Antibodies against T cells as therapeutics

Details Antibodies against T cells as therapeutics Antibodies against T cells as therapeutics

1998-08-14

2001-09-18

Chan, Christina Y. (Department: 1644)

Drug, bio-affecting and body treating compositions

Immunoglobulin, antiserum, antibody, or antibody fragment,...

C424S133100, C424S154100, C530S387100, C530S387300, C530S388100, C530S388750, C530S868000

Reexamination Certificate

active

06290955

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to antibodies against T cells which are useful as therapeutic agents for prolonging immunosuppression and for tumor cell elimination.
BACKGROUND OF THE INVENTION
Heretofore, transplant rejection has been treated with immunosuppressant agents, e.g., monoclonal, immunosuppressive antibodies against human T lymphocytes which have been generated from mice, rats or golden hamsters. However, the effect of these antibodies is limited, since the patient develops an immunoreaction to antibodies which are derived from another animal species. This results in what are called antiantibodies, which inhibit the immunosuppressive effect of the injected monoclonal antibodies. Thus, at present, e.g., patients with kidney transplants that suffer from transplant rejection crises, are usually treated with only a single antibody therapy. If another rejection crisis occurs, this treatment is usually not repeated because of the possible formation of antiantibodies.
So far, there is no clinical therapy of choice for prolonging the immunosuppressive effect of antibodies while avoiding the formation of antiantibodies. A repeated treatment with another monoclonal antibody can lead to an accelerated formation of antiantibodies (Chatenoud,
Transpl. Proc
., 25. 2(Suppl. 1):68 (1993)). In addition, patients have developed antiantibodies even against immunosuppressive antibodies that had been humanized using genetic engineering methods, i.e., where the antibodies have been substantially adapted to the patient's species, i.e., “primate species” or “species-adapted” antibodies (Isaacs et al, Lancet., 340:748 (1992)).
Experimentally, a clear prolongation of the survival time of skin transplants has been found in a mouse model, which was considered a tolerance induction. Such prolongation was observed after the injection of high doses of a rat antibody directed to mouse T(L3T4+Lyt−2) cells, followed by injection of a second antibody of the same species and the same cell binding specificity, which, however, differed from the first antibody by its low elimination of T cells from the blood circulation of the mouse (a “non-depleting”, i.e., eliminating antibody). Unlike the present invention, the described principle of action therein was not based on a combined therapy of at least two antibodies with species-different Fc regions (Cobbold et al,
Eur. J. Immunol
., 20:2747 (1990)).
Prolonged survival time of skin transplants and lack of formation of antiantibodies, were also found after the injection of a rat anti-mouse T(L3T4=CD4+lymphocyte subpopulation)-cell antibody, followed by injection of (Fab′)
2
fragments and unfragmented monoclonal hamster anti-mouse T(CD3) antibodies (Hirsch et al,
Transplantation
, 47:853 (1989)). Here, too, the described principle of action is not based on a combined therapy of two antibodies having species-different Fc regions that are directed to all T cells, as in the present invention, but, rather, on the suppression of the CD4+T lymphocyte subpopulation (Hirsch et al,
J. Immunol
., 140:3766 (1988)) achieved by means of the first antibody, which is, however, not sufficient.
Permanent tolerance of skin transplants can be achieved in irradiated mice after transplantation of bone marrow of the donor of the skin transplant, while protecting anti-T cell antibodies (Thierfelder et al,
Blood
, 68:818 (1986)). However, this technique involves risks.
So far, there is no therapy of choice for definitely preventing the formation of antiantibodies in a patient in the case of conventional poly- or monoclonal immunosuppressive antibodies. The first clinical experiences with antibodies that have recently been humanized by means of genetic engineering show that antiantibodies may be formed (Isaacs et al, supra) similarly to what was seen with murine immunosuppressive anti-mouse T cell antibodies (Kremmer et al,
Eur. J. Immunolp
., 23:1017 (1993)).
Also, a combination of immunosuppressive antibody treatment with chemotherapy, e.g., cyclophosphamide or busulfan, involves the risk of side-effects, particularly on hematopoiesis, and, also, on the transplanted tissue, due to lack of cell specificity of the chemotherapeutic agents (Cobbold et al, supra; and Leong et al,
Eur. J. Immunol
., 22:2825 (1992)).
SUMMARY OF THE INVENTION
An object of the present invention is to provide antibodies for clinical therapy for prolonging the immunosuppressive antibody effect, while avoiding the formation of antiantibodies.
The above-described object of the present invention has been met by the use of antibodies against T cells as a therapeutic for prolonged immunosuppression and tumor cell elimination, wherein the antibodies consist of at least two different groups A, B, which are administered at different times and in which at least one antibody type of group B differs from at least one antibody type of group A in the constant regions of their heavy chains, and wherein group A, which is first applied once or several times, has a T-cell eliminating effect, whereas the other group B (which is applied at a different time) has a T-cell eliminating and/or T-cell antigen modulating effect.


REFERENCES:
patent: 0336379 (1989-04-01), None
Lockwood, CM et al. Lancet 341:1620-22, Jun. 1993.*
Mathieson, PW et al. New Eng. J. Med. 323(4):250-254, Jul. 1990.*
Vandervegt et al,J. Exp. Med., 177:1587-1592 (1993).
Kremmer et al,Trans. Proc., 25(1):842-843 (1993).
Harlow et al,In Antibodies: A Laboratory Manual, Harlow and Lanes, eds., Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, pp. 354-355 (1988).
International Search Report vol. 140/No. 11/Jun. 1, 1998, Baltimore U.S.
Eur. J. Immunol., 23(5):1017-1022 (1993), Coden:EJIMAF; ISSN: 0014-2980.
Eur. J. Immunol., 24(10):2323-2328 (1994), Coden:EJIMAF; ISSN:0014-2980.
XIVTH International Congress of the Transplantation Society, Paris, France, Aug. 16-21, 1992.

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