Targeting the checkpoint regulator VISTA for treatment of inflammatory disease

ImmuNext已经鉴定和开发了一种假定的铅抗Vista单抗(MAb)，我们 目的将其带入临床用于治疗人类自身免疫性疾病。Vista是高度 成功的负检查点调节器(NCR)药物靶标家族，其成员已经证明 在诱导人类癌症长期缓解方面已被证明有效。我们认为抑制病毒的抗体 增强Vista功能的免疫功能将在广泛的人类自身免疫中被证明是有效的 疾病。Vista同时调节淋巴样细胞和髓样细胞的独特性质表明它的调节 将最适合于SLE的治疗，在SLE的两个亚群中都已发现缺陷。使用一个 强大的专利地位、最先进的方法和一支技术娴熟、经验丰富的药物开发团队，我们将 开发一种一流的NCR靶向治疗自身免疫性疾病的药物。在第一阶段，我们将 通过抗Vista的功能筛选鉴定食蟹交叉反应前导和后备单抗 人源抗体库。我们目前有一种人类CD3激活的T细胞呼叫试验用于我们的初级筛查。我们的 最佳功能抗体的选择和支持将来自：1)使用体外检测，2)通过确认 使用人-Vista基因敲入(HV-KI)小鼠品系的活性和3)两种自身免疫模型 炎症，刀豆蛋白A诱导的肝炎，并在选择后，移植物对宿主疾病模型。之后 选择最好的抗体和后备，我们将进入第二阶段，领先的优化和预 临床发展。前导抗体的恒定区将通过Ig同型和FcRN进行工程 我们将选择最好的一种作为最终的铅分子来开发。我们将对此线索进行评估 用于免疫原性和制造责任，并将用于研究作用机制(MOA)在 HV-KI小鼠。此外，我们还将研究这种新疗法诱导免疫性疾病的可能性。 使用移植模型的耐受性。将测量PK/PD关系并调查啮齿动物毒性。我们 还将开发PD生物标记物，以使用各种方法为未来的临床计划提供信息，包括 在药物治疗环境中用Phosflow和RNA-seq检查组织和细胞。通过检查Vista和 SLE患者样本中铅MOA与健康对照相比，我们可能会识别Vista 未来临床试验的生物标记物。有了合格的领先地位，我们将开始细胞系的开发和 非糖蛋白PK/PD与食蟹类非人类灵长类动物的毒理学评价我们召集了一次 专家小组，将帮助收集、分析和处理这些研究产生的数据，以概述 临床策略和一项支持IND的GLP毒素研究。 首屈一指的抗Vista单抗最终将为患者提供独特的检查点调节器 药物不仅治疗他们的症状，而且为他们提供重置免疫系统的机会 回到健康的自我平衡状态。

ImmuNext has identified and developed a putative lead anti-VISTA monoclonal antibody (mAb) that we aim to bring to the clinic for the treatment of human autoimmune disease. VISTA is a member of the highly successful negative checkpoint regulator (NCR) family of drug targets, whose members have demonstrated proven efficacy in inducing long-term remissions in human cancers. We contend that antibodies that suppress immune function by enhancing VISTA's function will prove effective in a broad array of human autoimmune diseases. The unique nature of VISTA to regulate both lymphoid and myeloid cells suggests that its modulation will be best suited toward the treatment of SLE, where defects in both subsets have been identified. With a strong patent position, state-of-the-art approaches and a skilled, experienced drug development team, we will develop a first-in-class NCR-targeted therapeutic for the treatment of autoimmune disease. In Phase 1 we will identify a cynomolgus cross-reactive lead and a backup mAb through functional screening of an anti-VISTA human antibody library. We currently have a human CD3-activated T call assay for our primary screen. Our choice of the best functional antibody and a backup will come from: 1) using in vitro assays, 2) by confirming activity using a human-VISTA knock-in (hV-KI) mouse strain and 3) with two models of autoimmune inflammation, concanavalin A induced hepatitis and, following selection, a graft vs. host disease model. After selection of the best antibody and a backup, we will advance into Phase 2 with lead optimization and pre- clinical development. The constant region of the lead antibody will be engineered through Ig isotype and FcRn engineering, and we will choose the best one to develop as the final lead molecule. This lead will be assessed for immunogenicity and manufacturing liabilities, and will be used to study the mechanism of action (MOA) in hV-KI mice. Additionally, we will examine the potential for this new therapeutic to induce immunological tolerance using transplant models. PK/PD relationships will be measured and rodent toxicity investigated. We will also develop PD biomarkers to inform future clinical plans using a variety of approaches, including examining tissues and cells by Phosflow and RNA-seq in drug-treated settings. By examining VISTA and the lead MOA in SLE human patient samples compared to healthy controls, we will potentially identify VISTA biomarkers for future clinical trials. With a qualified lead in hand, we will commence cell line development and non-GLP PK/PD and toxicological assessment in cynomolgus non-human primates. We have convened a panel of experts that will help collect, analyze and process the data generated from these studies to outline a clinical strategy and an IND-enabling GLP tox study. The first-in-class anti-VISTA mAb will ultimately provide patients with a unique checkpoint regulator drug to not only treat their symptoms, but also to provide them the opportunity to reset their immune system back to a healthy homeostatic state.