HER2 (biparatopic — extracellular domains II and IV)

Class

biparatopic anti-HER2 antibody-drug conjugate; humanized bispecific antibody (based on KN026, binding both the pertuzumab-binding domain II and the trastuzumab-binding domain IV of HER2) conjugated via a dibenzocyclooctyne tetrapeptide linker to a topoisomerase I inhibitor payload

Pathway

dual-epitope HER2 engagement drives efficient receptor clustering and internalization; the ADC traffics to the lysosome, where the topoisomerase I inhibitor payload is released, causing DNA damage and apoptosis

HER2 (human epidermal growth factor receptor 2) is a cell-surface receptor tyrosine kinase that, when overexpressed, drives uncontrolled growth signaling in a subset of cancers, most notably breast and gastric tumors. Because HER2 sits on the outside of the cell, it can be targeted directly by antibodies that bind its extracellular portion. This mechanism uses a biparatopic antibody—one that binds two distinct, non-overlapping sites on HER2 (domain II and domain IV) simultaneously—fused to a cytotoxic payload, forming an antibody-drug conjugate (ADC). Engaging both epitopes at once forces HER2 receptors into tight clusters on the cell surface, which the cell interprets as a signal to internalize them. This internalization is deliberately exploited: it delivers the attached chemotherapy payload directly into the cancer cell, where it is released and interferes with DNA replication, ultimately causing cell death. The rationale for pairing two epitopes rather than one is that dual engagement produces more efficient clustering and internalization than a single-epitope antibody, potentially improving payload delivery even in tumors with only moderate HER2 expression. This approach is broadly relevant to HER2-driven cancers, where matching cytotoxic potency to receptor-selective delivery aims to widen the therapeutic window compared with systemic chemotherapy alone.