Predevelopment of VV2003, a Novel CRAC Channel Inhibitor, to Improve Outcomes Associated with Checkpoint Inhibitor Immunotherapy

Vivreon Biosciences，LLC NCI阶段2 SBIR提交1R43CA224454-02 项目摘要 Vivreon生物科学公司很高兴为NCI的第二阶段SBIR提出申请。Vivreon生物科学公司是一家 一家创新的生命科学公司，正在开发一种新的小分子，钙离子通道抑制剂， VV2003，以改善接受检查点抑制免疫疗法的人的预后。 检查点抑制剂提高了许多癌症患者的总存活率，但小肠结肠炎 成为与这些疗法有关的最常见的剂量限制毒性。检查点 目前，抑制剂诱导的结肠炎的治疗方法是免疫抑制疗法，这种疗法可以钝化 检查点抑制免疫疗法的肿瘤杀伤力。VV2003是一个口语考生 选择性和安全地阻断检查点抑制剂诱导的小肠结肠炎的治疗方法 没有全身免疫抑制副作用。 Vivreon寻求NCI资金，以弥合发现和开发之间的差距。这笔赠款 旨在通过回答Key进一步验证VV2003作为安全有效的候选治疗方案 关于VV2003在全面推广前的药代动力学和疗效的问题 研究性新药(IND)-使研究成为人类临床评估的第一名。vt.在.的基础上 成功完成该计划，我们的临床前候选人将是第一个具体 特异性抑制钙释放激活钙通道的免疫抑制作用 到小肠结肠炎的地方。白细胞CRAC通道促进钙内流，这一过程是 包括白细胞增殖在内的许多小肠结肠炎致病过程的上游 和炎性细胞因子的分泌。VV2003的系统生物利用度较低，仍处于 口服后的肠腔。这允许VV2003实现冒号限制 免疫抑制，避免不必要的全身副作用。我们已经开发了几个 确认VV2003可与多个检查点抑制器结合使用的策略 免疫治疗，包括体外和体内检查点抑制物免疫治疗的疗效 化验。该提案的最终目标是对第一个CRAC通道进行表征和测试 用于解决检查点免疫治疗相关的小肠结肠炎的抑制剂。

Vivreon Biosciences, LLC NCI Phase 2 SBIR Submission 1R43CA224454-02 Project Summary Vivreon Biosciences is pleased to apply for NCI’s Phase 2 SBIR. Vivreon Biosciences is an innovative life sciences company that is developing a novel small molecule, Ca2+ channel inhibitor, VV2003, to improve outcomes in persons undergoing checkpoint inhibitor immunotherapy. Checkpoint inhibitors have improved overall survival in numerous cancers, but enterocolitis has emerged as the most frequent dose-limiting toxicity associated with these therapies. Checkpoint inhibitor induced colitis is currently treated with immunosuppressive therapy, which blunts the tumor-killing potential of the checkpoint inhibitor immunotherapy. VV2003 is an oral candidate therapeutic designed to selectively and safely block checkpoint inhibitor-induced enterocolitis without systemic immunosuppression side effects. Vivreon seeks NCI funding to bridge the gap between discovery and development. This grant aims to further validate VV2003 as a safe and effective candidate therapeutic by answering key questions regarding VV2003 pharmacokinetics and efficacy prior to advancing VV2003 into full Investigational New Drug (IND)-enabling studies and into first in human clinical evaluation. Upon successful completion of the program, our preclinical candidate will be the first to specifically inhibit Ca2+ release-activated Ca2+ (CRAC) channels for immunosuppression targeted specifically to sites of enterocolitis. Leukocyte CRAC channels facilitate Ca2+ influx, a process that is upstream of numerous enterocolitis disease-causing processes including leukocyte proliferation and inflammatory cytokine secretion. VV2003 has low systemic bioavailability and remains in the gut lumen following oral administration. This permits VV2003 to achieve colon-restricted immunosuppression, avoiding unwanted systemic side effects. We have developed several strategies to confirm that VV2003 can be used in combination with multiple checkpoint inhibitor immunotherapies, including in vitro and in vivo checkpoint inhibitor immunotherapy efficacy assays. The final aim for this proposal is characterization and testing of the first CRAC channel inhibitor to address enterocolitis associated with checkpoint immunotherapy.