Genentech, Inc., 1 DNA Way, South San Francisco, California.
Mol Cancer Ther. 2018 Mar;17(3):638-649. doi: 10.1158/1535-7163.MCT-17-0813. Epub 2017 Dec 27.
Luminal A (hormone receptor-positive) breast cancer constitutes 70% of total breast cancer patients. In an attempt to develop a targeted therapeutic for this cancer indication, we have identified and characterized Glial cell line-Derived Neurotrophic Factor (GDNF) Family Receptor Alpha 1 (GFRA1) antibody-drug conjugates (ADC) using a cleavable valine-citrulline-MMAE (vcMMAE) linker-payload. RNAseq and IHC analysis confirmed the abundant expression of GFRA1 in luminal A breast cancer tissues, whereas minimal or no expression was observed in most normal tissues. Anti-GFRA-vcMMAE ADC internalized to the lysosomes and exhibited target-dependent killing of GFRA1-expressing cells both and The ADCs using humanized anti-GFRA1 antibodies displayed robust therapeutic activity in clinically relevant cell line-derived (MCF7 and KPL-1) tumor xenograft models. The lead anti-GFRA1 ADC cross-reacts with rodent and cynomolgus monkey GFRA1 antigen and showed optimal pharmacokinetic properties in both species. These properties subsequently enabled a target-dependent toxicity study in rats. Anti-GFRA1 ADC is well tolerated in rats, as seen with other vcMMAE linker-payload based ADCs. Overall, these data suggest that anti-GFRA1-vcMMAE ADC may provide a targeted therapeutic opportunity for luminal A breast cancer patients. .
腔 A 型（激素受体阳性）乳腺癌占乳腺癌患者总数的 70%。为了针对这种癌症适应证开发靶向治疗药物，我们使用可裂解的缬氨酸-瓜氨酸-MMAE（vcMMAE）连接子-有效载荷，鉴定并表征了神经胶质细胞衍生神经营养因子（GDNF）家族受体α 1（GFRA1）抗体药物偶联物（ADC）。RNAseq 和 IHC 分析证实，GFRA1 在腔 A 型乳腺癌组织中大量表达，而在大多数正常组织中则很少表达或不表达。抗-GFRA-vcMMAE ADC 内化到溶酶体中，并表现出对表达 GFRA1 的细胞的靶依赖性杀伤作用，无论是在体内还是体外。使用人源化抗-GFRA1 抗体的 ADC 在临床上相关的细胞系衍生（MCF7 和 KPL-1）肿瘤异种移植模型中显示出强大的治疗活性。该抗-GFRA1 ADC 与啮齿动物和食蟹猴的 GFRA1 抗原发生交叉反应，并在这两种物种中均表现出最佳的药代动力学特性。这些特性随后使我们能够在大鼠中进行靶依赖性毒性研究。抗-GFRA1 ADC 在大鼠中具有良好的耐受性，与其他基于 vcMMAE 连接子-有效载荷的 ADC 相似。总的来说，这些数据表明，抗-GFRA1-vcMMAE ADC 可能为腔 A 型乳腺癌患者提供一种靶向治疗的机会。
