. Such prophylactic or therapeutic use is indicated in
conditions known or
suspected of preceding progression to neoplasia or cancer, in particular,
where non-neoplastic
cell growth consisting of hyperplasia, metaplasia or, most particularly,
dysplasia has occurred.
For a review of such abnormal cell growth see e.g., Robbins & Angell, 1976.
Basic PATHOLOGY,
2nd ed., W.B. Saunders Co., Philadelphia, PA.
Hyperplasia is a form of controlled cell proliferation involving an increase
in cell number
in a tissue or organ, without significant alteration in its structure or
function. For example, it has
been demonstrated that endometrial hyperplasia often precedes endometrial
cancer. Metaplasia is
a form of controlled cell growth in which one type of mature or fully
differentiated cell
substitutes for another type of mature cell. Metaplasia may occur in
epithelial or connective
tissue cells. Dysplasia is generally considered a precursor of cancer, and is
found mainly in the
epithelia. Dysplasia is the most disorderly form of non-neoplastic cell
growth, and involves a
loss in individual cell uniformity and in the architectural orientation of
cells. Dysplasia
characteristically occurs where there exists chronic irntation or
inflammation, and is often found
in the cervix, respiratory passages, oral cavity, and gall bladder.
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Alternatively, or in addition to the presence of abnormal cell growth
characterized as
hyperplasia, metaplasia, or dysplasia, the presence of one or more
characteristics of a
transformed or malignant phenotype displayed either in vivo or in vitro within
a cell sample
derived from a patient, is indicative of the desirability of
prophylactic/therapeutic administration
of a Therapeutic that possesses the ability to modulate activity of An
aforementioned protein.
Characteristics of a transformed phenotype include, but are not limited to:
(i) morphological
changes; (ii) looser substratum attachment; (iii) loss of cell-to-cell contact
inhibition; (iv) loss of
anchorage dependence; (v) protease release; (vi) increased sugar transport;
(vii) decreased serum
requirement; (viii) expression of fetal antigens, (ix) disappearance of the
250 kDal cell-surface
protein, and the like. See e.g., Richards, et al., 1986. MOLECULAR PATHOLOGY,
W.B. Saunders
Co., Philadelphia, PA.
In a specific embodiment of the present invention, a patient that exhibits one
or more of
the following predisposing factors for malignancy is treated by administration
of an effective
amount of a Therapeutic: (i) a chromosomal translocation associated with a
malignancy (e.g., the
Philadelphia chromosome (bcrlabl) for chronic myelogenous leukemia and
t(14;18) for follicular
lymphoma, etc.); (ii) familial polyposis or Gardner's syndrome (possible
forerunners of colon
cancer); (iii) monoclonal gammopathy of undetermined significance (a possible
precursor of
multiple myeloma) and (iv) a first degree kinship with persons having a cancer
or pre-cancerous
disease showing a Mendelian (genetic) inheritance pattern (e.g., familial
polyposis of the colon,
Gardner's syndrome, hereditary exostosis, polyendocrine adenomatosis, Peutz-
Jeghers syndrome,
neurofibromatosis of Von Recklinghausen, medullary thyroid carcinoma with
amyloid
production and pheochromocytoma, retinoblastoma, carotid body tumor, cutaneous
melanocarcinoma, intraocular melanocarcinoma, xeroderma pigmentosum, ataxia
telangiectasia,
Chediak-Higashi syndrome, albinism, Fanconi's aplastic anemia and Bloom's
syndrome).
In another embodiment, a Therapeutic of the present invention is administered
to a
human patient to prevent the progression to breast, colon, lung, pancreatic,
or uterine cancer, or
melanoma or sarcoma.
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Hyperproliferative and dysproliferative disorders
In one embodiment of the present invention, a Therapeutic is administered in
the
therapeutic or prophylactic treatment of hyperproliferative or benign
dysproliferative disorders.
The efficacy in treating or preventing hyperproliferative diseases or
disorders of a Therapeutic of
the present invention may be assayed by any method known within the art. Such
assays include
in vitro cell proliferation assays, in vitro or in vivo assays using animal
models of
hyperproliferative diseases or disorders, or the like. Potentially effective
Therapeutics may, for
example, promote cell proliferation in culture or cause growth or cell
proliferation in animal
models in comparison to controls.
Specific embodiments of the present invention are directed to the treatment or
prevention
of cirrhosis of the liver (a condition in which scarring has overtaken normal
liver regeneration
processes); treatment of keloid (hypertrophic scar) formation causing
disfiguring of the skin in
which the scarring process interferes with normal renewal; psoriasis (a common
skin condition
characterized by excessive proliferation of the skin and delay in proper cell
fate determination);
benign tumors; fibrocystic conditions and tissue hypertrophy (e.g., benign
prostatic hypertrophy).
Neurodegenerative disorders
Some ORFX proteins are found in cell types have been implicated in the
deregulation of
cellular maturation and apoptosis, which are both characteristic of
neurodegenerative disease.
Accordingly, Therapeutics of the invention, particularly but not limited to
those that modulate
(or supply) activity of an aforementioned protein, may be effective in
treating or preventing
neurodegenerative disease. Therapeutics of the present invention that modulate
the activity of an
aforementioned protein involved in neurodegenerative disorders can be assayed
by any method
known in the art for efficacy in treating or preventing such neurodegenerative
diseases and
disorders. Such assays include in vitro assays for regulated cell maturation
or inhibition of
apoptosis or in vivo assays using animal models of neurodegenerative diseases
or disorders, or
any of the assays described below. Potentially effective Therapeutics, for
example but not by
way of limitation, promote regulated cell maturation and prevent cell
apoptosis in culture, or
reduce neurodegeneration in animal models in comparison to controls.

