Antibody-Exatecan Conjugates with a Novel Self-immolative Moiety Overcome Resistance in Colon and Lung Cancer

Antibody-drug conjugates (ADC) using DNA topoisomerase I inhibitor DXd/SN-38 have transformed cancer treatment, yet more effective ADCs are needed for over-coming resistance. We have designed an ADC class using a novel self-immolative T moiety for traceless conjugation and release of exatecan, a more potent topoisomerase I inhibitor with less sensitivity to multidrug resistance (MDR). Characterized by enhanced therapeutic indices, higher stability, and improved intratumoral pharmacodynamic response, antibody-T moiety-exatecan conjugates target-ing HER2, HER3, and TROP2 overcome the intrinsic or treatment resistance of equivalent DXd/SN-38 ADCs in low-target-expression, large, and MDR + tumors. T moiety-exatecan ADCs display durable antitumor activity in patient-derived xenograft and organoid models representative of unmet clinical needs, including EGFR ex19del/T790M/C797S triple-mutation lung cancer and BRAF/KRAS-TP53 double-mutant colon cancer, and show synergy with PARP/ATR inhibitor and anti-PD-1 treatment. High tolerability of the T moiety-exatecan ADC class in nonhuman primates supports its potential to expand the responding patient population and tumor types beyond current ADCs. SIGNIFICANCE: ADCs combining a novel self-immolative moiety and topoisomerase I inhibitor exate-can as payload show deep and durable response in low-target-expressing and MDR + tumors resistant to DXd/SN-38 ADCs without increasing toxicity. This new class of ADCs has the potential to benefi t an additional patient population beyond current options.

Automated summary

This study introduces a novel class of ADCs with a self-immolative T moiety for traceless conjugation and release of exatecan. These ADCs overcome resistance faced by equivalent DXd/SN-38 ADCs in low-target-expression, large, and MDR+ tumors, and show synergy with PARP/ATR inhibitor and anti-PD-1 treatment.