ABBV-399, a c-Met Antibody-Drug Conjugate that Targets Both MET-Amplified and c-Met-Overexpressing Tumors, Irrespective of MET Pathway Dependence
ABBV-399, a c-Met Antibody-Drug Conjugate that Targets Both MET-Amplified and c-Met-Overexpressing Tumors, Irrespective of MET Pathway Dependence
复制标题
DOI：
10.1158/1078-0432.ccr-16-1568
复制
发表时间：
2017-02-01
影响因子：
11.5
通讯作者：
Reilly, Edward B.
中科院分区：
文献类型：
--
作者：
Wang, Jieyi;Anderson, Mark G.;Reilly, Edward B.
目的：尽管MET癌基因在许多恶性肿瘤中具有重要意义，但针对c-Met的临床策略仅使一小部分由c-Met信号通路驱动的肿瘤患者受益，因此需要选择MET扩增和/或c-Met激活的患者最有可能产生反应。靶向c-Met的ADC可以克服这些局限性，有潜力成为一种广谱治疗药物。实验设计：ADC ABBV-399由c- met靶向抗体ABT-700生成。在c-Met过表达或MET扩增的癌细胞和异种移植物（包括患者来源的异种移植物（PDX）模型和对其他c-Met抑制剂难治的异种移植物）中评估抗肿瘤活性。评估肿瘤和正常细胞系中c-Met表达与ABBV-399敏感性的相关性，以评估靶毒性风险。结果：敏感肿瘤细胞而非正常细胞表达c-Met的阈值水平是abbv -399介导的显著杀伤肿瘤细胞所必需的。活性扩展到c-Met或扩增MET细胞系和PDX模型，观察到显著的肿瘤生长抑制和退化。ABBV-399抑制其他c-Met抑制剂难治性异种移植肿瘤的生长，并与标准治疗化疗联合提供显著的治疗效果。结论：ABBV-399代表了一种新的治疗策略，可以向c- MET过表达的肿瘤细胞传递有效的细胞毒素，使细胞杀死而不依赖MET信号。ABBV-399已进入I期研究，在表达c- met的非小细胞肺癌（NSCLC）患者中具有良好的耐受性，并产生了客观反应。AACR (C) 2016人。
Purpose: Despite the importance of the MET oncogene in many malignancies, clinical strategies targeting c-Met have benefitted only small subsets of patients with tumors driven by signaling through the c-Met pathway, thereby necessitating selection of patients with MET amplification and/or c-Met activation most likely to respond. An ADC targeting c-Met could overcome these limitations with potential as a broad-acting therapeutic.Experimental Design: ADC ABBV-399 was generated with the c-Met-targeting antibody, ABT-700. Antitumor activity was evaluated in cancer cells with overexpressed c-Met or amplified MET and in xenografts including patient-derived xenograft (PDX) models and those refractory to other c-Met inhibitors. The correlation between c-Met expression and sensitivity to ABBV-399 in tumor and normal cell lines was assessed to evaluate the risk of on-target toxicity.Results: A threshold level of c-Met expressed by sensitive tumor but not normal cells is required for significant ABBV-399-mediated killing of tumor cells. Activity extends to c-Met or amplified MET cell line and PDX models where significant tumor growth inhibition and regressions are observed. ABBV-399 inhibits growth of xenograft tumors refractory to other c-Met inhibitors and provides significant therapeutic benefit in combination with standard-of-care chemotherapy.Conclusions: ABBV-399 represents a novel therapeutic strategy to deliver a potent cytotoxin to c-Met-overexpressing tumor cells enabling cell killing regardless of reliance on MET signaling. ABBV-399 has progressed to a phase I study where it has been well tolerated and has produced objective responses in c-Met-expressing non-small cell lung cancer (NSCLC) patients. (C)2016 AACR.