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Once a neurodegenerative disease or disorder has been shown to be amenable to
treatment by modulation activity, that neurodegenerative disease or disorder
can be treated or
prevented by administration of a Therapeutic that modulates activity. Such
diseases include all
degenerative disorders involved with aging, especially osteoarthritis and
neurodegenerative
S disorders.
Disorders related to organ transplantation
Some ORFX can be associated with disorders related to organ transplantation,
in
particular but not limited to organ rejection. Therapeutics of the invention,
particularly those that
modulate (or supply) activity, may be effective in treating or preventing
diseases or disorders
related to organ transplantation. Therapeutics of the invention (particularly
Therapeutics that
modulate the levels or activity of an aforementioned protein) can be assayed
by any method
known in the art for efficacy in treating or preventing such diseases and
disorders related to
organ transplantation. Such assays include in vitro assays for using cell
culture models as
described below, or in vivo assays using animal models of diseases and
disorders related to organ
transplantation, see e.g., below. Potentially effective Therapeutics, for
example but not by way of
limitation, reduce immune rejection responses in animal models in comparison
to controls.
Accordingly, once diseases and disorders related to organ transplantation are
shown to be
amenable to treatment by modulation of activity, such diseases or disorders
can be treated or
prevented by administration of a Therapeutic that modulates activity.
Cardiovascular Disease
GENX has been implicated in cardiovascular disorders, including in
atherosclerotic
plaque formation. Diseases such as cardiovascular disease, including cerebral
thrombosis or
hemorrhage, ischemic heart or renal disease, peripheral vascular disease, or
thrombosis of other
major vessel, and other diseases, including diabetes mellitus, hypertension,
hypothyroidism,
cholesterol ester storage disease, systemic lupus erythematosus,
homocysteinemia, and familial
protein or lipid processing diseases, and the like, are either directly or
indirectly associated with
atherosclerosis. Accordingly, Therapeutics of the invention, particularly
those that modulate (or
supply) activity or formation may be effective in treating or preventing
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atherosclerosis-associated diseases or disorders. Therapeutics of the
invention (particularly
Therapeutics that modulate the levels or activity) can be assayed by any
method known in the
art, including those described below, for efficacy in treating or preventing
such diseases and
disorders.
A vast array of animal and cell culture models exist for processes involved in
atherosclerosis. A limited and non-exclusive list of animal models includes
knockout mice for
premature atherosclerosis (Kurabayashi and Yazaki, 1996, Int. Angiol. 15: 187-
194), transgenic
mouse models of atherosclerosis (Kappel et al., 1994, FASEB J. 8: 583-592),
antisense
oligonucleotide treatment of animal models (Callow, 1995, Curr. Opin. Cardiol.
10: 569-576),
transgenic rabbit models for atherosclerosis (Taylor, 1997, Ann. N.Y. Acad.
Sci 811: 146-152),
hypercholesterolemic animal models (Rosenfeld, 1996, Diabetes Res. Clin.
Pract. 30 Suppl.:
1-11), hyperlipidemic mice (Paigen et al., 1994, Curr. Opin. Lipidol. 5: 258-
264), and inhibition
of lipoxygenase in animals (Sigal et al., 1994, Ann. N.Y. Acad. Sci. 714: 211-
224). In addition,
in vitro cell models include but are not limited to monocytes exposed to low
density lipoprotein
(Frostegard et al., 1996, Atherosclerosis 121: 93-103), cloned vascular smooth
muscle cells
(Suttles et al., 1995, Exp. Cell Res. 218: 331-338), endothelial cell-derived
chemoattractant
exposed T cells (Katz et al., 1994, J. Leukoc. Biol. 55: 567-573), cultured
human aortic
endothelial cells (Farber et al., 1992, Am. J. Physiol. 262: H1088-1085), and
foam cell cultures
(Libby et al., 1996, Curr Opin Lipidol 7: 330-335). Potentially effective
Therapeutics, for
example but not by way of limitation, reduce foam cell formation in cell
culture models, or
reduce atherosclerotic plaque formation in hypercholesterolemic mouse models
of
atherosclerosis in comparison to controls.
Accordingly, once an atherosclerosis-associated disease or disorder has been
shown to be
amenable to treatment by modulation of activity or formation, that disease or
disorder can be
treated or prevented by administration of a Therapeutic that modulates
activity.
Cytokine and Cell Proliferation/Differentiation Activity
A GENX protein of the present invention may exhibit cytokine, cell
proliferation (either
inducing or inhibiting) or cell differentiation (either inducing or
inhibiting) activity or may
induce production of other cytokines in certain cell populations. Many protein
factors discovered
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to date, including all known cytokines, have exhibited activity in one or more
factor dependent
cell proliferation assays, and hence the assays serve as a convenient
confirmation of cytokine
activity. The activity of a protein of the present invention is evidenced by
any one of a number of
routine factor dependent cell proliferation assays for cell lines including,
without limitation, 32D,
DA2, DA1G, T10, B9, B9/11, BaF3, MC9/G, M+ (preB M+ ), 2E8, RBS, DA1, 123,
T1165,
HT2, CTLL2, TF-1, Mo7e and CMK.
The activity of a protein of the invention may, among other means, be measured
by the
following methods: Assays for T-cell or thymocyte proliferation include
without limitation those
described in: CURRENT PROTOCOLS IN IMMUNOLOGY, Ed by Coligan et al., Greene
Publishing
Associates and Wiley-Interscience (Chapter 3 and Chapter 7); Takai et al.,
Jlmmunol
137:3494-3500, 1986; Bertagnoili et al., Jlmmunol 145:1706-1712, 1990;
Bertagnolli et al., Cell
Immunol 133:327-341, 1991; Bertagnolli, et al., Jlmmunol 149:3778-3783, 1992;
Bowman et
al., Jlmmunol 152:1756-1761, 1994.
Assays for cytokine production and/or proliferation of spleen cells, lymph
node cells or
thymocytes include, without limitation, those described by Kruisbeek and
Shevach, In: CURRENT
PROTOCOLS IN IMMUNOLOGY. Coligan et al., eds. Vol 1, pp. 3.12.1-14, John Wiley
and Sons,
Toronto 1994; and by Schreiber, In: CURRENT PROTOCOLS IN IMMUNOLOGY. Coligan
eds. Vol 1
pp. 6.8.1-8, John Wiley and Sons, Toronto 1994.
Assays for proliferation and differentiation of hematopoietic and
lymphopoietic cells
include, without limitation, those described by Bottomly et al., In: CURRENT
PROTOCOLS IN
IMMUNOLOGY. Coligan et al., eds. Vol 1 pp. 6.3.1-6.3.12, John Wiley and Sons,
Toronto 1991;
deVries et al., JExp Med 173:1205-1211, 1991; Moreau et al., Nature 336:690-
692, 1988;
Greenberger et al., Proc Natl Acad Sci U.S.A. 80:2931-2938, 1983; Nordan, In:
CURRENT
PROTOCOLS IN IMMUNOLOGY. Coligan et al., eds. Vol 1 pp. 6.6.1-5, John Wiley
and Sons,
Toronto 1991; Smith et al., Proc Natl Acad Sci U.S.A. 83:1857-1861, 1986;
Measurement of
human Interleukin 11-Bennett, et al. Iri: CURRENT PROTOCOLS IN IMMUNOLOGY.
Coligan et al.,
eds. Vol 1 pp. 6.15.1 John Wiley and Sons, Toronto 1991; Ciarletta, et al.,
In: CURRENT
PROTOCOLS IN IMMUNOLOGY. Coligan et al., eds. Vol 1 pp. 6.13.1, John Wiley and
Sons,
Toronto 1991.
Assays for T-cell clone responses to antigens (which will identify, among
others, proteins
that affect APC-T cell interactions as well as direct T-cell effects by
measuring proliferation and
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cytokine production) include, without limitation, those described In: CURRENT
PROTOCOLS IN
IMMUNOLOGY. Coligan et al., eds., Greene Publishing Associates and Wiley-
Interscience
(Chapter 3Chapter 6, Chapter 7); Weinberger et al., Proc Natl Acad Sci USA
77:6091-6095,
1980; Weinberger et al., Eur Jlmmun 11:405-411, 1981; Takai et al., Jlmmunol
137:3494-3500,
1986; Takai et al., Jlmmunol 140:508-512, 1988.
Immune Stimulating or Suppressing Activity
A GENX protein of the present invention may also exhibit immune stimulating or
immune suppressing activity, including without limitation the activities for
which assays are
described herein. A protein may be useful in the treatment of various immune
deficiencies and
disorders (including severe combined immunodeficiency (SCID)), e.g., in
regulating (up or
down) growth and proliferation of T and/or B lymphocytes, as well as effecting
the cytolytic
activity of NK cells and other cell populations. These immune deficiencies may
be genetic or be
caused by vital (e.g., HIV) as well as bacterial or fungal infections, or may
result from
autoimmune disorders. More specifically, infectious diseases causes by vital,
bacterial, fungal or
. other infection may be treatable using a protein of the present invention,
including infections by
HIV, hepatitis viruses, herpesviruses, mycobacteria, Leishmania species.,
malaria species. and
various fungal infections such as candidiasis. Of course, in this regard, a
protein of the present
invention may also be useful where a boost to the immune system generally may
be desirable,
i.e., in the treatment of cancer.
Autoimmune disorders which may be treated using a protein of the present
invention
include, for example, connective tissue disease, multiple sclerosis, systemic
lupus erythematosus,
rheumatoid arthritis, autoimmune pulmonary inflammation, Guillain-Barre
syndrome,
autoimmune thyroiditis, insulin dependent diabetes mellitus, myasthenia
gravis, graft-versus-host
disease and autoimmune inflammatory eye disease. Such a protein of the present
invention may
also to be useful in the treatment of allergic reactions and conditions, such
as asthma
(particularly allergic asthma) or other respiratory problems. Other
conditions, in which immune
suppression is desired (including, for example, organ transplantation), may
also be treatable
using a protein of the present invention.
Using the proteins of the invention it may also be possible to immune
responses, in a
number of ways. Down regulation may be in the form of inhibiting or blocking
an immune
response already in progress or may involve preventing the induction of an
immune response.
79

