Compositions and methods for modulating lymphocyte activity

Abstract

The present invention provides a novel lymphocyte inhibitory receptor termed BTLA which is expressed on both T and B cells, and identifies B7 family member B7x as interacting with BTLA to attenuate lymphocyte activity. Methods and compositions for modulating BTLA-mediated negative signaling and interfering with the interaction of BTLA and B7x for therapeutic, diagnostic and research purposes are also provided.

Description

STATEMENT OF RELATED APPLICATIONS[0001]This application is a continuation of U.S. application Ser. No. 11 / 875,537, filed Oct. 19, 2007 which is a divisional of U.S. application Ser. No. 10 / 600,997, filed Jun. 20, 2003 which claims priority under 35 U.S.C. §119 to U.S. Provisional Patent Application Ser. No. 60 / 390,653, filed Jun. 20, 2002, and to U.S. Provisional Patent Application Ser. No. 60 / 438,593, filed Jan. 6, 2003, the disclosures of which are expressly incorporated herein in their entirety by reference.FIELD OF THE INVENTION[0002]The present invention relates to immunomodulatory compositions and methods, and in particular, to novel lymphocyte regulatory molecules as well as compositions and methods exploiting the same for therapeutic, diagnostic and research purposes.BACKGROUND OF THE INVENTION[0003]Positive and negative costimulatory signals play critical roles in the modulation of T cell activity, and the molecules that mediate these signals have proven to be effective tar...

AI Technical Summary

Benefits of technology

[0017]Also disclosed for the first time herein is the identification of the new B7 family member B7x as a ligand for BTLA, as well as the previously unrecognized ability of B7x to negatively regulate B and T lymphocyte activity through its interaction with BTLA. The interaction of B7x with BTLA inhibits both B and T cell responses, and is a means by which B7x-positive tumor tissue inhibits the activity of tumor-specific T cells. Further, the present disclosure establishes that B7x is also expressed on non-tumor non-lymphoid tissue, thus identifying the B7x / BTLA interaction as a mechanism for maintaining immunological tolerance. These novel findings enable the use of therapeutic agents capable of interfering with the interaction of BTLA and B7x to modulate lymphocyte activity for the purpose of treating, among other conditions, cancer and autoimmune diseases.

[0037]In another preferred embodiment, bioactive agents and methods for mimicking or enhancing the interaction of B7x-positive non-tumor non-lymphoid cells with BTLA-positive T cells are provided, thereby decreasing T cell activity. In an especially preferred embodiment, the T cell is a CD4+ T cell or a CD8+ T cell. In a further embodiment, the CD4+ T cell is a Th1 cell.

[0038]In a further aspect, methods for treating cancers characterized by the presence of B7x-expressing tumor cells are provided. In one embodiment, these methods comprise administering to a mammalian subject at least one of the antagonists of BTLA-mediated signaling disclosed herein, either alone or in conjunction with alternative cancer immunotherapy, chemotherapy and / or radiotherapy protocols. In a preferred embodiment, at least one BTLA or B7x blocking agent is administered to a subject having B7x-positive tumor cells, wherein said blocking agent is capable of interfering with the interaction of BTLA and B7x and inhibiting BTLA-mediated signaling. Preferably, administration of said blocking agents is effective to increase T cell activity directed against tumor antigens other than B7x on the tumor cells, and in particular, to increase cytotoxic T cell activity. Still more preferably, administration of the subject antagonists is effective to inhibit the growth of the B7x-expressing tumor cells.

[0040]In a further aspect, methods for treating autoimmune disorders characterized by the absent or aberrant expression of B7x in non-tumor non-lymphoid host cells subjected to autoimmune attack are provided. In one embodiment, these methods comprise administering to a mammalian subject at least one of the agonists of BTLA-mediated signaling disclosed herein, either alone or in conjunction with alternative immunotherapy and / or immunosuppressive protocols. In a preferred embodiment, at least one BTLA or B7x mimicking agent is administered to a subject having autoreactive BTLA-positive lymphocytes, wherein said mimicking agent is capable of replacing and / or augmenting the interaction of BTLA and B7x and replacing or increasing BTLA-mediated signaling. Preferably, administration of said mimicking agents is effective to decrease autoreactive lymphocyte activity directed against non-tumor non-lymphoid host cells, and particularly autoreactive CD8+ CTL and CD4+ Th1 activity, and B cell activity.

[0041]In a still further aspect, methods for improving the outcome of organ and tissue transplantation and prolonging graft survival are provided. In one embodiment, these methods comprise administering to a transplant recipient at least one of the agonists of BTLA-mediated signaling disclosed herein, either alone or in conjunction with alternative immunotherapy and / or immunosuppressive protocols. In a preferred embodiment, at least one BTLA or B7x mimicking agent is administered to the transplant recipient, wherein said mimicking agent is capable of replacing and / or augmenting the interaction of BTLA and B7x and replacing or increasing BTLA-mediated signaling. Preferably, administration of said mimicking agents is effective to decrease the recipient immune response against donor antigens present in the graft, particularly the cytolytic CTL response and the B cell response. Still more preferably, administration of the subject mimicking agents is effective to bias to T helper cell response from an unfavorable Th-1 type response to a more favorable Th-2 type response, as described in more detail herein.

Problems solved by technology

In addition, immune responses to many different antigens (e.g., microbial antigens or tumor antigens), while detectable, are frequently of insufficient magnitude to afford protection against a disease process mediated by agents (e.g., infectious microorganisms or tumor cells) expressing those antigens.

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