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

难治性抗去势前列腺癌(CRCP)和高度绝经后前列腺癌的治疗选择 侵袭性形式的神经内分泌前列腺癌(NEPC)由于缺乏可操作的分子而受到限制 目标。免疫治疗药物，如免疫检查点抑制剂(ICIS)，也在很大程度上 对难治性CRPC和NEPC无效。 粘蛋白1(MUC1)在CRPC中异常过表达，与恶性进展和 总体存活率。MUC1由细胞外N-末端粘蛋白亚基(MUC1-N)组成，它从细胞外的 细胞表面，以及致癌的非脱落型跨膜C-末端亚单位(MUC1-C)。最近的研究结果表明 发现MUC1-C是推动CRPC向NEPC发展的谱系可塑性的主效应子 作为消除CRPC/NEPC肿瘤干细胞(CSCs)的潜在药物靶点。 我们已经产生了一种新的抗α-3螺旋的单抗，命名为3d1。 MUC1-C胞外区。单抗3d1已人源化，并作为抗体药物与MMAE偶联 共轭(ADC)。根据研究结果，huMAb-3d1-MMAE ADC对MUC1-C-C具有高效的治疗作用。 表达癌细胞，NCI Next计划正在为其潜在的临床研究提供IND支持 发展。 到目前为止，ICIS试验在治疗PC患者方面取得的成功有限，强调了 需要为这种疾病的免疫治疗开发新的方法。我们的假设是HuMAb- 3d1-MMAE ADCs对表达MUC1的PC CSCs的杀伤作用及对这些肿瘤细胞的杀伤作用 可以部分逆转表达MUC1-C的CSCs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对 CRPC/NEPC单独及与ICIS联合应用的体外和体内模型。如果我们的提议 研究成功地确认MUC1-C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是先进的。 总而言之，我们建议的研究的创新方面是：(I)确定了MUC1- C作为CRPC/NEPC CSC的重要目标，以及(Ii)生成针对MUC1-C的ADC 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.