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The functions of activated T cells may be inhibited by suppressing T cell
responses or by
inducing specific tolerance in T cells, or both. Immunosuppression of T cell
responses is
generally an active, non-antigen-specific, process which requires continuous
exposure of the T
cells to the suppressive agent. Tolerance, which involves inducing non-
responsiveness or energy
in T cells, is distinguishable from immunosuppression in that it is generally
antigen-specific and
persists after exposure to the tolerizing agent has ceased. Operationally,
tolerance can be
demonstrated by the lack of a T cell response upon re-exposure to specific
antigen in the absence
of the tolerizing agent.
Down regulating or preventing one or more antigen functions (including without
limitation B lymphocyte antigen functions (such as, for example, B7), e.g.,
preventing high level
lymphokine synthesis by activated T cells, will be useful in situations of
tissue, skin and organ
transplantation and in graft-versus-host disease (GVHD). For example, blockage
of T cell
function should result in reduced tissue destruction in tissue
transplantation. Typically, in tissue
transplants, rejection of the transplant is initiated through its recognition
as foreign by T cells,
followed by an immune reaction that destroys the transplant. The
administration of a molecule
which inhibits or blocks interaction of a B7 lymphocyte antigen with its
natural ligand(s) on
immune cells (such as a soluble, monomeric form of a peptide having B7-2
activity alone or in
conjunction with a monomeric form of a peptide having an activity of another B
lymphocyte
antigen (e.g., B7-1, B7-3)~or blocking antibody), prior to transplantation can
lead to the binding
of the molecule to the natural ligand(s) on the immune cells without
transmitting the
corresponding costimulatory signal. Blocking B lymphocyte antigen function in
this matter
prevents cytokine synthesis by immune cells, such as T cells, and thus acts as
an
immunosuppressant. Moreover, the lack of costimulation may also be sufficient
to energize the T
cells, thereby inducing tolerance in a subject. Induction of long-term
tolerance by B lymphocyte
antigen-blocking reagents may avoid the necessity of repeated administration
of these blocking
reagents. To achieve sufficient immunosuppression or tolerance in a subject,
it may also be
necessary to block the function of B lymphocyte antigens.
The efficacy of particular blocking reagents in preventing organ transplant
rejection or
GVHD can be assessed using animal models that are predictive of efficacy in
humans. Examples
of appropriate systems which can be used include allogeneic cardiac grafts in
rats and
xenogeneic pancreatic islet cell grafts in mice, both of which have been used
to examine the

