ACR335, a novel cMET/EGFR bispecific dual-payload antibody-drug conjugate, demonstrates potent and broad antitumor activity in preclinical models of solid tumors
Presenter: Zhenwei Miao, No Degree Session: Engineering the Next Wave of Antibody-Based Cancer Therapeutics Time: 4/20/2026 9:00:00 AM → 4/20/2026 12:00:00 PM
Authors
Zhenwei Miao , Feng Wang , Shanwei Weng , Li Yang , Wu Yao Hangzhou Adcoris Biopharma Co., Ltd, Hanghzou, China
Abstract
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 EC 50 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.
Disclosure
Z. Miao, Hangzhou Adcoris Biopharma Co., Ltd g., Board of Directors, non-salaried role). F. Wang, Hangzhou Adcoris Biopharma Co., Ltd Employment. S. Weng, Hangzhou Adcoris Biopharma Co., Ltd Employment. L. Yang, Hangzhou Adcoris Biopharma Co., Ltd Employment. W. Yao, Hangzhou Adcoris Biopharma Co., Ltd Employment.
Cited in
Control: 8714 · Presentation Id: 4332 · Meeting 21436