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

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 FcgammaR-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.