CA 02383592 2001-09-26
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immunosuppressive effects of CTLA4Ig fusion proteins in vivo as described in
Lenschow et al.,
Science 257:789-792 (1992) and Turka et al., Proc Natl Acad Sci USA, 89:11102-
11105 (1992).
In addition, marine models of GVHD (see Paul ed., FUNDAMENTAL IMMUNOLOGY,
Raven Press,
New York, 1989, pp. 846-847) can be used to determine the effect of blocking B
lymphocyte
antigen function in vivo on the development of that disease.
Blocking antigen function may also be therapeutically useful for treating
autoimmune
diseases. Many autoimmune disorders are the result of inappropriate activation
of T cells that are
reactive against self tissue and which promote the production of cytokines and
auto-antibodies
involved in the pathology of the diseases. Preventing the activation of
autoreactive T cells may
reduce or eliminate disease symptoms. Administration of reagents which block
costimulation of
T cells by disrupting receptor:ligand interactions of B lymphocyte antigens
can be used to inhibit
T cell activation and prevent production of auto-antibodies or T cell-derived
cytokines which
may be involved in the disease process. Additionally, blocking reagents may
induce
antigen-specific tolerance of autoreactive T cells which could lead to long-
term relief from the
1 S disease. The efficacy of blocking reagents in preventing or alleviating
autoimmune disorders can
be determined using a number of well-characterized animal models of human
autoimmune
diseases. Examples include marine experimental autoimmune encephalitis,
systemic lupus
erythematosis in MRL/lpr/lpr mice or NZB hybrid mice, marine autoimmune
collagen arthritis,
diabetes mellitus in NOD mice and BB rats, and marine experimental myasthenia
gravis (see
Paul ed., FUNDAMENTAL IMMUNOLOGY, Raven Press, New York, 1989, pp. 840-856).
Upregulation of an antigen function (preferably a B lymphocyte antigen
function), as a
means of up regulating immune responses, may also be useful in therapy.
Upregulation of
immune responses may be in the form of enhancing an existing immune response
or eliciting an
initial immune response. For example, enhancing an immune response through
stimulating B
lymphocyte antigen function may be useful in cases of viral infection. In
addition, systemic vital
diseases such as influenza, the common cold, and encephalitis might be
alleviated by the
administration of stimulatory forms of B lymphocyte antigens systemically.
Alternatively, anti-viral immune responses may be enhanced in an infected
patient by
removing T cells from the patient, costimulating the T cells in vitro with
viral antigen-pulsed
APCs either expressing a peptide of the present invention or together with a
stimulatory form of
a soluble peptide of the present invention and reintroducing the in vitro
activated T cells into the
81

CA 02383592 2001-09-26
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patient. Another method of enhancing anti-vital immune responses would be to
isolate infected
cells from a patient, transfect them with a nucleic acid encoding a protein of
the present
invention as described herein such that the cells express all or a portion of
the protein on their
surface, and reintroduce the transfected cells into the patient. The infected
cells would now be
capable of delivering a costimulatory signal to, and thereby activate, T cells
in vivo.
In another application, up regulation or enhancement of antigen function
(preferably B
lymphocyte antigen function) may be useful in the induction of tumor immunity.
Tumor cells
(e.g., sarcoma, melanoma, lymphoma, leukemia, neuroblastoma, carcinoma)
transfected with a
nucleic acid encoding at least one peptide of the present invention can be
administered to a
subject to overcome tumor-specific tolerance in the subject. If desired, the
tumor cell can be
transfected to express a combination of peptides. For example, tumor cells
obtained from a
patient can be transfected ex vivo with an expression vector directing the
expression of a peptide
having B7-2-like activity alone, or in conjunction with a peptide having B7-1-
like activity and/or
B7-3-like activity. The transfected tumor cells are returned to the patient to
result in expression
of the peptides on the surface of the transfected cell. Alternatively, gene
therapy techniques can
be used to target a tumor cell for transfection in vivo.
The presence of the peptide of the present invention having the activity of a
B
lymphocyte antigens) on the surface of the tumor cell provides the necessary
costimulation
signal to T cells to induce a T cell mediated immune response against the
transfected tumor cells.
In addition, tumor cells which lack MHC class I or MHC class II molecules, or
which fail to
reexpress sufficient amounts of MHC class I or MHC class II molecules, can be
transfected with
nucleic acid encoding all or a portion of (e.g., a cytoplasmic-domain
truncated portion) of an
MHC class I a chain protein and (32 microglobulin protein or an MHC class II a
chain protein
and an MHC class II ~i chain protein to thereby express MHC class I or MHC
class II proteins on
the cell surface. Expression of the appropriate class I or class II MHC in
conjunction with a
peptide having the activity of a B lymphocyte antigen (e.g., B7-1, B7-2, B7-3)
induces a T cell
mediated immune response against the transfected tumor cell. Optionally, a
gene encoding an
antisense construct which blocks expression of an MHC class II associated
protein, such as the
invariant chain, can also be cotransfected with a DNA encoding a peptide
having the activity of a
B lymphocyte antigen to promote presentation of tumor associated antigens and
induce tumor
82

