Note: Descriptions are shown in the official language in which they were submitted.
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Method to Improve the Efficacy of Therapeutic Radiolabeled Drugs
This application claims the benefit of the filing date of U.S. Provisional
Application Serial No. 60/528,473 filed December 11, 2003 and is incorporated
by
reference in its entirety herein.
Description
Method to improve the efficacy of a therapeutic radiolabeled drug using
radiosensitization.
Field of the Invention
The present invention relates to radiolabeled drugs and describes a method to
improve
their efficacy by using a radiosensitizer such that the radiosensitizer is
either part of the
radiolabeled drug by directly attaching the radiosensitizer to the
radiolabeled drug or by
producing a mixture of the radiolabeled drug and an analogue of the drug with
the
radiosensitizer attached to the drug instead of the radiolabel.
Technology Background
Radiolabeled antibodies are valuable diagnostic and therapeutic reagents. They
are
particularly useful as cancer therapeutics. The administration of a
radiolabeled antibody
with binding specificity for a tumor-specific antigen, coupled to a
radioisotope with a
short-range, high-energy radiation, has the potential to deliver a lethal dose
of radiation
directly to the tumor cell.
An example for a radiolabeled antibody is yttrium-90 labeled Zevalin, which
targets the
CD20 epitope located on B-cells and which is currently used in the treatment
of non-
Hodgkin Lymphoma (C. Emmanouilides, Semin Oncol. 2003; 30(4):531-44). The
radioisotope, yttrium-90, destroys the cells the antibody is attached to and
the cells within
the range of its radiation. The radiolytic activity of yttrium-90 has been
well described
(Salako et al. 1998, J. Nucl. Med. 39: 667; Chakrabarti et al., 1996, J. Nucl.
Med. 37:
1384).
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Further examples for yttrium-90-labeled antibodies are Theragyn (Hird et al.,
Br. J.
Cancer 1993, 68: 403), which is used for the treatment of ovarian cancer and
AngioMab,
which comprises the monoclonal antibody BC-1 bound through a linker to yttrium-
90 and
which is administered for treating solid tumors.
Methods relating to chelator and chelator conjugate synthesis are known in the
art (e.g.
US4,831,175, US5,099,069, US5,246,692, US5,286,850, and US5,124,471).
An example for a radiolabeled antibody using an iodine isotope instead of
yttrium-90 is
Bexxar, which is labeled with iodine-131. Bexxar also targets the CD20 epitope
of B-
cells and is used for the treatment of non-Hodgkin Lymphoma (BioDrugs. 2003;
17(4):290-5).
Although these radiolabeled drugs are very effective in their indications,
there is room for
improvement. It has now been found that their efficacy can be increased by
applying the
radiosensitizing principle such that either an analogue of the radiolabeled
drug with a
radiosensitizer moiety instead of the radiolabel-carrying moiety being
attached to the
drug or that an analogue is synthesized which is identical to the radiolabeled
drug except
for exchanging the radiolabel-carrying moiety for a radiosensitizing moiety.
Radiosensitizers are well known in the field (e.g. EP0316967, US2003166692,
US2001051760, US6589981).
Dual-agent compounds that combine the antitumor activity of an active drug
such as
paclitaxel with the radiosensitizing potential of an additional moiety
attached to this drug
have been described in W09640091 and in US5780653. However, these agents still
need
external radiation, which is unspecific and highly damaging to normal tissue,
whereas the
present invention utilizes its own radiation source and does not need external
radiation.
Gd-containing complexes used as radiosensitizers have been described in
US5457183
and in US2001051760 where Gd-Texaphyrins or Photofrins are used.
Instead of Gd, other metals with radiosensitizing potential might be utilized
such as
Co(III) or Fe(III) as described in US4727068.
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Radiosensitizers attached to liposomes have been described in W00045845
wherein a
radiosensitizer, e.g. 5-iodo-2'-deoxyuridine is attached to the lipids of the
lipisome via a
hydrophilic polymer chain.
Summary of the Invention
The current invention is related to the improvement of efficacy of
radiolabeled drugs by
radiosensitization, which is introduced via two possible routes. One route
consists in
attaching or linking a radiosensitizer moiety to the radiolabeled drug,
whereas in the
second route the radiolabeled drug is mixed with a drug analogue that contains
a
radiosensitizer in addition to or instead of the radiolabel.
Thus, in one aspect the invention relates to a method for improving the
efficacy of a
therapeutic radiolabeled drug comprising either
(i) combining the drug with a radiosensitizer moiety attached to the same
molecule or
(ii) co-administering a mixture of a radiolabeled drug and a radiosensitizer
provided that
the radiolabeled drug and the radiosensitizer have substantially the same
targeting
characteristics.
