Targeting the checkpoint regulator VISTA for treatment of inflammatory disease

靶向检查点调节因子 VISTA 治疗炎症性疾病

• 批准号: 9255938
• 负责人: JAY L ROTHSTEIN
• 金额: $ 29.99万
• 依托单位: IMMUNEXT, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-10 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9255938
• 关键词: Adverse effects; Affinity; Amino Acid Sequence; Anatomy; Animal Model; Antibodies; Antibody Activation; Antibody Response; Autoimmune Diseases; Autoimmune Process; Award; Back; Binding; Biological Assay; Biological Markers; Biology; Blood; CD3 Antigens; Cell Line; Cells; Chronic; Clinic; Clinical; Clinical Trials; Computer Simulation; Concanavalin A; Data; Defect; Development; Disease; Disease model; Disease remission; Dose; Drug Kinetics; Drug Targeting; Engineering; Family; Fc domain; Future; Gene Activation; Growth; Hand; Hepatitis; Human; Imiquimod; Immune; Immune Cell Activation; Immune Tolerance; Immune response; Immune system; Immunity; Immunoglobulin Constant Region; Immunoglobulins; Immunosuppressive Agents; In Vitro; Inflammation; Inflammatory; Injection of therapeutic agent; Knock-in Mouse; Laboratories; Lead; Legal patent; Leukocytes; Libraries; Link; Lupus; Lymphoid Cell; Malignant Neoplasms; Measures; Modeling; Monoclonal Antibodies; Mouse Strains; Mus; Myeloid Cells; Nature; Oligosaccharides; Pathologic; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology and Toxicology; Pharmacotherapy; Phase; Play; Positioning Attribute; Process; Protein Isoforms; Proteins; Psoriasis; Refractory; Rodent; Sampling; Scientist; Series; Site; Small Business Innovation Research Grant; Suppressor-Effector T-Lymphocytes; Symptoms; Systemic Lupus Erythematosus; T-Lymphocyte; Therapeutic; Therapeutic antibodies; Tissues; Toxic effect; Toxicology; Transplantation; Treatment Efficacy; antibody libraries; biomarker discovery; cancer therapy; collagen antibody induced arthritis; cross reactivity; cytokine; deamidation; drug development; experience; genetic regulatory protein; glycosylation; human disease; immune function; immunogenicity; in vitro Assay; in vivo; inhibitor/antagonist; member; neonatal Fc receptor; nonhuman primate; novel; novel drug class; novel therapeutics; oncology; oxidation; pharmacodynamic biomarker; preclinical development; programs; response; screening; targeted treatment; thermal stress; transcriptome sequencing

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.

ImmuNext已经鉴定并开发了一种推定的先导抗VISTA单克隆抗体（mAb）， 旨在将其应用于临床治疗人类自身免疫性疾病。VISTA是一个高度 成功的药物靶点负检查点调节因子（NCR）家族，其成员已经证明 在人类癌症中诱导长期缓解的有效性。我们认为，抗体抑制 通过增强VISTA的功能来增强免疫功能将证明在广泛的人类自身免疫性疾病中有效。 疾病VISTA调节淋巴细胞和骨髓细胞的独特性质表明，其调节 将最适合于SLE的治疗，其中两个子集的缺陷都已被确定。与 强大的专利地位，国家的最先进的方法和一个熟练的，经验丰富的药物开发团队，我们将 开发一流的NCR靶向治疗药物，用于治疗自身免疫性疾病。在第一阶段，我们将 通过抗VISTA功能筛选鉴定食蟹猴交叉反应性先导物和备用mAb 人抗体库。我们目前有一个人的CD 3激活T细胞检测我们的初步筛选。我们 最佳功能抗体和备用抗体的选择将来自：1）使用体外测定，2）通过确认 3）使用人VISTA敲入（hV-KI）小鼠品系和3）使用两种自身免疫性肿瘤模型， 炎症，伴刀豆球蛋白A诱导的肝炎，以及选择后的移植物抗宿主疾病模型。后 选择最好的抗体和备用抗体后，我们将进入第二阶段，进行先导优化和预 临床发展。先导抗体的恒定区将通过IG同种型和FcRn进行工程改造 我们将选择最好的一种作为最终的先导分子。将对该线索进行评估 用于免疫原性和生产责任，并将用于研究作用机制（MOA）， hV-KI小鼠。此外，我们将研究这种新的治疗方法诱导免疫反应的潜力。 移植模型的耐受性将测量PK/PD关系并研究啮齿动物毒性。我们 还将开发PD生物标志物，以使用各种方法为未来的临床计划提供信息，包括 通过Phosflow和RNA-seq在药物处理的环境中检查组织和细胞。通过检查VISTA和 与健康对照相比，SLE人类患者样品中的前导MOA，我们将潜在地鉴定VISTA 生物标志物用于未来的临床试验。有了合格的领导在手，我们将开始细胞系开发， 食蟹猴非人灵长类动物的非GLP PK/PD和毒理学评估。我们召集了一个 专家小组将帮助收集、分析和处理这些研究产生的数据， 临床策略和IND使能GLP毒性研究。 这款一流的抗VISTA mAb最终将为患者提供独特的检查点调节剂 这种药物不仅能治疗他们的症状，还能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