CA 02383592 2001-09-26
WO 00/58473 PCT/US00/08621
specific immunity. Thus, the induction of a T cell mediated immune response in
a human subject
may be sufficient to overcome tumor-specific tolerance in the subject.
The activity of a protein of the invention may, among other means, be measured
by the
following methods: Suitable assays for thymocyte or splenocyte cytotoxicity
include, without
limitation, those described In: CURRENT PROTOCOLS iN IMMUNOLOGY. Coligan et
al., eds. Greene
Publishing Associates and Wiley-Interscience (Chapter 3, Chapter 7); Herrmann
et al., Proc Natl
Acad Sci USA 78:2488-2492, 1981; Hernnann et al., Jlmmunol 128:1968-1974,
1982; Handa et
al., Jlmmunol 135:1564-1572, 1985; Takai et al., Jlmmunol 137:3494-3500, 1986;
Takai et al.,
Jlmmunol 140:508-512, 1988; Hemnann et al., Proc Natl Acad Sci USA 78:2488-
2492, 1981;
Herrmann et al., Jlmmunol 128:1968-1974, 1982; Handa et al., Jlmmunol 135:1564-
1572,
1985; Takai et al., Jlmmunol 137:3494-3500, 1986; Bowman et al., J Virology
61:1992-1998;
Takai et al., Jlmmunol 140:508-512, 1988; Bertagnolli et al., Cell Immunol
133:327-341, 1991;
Brown et al., Jlmmunol 153:3079-3092, 1994.
Assays for T-cell-dependent immunoglobulin responses and isotype switching
(which
will identify, among others, proteins that modulate T-cell dependent antibody
responses and that
affect Thl/Th2 profiles) include, without limitation, those described in:
Maliszewski, Jlmmunol
144:3028-3033, 1990; and Mond and Brunswick In: CURRENT PROTOCOLS IN
IMMUNOLOGY.
Coligan et al., (eds:) Vol 1 pp. 3.8.1-3.8.16, John Wiley and Sons, Toronto
1994.
Mixed lymphocyte reaction (MLR) assays (which will identify, among others,
proteins
that generate predominantly Thl and CTL responses) include, without
limitation, those described
In: CURRENT PROTOCOLS IN IMMUNOLOGY. Coligan et al., eds. Greene Publishing
Associates and
Wiley-Interscience (Chapter 3, Chapter 7); Takai et al., Jlmmunol 137:3494-
3500, 1986; Takai
et al., Jlmmunol 140:508-512, 1988; Bertagnolli et al., Jlmmunol 149:3778-
3783, 1992.
Dendritic cell-dependent assays (which will identify, among others, proteins
expressed by
dendritic cells that activate naive T-cells) include, without limitation,
those described in: Guery
et al., Jlmmunol 134:536-544, 1995; Inaba et al., JExp Med 173:549-559, 1991;
Macatonia et
al., Jlmmunol 154:5071-5079, 1995; Porgador et al., JExp Med 182:255-260,
1995; Nair et al.,
J Yirol 67:4062-4069, 1993; Huang et al., Science 264:961-965, .1994;
Macatonia et al., JExp
Med 169:1255-1264, 1989; Bhardwaj et al., J Clin Investig 94:797-807, 1994;
and Inaba et al., J
Exp Med 172:631-640, 1990.
83

CA 02383592 2001-09-26
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Assays for lymphocyte survival/apoptosis (which will identify, among others,
proteins
that prevent apoptosis after superantigen induction and proteins that regulate
lymphocyte
homeostasis) include, without limitation, those described in: Darzynkiewicz et
al., Cytometry
13:795-808, 1992; Gorczyca et al., Leukemia 7:659-670, 1993; Gorczyca et al.,
Cancer Res
53:1945-1951, 1993; Itoh et al., Cell 66:233-243, 1991; Zacharchuk, Jlmmunol
145:4037-4045,
1990; Zamai et al., Cytometry 14:891-897, 1993; Gorczyca et al.,
InternatJOncol 1:639-648,
1992.
Assays for proteins that influence early steps of T-cell commitment and
development
include, without limitation, those described in: Antica et al., Blood 84:111-
117, 1994; Fine et al.,
Cell Immunol 155: 111-122, 1994; Galy et al., Blood 85:2770-2778, 1995; Toki
et al., Proc Nat
Acad Sci USA 88:7548-7551, 1991.
Hematopoiesis Regulating Activity
A GENX protein of the present invention may be useful in regulation of
hematopoiesis
and, consequently, in the treatment of myeloid or lymphoid cell deficiencies.
Even marginal
1 S biological activity in support of colony forming cells or of factor-
dependent cell lines indicates
involvement in regulating hematopoiesis, e.g. in supporting the growth and
proliferation of
erythroid progenitor cells alone or in combination with other cytokines,
thereby indicating utility,
for example, in treating various anemias or for use in conjunction with
irradiation/chemotherapy
to stimulate the production of erythroid precursors and/or erythroid cells; in
supporting the
growth and proliferation of myeloid cells such as granulocytes and
monocytes/macrophages (i. e.,
traditional CSF activity) useful, for example, in conjunction with
chemotherapy to prevent or
treat consequent myelo-suppression; in supporting the growth and proliferation
of
megakaryocytes and consequently of platelets thereby allowing prevention or
treatment of
various platelet disorders such as thrombocytopenia, and generally for use in
place of or
complimentary to platelet transfusions; and/or in supporting the growth and
proliferation of
hematopoietic stem cells which are capable of maturing to any and all of the
above-mentioned
hematopoietic cells and therefore find therapeutic utility in various stem
cell disorders (such as
those usually treated with transplantation, including, without limitation,
aplastic anemia and
paroxysmal nocturnal hemoglobinuria), as well as in repopulating the stem cell
compartment
post irradiation/chemotherapy, either in-vivo or ex-vivo (i.e., in conjunction
with bone marrow
84

