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  Compositions and methods for modulating immune responsesUSPTO Application #: 20070054360Title: 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. (end of abstract)
Agent: Zymogenetics, Inc. Intellectual Property Department - Seattle, WA, US Inventors: Zeren Gao, Steven D. Levin, Janine Bilsborough, James W. West, Cameron S. Brandt, Frederick J. Ramsdell, Edward D. Howard, Erick M. Chadwick USPTO Applicaton #: 20070054360 - Class: 435069100 (USPTO) Related Patent Categories: Chemistry: Molecular Biology And Microbiology, Micro-organism, Tissue Cell Culture Or Enzyme Using Process To Synthesize A Desired Chemical Compound Or Composition, Recombinant Dna Technique Included In Method Of Making A Protein Or Polypeptide The Patent Description & Claims data below is from USPTO Patent Application 20070054360. Brief Patent Description - Full Patent Description - Patent Application Claims
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 prototypic T cell costimulatory molecule, emits signals that promote T cell proliferation and differentiation in response to TCR engagement, while the CD28 homologue cytotoxic T lymphocyte antigen-4 (CTLA-4) mediates inhibition of T cell proliferation and effector functions (Chambers et al., Ann. Rev. Immunol., 19:565-594, 2001; Egen et al., Nature Immunol., 3:611-618, 2002). [0003] Several new molecules with homology to the B7 family have been discovered (Abbas et al., Nat. Med., 5:1345-6,1999; Coyle et al., Nat. Immunol., 2: 203-9, 2001; Carreno et al., Annu. Rev. Immunol., 20: 29-53, 2002; Liang et al., Curr. Opin. Immunol., 14: 384-90, 2002), and their role in T cell activation is just beginning to be elucidated. These new costimulatory counter-receptors include B7h2, PD-L1, PD-L2, B7-H3 and B7-H4. [0004] B7h2 (Swallow et al., Immunity, 11: 423-32, 1999), also known as B7RP-1 (Yoshinaga et al., Nature, 402: 827-32, 1999), GL50 (Ling, et al., J. Immunol., 164:1653-7, 2000), B7H2 (Wang et al., Blood, 96: 2808-13, 2000), and LICOS (Brodie et al., Curr. Biol., 10: 333-6, 2000), binds to inducible costimulator (ICOS) on activated T cells, and costimulates T cell proliferation and production of cytokines such as interleukin 4 (IL-4) and IL-10. [0005] PD-L1 (Freeman et al., J. Exp. Med., 192: 1027-34, 2000), also known as B7-R1 in humans (Dong et al., Nat. Med., 5, 1365-9, 1999), and PD-L2 (Latchman et al., Nat. immunol., 2: 261-8, 2001), also known as B7-DC (Tseng et al., J. Exp. Med., 193, 839-46, 2001) bind to programmed death 1 (PD-1) receptor on T and B cells, although at present the function of these interactions is controversial. Some reports have demonstrated that PD-L1 and PD-L2 have inhibitory effects on T cell responses (Freeman et al., J. Exp. Med., 192: 1027-34, 2000; Latchman et al., Nat. Immunol., 2: 261-8, 2001), while others have shown that both counter-receptors (B7-R1 and B7-DC) positively regulate T cell proliferation and specifically enhance IL-10 or interferon gamma (IFN-.gamma.) production (Dong et al., Nat. Med., 5, 1365-9, 1999; Tseng et al., J. Exp. Med., 193, 839-46, 2001). [0006] Finally, B7-H3 and B7-H4, both newly identified B7 homologues, bind an as yet currently unknown counter-receptor(s) on activated T cells, and are reported to enhance proliferation of CD4+ T helper (Th) cells and CD8+ cytotoxic T lymphocytes (CTLs or Tcs) and selectively enhance IFN-.gamma. expression (Chapoval et al., Nat. Immunol., 2, 269-74, 2001; Sun et al., J. Immunol., 168, 6294-7, 2002). [0007] With the exception of PD-1 counter-receptors, which show some expression on non-lymphoid tissues, the expression of known B7 family members is largely restricted to lymphoid cells. Collectively, these studies have revealed that B7 family members are counter-receptors on lymphoid cells that interact with cognate receptors on lymphocytes to provide positive or negative costimulatory signals that play critical roles in the regulation of cell-mediated immune responses. [0008] In particular, many autoimmune disorders are known to involve autoreactive T cells and autoantibodies. Agents that are capable of inhibiting or eliminating autoreactive lymphocytes without compromising the immune system's ability to defend against pathogens are highly desirable. Conversely, many cancer immunotherapies, such as adoptive immunotherapy, expand tumor-specific T cell populations and direct them to attack and kill tumor cells (Dudley et al., Science 298:850-854, 2002; Pardoll, Nature Biotech., 20:1207-1208, 2002; Egen et al., Nature Immunol., 3:611-618, 2002). Agents capable of augmenting tumor attack are highly desirable. 