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

  • Nat Commun. 2026 Feb 24;17(1):3113. doi: 10.1038/s41467-026-69703-7.
Jian Guan  #  1 ,  Tiongsun Chia  #  1 ,  Bin Li  #  2 ,  Tianyu Zhu  1 ,  Zhengguang Liao  1 ,  Junjie Deng  3 ,  Fenggen Fu  2 ,  Weiwei Wu  3 ,  Chengtao Liu  1 ,  Ya Liu  3 ,  Ninghuan Li  2 ,  Lili Yue  1 ,  Lei Cao  3 ,  Jia Lu  3 ,  Mengjia Zhu  3 ,  Xiaomin Ling  2 ,  Huilin Zheng  1 ,  Shuming Lin  1 ,  Li Li  2 ,  Shuaixiang Zhou  4 ,  Kaijie He  5
Affiliations
  • 1. Department of Cancer Biology, Innovent Guoqing Academy, Suzhou, China.
  • 2. Department of Antibody Discovery and Protein Engineering, Innovent Guoqing Academy, Suzhou, China.
  • 3. Department of Pharmacology and Toxicology, Innovent Guoqing Academy, Suzhou, China.
  • 4. Department of Antibody Discovery and Protein Engineering, Innovent Guoqing Academy, Suzhou, China. [email protected].
  • 5. Department of Cancer Biology, Innovent Guoqing Academy, Suzhou, China. [email protected].
  • # Contributed equally.
PMID: 41735305 DOI: 10.1038/s41467-026-69703-7
Abstract

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.

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