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Optimization of a novel cancer immunotherapeutic antibody for human use

人用新型癌症免疫治疗抗体的优化

基本信息

批准号：
9453821
负责人：
JENNIFER D WU
金额：
$ 5万
依托单位：
CANCURE, LLC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9453821
关键词：
Animal Model Antibodies Biological Assay Biophysics Blood Circulation CD4 Positive T Lymphocytes CTLA4 gene Cancer Control Cancer Patient Cell Communication Cell Proliferation Collaborations Data Development Disabled Persons Faculty Goals Human Immune Immune response Immune system Immunization Immunologics Immunology Immunosuppression Immunotherapeutic agent Immunotherapy In Vitro Incidence Ligands Malignant Neoplasms Medical Mission Monoclonal Antibodies Mus Names Neoplasm Metastasis Oncogenic Outcome Patients Pharmaceutical Preparations Phase Population Positioning Attribute Primary Neoplasm Property Risk Sampling Small Business Technology Transfer Research South Carolina Stress Surface Technology Therapeutic Therapeutic Monoclonal Antibodies Therapeutic antibodies Toxic effect Treatment Efficacy Universities advanced disease base cancer cell cancer immunotherapy cancer survival cancer type checkpoint therapy clinical development commercialization humanized monoclonal antibodies immune checkpoint immune checkpoint blockade immunogenicity improved in vivo innovation melanoma neoplastic cell novel objective response rate phase 1 study phase 2 study pre-clinical preclinical study product development receptor response therapeutic evaluation tumor

项目摘要

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.

摘要本申请的目的是评估CanCure的人源化首次入组治疗的癌症治疗可行性。类免疫刺激性单克隆抗体（mAb）huB 10 G5（本品，也称CuraB 10）。期间在癌症发展中，响应于致癌性损伤或应激，几乎所有的人类癌细胞都被诱导为表达表面分子MIC（MHC I链相关分子），其被认为是警告和点燃免疫防御机制来消除癌症。然而，这种与生俱来的控制癌症的能力在1990年被禁用。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）进入循环。sMIC是高度免疫抑制性的，并劫持免疫系统，使癌症进展我们已经开发了一种小鼠mAb B10 G5，它可以中和sMIC，但不阻断相互作用。肿瘤细胞结合MIC及其免疫活化受体NKG 2D。动物模型的临床前研究表明B10 G5单独治疗显著诱导自发性的消退（>80%），晚期原发性肿瘤和消除转移，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。B10 G5治疗还增强了对免疫检查点的反应阻断疗法，当联合使用时。从机制上讲，B10 G5治疗不仅消除了 sMIC免疫抑制还通过新的免疫抑制剂增强内源性抗肿瘤免疫应答，机制等CanCure具有人源化B10 G5。在第一阶段的申请中，我们建议评估治疗可行性两个具有特定目的的huB 10 G5领先候选物：1）评估是否存在治疗可行性，使用我们的方法，huB 10 G5具有与亲代小鼠B10 G5相当的治疗功效和稳定性建立体外和体内试验; 2）评估不需要的ADA（抗药抗体）的风险使用良好建立的体外DC-T测定法测定huB 10 G5候选物的免疫原性。完成这些任务对于CanCure证明第二阶段产品开发的里程碑至关重要，商业化其结果将直接影响癌症患者的生存。拟定研究将通过CanCure与南卡罗来纳州医科大学的合作来完成，学术伙伴。