Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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The present invention relates to a method of
treatment of certain auto-immune conditions in a human
or animal subject.
The cells and molecules in an animal body do not
normally stimulate an adaptive immune response in that
body as a result of a number of mechanisms which
ensure a state referred to as "self-tolerance".
However, in certain circumstances these mechanisms may
fail to prevent the stimulation of such an immune
response and this condition is referred to as "auto-
immunity". A number of diseases in humans and animals
are now thought to result from autoimmunity.
One such condition is rheumatoid arthritis which
is associated with the production by an animal of
antibodies against its own IgG. The inflammation of
and consequent damage to the joints associated with
the disease are probably mediated via immune
complexes. Diseases in which inflammation of and
damage to the joints arise from autoimmunity are
referred to generically herein "T-cell mediated
inflammation of the joint synovium".
The CDw52 antigen (a 23kDa glycoprotein also
referred to as CAMPATH-1) is strongly expressed on the
surface of all human lymphocytes and most monocytes
but is absent from other blood cells including stem
cells. A number of antibodies have been developed
directed against CDw52 which is an unusually good
target for complement-mediated attack. Antibodies
against CDw52 bind to all lymphocytes and monocytes
but lyse only lymphocytes (T and B) in vivo. Antigens
similar to CDw52 are expressed in other mammalian
species.
Antibodies which have been developed against
CDw52 and which have been used in therapy include the
following:
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CAMPATH-1M is a rat IgM monoclonal antibody which
has been used extensively in vitro for purging bone
marrow harvests in order to deplete the T cell
population prior to bone marrow transplantation.
Marked reductions in the incidence and severity of
graft-versus-host disease has been seen with this
therapy.
CAMPATH-1G is a rat IgG2b class-switch variant of
an IgG2a antibody recognising the CDw52 antigen which
has been used in vivo to achieve immunosupression in
more than 100 patients undergoing organ and bone
marrow transplantation, management of organ rejection
and treatment of haematologic malignancies with a high
level of success. However, the rapid development of
an anti-rat immunoglobulin response, including the
possibility of anaphylaxis, is likely to limit the use
of rat monoclonal antibodies against the CDw52 antigen
in humans in vivo.
CAMPATH-1H is a genetically manipulated IgG
antibody obtained by grafting the complementarity
determining regions from CAMPATH-1G into human
framework regions. The resulting "humanized" antibody
is highly effective in vitro being equivalent to the
rat monoclonal antibody at complement lysis and two to
four times better in cell-mediated lysis of human
lymphocytes. No limiting anti-globulin response is
anticipated with this humanized antibody.
Expression of CAMPATH-1H was achieved initially in
rat myeloma cells by placing DNA encoding the
engineered antibody chains in genomic context under
control of the immunoglobulin promoter/enhancer.
CAMPATH-1H has recently been expressed to high levels
in Chinese hamster ovary (CHO) cells.
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It has now surprisingly been found that
antibodies against the CDw52 antigen are effective in
the treatment of T-cell mediated inflammation of the
joint synovium.
The present invention provides a method of
treatment of a human or animal subject suffering from
T-cell mediated inflammation of the joint synovium
which comprises administering to the said subject an
effective amount of an antibody recognising the CDw52
antigen.
The medicament according to the invention is
applicable to the treatment of any disease involving
T-cell mediated inflammation of the joint synovium.
The most common such disease is rheumatoid arthritis
which is a major cause of suffering and disability in
the developed world. Other diseases involving T-cell
mediated inflammation of the joint synovium include
variants of rheumatoid arthritis such as atypical
Still's disease. The medicament according to the
invention will find most applicability in the
treatment of humans but it may also find application
in veterinary medicine where animals with disease
involving T-cell mediated inflammation of the joint
synovium may also be treated with an appropriate
antibody.
