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

Abstract

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 EGFR 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.

Discovery and Development of Dolastatin 10-Derived Antibody Drug Conjugate Anticancer Drugs

“…He et al (2019) reported modifications of dolaproine along with aromatic ring halogenated analogues of MMAF ( 89 – 93 ). Cyclopropyl MMAF ( 89 ) and cyclopropyl- o -chloro-MMAF ( 90 ) showed excellent activity, with GI 50 values of 1.1 and 1.06 nM, respectively, against the SB-BR-3 HER2+ cell line.…”

“…Based on the highest cytotoxic activity ratio of >1500 of ADC and free toxin payload, the noncleavable anti-EGFR (hR3)-ADC SHR-A1307 (GI 50 0.031 nM) ( 94a ) containing cyclopropyl-fluoro-MMAF 93 (GI 50 47.7 nM) was selected for further characterization and development, with the expectation that the lysosomal released payload would not be subject to cellular efflux and thus exert less toxicity. SHR-A1307 showed broad-spectrum efficacy against a series of HER2+ tumor xenograft murine models at 1.2 and 4 mg/kg including drug-resistant models, without exhibiting overt toxicities at 40 mg/kg at repeated doses, indicating a 10–20-fold therapeutic window (2019) . However, it was not as well tolerated in cynomolgus monkeys at 10 mg/kg after repeated dosing.…”

Emerging strategies to overcome resistance to third-generation EGFR inhibitors

“…He et al developed a new ADC targeting EGFR, namely SHR-A1307 ( 47 ) (Fig. 13 ), for the treatment of solid tumors resistant or refractory to EGFR-targeted therapy [ 142 ]. SHR-A1307 ( 47 ) has intermediate ability to block EGFR affinity for hR3 and selectively binds to cancer cells expressing EGFR while avoiding inhibitory effects on normal cells.…”

Antibody-Drug Conjugates Containing Payloads from Marine Origin

“…Another MMAF analog considered for ADC development was a cyclopropyl fluoro derivative, which was incorporated into the ADCs 48 and 49 in an attempt to address some pharmacological issues such as toxicity, expecting that the payload would not be subject to cellular efflux and thus exert less toxicity. Thus, the ADCs, consisting of the anti-EGFR and of the anti-c-MET antibodies conjugates, were prepared, revealing a DAR of 2 [ 104 ]. While the first was not well tolerated in preclinical studies at 10 mg/kg doses, the second displayed a better pharmacological profile, combined with strong cytotoxic activity against c-MET-expressing cell lines, including NCI-H1993, MKN-45, and HCCLM3 with IC 50 values of 16.3, 7.8 and 3.2 ng/mL, respectively [ 105 ].…”