anti-B7-H4/MMAE ADC LNCB74

An antibody-drug conjugate (ADC) composed of a human immunoglobulin (Ig) G1 kappa monoclonal antibody directed against the T-cell checkpoint ligand B7-H4 (V-set domain-containing T-cell activation inhibitor 1; VTCN1; B7x; B7S1) conjugated, via a beta-glucuronidase-cleavable linker, to monomethyl auristatin E (MMAE), an auristatin derivative and a potent microtubule disrupting agent, with potential antineoplastic and immunomodulating activities. Upon administration of anti-B7-H4/MMAE ADC LNCB74, the anti-B7-H4 antibody targets and binds to B7-H4 expressed on tumor cells. Upon binding and internalization, MMAE is released upon cleavage by the cancer-associated lysosomal enzyme beta-glucuronidase. MMAE binds to tubulin and inhibits its polymerization, resulting in G2/M phase arrest and tumor cell apoptosis. This induces cell death in B7-H4-expressing cancer cells. LNCB74 also induces a bystander effect, thereby further killing neighboring tumor cells upon uptake of MMAE and induces an immune-mediated cell death. 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) while minimally expressed in normal, healthy tissues. It negatively regulates T-cell immune responses. LNCB74 contains a LALA-hG1 Fc region to minimize uptake and toxicity to immune cells, thereby further improving the safety profile.