Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Animal or plant cell
Reexamination Certificate
1998-11-23
2001-09-25
Bansal, Geetha P. (Department: 1642)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Animal or plant cell
C424S093710, C424S136100, C424S137100, C424S130100
Reexamination Certificate
active
06294167
ABSTRACT:
Pharmaceutical compositions for immunotherapy containing antibodies which specifically recognize the MHCII-antigen of a patient to be treated
The present invention relates to pharmaceutical compositions for immunotherapy, containing antibodies which specifically recognize the MHCII-antigen of a patient to be treated, or antibodies with one or more specificities which have at least one antigen-binding site which specifically recognizes the MHCII-antigen of a patient to be treated, and their use for preparing pharmaceutical compositions for immunotherapy. The herein described pharmaceutical compositions and antibodies are in particular suitable for immunotherapy after MHCII-incompatible bone marrow transplantation (KMT).
Bone marrow transplantation as such suggests itself as sufficient therapy for leukemic patients suffering from a recurrence of leukemia in spite of chemotherapy. Bone marrow transplantations permit long term remissions and curing, with the result that patients live 20 years and longer and can be considered to have been cured. However, many patients who have undergone bone marrow transplantation still die from leukemia recidivation, the metastatic spread of the original leukemia. Obviously, the reason therefor is that the irradiation of the whole body and the highly dosed chemotherapy which precede the transplantation of intact bone marrow to compensate for the patient's lost blood formation, are often insufficient to permanently eliminate the last malign leukemic cells. Within the last 14 years, no substantial progress in the reduction of the percentage of the patients with leukemia recidivation after bone marrow transplantation has been made. The therapeutical possibilities to date seem to be exhausted in this respect. New approaches to possible therapies to eliminate residual leukemic cells surviving chemotherapy and irradiation consider in particular a tumor-immunological cell therapy which should make use of antibodies recognizing cell markers which are specifically present on leukemic cells. A substantial, so far unsolved problem consists in the fact that it has not been possible to identify any tumor-specific marker antigens by which leukemic cells could be distinguished from non-malign blood cells (Kranz et al., Blood 73 (1989), 1942). Only B-cell tumors form individual-specific, idiotypical immunoglobulins which (relative to an individual patient) can be considered tumor-specific antigens. As investigations with chemically conjugated, bispecific antibodies have shown, these immunoglobulins on the cells tend to undergo modulation and mutation, thereby eluding recognition by antibodies specifically directed against them (Stevenson et al., Blood 77 (1991), 1071). Therefore, the knowledge existing to date is insufficient to eliminate leukemia cell clones by immunological cell therapy.
Hence, the present invention addresses the problem of providing antibodies and pharmaceutical compositions containing the same which allow particular target cells, in particular tumor cells, to be distinguished from other cells on account of the recognition of specific marker antigens, and which are therefore suitable for an immunological cell therapy.
This problem is solved by the provision of the embodiments characterised in the patent claims.
Thus, the present invention relates to pharmaceutical compositions containing antibodies having at least one specificity for the MHCII-antigen of the patient to be treated.
Such pharmaceutical compositions lend themselves to the in vivo and in vitro therapy of different tumor types and the suppression of host-versus-graft-reactions and autoimmune reactions and are suitable to generally elicit immunosuppression. They can, for instance, be used for immunological cell therapy in tumor recidivation after MHCII incompatible bone marrow transplantation, that is transplantation in which the donor's MHCII antigen differs from the receiver's. As described above, bone marrow transplantation is often resorted to as a last means to fight chemotherapy-resistant types of leukemia. Of these, especially B-cell lymphomas, but also other types of leukemia which derive from cells resulting from hematopoiesis frequently express the histocompatibility antigen MHCII. This surface antigen is highly polymorphous, and the different types can be recognized by specific antibodies. As all immunocompetent cells (from the donor) growing in the patient after an MHCII incompatible bone marrow transplantation possess an MHCII type different from that of the tumor, the tumor can be highly selectively identified and eliminated by antibodies recognizing the receiver's MHCII type. It is true that apart from the cells of the immunological system there are other types of cells which express MHCII-antigen, such as the liver cells, but the expression and antigen population on the cell surface is so low with these cell types compared to malign cells of the immunological system that a specific recognition of the tumor cells which express MHCII-antigen is ensured and other cells or tissues are not damaged by MHCII specific antibodies to any appreciable degree.
Not only hematopoietic cells of the immunological system but also cells of the epithelium (for instance insulin-producing cells of the Langerhans isles in the pancreas) and cells of the endothelium, especially in the degenerated state, or after stimulation express the MHCII-antigen in different forms. The proposed pharmaceutical compositions therefore also lend themselves to the immunotherapy of tumors deriving from such cells.
Apart from the use for tumor immunotherapy, the pharmaceutical compositions of the invention also lend themselves for instance to immunotherapy for attenuating or suppressing a host-versus-graft reaction. After an allogenic bone marrow transplantation, any residual MHCII positive cells of the receiver that have survived the patient's conditioning (for instance irradiation, chemotherapy) may lead to a graft rejection in the form of a host-versus-graft-reaction. Anti-MHCII antibodies (of the receiver's type) allow such immunocompetent cells of the receiver which prevent the “engraftment” (that is to say, taking, growing) of the new bone marrow or other donor organs, to be selectively attacked. The use of antibodies which apart from the receiver's MHCII-antigen recognize an antigen expressed on an immunocompetent MHCII positive cell, allows cells responsible for the rejection of the graft to be even more selectively eliminated.
Pharmaceutical compositions containing antibodies which specifically recognize activated T-cells, are for instance suitable to treat autoimmune reactions or lend themselves in general to selective immunosuppression.
The antibodies contained in the pharmaceutical compositions of the invention, may be antibodies possessing only one or more specificities. The term “specificity” as used herein means an antibody's capability of recognizing a particular antigen. The antigen can be recognized by one or more antigen binding sites of an antibody, and the binding sites are in turn able to recognize the same or different epitopes of the antigen.
In a preferred embodiment of the present invention the pharmaceutical compositions contain antibodies with one specificity only, which recognize the MHCII-antigen of a patient to be treated, that is to say the pharmaceutical compositions contain so-called monospecific antibodies. The use of such antibodies allows the elimination of MHCII-presenting cells, for instance by complement reactions or antibody-mediated cytotoxicity by means of Fc-receptor-carrying cells. The prerequisite therefor is that the antibodies that are used have an Fc-region.
Another preferred embodiment of the invention relates to pharmaceutical compositions containing antibodies with two or more specificities, one of which recognizes a patient's MHCII-antigen. In this case, one specificity recognizes the patient's MHCII-antigen, while another specificity may for instance recognize an antigen which is also present on the cell to
Lindhofer Horst
Thierfelder Stefan
Bansal Geetha P.
GSF-Forschungszentrum fur Umwelt und Gesundheit GmbH
Roylance Abrams Berdo & Goodman L.L.P.
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