Targeting ADAM9 with IMGC936: A Promising Anti-Tumor Strategy

ADAM9, part of the ADAM protease family, is linked to tumor progression, metastasis, and poor prognosis in various cancers. Given its overexpression in multiple solid tumors and the efficient internalization and degradation by tumor cells, ADAM9 is a compelling target for antibody-drug conjugate (ADC) therapies. IMGC936 is the first preclinically developed ADC designed to target ADAM9.

This novel ADC consists of a high-affinity humanized antibody conjugated to DM21, a next-generation linker-payload featuring a maytansinoid that disrupts microtubules. To enhance in vivo plasma half-life and exposure, the YTE mutation was introduced into the CH2 domain of the antibody. IMGC936 displayed targeted cytotoxicity against ADAM9-positive tumor cell lines with significantly greater potency than a non-targeting conjugate.

In multiple xenograft models of non-small cell lung, gastric, and colorectal cancers, IMGC936 exhibited significant anti-tumor activity. Notably, in a non-small cell lung cancer model with moderate ADAM9 expression, a single intravenous dose of IMGC936 resulted in complete and durable remissions in all treated mice.

The ADC showed a favorable pharmacokinetic profile and stability in non-human primates, along with good tolerability and no target-related toxicities at doses surpassing those required for efficacy in murine models. These preclinical findings indicate that IMGC936 is a promising therapeutic candidate for a broad spectrum of ADAM9-expressing tumors.