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

难治性去势抵抗性前列腺癌（CRCP）患者和高血压患者的治疗选择 神经内分泌前列腺癌（NEPC）的侵袭性形式受到缺乏可操作分子的限制， 目标的免疫抑制剂，如免疫检查点抑制剂（ICI），也已经在很大程度上被应用于免疫系统。 对难治性CRPC和NEPC无效。 粘蛋白1（MUC 1）在CRPC中异常过表达，与CRPC的无进展和 总体生存率。MUC 1由细胞外N-末端粘蛋白亚基（MUC 1-N）组成，该亚基从细胞外基质脱落。 细胞表面，和致癌的非脱落跨膜C-末端亚基（MUC 1-C）。最近的调查结果表明， 将MUC 1-C鉴定为谱系可塑性的主要效应物，其驱动CRPC向NEPC的进展， 作为消除CRPC/NEPC癌症干细胞（CSC）的潜在药物靶点。 我们已经产生了一种新的单克隆抗体（MAb），命名为3D 1，针对α-3螺旋， MUC 1-C胞外域。MAb 3D 1已被人源化并作为抗体药物与MMAE缀合 偶联物（ADC）。基于huMAb-3D 1-MMAE ADC对MUC 1-C-1非常有效的发现， 表达癌细胞，NCI NExT计划正在支持IND使能研究， 发展 迄今为止，ICI试验在治疗PC患者方面的成功有限，强调了 需要开发用于这种疾病的免疫疗法的新方法。我们的假设是人单抗- 3D 1-MMAE ADC将有效对抗表达MUC 1的PC CSC，并且消除这些肿瘤细胞 可以部分逆转表达MUC 1-C的CSC对肿瘤的免疫抑制作用， 微环境 拟议工作的目的是评估huMAb-3D 1-MMAE ADC对以下患者的有效性： CRPC/NEPC单独使用和与ICI联合使用时的体外和体内模型。如果我们的提议 研究成功验证MUC 1-C作为CRPC/NEPC的靶点，huMAb-3D 1-MMAE ADC将 推进在难治性疾病患者中进行早期试验。 总之，我们提出的研究的创新方面是，我们已经（i）确定MUC 1- C作为CRPC/NEPC CSC的重要靶标，和（ii）产生针对MUC 1-C的ADC，用于CRPC/NEPC CSC的治疗。 难治性CRPC/NEPC患者的潜在治疗。

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.