Topoisomerase-Based CDH17 Antibody Drug Conjugates Overcome P-gp Resistance but Undergo Target Mediated Clearance in Colorectal Cancer

PURPOSE: Cadherin 17 (CDH17) is an emerging therapeutic target in colorectal cancer (CRC), but the effects of drug efflux and physiological CDH17 expression on the activity and pharmacokinetics of CDH17-directed antibody-drug conjugates (ADCs) remain poorly understood. We evaluated the impact of payload selection and target-mediated clearance on CDH17-directed ADCs. EXPERIMENTAL DESIGN: CDH17-directed ADCs carrying either monomethyl auristatin E (MMAE) or the topoisomerase 1 inhibitor exatecan were evaluated in CRC models with variable P-glycoprotein (P-gp) expression. The effects of P-gp modulation on ADC sensitivity were assessed. CDH17 expression in human tissues was characterized by immunohistochemistry, and pharmacokinetic studies were performed in cynomolgus monkeys and mice engineered to express human CDH17. RESULTS: CDH17-exatecan ADCs demonstrated greater antitumor activity than CDH17-MMAE ADCs in P-gp-expressing CRC models. Forced P-gp expression induced resistance to CDH17-MMAE ADCs without affecting sensitivity to CDH17-exatecan ADCs, whereas genetic or pharmacological inhibition of P-gp restored CDH17-MMAE activity. CDH17 was highly expressed in CRC and localized to the lateral membranes of gastrointestinal epithelial cells in normal tissues. In mice expressing human CDH17, CDH17-directed antibodies and ADCs exhibited approximately four-fold faster clearance than in wild-type mice or cynomolgus monkeys, consistent with substantial target mediated systemic drug clearance. CONCLUSIONS: Together, these findings identify topoisomerase I inhibitor payloads, such as exatecan, as advantageous for targeting P-gp-expressing CRCs while highlighting target-mediated clearance and potential on-target, off-tumor toxicity as important translational challenges for CDH17-directed therapeutics and other ADCs targeting antigens with substantial normal tissue expression.