Optimization of a novel cancer immunotherapeutic antibody for human use

摘要 这项应用的目标是评估CanCure人性化的First-in-in-1治疗癌症的可行性。 类免疫刺激单抗(MAb)huB10G5(产品，又称CuraB10)。在.期间 癌症的发展，作为对致癌的侮辱或压力的反应，几乎所有的人类癌细胞都被诱导 表达一种表面分子MIC(MHC I链相关分子)，它被认为是警示和点燃 消除癌症的免疫防御机制。然而，这种与生俱来的癌症控制能力在 癌症患者，因为人类癌细胞进化到脱落表面MIC并释放可溶性MIC(SMIC) 进入血液循环。中芯国际具有高度的免疫抑制作用，并劫持免疫系统以允许癌症 进步。我们开发了一种小鼠单抗B10G5，它能中和SMIC，但不能阻止相互作用 肿瘤细胞结合的MIC及其免疫激活受体NKG2D。在动物模型中的临床前研究已经 B10G5单独治疗可显著诱导自发性神经功能减退(80%) 晚期原发肿瘤和消除转移，即使在对电流无反应的肿瘤中也是如此 免疫检查点阻断疗法。B10G5疗法也增强了对免疫检查点的应答 封锁疗法，当组合使用时。从机理上讲，B10G5疗法不仅消除了 中芯国际的免疫抑制作用也通过新颖的方式激活内源性抗肿瘤免疫反应 机械装置。CanCure使B10G5人性化。在此第一阶段应用程序中，我们建议评估 治疗可行性的两个huB10G5领先的候选人有特定的目的：1)评估是否一个 HuB10G5的治疗效果和稳定性与亲本小鼠B10G5相当 建立体外和体内检测；2)评估不需要的ADA(抗药抗体)的风险 体外DC-T法检测huB10G5候选抗体的免疫原性。完成这些工作 任务对于CanCure来说至关重要，以证明第二阶段产品开发的里程碑是正确的 商业化。其结果将直接影响癌症患者的生存。建议进行的研究 将通过CanCure与南卡罗来纳医科大学的合作完成 学术伙伴。

ABSTRACT The goal of this application is to evaluate the cancer therapeutic feasibility of CanCure's humanized first-in- class immunostimulatory monoclonal antibody (mAb) huB10G5 (the Product, also names CuraB10). During cancer development, in response to oncogenic insult or stress, almost ALL human cancer cells are induced to express a SURFACE molecule MIC (MHC I chain-related Molecule) which deems to alert and ignite the immune defense machinery to eliminate cancers. However, this innate power of cancer control was disabled in cancer patients, because human cancer cells evolved to shed the surface MIC and release soluble MIC (sMIC) into the circulation. sMIC is highly immune suppressive and hijacks the immune systems to allow cancers to progression. We have developed a mouse mAb B10G5 that neutralizes sMIC but does not block the interaction of tumor cell-bound MIC with its immunoactivating receptor NKG2D. Pre-clinical studies in animal models have demonstrated that B10G5 stand-alone therapy remarkably induced regression (>80%) of spontaneous advanced primary tumors and eliminated metastasis, even in tumors that are non-responsive to current immune checkpoint blockade therapy. B10G5 therapy also enhanced responses to immune checkpoint blockade therapies, when used in combination. Mechanistically, B10G5 therapy not only eliminates the immune suppression of sMIC but also invigorates endogenous anti-tumor immune responses through novel mechanisms. CanCure has humanized B10G5. In this Phase I application, we propose to evaluate the therapeutic feasibility the two huB10G5 leading candidates with Specific Aims: 1) to evaluate whether a huB10G5 has comparable therapeutic efficacy and stability to the parental mouse B10G5 using our established in vitro and in vivo assays; 2) to assess the risk of unwanted ADA (anti-drug antibody) immunogenicity of the huB10G5 candidates using well established in vitro DC-T assay. Completion of these tasks is critical for CanCure to justify the milestones for Phase II product development towards commercialization. The outcome will have direct impact on the survival of cancer patients. The proposed study will be accomplished through a collaboration of CanCure with the Medical University of South Carolina, the academic partner.