CA 02383592 2001-09-26
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transplantation or with peripheral progenitor cell transplantation (homologous
or heterologous))
as normal cells or genetically manipulated for gene therapy.
The activity of a protein of the invention may, among other means, be measured
by the
following methods:
Suitable assays for proliferation and differentiation of various hematopoietic
lines are
cited above.
Assays for embryonic stem cell differentiation (which will identify, among
others,
proteins that influence embryonic differentiation hematopoiesis) include,
without limitation,
those described in: Johansson et al. Cellular Biology 15:141-151, 1995; Kelley
et al., Mol. Cell.
Biol. 13:473-486, 1993; McClanahan et al., Blood 81:2903-2915, 1993.
Assays for stem cell survival and differentiation (which will identify, among
others,
proteins that regulate lympho-hematopoiesis) include, without limitation,
those described in:
Methylcellulose colony forming assays, Freshney, In: CULTURE OF HEMATOP01ETIC
CELLS.
Freshney, et al. (eds.) Vol pp. 265-268, Wiley-Liss, Inc., New York, N.Y 1994;
Hirayama et al.,
Proc Natl Acad Sci USA 89:5907-5911, 1992; McNiece and Briddeli, In: CULTURE
OF
HEMATOPOIETIC CELLS. Freshney, et al. (eds.) Vol pp. 23-39, Wiley-Liss, Inc.,
New York, N.Y.
1994; Neben et al., Exp Hematol 22:353-359, 1994; Ploemacher, In: CULTURE OF
HEMATOPOIETIC CELLS. Freshney, et al. eds. Vol pp. 1-21, Wiley-Liss, Inc., New
York, N.Y.
1994; Spoonceret al., In: CULTURE OF HEMATOPOIETIC CELLS. Freshhey, et al.,
(eds.) Vol pp.
163-179, Wiley-Liss, Inc., New York, N.Y. 1994; Sutherland, In: CULTURE OF
HEMATOPOIETIC
CELLS. Freshney, et al., (eds.) Vol pp. 139-162, Wiley-Liss, Inc., New York,
N.Y. 1994.
Tissue Growth Activity
A GENX protein of the present invention also may have utility in compositions
used for
bone, cartilage, tendon, ligament and/or nerve tissue growth or regeneration,
as well as for
wound healing and tissue repair and replacement, and in the treatment of
burns, incisions and
ulcers.
A protein of the present invention, which induces cartilage and/or bone growth
in
circumstances where bone is not normally formed, has application in the
healing of bone
fractures and cartilage damage or defects in humans and other animals. Such a
preparation
employing a protein of the invention may have prophylactic use in closed as
well as open
fracture reduction and also in the improved fixation of artificial joints. De
novo bone formation

CA 02383592 2001-09-26
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induced by an osteogenic agent contributes to the repair of congenital, trauma
induced, or
oncologic resection induced craniofacial defects, and also is useful in
cosmetic plastic surgery.
A protein of this invention may also be used in the treatment of periodontal
disease, and
in other tooth repair processes. Such agents may provide an environment to
attract bone-forming
cells, stimulate growth of bone-forming cells or induce differentiation of
progenitors of
bone-forming cells. A protein of the invention may also be useful in the
treatment of
osteoporosis or osteoarthritis, such as through stimulation of bone and/or
cartilage repair or by
blocking inflammation or processes of tissue destruction (collagenase
activity, osteoclast
activity, etc.) mediated by inflammatory processes.
Another category of tissue regeneration activity that may be attributable to
the protein of
the present invention is tendon/ligament formation. A protein of the present
invention, which
induces tendon/ligament-like tissue or other tissue formation in circumstances
where such tissue
is not normally formed, has application in the healing of tendon or ligament
tears, deformities
and other tendon or ligament defects in humans and other animals. Such a
preparation employing
a tendon/ligament-like tissue inducing protein may have prophylactic use in
preventing damage
to tendon or ligament tissue, as well as use in the improved fixation of
tendon or ligament_to
bone or other tissues, and in repairing defects to tendon or ligament tissue.
De novo
tendon/ligament-like tissue formation induced by a composition of the present
invention
contributes to the repair of congenital, trauma induced, or other tendon or
ligament defects of
other origin, and is also useful in cosmetic plastic surgery for attachment or
repair of tendons or
ligaments. The compositions of the present invention may provide an
environment to attract
tendon- or ligament-forming cells, stimulate growth of tendon- or ligament-
forming cells, induce
differentiation of progenitors of tendon- or ligament-forming cells, or induce
growth of
tendon/ligament cells or progenitors ex vivo for return in vivo to effect
tissue repair. The
compositions of the invention may also be useful in the treatment of
tendonitis, carpal tunnel
syndrome and other tendon or ligament defects. The compositions may also
include an
appropriate matrix and/or sequestering agent as a career as is well known in
the art.
The protein of the present invention may also be useful for proliferation of
neural cells
and for regeneration of nerve and brain tissue, i. e. for the treatment of
central and peripheral
nervous system diseases and neuropathies, as well as mechanical and traumatic
disorders, which
involve degeneration, death or trauma to neural cells or nerve tissue. More
specifically, a protein
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CA 02383592 2001-09-26
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may be used in the treatment of diseases of the peripheral nervous system,
such as peripheral
nerve injuries, peripheral neuropathy and localized neuropathies, and central
nervous system
diseases, such as Alzheimer's, Parkinson's disease, Huntington's disease,
amyotrophic lateral
sclerosis, and Shy-Drager syndrome. Further conditions which may be treated in
accordance with
the present invention include mechanical and traumatic disorders, such as
spinal cord disorders,
head trauma and cerebrovascular diseases such as stroke. Peripheral
neuropathies resulting from
chemotherapy or other medical therapies may also be treatable using a protein
of the invention.
Proteins of the invention may also be useful to promote better or faster
closure of
non-healing wounds, including without limitation pressure ulcers, ulcers
associated with vascular
insufficiency, surgical and traumatic wounds, and the like.
It is expected that a protein of the present invention may also exhibit
activity for
generation or regeneration of other tissues, such as organs (including, for
example, pancreas,
liver, intestine, kidney, skin, endothelium), muscle (smooth, skeletal or
cardiac) and vascular
(including vascular endothelium) tissue, or for promoting the growth of cells
comprising such
1 S tissues. Part of the desired effects may be by inhibition or modulation of
fibrotic scarnng to
allow normal tissue to regenerate. A protein of the invention may also exhibit
angiogenic
activity.
A protein of the present invention may also be useful for gut protection or
regeneration
and treatment of lung or liver fibrosis, reperfusion injury in various
tissues, and conditions
resulting from systemic cytokine damage.
A protein of the present invention may also be useful for promoting or
inhibiting
differentiation of tissues described above from precursor tissues or cells; or
for inhibiting the
growth of tissues described above.
The activity of a protein of the invention may, among other means, be measured
by the
following methods:
Assays for tissue generation activity include, without limitation, those
described in:
International Patent Publication No. W095/16035 (bone, cartilage, tendon);
International Patent
Publication No. W095/05846 (nerve, neuronal); International Patent Publication
No.
W091/07491 (skin, endothelium).
Assays for wound healing activity include, without limitation, those described
in: Winter,
EPIDERMAL WOUND HEALING, pp. 71-112 (Maibach and Rovee, eds.), Year Book
Medical
87