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. It is often desirable to administer to the subject, in conjunction with the antigen, an adjuvant that serves to enhance the immune response to the antigen in the subject. It is also desirable to inhibit normal immune responses to antigen under certain circumstances. For example, the suppression of normal immune responses in a patient receiving a transplant is desirable, and agents that exhibit such immunosuppressive activity are highly desirable. [0009] Costimulatory signals, particularly positive costimulatory signals, also play a role in the modulation of B cell activity. For example, B cell activation and the survival of germinal center B cells require T cell-derived signals in addition to stimulation by antigen. CD40 counter-receptor present on the surface of helper T cells interacts with CD40 on the surface of B cells, and mediates many such T-cell dependent effects in B cells. Interestingly, negative costimulatory receptors analogous to CTLA-4 have not been identified on B cells. This suggests fundamental differences may exist in the way T cells and B cells are induced to respond to antigen, which has implications for mechanisms of self-tolerance as well as the inhibition of B cell effector functions, such as antibody production. Were a functional CTLA-like molecule to be found on B cells, the finding would dramatically shift our understanding of the mechanisms of B cell stimulation. Further, the identification of such receptors could provide for the development of novel therapeutic agents capable of modulating B cell activation and antibody production, and useful in the modulation of immunologic responses. [0010] Accordingly, there is a need in the art for the identification of additional B7 family members, their counter-receptors and molecules derived therefrom, that have either or both a T cell costimulatory activity and/or a B cell costimulatory activity . This need is based largely on their fundamental biological importance and the therapeutic potential of agents capable of affecting their activity. Such agents capable of modulating costimulatory signals would find significant use in the modulation of immune responses, and are highly desirable. [0011] The present invention provides such polypeptides for these and other uses that should be apparent to those skilled in the art from the teachings herein. DETAILED DESCRIPTION OF THE INVENTION 1. OVERVIEW [0012] The present invention is directed to the identification and characterization of zB7R1, a novel inhibitory lymphocytic receptor, and the discovery of its ability to bind to CD155 (PVR). Thus, the present invention provides a newly identified B7 receptor that is a PD-1-like molecule and is expressed in T lymphocytes. The novel receptor of the present invention is denominated "zB7R1" and is distinct from CD28, CTLA-4, ICOS, PD-1 and zB7R1. Methods and compositions for modulating zB7R1-mediated lymphocyte signaling such as, e.g., modulating the natural interaction of zB7R1 and its counter-receptor are also provided, having multiple therapeutic applications for immunological tolerance, autoimmunity, immunosuppression, and immunotherapy including cancer immunotherapy. [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. [0014] CD155 (PVR) was identified as the counterstructure for ZB7r1. CD155 has been reported to be the counterstructure for at least 2 other receptors including CD226 (DNAM-1) and CD96 (Tactile). CD226 and CD96 have been shown to be activating receptors expressed on T cells and NK cells and CD155 can trigger activation through these molecules. CD155 has been reported to be widely expressed in non-hematopoietic tissues and may be overexpressed in