Epidermal growth factor receptor (EGFR) and Human epidermal growth factor receptor 3 (HER3) with concurrent DNA topoisomerase 1 inhibition (EGFR/HER3-Top1i)

This therapeutic target profile involves the dual inhibition of the Epidermal Growth Factor Receptor (EGFR) and Human Epidermal Growth Factor Receptor 3 (HER3) combined with the cytotoxic action of a Topoisomerase I inhibitor. EGFR and HER3 are members of the ErbB family of receptor tyrosine kinases that are frequently overexpressed or mutated in various solid tumors, driving cell proliferation and survival through the MAPK and PI3K/Akt pathways (PMID: 31439558). HER3 is particularly noted for its role in mediating resistance to standard EGFR-targeted therapies. By utilizing a bispecific antibody-drug conjugate (ADC) approach, drugs targeting this complex bind to both receptors, facilitating efficient internalization and delivery of a Topoisomerase I inhibitor payload directly into the tumor cell. Once released, the payload inhibits DNA re-ligation during replication, leading to double-strand breaks and apoptosis (StatPearls: Topoisomerase Inhibitors). This multi-pronged strategy aims to overcome resistance mechanisms and enhance anti-tumor efficacy in cancers such as non-small cell lung cancer and breast cancer (ASCO 2023, Abstract 3001). The bispecific nature of the antibody component increases selectivity for tumor cells overexpressing both receptors, potentially widening the therapeutic window. Clinical development of agents like BL-B01D1 has demonstrated significant clinical activity in patients who have failed multiple prior lines of therapy, including third-generation EGFR tyrosine kinase inhibitors.

Other names

EGFR/HER3 bispecific antibody-drug conjugateEGFR-HER3-Top1 inhibitor conjugateErbB1/ErbB3 dual targeting with Topoisomerase I inhibitionBL-B01D1 target complex

Simultaneous binding to EGFR and HER3 receptors on the cell surface followed by receptor-mediated endocytosis and intracellular release of a topoisomerase I inhibitor payload, which induces DNA damage and cell death.