VISTA: A Novel Therapeutic Target That Negatively Regulates Immunity

描述(由申请人提供)：我们发现了一种新的免疫抑制配体，并对其进行了表征和功能定义。该配体是造血表达的，是B7免疫球蛋白超家族的远亲成员，它的胞外区与B7家族的配体PD-L1同源。该分子被命名为V域免疫球蛋白T细胞激活抑制因子(VistA)。与PD-L1不同，VistA的表达仅在造血室内，并受髓系抗原提呈细胞(APC)的高度调控。一种可溶性的Vista-Ig融合蛋白，或在APC上的VistA表达，在体外可以深刻地抑制T细胞的增殖和细胞因子的产生。一种特异性的抗Vista单抗在体外干扰Vista诱导的Vista APC抑制T细胞反应。肿瘤微环境中髓系抑制细胞(MDSC)上VistA的表达水平极高，提示MDSC上的VistA可能通过维持肿瘤微环境的抑制性而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单抗可以逆转Vista抑制，大大减少实体瘤的生长，提高宿主生存。由于初步观察到阻断Vista可系统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疗法将被证明特别有效。与其他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，以及其在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，我们的发现说明Vista在功能上是一个非冗余的、负的免疫调节因子。 这项建议的具体目标是： 1)测定Avista对小鼠肿瘤消退的影响； 2)制备抗人VistA的单抗。 HVISTA-Ig将用于通过与BioAtla的分包合同来选择GigaMab(Tm)单抗。BioAtla已经构建并验证了人类全长抗体库(GigaMab(Tm)Full Human库)，这是在哺乳动物细胞中表达的数量最多的高多样性全人类抗体之一。使用他们专有的生物信息学分析工具和合理的设计策略，他们有望最大限度地利用定制文库中人类免疫球蛋白重链和轻链的组合多样性，以确保产生高亲和力抗体。 VistA抑制通路的治疗干预代表了一种新的方法来调节T细胞介导的免疫来治疗各种癌症。我们将瞄准的第一个目标是卵巢癌，在美国，每年有13,850名女性死于卵巢癌。 公共卫生相关性：诱导免疫是根除疾病的有效方法。我们已经了解到，免疫系统内置了一些分子，这些分子控制着免疫反应的强度。通常情况下，这些刹车可以限制损害。然而，如果我们在有限的时间内踩下刹车，我们就可以诱导免疫系统更有力地攻击这种疾病。我们已经发现了一种新的“刹车”，并正在开发技术来关闭它。

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.