a large number of tumors and transformed cell types. The role of CD155 on T cell responses to these tumors is mostly CD155's engagement of zB7R1 which suppresses T and NK cell responses to the tumor. Thus, a reagent that blocks zB7R1-CD155 interaction, including blocking antibodies to either molecule, or soluble forms of either protein, will facilitate T and NK cell responses to the tumor by eliminating or minimizing the inhibitory signal through ZB7r1. Because of the demonstrated inhibitory effect of engaging zB7R1 on T cells with agonistic antibodies as shown herein, agonistic anti-ZB7r1 antibodies or soluble receptors are suitable candidates to suppress T cell responses in T cell mediated inflammatory and autoimmune diseases. [0015] Accordingly, the present invention provides novel uses for zB7R1 modulators, such as zB7R1 agonists or antagonists. These modulators could be a soluble receptor or antibodies to zB7R1 or its counter-receptor, i.e. CD155. The present invention also provides soluble zB7R1 polypeptide fragments and fusion proteins, for use in human inflammatory and autoimmune diseases. The zB7R1 antibodies, and soluble zB7R1 receptors of the present invention, can be used to modulate, agonize, block, increase, inhibit, reduce, antagonize or neutralize the activity of either zB7R1 or its counter-receptor(s) (i.e. CD155) in the treatment of specific human diseases such as cancer, rheumatoid arthritis, psoriasis, psoriatic arthritis, arthritis, endotoxemia, inflammatory bowel disease (IBD), colitis, and other inflammatory conditions disclosed herein. [0016] An illustrative nucleotide sequence that encodes human zB7R1 (also interchangeably known as zB7R1x1 is provided by SEQ ID NO:1; the encoded polypeptide is shown in SEQ ID NO:2. zB7R1 is a B7 receptor that binds to yet another B7 family member, or counter-receptor. Analysis of a human cDNA clone encoding zB7R1(SEQ ID NO:1) revealed an open reading frame encoding 244 amino acids (SEQ ID NO:2) comprising an extracellular domain of approximately 125 amino acid residues (residues 16-140 of SEQ ID NO:2; SEQ ID NO:3), a transmembrane domain of approximately 23 amino acid residues (residues 141-163 of SEQ ID NO:2), and an intracellular domain of approximately 81 amino acid residues (residues 164 to 244 of SEQ ID NO:2). zB7R1 also has an IgV domain of approximately 96 amino acid residues (residues 32-127 of SEQ ID NO:2). [0017] Within zB7R1, there are two ITIM domains, YFNV (amino acid residues 225-228 of SEQ ID NO:2) and YRSL (amino acid residues 231-234). The presence of an ITIM domain is an indication that zB7R1 can have an inhibitory effect. Within zB7R1, there are also two SH-3-kinase binding domains, PSAP (amino acid residues 191-194 of SEQ ID NO:2) and PSPP (amino acid residues 194-197). [0018] zB7R1 also has a polymorphism at polynucleotide 289 of SEQ ID NO:1, indicated as n, where n can be either C or T. zB7R1 also has at least a second polymorphism at polynucleotide 359 of SEQ ID NO:1, indicated as n, where n can be either A or G, and where the conversion of A to G leads to a change in the amino acid residue 117 of SEQ ID NO:2 (indicated as Xaa) from Thr to Ala. [0019] An another illustrative nucleotide sequence that encodes a variant human zB7R1 (also interchangeably known as zB7R1x2) is provided by SEQ ID NO:5; the encoded polypeptide is shown in SEQ ID NO:6. zB7R1x2 is a B7 receptor that binds to yet another B7 family member, or counter-receptor. Analysis of a human cDNA clone encoding zB7R1x2 (SEQ ID NO:5) revealed an open reading frame encoding 311 amino acids (SEQ ID NO:6) comprising an extracellular domain of approximately 182 amino acid residues (residues 27-208 of SEQ ID NO:6; SEQ ID NO:7), a transmembrane domain of approximately 22 amino acid residues (residues 209-230 of SEQ ID NO:6), and an intracellular domain of approximately 81 amino acid residues (residues 231 to 311 of SEQ ID NO:6). [0020] An illustrative nucleotide sequence that encodes a murine zB7R1 is provided by SEQ ID NO:8; the encoded polypeptide is shown in SEQ ID NO:9. The extracellular domain is shown in SEQ ID NO:10. Continue reading... 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