Human epidermal growth factor receptor 2 and DNA topoisomerase 1 (HER2/TOP1)

The combined mechanism of KN026 and irinotecan involves the simultaneous targeting of the Human Epidermal Growth Factor Receptor 2 (HER2) and DNA Topoisomerase 1 (TOP1) to treat HER2-positive malignancies (UniProt P04626, P11387). KN026 is a bispecific antibody that binds to two non-overlapping epitopes on the extracellular domain of HER2, effectively blocking downstream signaling pathways such as PI3K/Akt and MAPK that drive cell proliferation (Alphamab Oncology). Irinotecan, a prodrug converted to the potent topoisomerase I inhibitor SN-38, interferes with DNA replication by stabilizing the cleavable complex between TOP1 and DNA, leading to lethal double-strand breaks (PubChem CID 60838). This combination therapy is primarily investigated in HER2-positive cancers, such as gastric and breast cancers, where the dual inhibition of oncogenic signaling and DNA maintenance provides a synergistic effect to overcome resistance (ClinicalTrials.gov NCT04040634). By targeting HER2-mediated survival signals while simultaneously inducing genomic instability, the regimen aims to enhance apoptosis and improve clinical outcomes in patients with advanced solid tumors. The strategy leverages the high specificity of the bispecific antibody for tumor cells and the potent cytotoxicity of the topoisomerase inhibitor to maximize therapeutic efficacy.

Other names

ERBB2HER2/neuTOP1Topoisomerase IKN026 and Irinotecan targetsHER2 and Topoisomerase 1 combination

KN026 is a bispecific antibody that binds to two distinct epitopes of HER2 (domains II and IV), leading to dual blockade of HER2 signaling and enhanced receptor internalization (Alphamab Oncology). Irinotecan, via its active metabolite SN-38, inhibits DNA Topoisomerase 1 by stabilizing the DNA-enzyme cleavable complex, which causes lethal double-strand breaks during DNA replication (PubChem CID 60838). The combination provides synergistic anti-tumor activity by simultaneously inhibiting oncogenic growth signaling and inducing genomic instability.