For the treatment of humans it is preferred to
use an anti-CDw52 antibody which does not carry with
it the risk of the development of an immune reaction
against the antibody itself. Accordingly whilst it is
possible to use mouse or rat mono-clonal antibodies it
is preferred to use antibodies which have been
produced by recombinant DNA technology and which have
been engineered to reduce the risk of causing an
immune reaction. Thus it is possible to use a
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chimeric antibody in which the constant domains of a
mouse or rat anti-CDw52 antibody have been replaced by
the constant domains of a human antibody. However, it
is preferred to use a humanized or CDR-grafted
antibody for the treatment of humans, i.e. an antibody
in which the complementarity determining regions from
a mouse or rat antibody are combined with framework
regions and constant domains from one or more human
antibodies.
Most preferably the method according to the
invention is carried out using the CRD-grafted
antibody CAMPATH-1H (see Reichman et al, Nature, 322,
323-327 (1988)). As noted above, the antibody
CAMPATH-1H can be produced in rat myeloma cells as
originally described or it can be produced in any
other expression system, particularly an expression
system suitable for the production of a correctly
folded, glycosylated, mammalian protein. High yields
of CAMPATH-1H have been obtained by expression in a
genetically manipulated CHO cell line (Page and
Sydenham, Biotechnoloav, 9, 64-68 (1991)).
The dosages of anti-CDw52 antibody, preferably
CAMPATH-1H, to be administered to a patient suffering
from a disease involving T-cell mediated inflammation
of the joint synovium will vary with the condition
being treated and the recipient of the treatment. The
dose will generally be in the range 1 to about 100mg
for an adult patient, usually administered daily for a
period between 1 and 30 days. The preferred daily
dose is 1 to 10 mg per day although in some instances
larger doses of up to 40mg per day may be used.
._
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The anti-CDw52 antibody, particularly CAMPATH-1H
will generally be administered to the patient in the
form of a pharmaceutical formulation. Such
formulations preferably include, in addition to the
antibody, a physiologically acceptable carrier or
diluent, possibly in admixture with one or more other
agents such as other antibodies or drugs, such as an
antibiotic. Suitable carriers include, but are not
limited to, physiological saline, phosphate buffered
saline, phosphate buffered saline glucose and buffered
saline. Alternatively the antibody may be lyophilised
(freeze dried) and reconstituted for use when needed
by the addition of an aqueous buffered solution as
described above. Routes of administration are
routinely parenteral, including intravenous, intra-
muscular, subcutaneous and intraperitoneal injection
or delivery.
The anti-CDw52 antibody may be administered in
combination with or sequentially with other drugs, in
particular other drugs conventionally used in the
treatment of T-cell mediated inflammation of the joint
synovium, such as steroids, for example, hydro-
cortisones, or non-steroidal anti-inflammatory drugs.
Sequential administration of the antibody with another
drug may be appropriate in some cases. For example,
the anti-CDw52 antibody may re-establish the
effectiveness of steroids in patients where steroid
therapy has ceased to be effective so that treatment
with the antibody may conveniently be followed by
steroid therapy.
The invention is illustrated by the following
case histories of patients treated with the CDR-
grafted anti-CDw52 antibody CAMPATH-1H.
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The antibody used in Case No. 1 was produced in
rat Y-0 myeloma cells. The antibody used in Case No.
2 was produced by expression in a recombinant CHO cell
line (Page and Sydenham, Biotechnoloav, 9, 64-68
(1991)). In both cases the antibodies were extracted
from the cell culture medium and subsequently
purified.
It is to be understood that these case histories
are not intended to be in any way limiting on the
scope of the invention.
CASE N0. 1
The patient was a female born in 1940 who was a
typical case of a patient with severe aggressive
rheumatoid arthritis who had failed to respond or had
reacted adversely to several disease modifying anti-
rheumatic drugs.
Immediately prior to commencement of treatment
with CAMPATH-1H, the patient had restricted joint
mobility and had shown a poor response to increasing
doses of penicillamine which had been discontinued.
