VISTA: A Novel Therapeutic Target That Negatively Regulates Immunity

描述（由申请人提供）：我们已经发现，表征和功能定义了一种新的免疫抑制配体。该配体是造血表达的，是B7 ig超家族的远亲成员，其细胞外结构域与B7家族配体PD-L1具有同源性。该分子被指定为T细胞活化的v域免疫球蛋白抑制因子（VISTA）。与PD-L1不同，VISTA的表达仅在造血室内，并在髓系抗原呈递细胞（APCs）上受到高度调节。可溶性的VISTA- ig融合蛋白或VISTA在APCs上的表达深刻地抑制体外T细胞增殖和细胞因子的产生。一种特异性抗VISTA单克隆抗体在体外干扰VISTA+ APCs对VISTA诱导的T细胞反应的抑制。肿瘤微环境中骨髓抑制细胞（myeloid suppression cells， MDSC）上的VISTA表达水平极高，提示MDSC上的VISTA可能通过维持肿瘤微环境的抑制特性来阻碍肿瘤特异性免疫的发展。在小鼠膀胱癌模型中，我们发现（VISTA mab）可以逆转VISTA抑制，大大降低实体瘤生长并提高宿主存活率。由于初步观察到阻断VISTA系统地增强细胞介导的免疫，我们假设在MDSCs似乎具有免疫调节作用的实体肿瘤中，VISTA治疗将被证明特别有效。与许多其他PD-L家族成员（B7-H3, H4, H6）不同，VISTA的造血限制（优先是髓系）以及其深刻的抑制活性，以及在MDSCs上的高表达，使其成为癌症免疫干预的独特靶点。综上所述，我们的研究结果表明，VISTA在功能上是一种非冗余的免疫负调节因子。

DESCRIPTION (provided by applicant): We have discovered, characterized and functionally defined a novel, immune inhibitory ligand. This ligand is hematopoietically-expressed, a distant member of the B7 Ig-superfamily, and its extracellular domain bears homology to the B7 family ligand PD-L1. This molecule is designated as V-domain Immunoglobulin Suppressor of T cell Activation (VISTA). Distinct from PD-L1, expression of VISTA is exclusively within the hematopoietic compartment and is highly regulated on myeloid antigen-presenting cells (APCs). A soluble VISTA-Ig fusion protein, or VISTA expression on APCs profoundly inhibits in vitro T cell proliferation and cytokine production. A specific anti-VISTA monoclonal antibody interfered with VISTA-induced suppression of T cell responses by VISTA+ APCs in vitro. VISTA expression on myeloid suppression cells (MDSC) within the tumor microenvironment was expressed at extremely high levels, suggesting that VISTA on MDSCs likely impedes the development of tumor specific immunity by maintaining the suppressive character of the tumor microenvironment. In a murine model of bladder carcinoma, we show that an (VISTA mab that can reverse VISTA suppression, greatly reduced solid tumor growth and enhanced host survival. Due to the preliminary observation that blocking VISTA systemically enhances cell-mediated immunity, we hypothesize that in solid tumors where MDSCs appear to be immunomodulatory, (VISTA therapy will prove to be particularly effective. Unlike many of the other PD-L family members (B7-H3, H4, H6), the hematopoietic restriction (preferentially myeloid) of VISTA together with its profound suppressive activities, and its high expression on MDSCs, makes it a unique target for immune intervention in cancer. Taken together, our findings illustrate that VISTA is a functionally non-redundant, negative regulator of immunity. The Specific Aims of this proposal are: 1) Determine the Effect of aVISTA on Tumor Regression in Murine Models.; and 2) Produce human ahuman VISTA specific monoclonal antibodies. hVISTA-Ig will be used to select GigaMab(tm) mabs through subcontract with BioAtla. BioAtla has constructed and validated a human full length IgG library (GigaMab(tm) Fully Human library) one of the largest numbers of high diversity fully human antibodies expressed in mammalian cells. Using their proprietary bioinformatic analysis tools and rational design strategies, they are expected to maximize the combinatorial diversity of human immunoglobulin heavy and light chains in a custom library to ensure generation of high affinity antibodies. Therapeutic intervention of the VISTA inhibitory pathway represents a novel approach to modulate T cell- mediated immunity for the treatment of a wide variety of cancers. The first indication we will target is ovarian cancer, which kills 13,850 women per year in the US. PUBLIC HEALTH RELEVANCE: Inducing immunity is an effective way to eradicate disease. We have learned that the immune system has built in molecules that put the brakes on how vigorous the immune response can get. Normally, these brakes limit damage. However, if we take the brakes off, for a limited amount of time, we can induce the immune system to attack the disease more vigorously. We have discovered a new "brake" and are developing technologies to turn it off.