(A) Per cent survival of mB7-H4-Renca tumor-bearing mice treated with 3 weekly doses of 1 1 mg/kg ADC and 0.3 mg/kg anti-PD-1 antibody alone or in combination. the antitumor activity of SGN-B7H4V as monotherapy and in combination with an anti-programmed cell death-1 (PD-1) agent was evaluated using an immunocompetent murine B7-H4-expressing Renca tumor model. == Results == Immunohistochemistry confirmed B7-H4 expression across multiple solid tumors, with the highest prevalence in breast, endometrial, and ovarian tumors. In vitro, SGN-B7H4V killed B7-H4-expressing tumor cells by MMAE-mediated direct cytotoxicity and antibody-mediated effector functions including antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. In Liquiritin vivo, SGN-B7H4V demonstrated strong antitumor activity in multiple xenograft models of breast and ovarian cancer, including xenograft tumors with heterogeneous B7-H4 expression, consistent with the ability of vedotin ADCs to elicit a bystander effect. In an immunocompetent murine B7-H4-expressing tumor model, SGN-B7H4V drove robust antitumor activity as a monotherapy that was enhanced when combined with an anti-PD-1 agent. == Conclusion == The immune checkpoint ligand B7-H4 is a promising molecular target expressed by multiple solid tumors. SGN-B7H4V demonstrates Liquiritin robust antitumor activity in preclinical models through multiple potential RIEG mechanisms. Altogether, these preclinical data support the evaluation of SGN-B7H4V as a monotherapy in the ongoing phase 1 study of SGN-B7H4V in advanced solid tumors (NCT05194072) and potential future clinical combinations with immunotherapies. Keywords:Drug Evaluation, Preclinical; Drug Therapy, Combination; Therapies, Investigational; Translational Medical Research; Tumor Microenvironment == WHAT IS ALREADY KNOWN ON THIS TOPIC == B7-H4 is an immune checkpoint ligand known to have elevated expression on a variety of solid tumors, but the mechanism of action and antitumor activity of the B7-H4-directed antibodydrug conjugate SGN-B7H4V had yet to be characterized. == WHAT THIS STUDY ADDS == Our results suggest that SGN-B7H4V internalizes following binding to B7-H4, and kills tumor cells via monomethyl auristatin E -mediated direct cytotoxicity as well as antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis in vitro. SGN-B7H4V demonstrated robust antitumor activity in in vivo xenograft models of breast and ovarian cancer. SGN-B7H4V in combination with an anti-programmed cell death-1 (PD-1) agent led to improved antitumor activity and elicited durable immune memory. == HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY == This study demonstrates that SGN-B7H4V has promising antitumor activity in preclinical models as a monotherapy and in combination with an anti-PD-1 agent in vivo, and is currently being evaluated in clinical trials as a treatment for certain solid tumors. == Background == SGN-B7H4V is a novel investigational vedotin antibodydrug conjugate (ADC) comprising three components: a fully human IgG1 monoclonal antibody (mAb) that binds to the immune checkpoint ligand B7-H4 (VTCN1) on the cell surface, approximately four molecules (ie, drugantibody ratio (DAR) of ~4) of the microtubule-disrupting agent monomethyl auristatin E (MMAE), and a protease-cleavable maleimidocaproyl valine-citrulline (mc-vc) linker.1This vedotin linker-payload system has been clinically validated in several approved therapeutics including brentuximab vedotin, enfortumab vedotin, Liquiritin and tisotumab vedotin.24SGN-B7H4V is the first vedotin ADC targeting an immune checkpoint ligand and is currently under investigation in a phase 1, first-in-human trial (SGNB7H4V-001,NCT05194072) evaluating SGN-B7H4V monotherapy in patients with select advanced tumors.5 B7-H4 is a member of the B7 family of immune checkpoint ligands and binds to an unknown receptor on T cells, and like the widely known programmed death-ligand 1 (PD-L1)/B7-H1 checkpoint ligand, has been shown to negatively regulate T-cell function by inhibiting T-cell proliferation and cytokine production.69In contrast to its limited expression in normal tissues, B7-H4 is elevated across a broad range of solid tumors, including ovarian cancer, breast cancer, endometrial carcinoma, cholangiocarcinoma, gallbladder carcinoma, and squamous non-small cell lung cancer (NSCLC) where it is hypothesized to help tumor cells avoid immune surveillance.916Consistent with its immunosuppressive function, B7-H4 expression in tumors has been associated with lower survival rates, advanced clinical stage, increased lymph Liquiritin node involvement, and decreased tumor T-cell infiltration.17Accordingly, targeting B7-H4-expressing tumor cells and removal of the B7-H4/ADC complex from the cell surface via internalization may relieve B7-H4-mediated immunosuppression.68 18 Like other vedotin ADCs, SGN-B7H4V is hypothesized to have a multimodal mechanism of action (MOA) and may kill target cells through both MMAE-mediated cytotoxicity and antibody-mediated effector functions. Vedotin ADCs can induce MMAE-mediated direct cytotoxicity by.