Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Structurally-modified antibody – immunoglobulin – or fragment...
Reexamination Certificate
1999-08-17
2001-07-24
Saunders, David (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Structurally-modified antibody, immunoglobulin, or fragment...
C424S192100, C424S193100, C424S194100, C435S069100, C435S325000, C435S328000, C530S350000, C530S387300, C530S391100, C530S413000, C530S416000, C530S417000, C530S412000, C530S868000, C514S008100, C514S885000
Reexamination Certificate
active
06264950
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a product and process for immunosuppression of subjects having undesired immunological reactivities and in subjects in need of cell, tissue or organ transplant survival. More particularly, the present invention relates to a T lymphocyte veto molecule (hereinafter defined) and the use of such a molecule as an immunoregulator to effect therapeutic objectives.
BACKGROUND OF-THE INVENTION
A wide variety of medical treatments require regulation of the immune response in a patient. Such treatments include, for example, vaccinations, treatments for autoummune diseases, immunodeficiency diseases, immunoproliferative diseases and treatments involving the transplantation of organs and skin. Traditional reagents and methods used to regulate a subject's immune response often results in unwanted side effects. For example, immunosuppressive reagents such as cyclosporin A, azathioprine and prednisone are used to suppress the immune system of a patient with an autoimmune disease or patients receiving transplants. Such reagents, however, suppress a patient's entire immune response, thereby crippling the ability of the patient to mount an immune response against infectious agents not involved in the original disease. Due to such harmful side effects and the medical importance of immune regulation, reagents and methods to regulate specific parts of the immune system have been the subject of study for many years.
Introduction of an antigen into a host initiates a series of events culminating in an immune response. In addition, self-antigens can result in immunological tolerance or activation of an immune response against self-antigens. A major portion of the immune response is regulated by the interaction of a stimulator cell (defined in detail below) with a responding cell (defined in detail below).
Particular reagents having immunoregulatory potential of cell to cell interactions have been suggested by various investigators. Tykocinski et al. disclose in U.S. Pat. No. 5,242,687, issued Sep. 7, 1993, a composition comprising a CD8 peptide associated with a secondary ligand, including an Fc domain of immunoglobulin or a major histocompatibility molecule (MHC). Tykocinski et al. do not teach or suggest such a composition involving CD4, CD2, CD28, CTLA4 or fas-ligand proteins which are known to have significantly different functions in various immunity mechanisms.
In U.S. Pat. No. 5,336,603, issued Aug. 9, 1994, Capon et al. disclose “immunoadhesons” useful for immunomodulatory therapy. Capon et al. disclose adhesons as cell surface polypeptides, examples of which include CD8, CD4 and CD2, that can be combined with an immunologically active non-adheson polypeptide. Capon et al., however, do not teach or suggest a T cell veto molecule useful for immunosuppression and particularly a molecule that prevents the specific activation of responding cells by stimulator cells to suppress an immune response.
As such, there remains a need for therapeutic reagents and strategies that suppress an immune response in a safe and effective manner.
SUMMARY
The present invention relates to a novel product and process for treatment of subjects in need of the abrogation of immunological reactivities. According to the present invention there are provided soluble or membrane-bound T lymphocyte veto molecules for immunosuppression in vivo or in vitro. The present invention overcomes traditional problems with immunoregulatory reagents by specifically regulating stimulator cell activation of responding cells capable of killing transplanted cells or capable of responding to autoantigens. This act of regulation is referred to herein as T cell veto. A molecule capable of T cell veto is referred to herein as a T cell veto molecule. In addition, the immunoregulatory reagents of the present invention can be administered locally, thereby alleviating problems that arise from extensive immunosuppression in an animal.
More specifically, one embodiment of the present invention includes a T lymphocyte veto molecule which includes a chimeric molecule having a protein selected from the group consisting of CD4 protein, CD2 protein, CD28 protein, CTLA4 protein, Fas-ligand protein, CD5 protein, CD7 protein, CD9 protein, CD11 protein, CD18 protein, CD27 protein, CD43 protein, CD45 protein, CD48 protein, B7.1 protein and B7.2 protein. The protein is linked to a targeting polypeptide that binds to a molecule that differentiates a host cell from a tissue graft cell. A further embodiment of the present invention is a T lymphocyte veto molecule which includes a chimeric molecule having one of such proteins. In this embodiment, the protein is linked to a targeting polypeptide that binds to a molecule which selectively targets a stimulator cell involved in an autoimmune response. In further aspects of these embodiments, the targeting polypeptide can be an immunoglobulin molecule, a growth factor or a tissue specific antigen. Such T lymphocyte veto molecules can be included in therapeutic compositions which also include pharmaceutically acceptable carriers.
A further embodiment of the present invention includes a recombinant cell, which has a first recombinant molecule having a nucleic acid molecule operatively linked to an expression vector, wherein the nucleic acid molecule has a sequence which encodes one of the proteins mentioned above. The recombinant cell further includes a second recombinant molecule having a nucleic acid molecule operatively linked to an expression vector wherein the nucleic acid molecule encodes a protein which is a targeting molecule that differentiates between a host cell and a tissue graft cell.
A further aspect of the present invention includes a method for producing a T lymphocyte veto molecule. This method includes providing a first protein as mentioned above, providing a second protein which is a targeting molecule that differentiates a host cell from a tissue graft cell, and linking the first protein to the second protein to form a chimeric molecule.
The present invention also includes a method to suppress an immune response which includes exposing chimeric molecules of the present invention to a stimulator cell that can interact specifically with the chimeric molecule under conditions for reduction of an immune response.
A further aspect of the present invention is a method to alleviate tissue transplant rejection. This method includes administering to an animal an effective amount of a therapeutic composition which includes a T lymphocyte veto molecule of the present invention.
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DeCloux Amy
National Jewish Medical and Research Center
Saunders David
Sheridan & Ross P.C.
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