B7H3 and PTK7 (bispecific, co-expression-dependent internalization)

Class

Bispecific antibody-drug conjugate (TOP1 inhibitor payload)

Pathway

DNA damage via topoisomerase I inhibition, dual-antigen-restricted internalization

B7H3 (also called CD276) and PTK7 are two proteins frequently found at elevated levels on the surface of various solid tumor cells, though each is also present at lower levels on some normal tissues. This mechanism uses a bispecific antibody-drug conjugate (ADC): an antibody engineered to recognize both B7H3 and PTK7 simultaneously, requiring a cell to display both markers together before the ADC is efficiently taken up (internalized). This co-expression requirement is a strategy to sharpen tumor selectivity, since a healthy cell expressing only one of the two antigens is less likely to trigger sufficient uptake, whereas a tumor cell expressing both is targeted more effectively. Once internalized, the ADC releases its attached drug payload, a topoisomerase I (TOP1) inhibitor, inside the cell. TOP1 is an enzyme needed for relieving tension in DNA during replication; blocking it causes unresolved DNA damage that is particularly lethal to rapidly dividing cancer cells. This general approach—antigen-restricted delivery of a potent DNA-damaging payload—broadly matters in oncology because it aims to concentrate cytotoxic activity in tumor tissue while limiting exposure of normal organs, addressing the narrow therapeutic window that has historically limited direct use of such DNA-damaging agents.