3H-10000的临床前开发：一种用于治疗FGFR2b表达癌症的新型vedotin抗体偶联药物

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 & PDX) across a range of FGFR2b expression levels from low to high. More important is that there existed significant synergy in tumor growth inhibition and regression in SNU-16 CDX study, when 3H-10000 was combined with a FGFR2 selective small molecule inhibitor 3HP-2827, which would strongly support clinic trail exploration of the combined therapy strategy of FGFR2b-ADC and 3HP-2827 to overcome drug resistance and perform persistent therapeutic efficacy. The safety study demonstrated that 3H-10000 spared corneal toxicity in mice compared with Bemarituzumab. Furthermore, 3H-10000 also demonstrated good tolerability in cynomolgus monkeys, with the highest non-severely toxic dose (HNSTD) determined to be 9 mg/kg administered once every two weeks for a total of three doses. Overall, 3H-10000, the novel FGFR2b ADC, is a highly potent targeted therapy candidate against cancers. Overall, this study is the first to our knowledge where the combinational treatment of FGFR2b ADC and FGFR2 selective kinase inhibitor demonstrated synergic inhibition of tumor cell growth. These results strongly support advancing 3H-10000 into clinical evaluation in treatment of unnormal FGFR2 expressing solid tumors, and a phase I study has (CTR20254555) is ongoing.