Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector
Reexamination Certificate
1997-12-29
2001-09-11
Borin, Michael (Department: 1631)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
C514S885000, C530S300000, C530S868000
Reexamination Certificate
active
06287563
ABSTRACT:
BACKGROUND ART
This invention relates to therapeutic agents for use in the treatment of mammalian, particularly human, autoimmune diseases. The invention also relates to therapeutic agents useful in the treatment of human leukaemias of a T cell origin, as so-called “vaccine carriers”, and as agents for use in the prevention of human transplantation rejection and graft versus host disease (GVHD).
In an article entitled “Morphologic and Functional Alterations of Mucosal T Cells by Cholera Toxin and its B subunit” by Charles O. Elson et al., The Journal of Immunology, 1995, 154; 1032-1040 it is disclosed that the cholera toxin (Ctx) and the CtxB subunit inhibit CD8
+
and CD4
+
T cells.
Reference is also made to the paper entitled “Prevention of Acute Graft-Versus-Host Disease by Treatment with a Novel Immunosuppressant” by B. Yankelevich et al., The Journal of Immunology, 1995, 154: 3611-3617. This identifies CtxB as an agent for use in bone marrow transplantation for the prevention of acute graft-versus-host disease (GVHD).
WO 95/10301 discloses an immunological tolerance-inducing agent comprising a mucosa-binding molecule linked to a specific tolerogen.
As used herein, the term “Ctx” refers to the cholera toxin and “CtxB” to the B subunit of the cholera toxin. In other texts, these may sometimes be identified as “CT” or “Ct” and “CTB” or “CtB” respectively. The term “Etx” herein means the
E. coli
heat labile enterotoxin, and “EtxB” is the B subunit of Etx. In other texts, these may sometimes be identified as “LT” or “Lt” and “LTB” or “LtB” respectively.
The basis for all aspects of the present invention is the finding that EtxB (the pure B-subunit of the
E. coli
heat labile enterotoxin) binds to GM1-ganglioside receptors which are found on the surfaces of mammalian cells, and that this binding induces differential effects on lymphocyte populations, including a specific depletion of CD8
+
T cells and an associated activation of B cells. These effects are absent when a mutant EtxB protein lacking GM1 binding activity is employed.
Autoimmune Disease
Autoimmunity is the term used to describe the mechanism by which the body generates an immune response to self-antigens.
SUMMARY OF THE INVENTION
In accordance with a first aspect of the invention, there is provided:
(i) an agent having GM-1 binding activity, other than Ctx or Etx, or the B subunits of Ctx and Etx; or
(ii) an agent having an effect on GM-1 mediated intracellular signalling events, but no GM-1 binding activity;
for use as an agent in the treatment or the prevention of an autoimmune disease.
Agents in accordance with the present invention have been found to modulate lymphocyte populations leading to the induction of apoptosis in CD8
+
T cells, the enhanced activation of CD4
+
cells and polyclonal activation of B cells. These events are likely to shift the immune response towards induction of Th2 associated cytokines. Such responses to self or cross-reacting antigens are understood to mediate protection for certain autoimmune diseases.
In a first embodiment of this first aspect of the present invention, the agent is used in a method of treating an autoimmune disease which is in progress.
In this embodiment, the agent is administered to a patient with or without co-administration of a self or cross-reacting antigen. Administration of the agent in accordance with this embodiment of the first aspect of the invention modulates the nature of the immune response towards the self-antigen away from the activation of disease-causing inflammation and hence protects against autoimmune disease.
In a second embodiment of this first aspect of the present invention, the agent is used in a method for the “vaccination” of a mammalian subject against an autoimmune disease, in which the agent is co-administered with the self or cross-reacting antigenic determinant (or a combination of different self or cross-reacting antigenic determinants) associated with said disease. In such a manner, the subject's immune response to the self-antigen or cross-reacting antigen is switched away from the activation of pathogenesis, which therefore protects against a future autoimmune response to the self-antigen.
In this first aspect of the invention, the therapeutic agent and the self or cross-reacting antigenic determinant are, or may be, co-administered to the subject. By this we mean that the site and time of administration of each of the therapeutic agent and the antigenic determinant are such that the necessary modulation of the immune system is achieved. Thus, whilst the therapeutic agent and the antigenic determinant may be administered at the same moment in time and at the same site, there may be advantages in administering the therapeutic agent at a different time and to a different site from the antigenic determinant.
Whilst single doses of the therapeutic agent and the antigenic determinant may be satisfactory, multiple doses are contemplated within the scope of this aspect of the invention.
In this second embodiment of the first aspect of the invention, the therapeutic agent and the antigenic determinant may be linked, for example covalently linked, to form a single active agent, although separate administration, in which the therapeutic agent and the antigenic determinant are not so linked is preferred because it enables separate administration of the different moieties.
Specific autoimmune diseases which may be treated in accordance with this aspect of the present invention are the autoimmune diseases where pathology is associated with cell-mediated immunity, such as rheumatoid arthritis, multiple sclerosis and diabetes.
Additionally, under this first aspect of the present invention, there is provided the use of Ctx, Etx or the B subunit of Ctx or Etx, for the manufacture of a medicament for use as an agent for the prevention of an autoimmune disease.
Also provided is a pharmaceutical composition for the treatment of a human autoimmune disease comprising
(i) an agent having GM-1 binding activity; or
(ii) an agent having an effect on GM-1 mediated intracellular signalling events, but no GM-1 binding activity;
and a pharmaceutically acceptable carrier or di-luent therefor.
The pharmaceutical composition of this aspect of the invention may be formulated to be delivered by a mucosal route, for example as a nasal spray, or parenterally in which the composition is formulated in an injectable form, for delivery by, for example, an intravenous, intramuscular or subcutaneous route.
The pharmaceutical composition may be formulated together with the appropriate self or cross-reacting antigen. Alternatively, a kit may be provided comprising separate compositions for each of the therapeutic agent and the antigenic determinant.
Specific therapeutic agents which may be used in this aspect of the invention are EtxB and CtxB or mutants thereof retaining GM1 binding activity.
The agents for use in the first aspect of the present invention should preferably be substantially non-toxic, although some degree of toxicity may be tolerated in a severe therapy of this kind.
This first aspect of the invention extends to cover the use of all agents having GM1 binding activity, for use in the treatment of mammalian autoimmune disease, as well as those agents having an effect on GM-1 mediated intracellular signalling events, and which therefore mimic GM-1 binding agents. Thus, this first aspect of the present invention is not limited to the use of EtxB protein as a therapeutic agent in the treatment of a human autoimmune disease. However, the use of the EtxB protein (which is a pentamer of five identical subunits) for such a treatment represents a preferred embodiment of the present invention. In addition to the wild type EtxB, this preferred aspect of the invention also extends to mutants of EtxB which have GM-1 binding activity as well as to other equivalent proteins, such as the cholera toxin B subunit (CtxB) and mutants thereof which have GM1 binding activity.
Other therapeutic agents for the treatment of autoimmune disease in a
Hirst Timothy Raymond
Nashar Toufic Osman
Williams Neil Andrew
Borin Michael
Krinsky Mary M.
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