B7-H3-mediated cis-inhibition of EGFR by a tumor-selective bispecific antibody enhances anti-tumor efficacy and minimizes toxicities - PubMed
4 hours ago
- #EGFR
- #Bispecific Antibody
- #Cancer Therapy
- Therapeutic targeting of EGFR in solid tumors is limited by on-target/off-tumor toxicities, necessitating tumor-selective anti-EGFR therapies.
- B7-H3 is markedly upregulated in EGFR-positive malignancies but minimally expressed in healthy tissues.
- IBI334, a bispecific antibody (bsAb) targeting EGFR/B7-H3, shows exceptional tumor selectivity and outperforms conventional EGFR antibodies in preclinical models.
- IBI334 enhances EGFR occupancy, ligand-blocking efficacy, receptor degradation, and suppression of downstream EGFR signaling via B7-H3-mediated cis-inhibition.
- Cryo-EM reveals the human B7-H3 extracellular domain (ECD) in complex with anti-B7-H3 Fab, identifying critical residues for antibody-B7-H3 interaction.
- IBI334 demonstrates robust antitumor activity in EGFR-driven tumor models and synergizes effectively with KRAS inhibitors.
- Toxicological evaluations in non-human primates show a favorable safety profile, with no EGFR-related adverse effects at doses up to 120 mg/kg over 4 weeks.
- IBI334 has advanced to a phase 1 clinical trial (NCT05774873) for advanced/metastatic solid tumors.