Discovery of A Novel EGFR-Targeting Antibody-Drug Conjugate, SHR-A1307, for the Treatment of Solid Tumors Resistant or Refractory to Anti-EGFR Therapies

摘要

Although inhibiting EGFR-mediated signaling proved to be effective in treating certain types of cancers, a quickly evolved mechanism that either restores the EGFR signaling or activates an alternative pathway for driving the proliferation and survival of malignant cells limits the efficacy and utility of the approach via suppressing the EGFR functionality. Given the fact that overexpression of EGFR is commonly seen in many cancers, an EGFR-targeting antibody-drug conjugate (ADC) can selectively kill cancer cells independently of blocking EGFR-mediated signaling. Herein, we describe SHR-A1307, a novel anti-EGFR ADC, generated from an anti-EGFR antibody with prolonged halflife, and conjugated with a proprietary toxin payload that has increased index of ECFR targeting-dependent versus EGFR targeting-independent cytotoxicity. SHR-A1307 demonstrated strong and sustained antitumor activities in EGFR-positive tumors harboring different oncogenic mutations on EGFR, KRAS, or PIK3CA. Antitumor efficacy of SHR-A1307 correlated with EGFR expression levels in vitro and in vivo, regardless of the mutation status of EGFR signaling mediators and a resultant resistance to EGFR signaling inhibitors. Cynomolgus monkey toxicology study showed that SHR-A1307 is well tolerated with a wide therapeutic index. SHR-A1307 is a promising therapeutic option for EGFR-expressing cancers, including those resistant or refractory to the EGFR pathway inhibitors.