LY4170156，一种靶向叶酸受体α的抗体偶联药物，在临床前卵巢癌模型中与标准治疗联用时表现出增强的抗肿瘤活性

LY4170156 is an antibody-drug conjugate targeting folate receptor alpha (FRalpha). It is composed of a humanized IgG1 monoclonal antibody with silenced Fc function, a proprietary polysarcosine hydrophobicity-masking agent with a dipeptide-cleavable linker, and a topoisomerase I inhibitor exatecan payload with a drug-to-antibody ratio of 8:1. In preclinical studies, LY4170156 was active against various FRalpha-expressing tumors 1 , including those with low/moderate (0 - <75%) 2 FRalpha expression. 1 The Phase 1 trial (NCT06400472) indicated that LY4170156 was well-tolerated and resulted in durable clinical efficacy in heavily pretreated patients with platinum-resistant ovarian cancer (PROC), regardless of FRalpha levels or prior mirvetuximab soravtansine-gynx treatment, and without grade ≥3 drug-related ocular, neuropathy, or alopecia events. 3 The Phase 3 study (NCT07213804) evaluates LY4170156 as monotherapy in patients with PROC and in combination with bevacizumab in patients with platinum-sensitive ovarian cancer (PSOC). This study reports the preclinical activity of LY4170156, as a single agent and in combination with standard of care therapies (SoC) in ovarian cancer (OC) cell lines using in vitro 3D cell culture, and cell line-derived or patient-derived xenograft models. Sequencing of treatments was also assessed. CellTiter-Glo assay was used for evaluating cell viability in vitro after treatment of 7 days. Tumor volume and mice body weight were measured twice a week throughout the in vivo study. Assays using 5 OC cell lines demonstrated that when LY4170156 was combined with various SoC, it exerted enhanced growth inhibitory effects, independent of FRalpha expression levels. In vivo efficacy studies showed that LY4170156 combined with cisplatin with or without bevacizumab, bevacizumab, doxorubicin, or carboplatin plus paclitaxel resulted in superior and more durable antitumor responses compared to SoC alone. In addition, LY4170156 plus bevacizumab was highly effective as both first- and second-line treatment in tumor models with moderate responses to SoC. Furthermore, LY4170156 plus olaparib demonstrated enhanced antitumor activity in DNA repair-deficient models. Collectively, these findings offer further support for the clinical assessment of LY4170156 in patients requiring improved treatment options, including those with PROC and PSOC. 1 Viricel et al. AACR; Cancer Res. 2023; 83(7). 2 Moore K, et al. N Engl J Med . 2023;389(23):2162-2174 3 Ray-Coquard et al. Presented at ESMO 2025.