Compositions and methods for modulating immune responses

Abstract

The present invention provides a newly identified B7 receptor, zB7R1 that functions as lymphocyte inhibitory receptor, which is a PD-1-like molecule and is expressed on T cells. The present invention also provides the discovery of zB7R1's ability to bind to CD155. Methods and compositions for modulating zB7R1-mediated negative signaling and interfering with the interaction of its counter-receptor for therapeutic, diagnostic and research purposes are also provided.

Description

REFERENCE TO RELATED INVENTIONS [0001] This application claims the benefit of U.S. Provisional Application Ser. No. 60 / 680,374, filed May 12, 2005, U.S. Provisional Application Ser. No. 60 / 791,626, filed Apr. 13, 2006, and U.S. Provisional Application Ser. No. 60 / 795,005, filed Apr. 26, 2006 all of which are incorporated in their entirety herein by reference.BACKGROUND OF THE INVENTION [0002] 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 targets for immunomodulatory agents. Positive costimulation, in addition to T cell receptor (TCR) engagement, is required for optimal activation of naive T cells, whereas negative costimulation is believed to be required for the acquisition of immunologic tolerance to self, as well as the termination of effector T cell functions. Upon interaction with B7-1 or B7-2 on the surface of antigen-presenting cells (APC), CD28, the...

AI Technical Summary

Benefits of technology

[0013] As disclosed for the first time herein, zB7R1 acts a negative regulator of T lymphocyte activity, wherein signaling mediated by zB7R1 results in the inhibition of zB7R1-positive lymphocyte activity. In zB7R1-positive T cells zB7R1 signaling could, for instance, inhibit TCR-induced T cell responses, such as cell cycle progression, proliferation, differentiation, survival, cytokine production and cytolytic activation. Further, in zB7R1-positive B cells, zB7R1 signaling could an inhibit B cell antigen receptor-induced B cell responses, such as cell cycle progression, proliferation, differentiation, survival, antigen presentation and antibody production. These findings enable the use of therapeutic agents capable of interfering with the interaction of zB7R1 and its counter-receptor to modulate lymphocyte activity for the purpose of treating, among other conditions, cancer and autoimmune diseases.

[0143] Different species can exhibit “preferential codon usage.” In general, see, Grantham et al., Nucl. Acids Res. 8:1893 (1980), Haas et al. Curr. Biol. 6:315 (1996), Wain-Hobson et al., Gene 13:355 (1981), Grosjean and Fiers, Gene 18:199 (1982), Holm, Nuc. Acids Res. 14:3075 (1986), Ikemura, J. Mol. Biol. 158:573 (1982), Sharp and Matassi, Curr. Opin. Genet. Dev. 4:851 (1994), Kane, Curr. Opin. Biotechnol. 6:494 (1995), and Makrides, Microbiol. Rev. 60:512 (1996). As used herein, the term “preferential codon usage” or “preferential codons” is a term of art referring to protein translation codons that are most frequently used in cells of a certain species, thus favoring one or a few representatives of the possible codons encoding each amino acid (See Table 2). For example, the amino acid threonine (Thr) may be encoded by ACA, ACC, ACG, or ACT, but in mammalian cells ACC is the most commonly used codon; in other species, for example, insect cells, yeast, viruses or bacteria, different Thr codons may be preferential. Preferential codons for a particular species can be introduced into the polynucleotides of the present invention by a variety of methods known in the art. Introduction of preferential codon sequences into recombinant DNA can, for example, enhance production of the protein by making protein translation more efficient within a particular cell type or species. Therefore, the degenerate codon sequences disclosed herein serve as a template for optimizing expression of polynucleotides in various cell types and species commonly used in the art and disclosed herein. Sequences containing preferential codons can be tested and optimized for expression in various species, and tested for functionality as disclosed 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.