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Publishers, Inc., Chicago, as modified by Eaglstein and Menz, J. Invest.
Dermatol 71:382-84
(1978).
Activin/Inhibin Activity
A GENX protein of the present invention may also exhibit activin- or inhibin-
related
activities. Inhibins are characterized by their ability to inhibit the release
of follicle stimulating
hormone (FSH), while activins and are characterized by their ability to
stimulate the release of
follicle stimulating hormone (FSH). Thus, a protein of the present invention,
alone or in
heterodimers with a member of the inhibin a family, may be useful as a
contraceptive based on
the ability of inhibins to decrease fertility in female mammals and decrease
spermatogenesis in
male mammals. Administration of sufficient amounts of other inhibins can
induce infertility in
these mammals. Alternatively, the protein of the invention, as a homodimer or
as a heterodimer
with other protein subunits of the inhibin-b group, may be useful as a
fertility inducing
therapeutic, based upon the ability of activin molecules in stimulating FSH
release from cells of
the anterior pituitary. See, for example, U.S. Pat. No. 4,798,885. A protein
of the invention may
also be useful for advancement of the onset of fertility in sexually immature
mammals, so as to
increase the lifetime reproductive performance of domestic animals such as
cows, sheep and
pigs.
The activity of a protein of the invention may, among other means, be measured
by the
following methods:
Assays for activin/inhibin activity include, without limitation, those
described in: Vale et
al., Endocrinology 91:562-572, 1972; Ling et al., Nature 321:779-782, 1986;
Vale et al., Nature
321:776-779, 1986; Mason et al., Nature 318:659-663, 1985; Forage et al., Proc
Natl Acad Sci
USA 83:3091-3095, 1986.
Chemotactic/Chemolcinetic Activity
A protein of the present invention may have chemotactic or chemokinetic
activity (e.g.,
act as a chemokine) for mammalian cells, including, for example, monocytes,
fibroblasts,
neutrophils, T-cells, mast cells, eosinophils, epithelial and/or endothelial
cells. Chemotactic and
chemokinetic proteins can be used to mobilize or attract a desired cell
population to a desired site
of action. Chemotactic or chemokinetic proteins provide particular advantages
in treatment of
wounds and other trauma to tissues, as well as in treatment of localized
infections. For example,
88

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attraction of lymphocytes, monocytes or neutrophils to tumors or sites of
infection may result in
improved immune responses against the tumor or infecting agent.
A protein or peptide has chemotactic activity for a particular cell population
if it can
stimulate, directly or indirectly, the directed orientation or movement of
such cell population.
S Preferably, the protein or peptide has the ability to directly stimulate
directed movement of cells.
Whether a particular protein has chemotactic activity for a population of
cells can be readily
determined by employing such protein or peptide in any known assay for cell
chemotaxis.
The activity of a protein of the invention may, among other means, be measured
by
following methods:
Assays for chemotactic activity (which will identify proteins that induce or
prevent
chemotaxis) consist of assays that measure the ability of a protein to induce
the migration of cells
across a membrane as well as the ability of a protein to induce the adhesion
of one cell
population to another cell population. Suitable assays for movement and
adhesion include,
without limitation, those described in: CURRENT PROTOCOLS tN IMMUNOLOGY,
Coligan et al.,
eds. (Chapter 6.12, MEASUREMENT OF ALPHA AND BETA CHEMOKINES 6.12.1-6.12.28);
Taub et
al. J Clin Invest 95:1370-1376, 1995; Lind et al. APMIS 103:140-146, 1995;
Muller et al., Eur J
Immunol 25: 1744-1748; Gruberet al. Jlmmunol 152:5860-5867, 1994; Johnston et
al., J
Immunol 153: 1762-1768, 1994.
Hemostatic and Thrombolytic Activity
?0 A protein of the invention may also exhibit hemostatic or thrombolytic
activity. As a
result, such a protein is expected to be useful in treatment of various
coagulation disorders
(including hereditary disorders, such as hemophilias) or to enhance
coagulation and other
hemostatic events in treating wounds resulting from trauma, surgery or other
causes. A protein of
the invention may also be useful for dissolving or inhibiting formation of
thromboses and for
ZS treatment and prevention of conditions resulting therefrom (such as, for
example, infarction of
cardiac and central nervous system vessels (e.g., stroke).
The activity of a protein of the invention may, among other means, be measured
by the
following methods:
Assay for hemostatic and thrombolytic activity include, without limitation,
those
30 described in: Linet et al., J. Clin. Pharmacol. 26:131-140, 1986; Burdick
et al., Thrombosis Res.
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CA 02383592 2001-09-26
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45:413-419, 1987; Humphrey et al., Fibrinolysis 5:71-79 (1991); Schaub,
Prostaglandins
35:467-474, 1988.
Receptor/Ligand Activity
A protein of the present invention may also demonstrate activity as receptors,
receptor
ligands or inhibitors or agonists of receptor/ligand interactions. Examples of
such receptors and
ligands include, without limitation, cytokine receptors and their ligands,
receptor kinases and
their ligands, receptor phosphatases and their ligands, receptors involved in
cell~ell
interactions and their ligands (including without limitation, cellular
adhesion molecules (such as
selectins, integrins and their ligands) and receptor/ligand pairs involved in
antigen presentation,
antigen recognition and development of cellular and humoral immune responses).
Receptors and
ligands are also useful for screening of potential peptide or small molecule
inhibitors of the
relevant receptor/ligand interaction. A protein of the present invention
(including, without
limitation, fragments of receptors and ligands) may themselves be useful as
inhibitors of
receptor/ligand interactions.
1 S The activity of a protein of the invention may, among other means, be
measured by the
following methods:
Suitable assays for receptor-ligand activity include without limitation those
described in:
CURRENT PROTOCOLS IN IMMUNOLOGY, Ed by Coligan, et al., Greene Publishing
Associates and
Wiley-Interscience (Chapter 7.28, Measurement of Cellular Adhesion under
static conditions
7.28.1-7.28.22), Takai et al., Proc Natl Acad Sci USA 84:6864-6868, 1987;
Bierer et al., J. Exp.
Med. 168:1145-1156, 1988; Rosenstein et al., J. Exp. Med. 169:149-160 1989;
Stoltenborg et al.,
Jlmmunol Methods 175:59-68, 1994; Stitt et al., Cell 80:661-670, 1995.
Anti-Inflammatory Activity
Proteins of the present invention may also exhibit anti-inflammatory activity.
The
anti-inflammatory activity may be achieved by providing a stimulus to cells
involved in the
inflammatory response, by inhibiting or promoting cell~ell interactions (such
as, for example,
cell adhesion), by inhibiting or promoting chemotaxis of cells involved in the
inflammatory
process, inhibiting or promoting cell extravasation, or by stimulating or
suppressing production
of other factors which more directly inhibit or promote an inflammatory
response. Proteins
exhibiting such activities can be used to treat inflammatory conditions
including chronic or acute