In other aspects, the invention relates to such methods
wherein said drug has two moieties linked to it, one moiety containing a
radiolabel and
the other moiety containing a radiosensitizer; and/or
wherein said drug is a small molecule, preferably labeled with a radioisotope;
and/or
wherein said drug is a chelate; and/or
wherein said drug contains a chelate; and/or
wherein said drug is a protein; and/or
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wherein said drug is a polymer or biopolymer; and/or
wherein said drug is an antibody or an antibody fragment; and/or
wherein said drug is a DNA or RNA or a fragment thereof; and/or
wherein said drug is a carbohydrate; and/or
wherein said drug is a dendrimeric compound; and/or
wherein said drug is contained in or on a liposome or micelle; and/or
wherein said drug comprises a mixture of a radiolabeled drug and an analogue
of this
drug functioning as or containing a radiosensitizer provided that the
radiolabeled drug
and the radiosensitizer have substantially the same targeting characteristics;
and/or
wherein said radiolabel is selected from alpha, beta and gamma emitters;
and/or
wherein said radiolabel is selected from the group of lanthanides; and/or
wherein said radiolabel is yttrium; and/or
wherein said radiolabel is a radioactive halogen; and/or
wherein said radiolabel is iodine; and/or
wherein said radiosensitizer is or contains gadolinium, iodine or boron;
and/or
wherein said radiolabel is attached or linked to the drug by a chelator linked
to the drug
via a bridge; and/or
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wherein said chelator or chelate comprises an EDTA, DTPA, or DOTA moiety;
and/or
wherein said linked or unlinked chelator or chelate comprises MX-DTPA, phenyl-
DTPA,
benzyl-DTPA, or CHX-DTPA; and/or
wherein said radiosensitizer is a triiodobenzene moiety; and/or
wherein said radiosensitizer is a borane or carborane moiety; and/or
wherein said antibody is Zevalin; and/or
comprising loading the chelator or chelate on the antibody with a mixture of a
radioactive
isotope and gadolinium, cobalt or iron; and/or
comprising loading the chelator or chelate on the antibody with a mixture of
yttrium-90
and gadolinium, cobalt or iron; and/or
comprising mixing a drug labeled with a radioactive isotope and a drug
analogue labeled
with gadolinium, cobalt or iron; and/or
comprising mixing yttrium-90 labeled Zevalin with gadolinium-, cobalt- or iron-
labeled
Zevalin.
Detailed Description of the Invention
Radiosensitizing so far has been understood as administering a compound that
is able to
increase the damaging potential of external radiation at the site of a tumor.
This means
that the radiosensitizer has to reach the tumor site at a concentration that
is high enough
to act as a radiosensitizer and low enough to exclude adverse reactions and to
apply
external radiation to exactly this site without damaging normal tissue on its
way to the
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tumor site. Since this goal has not yet been achieved satisfactorily, the use
of
radiosensitizers in medicine has been very limited.
We have now found a way of circumventing these difficulties. With the new
method,
external radiation is no longer necessary. Instead, radiation is delivered to
the tumor site
via administration of a radiolabeled drug which accumulates at the tumor site
and which
subsequently destroys the tumor cells. By combining this targeted delivery of
radiation
with a targeted delivery of a radiosensitizer, which is either part of the
radiolabeled drug
or which is delivered concurrently, before or after administration of the
radiolabeled
drug, the efficacy of treatment is increased further.
Accordingly, there are two possible routes to increase the efficacy of
radiolabeled drugs.
The first route can be described as follows. An additional moiety with
radiosensitizing
potential is attached to a radiolabeled drug without affecting its targeting
characteristics.
An example for this approach is a monoclonal antibody to which a chelator is
attached
via a linker. The chelator is able to bind radiolabeled isotopes such as
yttrium-90. The
antibody is directed to an epitope on tumor cells and carries the radioactive
isotope
directly to the tumor site where the tumor cells are destroyed by radiation.
Normally
more than one chelator is attached to an antibody. This means that the
chelators can be
utilized to bind not only the radioisotope but additionally other metal ions
that function as
radiosensitizers such as gadolinium, cobalt or iron. The advantage of this
approach is that
radiation and radiosensitizer are in very close proximity - they are combined
in the same
molecule - and therefore allow for a high sensitizing yield.
Alternatively, the same type of drug - a monoclonal antibody with a chelator
attached to
it via a linker - can be loaded either with the radioactive isotope (e.g.
yttrium-90) or with
the radiosensitizing metal (e.g. gadolinium) and the two drugs, which
preferably target
the same epitope, can be delivered either as a mixture or subsequently to the
patient.
Alternatively, two different targeting moieties, antibodies, can be used which
localize to
the same site, e.g., to different epitopes on the same cell. Both drugs will
target the tumor
and therefore will be in close proximity to each other on the tumor so that
effective
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radiation and radiosensitization is possible. The proximity might, however,
not be as
close as in the first example, where radiolabel and radiosensitizer are
combined in one
molecule and therefore not only co-localize on the tumor but also attach to
the very same
tumor cell.
