Abstract 1776: ALK101sc, a novel afucosylated bispecific antibody targeting EGFR and c-MET with common light chain demonstrates potent, broad-spectrum antitumor activity

Abstract Acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) represents a major clinical challenge in treating EGFR-mutant non-small cell lung cancer (NSCLC). This resistance arises either from secondary EGFR mutations (e.g., C797S) or via bypass signaling through the c-MET pathway—including c-MET mutation, gene amplification, or hepatocyte growth factor (HGF) upregulation. To overcome these mechanisms, we developed ALK101sc, an afucosylated IgG1 bispecific antibody (bsAb) co-formulated with hyaluronidase, designed to simultaneously target EGFR and c-MET. ALK101sc (120 mg/mL) was produced using a single-cell common-light-chain (CLC) platform, which ensured correct heterodimerization and scalable manufacturing without chain mispairing or exchange. In vitro functional assays demonstrated that ALK101sc effectively bound to EGFR/c-MET double-positive tumor cells, inducing receptor internalization and lysosomal degradation, and potently suppressed ligand-induced downstream signaling of both EGFR and c-MET, including phosphorylation of ERK and AKT. The afucosylated Fc region enhanced antibody-dependent cellular cytotoxicity (ADCC), thereby boosting FcγR-mediated antitumor immunity. In vivo, ALK101sc monotherapy induced significant tumor regression in both cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models, including those with EGFR mutations and/or c-MET-driven resistance. Furthermore, combining ALK101sc with osimertinib produced synergistic antitumor efficacy, even in the presence of TKI-insensitive mutations. Pharmacokinetic (PK) and GLP toxicology studies in cynomolgus monkeys following subcutaneous administration revealed typical antibody-like PK profiles, with systemic exposures comparable to amivantamab at equivalent doses and a bioavailability of approximately 89%. No significant abnormalities in safety pharmacology or toxicity were observed, with a no-observed-adverse-effect level (NOAEL) of 120 mg/kg. Together, these results demonstrate that ALK101sc exhibits antitumor potency comparable to amivantamab across preclinical models. Moreover, its CLC-based design provides a streamlined CMC development pathway, positioning it as a promising therapeutic candidate for overcoming EGFR TKI resistance. Compared with intravenous formulations, subcutaneous ALK101sc can substantially reduce administration time, improve patient convenience, and is expected to have a more favorable safety profile—characterized by meaningful reductions in infusion-related reactions (IRR) and venous thromboembolism (VTE) rates. Citation Format: Li Li, Hongwang He, Mengfan Peng, Meiyu Yang, Jiajia Pan, Hui Feng. ALK101sc, a novel afucosylated bispecific antibody targeting EGFR and c-MET with common light chain demonstrates potent, broad-spectrum antitumor activity [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 1776.