Preclinical Development of MGC028, an ADAM9-Targeted, Glycan-Linked, Exatecan-Based Antibody–Drug Conjugate for the Treatment of Solid Cancers

ADAM9, a member of the a disintegrin and metalloproteinase (ADAM) family of multifunctional type 1 transmembrane proteins, is an attractive target for cancer treatment owing to its overexpression in multiple tumors and its role in tumorigenesis and cancer progression. A maytansine-based ADAM9-targeting antibody-drug conjugate (ADC), IMGC936, was affected by dose-limiting ocular adverse events, including blurred vision and keratopathy, that were observed both preclinically and in a first-in-human clinical study. Ocular toxicity is a well-known adverse event associated with microtubule inhibitor-based ADC payloads and has been reported for several approved ADCs. Although IMGC936 ocular toxicity was dose-limiting and likely constrained its clinical activity, no other prominent safety signals were observed. To date, topoisomerase 1-inhibitor ADCs have shown good clinical activity without the dose-limiting ocular toxicities experienced with microtubule inhibitor payloads. Given the attractiveness of ADAM9 for targeted therapy, we sought to develop a topoisomerase 1-inhibitor ADAM9 ADC. Here, we report the preclinical evaluation of MGC028, an ADAM9-targeting ADC that incorporates the cleavable linker-payload, bicyclononyne carbamoyl sulfamide Val-Ala-PABC exatecan (SYNtecan E), site-specifically conjugated at asparagine 297 of the heavy chain through enzymatic glycan remodeling and metal-free click chemistry. MGC028 demonstrated in vitro cytotoxicity toward ADAM9-positive human tumor cell lines and mediated bystander killing. MGC028 exhibited specific, dose-dependent in vivo antitumor activity toward ADAM9-positive cell line-derived and patient-derived xenograft models and was well tolerated in a repeat-dose nonhuman primate toxicology study, with no evidence of the ocular toxicities observed with IMGC936. A first-in-human study of MGC028 in patients with advanced solid tumors has been initiated (NCT06723236).