B7-H3-mediated cis-inhibition of EGFR by a tumor-selective bispecific antibody enhances anti-tumor efficacy and minimizes toxicities

Therapeutic targeting of epidermal growth factor receptor (EGFR) in solid tumors faces significant limitations due to on-target/off-tumor toxicities, underscoring the urgent need for tumor-selective anti-EGFR therapies. Comprehensive bioinformatics and histopathological analyses identify marked upregulation of B7-H3 across EGFR-positive malignancies, contrasting with its minimal expression in healthy tissues. Leveraging an unbiased functional screen of bispecific antibodies (bsAbs) combining diverse B7-H3 and EGFR binders, we develop IBI334, a EGFR/B7-H3 bsAb exhibiting exceptional tumor selectivity. In preclinical models, IBI334 outperforms conventional EGFR antibodies by demonstrating superior EGFR occupancy, enhanced ligand-blocking efficacy, accelerated receptor degradation, and potent suppression of downstream EGFR signaling. Mechanistic studies demonstrate B7-H3-mediated cis-inhibition. The human B7-H3 extracellular domain (ECD) in complex with anti-B7-H3 Fab is resolved by cryo-EM, revealing critical residues for the antibody-B7-H3 interaction. IBI334 demonstrates robust antitumor activity in vitro and in vivo across EGFR-driven tumor models and synergized effectively with KRAS inhibitors. Toxicological evaluations in non-human primates reveals a favorable safety profile, with no EGFR-related adverse effects observed at doses up to 120 mg/kg over 4 weeks. Supported by these preclinical findings, IBI334 has advanced to a phase 1 clinical trial (NCT05774873) for advanced/metastatic solid tumors. EGFR-targeted therapy is often used in patients with EGFR-driven cancer but is limited by on-target/off-tumor toxicities. Here, the authors develop a bispecific antibody targeting both EGFR and B7-H3 and demonstrate improved EGFR targeting and tumor selectivity in preclinical models of multiple solid tumors.