anti-B7-H4/TOP1i antibody-drug conjugate GSK5733584

An antibody-drug conjugate (ADC) composed of a humanized immunoglobulin G1 (IgG1) monoclonal antibody directed against B7-H4 (V-set domain-containing T-cell activation inhibitor 1; VTCN1; B7x; B7S1) linked, via a protease-cleavable linker, to a topoisomerase-1 inhibitor (TOP1i; TOP-Ii), with potential antineoplastic activity. Upon administration of anti-B7-H4/ TOP1i ADC GSK5733584, the anti-B7-H4 monoclonal antibody moiety targets and binds to B7-H4 expressed on tumor cells. Upon binding and internalization, the TOP1i moiety binds to TOP1 and stabilizes cleaved DNA-TOP1 complexes. This prevents DNA re-ligation, induces irreversible DNA strand breaks, prevents DNA repair, and leads to cycle arrest and apoptosis specifically in tumor cells expressing B7-H4. B7-H4, a member of the B7 family of immune modulators, is upregulated in a variety of tumor cell types and tumor-associated macrophages. It negatively regulates T-cell immune responses.