Abstract LB268: Preclinical development of 3H-10000, a novel vedotin antibody-drug conjugate for treatment of FGFR2b-expressing cancers

Abstract FGFR2b overexpression across multiple cancer types promotes dysregulated tyrosine kinase activation and results in tumor progression and unchecked malignance with exciting potential for targeted therapies in solid tumors. 3H-10000 is a novel vedotin antibody-drug conjugate (ADC) comprising a specific anti-FGFR2b human monoclonal antibody conjugated to the cytotoxic payload monomethyl auristatin E (MMAE) via a protease-cleavable maleimidocaproyl valine citrulline (mc-vc) linker. FGFR2b mAb as carrier, selectively target and deliver ADC (3H-10000) molecules to tumors, reducing systemic toxicity and enhancing therapeutic efficacy; the linker is stable in circulation, effectively cleaves and releases payload inside tumor cells, reducing off-target toxicity, and exerts bystander effect to address tumor heterogeneity; the applied payload is cytotoxic and highly efficient. In vitro, 3H-10000 demonstrated FGFR2b-specific binding to cells, efficient internalization, FGFR2b-expression-dependent cytotoxicity, and bystander effects. Pharmacokinetic analyses in mice bearing FGFR2-positive SNU-16 tumors showed that MMAE, the payload of 3H-10000 achieves tumor exposure that is more than 400-fold higher than plasma exposure. Efficacy studies demonstrated robust and sustained antitumor activity in gastric carcinoma and sqNSCLC xenograft mouse models (CDX Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB268.