S DUAL™：一种兼具实用可制造性和增强治疗疗效的先进双特异性抗体平台

Background - Receptor tyrosine kinases (RTKs) drive tumor progression through ligand‑dependent or ligand‑independent dimerization, which brings the intracellular kinase domains into proximity, triggers autophosphorylation, and recruits adaptor proteins such as GRB2 and Shc. The resulting RAS‑MAPK and PI3K‑AKT cascades sustain cancer cell proliferation, survival and differentiation. Among RTKs, HER2 (ErbB2) is an orphan receptor that preferentially forms homodimers and heterodimers with other ErbB family members. HER2 over‑expression or the generation of truncated forms (e.g., p95HER2) is strongly associated with aggressive disease and resistance to HER2‑directed therapies. Clinically - approved HER2 antibodies-trastuzumab (domain IV) and pertuzumab (domain II)-bind distinct extracellular epitopes yet only partially inhibit HER2‑driven signaling, especially in tumors with high HER2 density or in which the receptor is mutated/truncated. Consequently, patients often develop intrinsic or acquired resistance. Approach - To overcome these limitations, we employed Samsung Biologics' S‑DUAL TM platform to generate a heterodimeric bispecific antibody (BsAb) that simultaneously engages HER2 epitopes II and IV. The two Fab arms are engineered to heterodimerize via a “knob‑into‑hole” Fc architecture, preserving native IgG1 Fc effector function while enforcing defined Fab geometry. Results - In HER2‑positive cell lines, S‑DUAL TM reduced HER2 autophosphorylation by ~27.9 % (p < 0.05) and downstream p‑ERK1/2 and p‑AKT levels by 18.6 % and 25.3 %, respectively, resulting in a maximal inhibition (Emax) of 64.4 % in cell proliferation (IC 50  ≈ 1.64 nM). Cell surface binding affinity and Fc‑mediated ADCC activity remained comparable to reference platform. In HER2‑positive xenograft models, weekly intravenous administration of S‑DUAL TM substantially reduced tumor growth relative to the isotype control, achieving a marked suppression of tumor volume without evident toxicity. Conclusion - Simultaneous blockade of two non‑overlapping HER2 extracellular domains by a biparatopic BsAb can fully suppress ligand‑independent HER2 signaling while preserving immune effector mechanisms. This “dual‑epitope, Fab‑geometry‑tuned” strategy defines a new design principle for next‑generation HER2 therapeutics and offers a potential solution to overcome resistance arising from HER2 over‑expression, truncation, or mutation.