Targeting MUC1-C with an antibody drug conjugate for the therapy of advanced prostate cancer

使用抗体药物偶联物靶向 MUC1-C 治疗晚期前列腺癌

• 批准号: 10512804
• 负责人: DONALD W. KUFE
• 金额: $ 44.22万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10512804
• 关键词: Androgen Receptor; Antibody-drug conjugates; Automobile Driving; Binding; C-terminal; Cell surface; Clinic; Clinical; Development; Disease; Effectiveness; Evaluation; Extracellular Domain; Genetically Engineered Mouse; Immune; Immune Evasion; Immune checkpoint inhibitor; Immunocompetent; Immunotherapeutic agent; Immunotherapy; In Vitro; Medical; Molecular Target; Monoclonal Antibodies; Mucin 1 protein; Mucins; N-terminal; Neuroendocrine Prostate Cancer; Neurosecretory Systems; Oncoproteins; Outcome; Pathway interactions; Patients; Prostate Cancer therapy; Refractory; Refractory Disease; Research; Resistance; Surface; Work; advanced prostate cancer; base; cancer cell; cancer stem cell; castration resistant prostate cancer; clinical candidate; clinical development; druggable target; early phase clinical trial; early phase trial; effectiveness evaluation; extracellular; human monoclonal antibodies; humanized monoclonal antibodies; improved; in vivo Model; innovation; insight; neoplastic cell; non-oncogenic; novel; novel strategies; overexpression; pluripotency; programs; self-renewal; success; targeted agent; targeted treatment; therapy resistant; tumor microenvironment; tumor-immune system interactions

Treatment options for patients with refractory castrate resistant prostate cancer (CRCP) and the highly aggressive form of neuroendocrine prostate cancer (NEPC) are limited by a lack of actionable molecular targets. Immunotherapeutic agents, such as immune checkpoint inhibitors (ICIs), have also been largely ineffective against refractory CRPC and NEPC. Mucin 1 (MUC1) is aberrantly overexpressed in CRPC and is associated with poor progression-free and overall survival. MUC1 consists of an extracellular N-terminal mucin subunit (MUC1-N) that is shed from the cell surface, and an oncogenic non-shed transmembrane C-terminal subunit (MUC1-C). Recent findings have identified MUC1-C as a master effector of lineage plasticity driving progression of CRPC to NEPC and as a potential druggable target for eliminating CRPC/NEPC cancer stem cells (CSCs). We have generated a novel monoclonal antibody (MAb), designated 3D1, against the alpha-3 helix in MUC1-C extracellular domain. MAb 3D1 has been humanized and conjugated to MMAE as an antibody-drug conjugate (ADC). Based on findings that the huMAb-3D1-MMAE ADC is highly effective against MUC1-C- expressing cancer cells, the NCI NExT Program is supporting IND-enabling studies for their potential clinical development. To date, trials with ICIs have had limited success in the treatment of patients with PC, emphasizing the need for developing novel approaches for the immunotherapy of this disease. Our hypothesis is that huMAb- 3D1-MMAE ADCs will be effective against MUC1-expressing PC CSCs and that eliminating these tumor cells could reverse, in part, the immune suppressive effects of MUC1-C-expressing CSCs on the tumor microenvironment. The objective of the proposed work is to assess the effectiveness of the huMAb-3D1-MMAE ADC against in vitro and in vivo models of CRPC/NEPC when used alone and in combination with ICIs. If our proposed studies are successful in validating MUC1-C as a target for CRPC/NEPC, the huMAb-3D1-MMAE ADC would be advanced for conducting the early phase trials in patients with refractory disease. In summary, the innovative aspects of our proposed research are that we have (i) identified MUC1- C as a target of importance for CRPC/NEPC CSCs, and (ii) generated an ADC against MUC1-C for the potential treatment of patients with refractory CRPC/NEPC.

难治性去势抵抗性前列腺癌 (CRCP) 和高度复发性前列腺癌患者的治疗选择 侵袭性神经内分泌前列腺癌（NEPC）因缺乏可操作的分子治疗而受到限制 目标。免疫治疗药物，例如免疫检查点抑制剂（ICIs），也已在很大程度上被 对难治性CRPC和NEPC无效。 粘蛋白 1 (MUC1) 在 CRPC 中异常过度表达，并且与无进展和不良进展相关 总体生存率。 MUC1 由细胞外 N 末端粘蛋白亚基 (MUC1-N) 组成，该亚基从 细胞表面和致癌的非脱落跨膜 C 端亚基 (MUC1-C)。最近的研究结果有 确定 MUC1-C 是谱系可塑性的主要效应器，驱动 CRPC 进展为 NEPC，并且 作为消除 CRPC/NEPC 癌症干细胞 (CSC) 的潜在药物靶点。 我们已经生成了一种新型单克隆抗体 (MAb)，命名为 3D1，针对 α-3 螺旋 MUC1-C 胞外域。 MAb 3D1 已人源化并与 MMAE 缀合作为抗体药物 共轭（ADC）。基于 huMAb-3D1-MMAE ADC 对 MUC1-C- 非常有效的研究结果 表达癌细胞，NCI NExT 计划正在支持其潜在临床研究的 IND 研究 发展。 迄今为止，ICIs 试验在治疗 PC 患者方面取得的成功有限，强调 需要开发这种疾病的免疫疗法的新方法。我们的假设是，huMAb- 3D1-MMAE ADC 将有效对抗表达 MUC1 的 PC CSC，并消除这些肿瘤细胞 可以部分逆转表达 MUC1-C 的 CSC 对肿瘤的免疫抑制作用 微环境。 拟议工作的目标是评估 huMAb-3D1-MMAE ADC 的有效性 单独使用以及与 ICI 联合使用时的 CRPC/NEPC 体外和体内模型。如果我们提出的 研究成功验证了 MUC1-C 作为 CRPC/NEPC 的靶标，huMAb-3D1-MMAE ADC 将 在难治性疾病患者中进行早期试验取得进展。 总之，我们提出的研究的创新之处在于我们（i）确定了 MUC1- C 作为 CRPC/NEPC CSC 的重要目标，并且 (ii) 生成针对 MUC1-C 的 ADC 难治性 CRPC/NEPC 患者的潜在治疗方法。