9LY6
antibody 20G5 (Fab')2 in complex with human B7-H3
Summary for 9LY6
| Entry DOI | 10.2210/pdb9ly6/pdb |
| EMDB information | 63505 |
| Descriptor | CD276 antigen, antibody 20G5 Fab heavy chain, antibody 20G5 Fab light chain (3 entities in total) |
| Functional Keywords | b7-h3, antibody, complex, antitumor protein/immune system, antitumor protein-immune system complex |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 5 |
| Total formula weight | 143681.53 |
| Authors | |
| Primary citation | Guan, J.,Chia, T.,Li, B.,Zhu, T.,Liao, Z.,Deng, J.,Fu, F.,Wu, W.,Liu, C.,Liu, Y.,Li, N.,Yue, L.,Cao, L.,Lu, J.,Zhu, M.,Ling, X.,Zheng, H.,Lin, S.,Li, L.,Zhou, S.,He, K. B7-H3-mediated cis-inhibition of EGFR by a tumor-selective bispecific antibody enhances anti-tumor efficacy and minimizes toxicities. Nat Commun, 17:-, 2026 Cited by PubMed 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. PubMed: 41735305DOI: 10.1038/s41467-026-69703-7 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.67 Å) |
Structure validation
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