anti-B7-H4 antibody-drug conjugate XMT-1660

An antibody-drug conjugate (ADC) composed of XMT-1604, a human immunoglobulin G1 (IgG1) monoclonal antibody directed against the T-cell checkpoint ligand B7-H4 (V-set domain-containing T-cell activation inhibitor 1; VTCN1; B7x; B7S1), site-specifically conjugated to six cytotoxic auristatin derivative auristatin F-HPA (AF-HPA; auristatin F-hydroxypropylamide) payloads per antibody, with potential antineoplastic activity. Upon administration of anti-B7-H4 ADC XMT-1660, the anti-B7-H4 monoclonal antibody moiety targets and binds to B7-H4 expressed on tumor cells. Upon binding, internalization and linker cleavage, membrane permeating AF-HPA is metabolically converted to membrane non-permeating auristatin F, which binds to tubulin and inhibits microtubule polymerization. This results in G2/M phase arrest and the apoptosis of B7-H4-expressing tumor cells. B7-H4, a member of the B7 family of immune modulators, is upregulated in a variety of tumor cell types and tumor-associated macrophages (TAMs). It negatively regulates T-cell immune responses. The metabolic conversion of membrane permeating AF-HPA to membrane non-permeating auristatin F results in a controlled bystander effect, and prevents or lessens neutropenia as an adverse effect of auristatin.