VISTA: A Novel Therapeutic Target That Negatively Regulates Immunity

VISTA：一种负调节免疫的新型治疗靶点

• 批准号: 8200942
• 负责人: Susan Dana Jones
• 金额: $ 30万
• 依托单位: IMMURX LLC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-02 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8200942
• 关键词: Antibodies; Antibody Affinity; Antigen-Presenting Cells; Binding; Bioinformatics; Blocking Antibodies; CD27 Antigens; CD80 gene; CD8B1 gene; Cell surface; Cellular Immunity; Chimeric Proteins; Clinical; Clinical Trials; Custom; Development; Disease; Distant; Dose; Ensure; Extracellular Domain; Family; Family member; Fc domain; Future; Generations; Hematopoietic; Human; IgG1; Immune; Immune Targeting; Immune response; Immune system; Immunity; Immunoglobulin Domain; Immunoglobulin G; Immunoglobulins; Immunotherapy; In Vitro; Intervention; Investigation; Learning; Length; Libraries; Ligands; Light; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Cell; Modeling; Monoclonal Antibodies; Mus; Myelogenous; Myeloid Cell Suppression; Outcome; Pathway interactions; Patients; Phase; Production; Randomized Controlled Trials; Solid Neoplasm; Staging; Structure; Suppressor-Effector T-Lymphocytes; T cell response; T-Cell Activation; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; Technology; Therapeutic; Therapeutic Intervention; Time; Tumor Immunity; Ursidae Family; White Blood Cell Count procedure; Woman; base; bladder Carcinoma; cancer immunotherapy; combinatorial; cytokine; design; improved; in vivo; killings; melanoma; member; new therapeutic target; novel; novel strategies; programs; receptor; response; standard of care; tool; tumor; tumor growth

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.

描述（由申请人提供）：我们发现、表征并功能性定义了一种新型免疫抑制配体。该配体是造血表达的，是B7 Ig超家族的远缘成员，其胞外结构域与B7家族配体PD-L1具有同源性。该分子被命名为T细胞活化的V结构域免疫球蛋白抑制剂（VISTA）。与PD-L1不同的是，VISTA的表达仅在造血区室内，并在骨髓抗原呈递细胞（APC）上受到高度调节。APC上的可溶性VISTA-Ig融合蛋白或VISTA表达深刻地抑制体外T细胞增殖和细胞因子产生。特异性抗VISTA单克隆抗体在体外通过VISTA+ APC干扰VISTA诱导的T细胞应答抑制。肿瘤微环境内的骨髓抑制细胞（MDSC）上的VISTA表达以极高水平表达，表明MDSC上的VISTA可能通过维持肿瘤微环境的抑制特性而阻碍肿瘤特异性免疫的发展。在膀胱癌的鼠模型中，我们显示可逆转VISTA抑制的VISTA单抗极大地减少实体瘤生长并增强宿主存活。由于初步观察到阻断VISTA全身性增强细胞介导的免疫，我们假设在MDSC似乎具有免疫调节作用的实体瘤中，VISTA疗法将被证明特别有效。与许多其他PD-L家族成员（B7-H3、H4、H6）不同，VISTA的造血限制（优选骨髓）连同其深刻的抑制活性及其在MDSC上的高表达使其成为癌症中免疫干预的独特靶标。综上所述，我们的研究结果表明VISTA是一种功能上非冗余的免疫负调节剂。 该提案的具体目标是： 1)在小鼠模型中确定aVISTA对肿瘤消退的作用;和 2)产生人VISTA特异性单克隆抗体。 hVISTA-Ig将用于通过BioAtla筛选GigaMab（tm）单克隆抗体。BioAtla构建并验证了人全长IgG文库（GigaMab（tm）全人抗体文库），这是哺乳动物细胞中表达的最大数量的高多样性全人抗体之一。利用其专有的生物信息学分析工具和合理的设计策略，他们有望在定制文库中最大限度地提高人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抑制途径的治疗性干预代表了调节T细胞介导的免疫以治疗多种癌症的新方法。我们将针对的第一个适应症是卵巢癌，在美国每年有13，850名妇女死于卵巢癌。 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，免疫系统已经内置了一些分子，这些分子可以抑制免疫反应的强烈程度。通常，这些制动器会限制损坏。然而，如果我们在有限的时间内松开刹车，我们可以诱导免疫系统更有力地攻击疾病。我们已经发现了一个新的“刹车”，并正在开发关闭它的技术。