Abstract 1578: Preclinical evaluation of BLB-101, a topoisomerase-inhibitor-based anti-CLDN6/9 antibody-drug conjugate featuring a proprietary hydrophilic linker

Abstract Claudin 6 (CLDN6) is a tight junction protein that is highly expressed in various human cancers, including ovarian and endometrial cancers, while it is not found in normal adult tissues. Claudin 9 (CLDN9), which shares significant homology with CLDN6, displays similar expression patterns, being nearly absent in normal tissues but upregulated in ovarian and endometrial cancers. We propose to target both CLDN6 and CLDN9 simultaneously to enhance anti-tumor efficacy and broaden treatment options for more patients. We successfully discovered an antibody that binds with high affinity to CLDN6 and CLDN9 while sparing other claudin family members. The humanized version of this candidate antibody demonstrates stronger binding and higher internalization compared to a benchmark antibody currently in clinical development. BLB-101 is an antibody-drug conjugate (ADC) candidate featuring a topoisomerase-inhibitor-based payload optimized in-house with a proprietary hydrophilic linker. Design features of the linker enable efficient delivery of hydrophobic drug payloads and low likelihood of off-target endocytosis. BLB-101 has drug-to-antibody ratio of 8 (DAR8), demonstrates enhanced potency, favorable in vivo PK, and excellent plasma stability. In vitro studies revealed that BLB-101 ADC quickly internalizes in CLDN6+ or CLDN9+ cancer cells. BLB-101 exhibited strong cytotoxic effects across several cancer cell lines, including PA-1 and JEG-3. In addition, we confirmed the bystander killing effect of BLB-101 under a coculture condition of CLDN6-positive cells and negative cells in vitro. Furthermore, BLB-101 maintains the mAb's capability to induce antibody-dependent cellular cytotoxicity. In xenograft models expressing CLDN6, BLB-101 treatment led to a substantial reduction in tumor size. Additionally, repeated administration of BLB-101 was well tolerated in both mice and in non-human primates. Together, these findings provide strong support for the continued development of BLB-101directed against CLDN6/CLDN9 positive tumors. Citation Format: Suk Hyung Lee, Alice Juang, Aastha Jain, Jun Liu, Wen Zhang, Zuoan Yi, Darren Buchwald, Alice Chen. Preclinical evaluation of BLB-101, a topoisomerase-inhibitor-based anti-CLDN6/9 antibody-drug conjugate featuring a proprietary hydrophilic linker [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 1578.