ACR335: Novel cMET/EGFR Bispecific Antibody-Drug Conjugate Shows Antitumor Activity

Background: cMET and EGFR are frequently co-expressed oncogenic drivers in solid tumors, with pathway crosstalk driving therapeutic resistance. This combination is clinically validated by amivantamab, a bispecific antibody (BsAb) targeting cMET and EGFR approved for EGFR-mutant NSCLC. To enhance efficacy and overcome resistance, we developed ACR335, a bispecific ADC (BsADC) that simultaneously targets both receptors. Furthermore, ACR335 is engineered as a dual-payload ADC, combining a Topoisomerase I (Top1) inhibitor and a non-Top/non-Tubulin inhibitor, a strategy designed to synergistically maximize tumor cell killing. Methods: The BsAb IBR335 combines a fully human anti-cMET antibody (isolated from a naïve phage library) with an engineered version of panitumumab (anti-EGFR). Binding affinity for cMET and EGFR was determined by BLI, tumor cell binding by flow cytometry, and internalization efficiency by a Fab-ZAP cytotoxicity assay. ACR335 was generated by site-specifically conjugating IBR335 to a Top1 inhibitor and a non-Top/non-Tubulin inhibitor using the MuSC™ platform, achieving a DAR of 4+4. Antitumor efficacy was evaluated in multiple cMET/EGFR-positive CDX models, including KATO-III (gastric), H1650 (NSCLC, EGFR Ex19del), Calu-6 (NSCLC, EGFR-wt), HT1376, and SW780 (bladder), with single-payload ADCs or a Dxd-ADC as benchmarks. Results: IBR335 exhibited a 27.5-fold higher binding affinity for human cMET (KD = 0.149 nM) than for EGFR (KD = 4.1 nM), with sub-nanomolar EC50 binding to cMET/EGFR-positive tumor cells comparable to amivantamab and efficient internalization. This preferential targeting strategy mitigates potential on-target off-tumor toxicity associated with broad EGFR inhibition. The resulting ADC, ACR335, was homogeneous with a DAR of 4+4. It demonstrated potent in vitro cytotoxicity and induced significant tumor growth inhibition and regression across multiple CDX models, showing superior efficacy to single-payload ADCs and the Dxd-ADC benchmark. ACR335 was well-tolerated with no significant toxicity observed. Pharmacokinetic and safety studies in cynomolgus monkeys are ongoing. Conclusions: ACR335 is a first-in-class cMET/EGFR bispecific dual-payload ADC with a unique pharmacological profile. The compelling preclinical data underscore its potential as a targeted therapy with an optimized safety profile. Phase I clinical trials are expected to commence in Q2 2026. Citation Format: Zhenwei Miao, Feng Wang, Shanwei Weng, Li Yang, Wu Yao. ACR335, a novel cMET/EGFR bispecific dual-payload antibody-drug conjugate, demonstrates potent and broad antitumor activity in preclinical models of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1775.