Discovery and Optimization of AMT-676, a CDH17-Targeting ADC for the Treatment of Advanced Gastrointestinal Cancers

Advanced-stage gastrointestinal (GI) cancers present an unmet need for innovative therapies, and antibody-drug conjugates (ADCs) offer promising solutions. This study investigates the antitumor efficacy and toxicity of AMT-676, a novel ADC targeting Cadherin 17 (CDH17), in GI cancers. Utilizing MabArray screening and immunohistochemistry, CDH17 was identified as a promising ADC target in GI tumors with minimal expression in healthy organs. The ADC was optimized through comprehensive in vitro and in vivo evaluations of binding affinity, cytotoxicity, pharmacokinetics, and toxicity, with antitumor potential evaluated using cell line-derived (CDX) and patient-derived tumor xenograft (PDX) models. Leveraging the T moiety-exatecan platform, we synthesized AMT-676, comprising a high-affinity CDH17-specific antibody, a hydrophilic self-immolative T1000 linker, and exatecan with a Drug-to-Antibody Ratio (DAR) of 4. AMT-676 demonstrated sustained antitumor responses across CDX and PDX GI models with diverse CDH17 expression, notably inhibiting metastatic growth in a colorectal cancer model. Cynomolgus monkey studies revealed favorable pharmacokinetics and manageable toxicity associated with AMT-676. In conclusion, we developed a novel CDH17-targeting ADC characterized by a high therapeutic index and tolerable toxicity profile, highlighting its promise for GI cancer treatment. A first-in-human, phase I clinical trial of AMT-676 in patients with advanced solid tumors is currently underway (NCT06400485).