A novel ADAM9 ADC with robust anti-tumor efficacy and remarkable preclinical safety profile

ADAM9 (A Disintegrin And Metalloproteinase 9) is a transmembrane metalloproteinase overexpressed in a wide range of solid tumors, where it promotes tumor progression, metastasis, and poor prognosis. Internal immunohistochemistry analysis confirmed ADAM9 expressed at very low levels in most normal tissues, significant ADAM9 upregulation in tumor tissues, makes it a highly attractive and viable target for antibody-drug conjugate (ADC) development. An affinity optimized, humanized monoclonal antibody (HC031) was generated against human ADAM9. HC031 cross reacts with cyno ADAM9 with similar affinity. HC031 exhibited specific binding to human ADAM9 with no detectable binding to other ADAM family isoforms. HC031 selectively binds to membrane form of ADAM9 but not to short soluble ADAM9 predicting a regular pharmacokinetic profile unimpeded by soluble ADAM9. Furthermore, HC031 binding is partially dependent of bivalent cation, which may contribute to an improved safety profile. HC031 ADC was generated through conjugation with a novel, proprietary cytotoxic payload (camptothecin derivatives) via a highly stable linker. The resulting ADC demonstrated potent, target-specific cell killing in vitro and induced robust and sustained tumor regression in multiple xenograft models. Exploratory toxicology studies in non-human primates revealed an exceptionally maximum tolerated dose (MTD) of 120 mg/kg. No drug-related severe adverse events or significant abnormalities in hematological, biochemical, or coagulation parameters were observed. HC031 ADC exhibited favorable and dose-proportional PK profiles, with extended exposure of the intact ADC. Critically, the linker-payload demonstrated superior plasma stability.HC031 ADC drives potent anti-tumor activity in vitro and in vivo . Its exceptional stability in circulation and remarkable preclinical safety profile in NHPs predicts a significantly broader therapeutic window compared to existing ADAM9 ADCs.