CA 02383592 2001-09-26
WO 00/58473 PCT/US00/08621
conditions), including without limitation inflammation associated with
infection (such as septic
shock, sepsis or systemic inflammatory response syndrome (SIRS)), ischemia-
reperfusion injury,
endotoxin lethality, arthritis, complement-mediated hyperacute rejection,
nephritis, cytokine or
chemokine-induced lung injury, inflammatory bowel disease, Crohn's disease or
resulting from
over production of cytokines such as TNF or IL-1. Proteins of the invention
may also be useful
to treat anaphylaxis and hypersensitivity to an antigenic substance or
material.
Tumor Inhibition Activity
In addition to the activities described above for immunological treatment or
prevention of
tumors, a protein of the invention may exhibit other anti-tumor activities. A
protein may inhibit
tumor growth directly or indirectly (such as, for example, via ADCC). A
protein may exhibit its
tumor inhibitory activity by acting on tumor tissue or tumor precursor tissue,
by inhibiting
formation of tissues necessary to support tumor growth (such as, for example,
by inhibiting
angiogenesis), by causing production of other factors, agents or cell types
which inhibit tumor
growth, or by suppressing, eliminating or inhibiting factors, agents or cell
types which promote
tumor growth.
Other Activities
A protein of the invention may also exhibit one or more of the following
additional
activities or effects: inhibiting the growth, infection or function of, or
killing, infectious agents,
including, without limitation, bacteria, viruses, fungi and other parasites;
effecting (suppressing
or enhancing) bodily characteristics, including, without limitation, height,
weight, hair color, eye
color, skin, fat to lean ratio or other tissue pigmentation, or organ or body
part size or shape
(such as, for example, breast augmentation or diminution, change in bone form
or shape);
effecting biorhythms or circadian cycles or rhythms; effecting the fertility
of male or female
subjects; effecting the metabolism, catabolism, anabolism, processing,
utilization, storage or
elimination of dietary fat, lipid, protein, carbohydrate, vitamins, minerals,
cofactors or other
nutritional factors or component(s); effecting behavioral characteristics,
including, without
limitation, appetite, libido, stress, cognition (including cognitive
disorders), depression
(including depressive disorders) and violent behaviors; providing analgesic
effects or other pain
reducing effects; promoting differentiation and growth of embryonic stem cells
in lineages other
than hematopoietic lineages; hormonal or endocrine activity; in the case of
enzymes, correcting
91

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WO 00/58473 PCT/US00/08621
deficiencies of the enzyme and treating deficiency-related diseases; treatment
of
hyperproliferative disorders (such as, for example, psoriasis); immunoglobulin-
like activity (such
as, for example, the ability to bind antigens or complement); and the ability
to act as an antigen
in a vaccine composition to raise an immune response against such protein or
another material or
entity which is cross-reactive with such protein.
Neural disorders in general include Parkinson's disease, Alzheimer's disease,
Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS),
peripheral
neuropathy, tumors of the nervous system, exposure to neurotoxins, acute brain
injury, peripheral
nerve trauma or injury, and other neuropathies, epilepsy, and/or tremors.
EQUIVALENTS
From the foregoing detailed description of the specific embodiments of the
invention, it
should be apparent that particular novel compositions and methods involving
nucleic acids,
polypeptides, antibodies, detection and treatment have been described.
Although these particular
embodiments have been disclosed herein in detail, this has been done by way of
example for
purposes of illustration only, and is not intended to be limiting with respect
to the scope of the
appended claims that follow. In particular, it is contemplated by the
inventors that various
substitutions, alterations, and modifications may be made as a matter of
routine for a person of
ordinary skill in the art to the invention without departing from the spirit
and scope of the
invention as defined by the claims. Indeed, various modifications of the
invention in addition to
those described herein will become apparent to those skilled in the art from
the foregoing
description and accompanying figures. Such modifications are intended to fall
within the scope
of the appended claims.
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CA 02383592 2001-09-26
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CA 02383592 2001-09-26
WO 00/58473 PCT/US00/08621
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173

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WO 00/58473 PCT/US00/08621
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CA 02383592 2001-09-26
WO 00/58473 PCT/US00/08621
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175

CA 02383592 2001-09-26
WO 00/58473 PCT/US00/08621
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WO 00/58473 PCT/US00/08621
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WO 00/58473 PCT/US00/08621
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CA 02383592 2001-09-26
WO 00/58473 PCT/US00/08621
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WO 00/58473 PCT/US00/08621
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WO 00/58473 PCT/US00/08621
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WO 00/58473 PCT/US00/08621
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248

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