Development of a novel class of immunotherapeutic antibody for metastatic prostate cancer

摘要 这项应用的首要目标是开发一种治疗转移瘤的新的免疫疗法。 前列腺癌(MPC)是一种致命的疾病，治疗选择有限。免疫疗法显著提高了存活率 然而，在患有各种实体瘤的患者中，它对转移性前列腺的疗效有限。 癌症患者。因此，为MPC开发有效的免疫疗法是一个尚未得到满足的需求。基于 转移性前列腺癌细胞转化应激诱导的免疫刺激细胞表面的研究 分子，即MHC I链相关分子(MIC)，为高度免疫抑制的可溶性MIC(SMIC)。 CanCure开发了一种一流的SMIC靶向单抗(MAb)B10G5，该抗体具有 作为单一药物，在临床前模型中显示出显著的消除前列腺癌转移的效果。 联合使用时，B10G5与免疫检查点阻断疗法有协同作用，并消除免疫 检查点治疗引起的结肠毒性。我们发现B10G5通过两种途径赋予其治疗效果 明确的行动机制。CanCure已研制出供人使用的B10G5单抗(指定和 HuB10G5)，并在非人类灵长类动物(NHP)的中试毒性研究中测试了huB10G5的安全性。HuB10G5是 准备好支持IND的研究。为了实现我们的目标，CanCure提出了两个具体目标：1)确定 B10G5联合一线AR靶向治疗MPC的疗效；2)进行临床前IND使能 GLP生产及毒理学研究。拟议研究的结果将确定道路，并提供强有力的 关于如何将我们的新疗法转化为早期临床试验的科学原理。 。

Abstract The overarching goal of this application is to development a novel immunotherapy for treatment of metastatic prostate cancer (mPC), a lethal with limited treatment options. Immunotherapy has significantly improved survival in patients with a variety of solid tumors, however it has only presented limited efficacy in metastatic prostate cancer patients. Thus, there is an unmet need to develop effective immunotherapies for mPC. Based on the findings that metastatic prostate tumor cells convert the stress-induced immune stimulatory cell surface molecule, the MHC I Chain related molecule (MIC), to a highly immune suppressive soluble MIC (sMIC). CanCure has developed a first-in-class sMIC-targeting monoclonal antibody (mAb) B10G5 that has demonstrated remarkable efficacy in eliminating prostate metastatic as a single agent in preclinical models. When used in combination, B10G5 synergizes with immune checkpoint blockade therapy and eliminates immune checkpoint therapy-induced colon toxicity. We show that B10G5 confers its therapeutic efficacy through two defined mechanisms of action. CanCure has formulated the B10G5 mAb for human use (designated and huB10G5) and tested the safety of huB10G5 in pilot toxicity study in non-human primates (NHP). HuB10G5 is ready for IND-enabling studies. To achieve our goal, CanCure proposes two specific Aims: 1) Determine therapeutic efficacy of B10G5 with frontline AR-targeting therapy for mPC; 2) Conduct pre-clinical IND-enabling GLP production and toxicology study. The outcome of proposed study would define the path and provide a strong scientific rationale on how to translate our new therapy into early clinical trials. .