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、表征并在功能上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 超家族的远亲成员，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 细胞激活的 V 结构域免疫球蛋白抑制因子 (VISTA)。与 PD-L1 不同，VISTA 的表达完全在造血室内，并且在骨髓抗原呈递细胞 (APC) 上受到高度调节。可溶性 VISTA-Ig 融合蛋白或 APC 上的 VISTA 表达可显着抑制体外 T 细胞增殖和细胞因子产生。体外，一种特异性抗 VISTA 单克隆抗体可干扰 VISTA 诱导的 VISTA+ APC 对 T 细胞反应的抑制。肿瘤微环境中的骨髓抑制细胞（MDSC）上的 VISTA 表达水平极高，表明 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。在膀胱癌的小鼠模型中，我们展示了一种 (VISTA mab) 可以逆转 VISTA 抑制，大大减少实体瘤生长并提高宿主存活率。由于初步观察到阻断 VISTA 可以系统性增强细胞介导的免疫，我们假设MDSC 似乎具有免疫调节作用的实体瘤（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，造血限制VISTA 的（优先骨髓）及其深刻的抑制活性及其在 MDSC 上的高表达，使其成为癌症免疫干预的独特靶标。总而言之，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) 确定 aVISTA 对小鼠模型肿瘤消退的影响。和 2) 生产人非人VISTA特异性单克隆抗体。 hVISTA-Ig 将用于通过与 BioAtla 的分包合同选择 GigaMab(tm) 单克隆抗体。 BioAtla 构建并验证了人全长 IgG 文库（GigaMab(tm) Full Human 文库），这是在哺乳动物细胞中表达的数量最多的高多样性全人抗体之一。利用其专有的生物信息分析工具和合理的设计策略，他们有望最大限度地提高定制文库中人免疫球蛋白重链和轻链的组合多样性，以确保生成高亲和力抗体。 VISTA 抑制途径的治疗干预代表了一种调节 T 细胞介导的免疫以治疗多种癌症的新方法。我们针对的第一个适应症是卵巢癌，在美国每年有 13,850 名女性死于卵巢癌。 公共卫生相关性：诱导免疫力是根除疾病的有效方法。我们了解到，免疫系统内置了一些分子，这些分子会抑制免疫反应的剧烈程度。通常，这些制动器可以限制损坏。然而，如果我们在有限的时间内松开刹车，我们就可以诱导免疫系统更积极地攻击疾病。我们发现了一种新的“制动器”，并正在开发将其关闭的技术。