Instead of using a chelator for binding a radiosensitizing moiety, other
radiosensitizing
moieties well known in the art might be used. Examples for other
radiosensitizing
moieties which might be attached to the drug include iodine atoms or iodine-
containing
moieties, e.g. triiodobenzene derivatives, or boron atoms or boron-containing
moieties
such as boranes or carboranes. However, any other radiosensitizing moiety
known in the
field might be used as well, e.g. platinum-containing moieties, imidazoles or
others.
Instead of coupling the radiosensitizing moiety directly to the radiolabeled
drug, an
analogue of the radiolabeled drug might be synthesized such that the
radiolabel-
containing part is exchanged for a moiety containing the radiosensitizer, i.e.
an analogue
of the radiolabed drug where a radiosensitizer is in the place of the
radiolabel. This means
that the antibody of the above-mentioned example would contain a
radiosensitizer moiety
coupled to it.
However, this principle does not exclusively work with antibodies but also
with other
carriers such as any biopolymer, polymer, liposome or micelle preparation.
Even non-
polymeric drugs big enough to carry an additional moiety can be utilized for
this
principle. For example paclitaxel might be modified such that it contains a
chelator
coupled to it via a linker. The chelator then could bind a radiolabel, e.g.
yttrium-90 and/or
a radiosensitizing metal ion such as gadolinium.
Further examples would include chelates themselves that are not coupled to any
other
drugs but which are drugs on its own. In this case the chelates would bind
both the
radioisotope and the radiosensitizing metal ion, not necessarily in the same
molecule, but
in the same solution or in a separate preparation.
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Instead of using radioisotopes attached to the carrier drug via chelates, the
radioisotopes
might be attached to the carrier drug directly for example by radioiodination
of an
antibody. In this case, the same procedure for preparation might be used to
couple non-
radioactive iodine to the antibody which then functions as a radiosensitizer.
This could be
done in the same molecule by simply adding non-radioactive iodine to the
radioisotope
which is used for radioiodination or by coupling non-radioactive iodine to the
antibody.
Alternatively, the radiosensitizing potential can be increased by not only
coupling single
iodine atoms to the drug molecule but iodine carriers such as triiodobenzene
derivatives.
The agents) can be used in the same doses and in the same regimens as for the
non-
sensitized agent, but lower doses may also be used as a result of the
sensitization. When
two molecules are involved, they can be administered simultaneously or
sequentially in
either order. In the latter case one, e.g., the radiosensitizing agent is
administered shortly
before the other, e.g., the radioactive drug, e.g., about 15-60 minutes
before, longer and
shorter times also being possible.
All molecules discussed herein can be prepared conventionally by well known
labeling,
linking, chelating etc., techniques, e.g., as documented in the cited
references and others.
Without further elaboration, it is believed that one skilled in the art can,
using the
preceding description, utilize the present invention to its fullest extent.
The following
preferred specific embodiments are, therefore, to be construed as merely
illustrative, and
not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth
uncorrected
in degrees Celsius and, all parts and percentages are by weight, unless
otherwise
indicated.
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Examples
Example 1
Radiolabeling of Ibritumomab tiuxetan (Zevalin) with 9°Y is performed
according to the
procedure described in W00052031.
Gd-labeled Zevalin (Gd-Zevalin) is synthesized accordingly using a solution of
GdCl3
instead of YC13. Alternative methods for reacting GdCl3 with a chelator have
been
described in the literature and persons skilled in the art are familiar with
these
procedures.
Subsequently, both solutions are injected independently into a patient.
Example 2
Radiolabeling of Zevalin with 9°Y and Gd is performed according to the
procedure
described in example 1.
Subsequently, both solutions are mixed with each other and the mixture is then
injected
into a patient.
Example 3
Radiolabeling of Zevalin with 9°Y and Gd is performed by mixing the
solutions of YC13
and of GdCl3 each other and using this mixture for labeling of Zevalin.
Optimal binding
of Gd and 9°Y is obtained when both lanthanides are present on an
equimolar basis. Since
YC13 normally is used carrier-free, a non-radioactive Y isotope might be
added.
Subsequently, the solution is injected into a patient.
Example 4
Polymers with attached chelates are synthesized as described for example in
US2003206865 or in W003013617. Labeling of these polymers with 9°Y
and Gd is
performed according to procedures described in the literature.
9
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Example 5
Liposomes with radiosensitizers attached to the surface are prepared as
described in
W00045845. 9°Y-DTPA is present during the preparation and is
subsequently enclosed
within the liposomes, which now contain a radiolabeled drug within the
micelles and a
radiosensitizer on its surface. US6475515 describes in detail how to prepare
liposomes
containing chelates.
The entire disclosures of all applications, patents and publications, cited
herein and of
corresponding U.S. Provisional Application Serial No. 60/528,473, filed
December 11,
2003 is incorporated by reference herein.
The preceding examples can be repeated with similar success by substituting
the
generically or specifically described reactants and/or operating conditions of
this
invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain
the essential
characteristics of this invention and, without departing from the spirit and
scope thereof,
can make various changes and modifications of the invention to adapt it to
various usages
and conditions.
