Abstract 2945: PLB-002 is a novel Claudin 6 antibody-drug conjugate for ovarian cancer and testicular germ cell cancer

Abstract Background: Claudin 6 (CLDN6) is a clinically validated target for many solid tumors notably ovarian, endometrial, and testicular cancer. Its expression is restricted to tumor cells and fetal tissues with little or no detectable in normal tissues. As such, CLDN6 represents an attractive therapeutic target for the development of an antibody drug conjugate (ADC). Here, we describe the development and preclinical characterization of a novel ADC called PLB-002, which consists of a highly selective CLDN6 targeting antibody, PLB-002-ab7, conjugated to a FDA-approved microtubule inhibitor, eribulin, via a Primelink Biotherapeutics proprietary enzyme-cleavable linker with an optimized average drug-to-antibody ratio (DAR) of 4.0. PLB-002-ab7 is a novel humanized anti-CLDN6 single-domain antibody (Mw. 78.8 kDa) with highly binding affinity and selectivity to CLDN6 with barely binding to related CLDN family members (CLDN9, CLDN3, and CLDN4) in protein and cell based binding assays. Methods: The in vitro binding affinity of the PLB-002 was determined by flow cytometry on OVCAR3, PA-1, OVCA429, OV90, and NEC-8 cells. Cell internalization effect was evaluated by an in-direct flow cytometry assay on OVCAR3, PA-1, and OV90 cells. In vitro cytotoxicity was measured using Cell-Titer Glo assay on OVCAR3, OV90, and NEC-8 cells. In vivo anti-tumor efficacy was investigated using several cancer cell derived xenograft (CDX) models of OVCAR3, OV90, and NEC-8 cells, as well as patient derived xenograft (PDX) models of ovarian cancer with CLDN6 high, moderate, low and negative expression. A dose-range finding (DRF) safety study of PLB-002 was performed in cynomolgus monkeys. Pharmacokinetics (PK) and pharmacodynamics (PD) data of PLB-002 in CDX mice were determined by LC-MS/MS method. Results: PLB-002 exhibited strong binding, rapid internalization effect, and potent antitumor activity in vitro on OV90 (CLDN6 low expression) and OVCAR3 (CLDN6 high expression) cells with nano-molar range of IC50. When evaluated in OVCAR3 and OV90 CDXs of ovarian cancer, NEC-8 CDX of testicular germ cell tumor, and OV PDXs, PLB-002 showed strong tumor regression in a dose-dependent manner, which is consistent with the PK analyses showing high exposure, slow clearance and long half-life for both total antibody and conjugated drug. In a non-human primate study using cynomolgus monkey, PLB-002 showed favorable safety profile with no clinical symptoms of toxicities up to the highest tested dose. Conclusions: These results show that PLB-002 has remarkable antitumor activity and support the clinical development as a therapeutic ADC for the treatment of ovarian cancer and other CLDN6 expressing solid cancer. Citation Format: Haitao Pan, Qing Zhang, Ganyuan Xiao, Guangchao Zhang, Jiaxin Li, Ling Xin, Kia J. Puan, Ling Xu, Yingdong Lu, Mao Yin. PLB-002 is a novel Claudin 6 antibody-drug conjugate for ovarian cancer and testicular germ cell cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2945.