Treatment with CAMPATH-1H commenced September 1988 and
the patient was given 12 doses of 2mg CAMPATH-1H
intravenously in 500m1 normal saline over a 14 day
period. This brought about a "remarkable" subjective
improvement in the condition of the patient. There
was also an objective improvement based on a number of
conventional clinical criteria and in the sense that
she was able to undertake her own self-care and also
such activities as walking and knitting. The patient
also received 500mg Naprosyn (Trade-mark) twice daily.
The treatment with CAMPATH-1H brought about a
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relatively long lasting lymphopenia. By about 20 weeks
after treatment the patient's lymphocyte count had returned
to above 1.0 which was matched by a reactivation of her
disease. Treatment commenced with pyritinol (a second-line
anti-rheumatic agent undergoing trials) and this treatment
was continued for 12 months. Treatment then commenced with
cyclosporin 125mg daily and 25 months after the
commencement of treatment with CAMPATH-1H the patient
continues to do reasonably well on cyclosporin.
CASE NO. 2
The patient was a female born in 1971 who has been
diagnosed as suffering from a particularly severe case of
atypical Still's disease (a variant of rheumatiod arthritis
occurring in younger patients).
At the age of 15 (in 1986) she developed fever, a
brief episode of nausea and vomiting and abdominal pain and
then a painful red right ankle. She was admitted to
hospital and a small amount of pus was extracted from the
ankle joint. At the same time she was found to have a
symmetrical synovitis, right hypochondrial pain, pleuritic
pain and a rash. These have persisted intermittently ever
since, the polyarthropathy being dominant and immobilising.
Over the period 1988 to 1990 various investigations
showed anaemia (normochronic, normocytic), thrombocytosis,
hyperglobulinaemia, abnormal liver function (both alkaline
phosphatase and transferases), fluctuating creatinine
clearances (possibly related to NSAID therapy),
hypoalbuminaemia (without proteinuria), white cell scan
(uptake in joints), respiratory function tests, ECG
(inverted T waves), positive ANCA. ANA, DNAB, Rh factor,
complement, bone scans have always been normal as were
renal, liver and skin biopsies. A synovial biopsy in June
1990 showed a predominantly T cell infiltrate and
peripheral subsets showed these to be mostly T also (T 80%,
B 11%).
Therapies during the above period included steroids,
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penicillamine, azathioprine, cyclophosphamide,
methotrexate, plasma exchange, high dose intravenous gamma-
globulin and cyclosporin A. Partial control was achieved
with steroids, plasma exchange and cyclosporin A but
remissions proved to be short lived. The progression of
her disease and her lack of response to conventional and
aggressive therapy resulted in her being an inpatient in
hospital for long periods during 1990.
The patient commenced treatment with CAMPATH-1H in
December 1990 and she received 6 daily doses of 2mg each of
CAMPATH-1H followed by 6 doses of l0mg each over a 7 day
period. The antibody was administered intravenously in
saline. Towards the end of the treatment period a definite
symptomatic improvement was noted and by the end of the
treatment the patients joints were less inflamed and she
had a lower C-reactive protein value and thermographic
index as well as lowered erythrocyte sedimentation rate.
Shortly after the end of treatment she developed a skin
abscess on her left thigh at the site of subcutaneous
injection which was treated with antibiotics. Two and a
half weeks after the end of treatment she changed from
total parenteral nutrition to oral feeds. Four weeks after
the end of treatment her condition was remarkably improved
and she was discharged from hospital and allowed to return
home.
Approximately 9 months after the initial treatment,
she suffered a relapse with multiple joint involvement.
After initial testing for sensitivity with a low dose, she
was given a further course of treatment with lOmg/day
CAMPATH-1H for 10 days which produced a remission.
In addition to the above two case histories, five
further patients suffering from rheumatoid arthritis and
refractory to conventional therapies were treated with
CAMPATH-1H using a protocol similar to that used for the
patient in Case No. 2 above. Four of the five patients
responded to treatment although the duration of the effect
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