Antitumor activity of the investigational B7-H3 antibody-drug conjugate, vobramitamab duocarmazine, in preclinical models of neuroblastoma

• DOI: 10.1136/jitc-2023-007174
• Publication Date: 2023-09-29T04:20:40Z
• Authors: Chiara Brignole; Enzo Calarco; Veronica Bensa; Elena Giusto; Patrizia Perri; Eleonora Ciampi; Maria Valeria Cor...; Simonetta Astigiano; Michele Cilli; Derik Loo; Ezio Bonvini; Fabio Pastorino; Mirco Ponzoni
• Keywords: Investigational Drugs; Antibody-drug conjugate; Conjugate

Introduction B7-H3 is a potential target for pediatric cancers, including neuroblastoma (NB). Vobramitamab duocarmazine (also referred to as MGC018 and herein vobra duo) an investigational duocarmycin-based antibody-drug conjugate (ADC) directed against the antigen. It composed of anti-B7-H3 humanized IgG1/kappa monoclonal antibody chemically conjugated through cleavable valine-citrulline linker du ocarmycin-hydroxy b enzamide zaindole (vc-seco-DUBA). Vobra duo has shown preliminary clinical activity in B7-H3-expressing tumors. Methods expression was evaluated by flow-cytometry panel human NB cell lines. Cytotoxicity monolayer multicellular tumor spheroid (MCTS) models water-soluble tetrazolium salt,MTS, proliferation assay Cell Titer Glo 3D viability assay, respectively. Apoptotic death investigated annexin V staining. Orthotopic, pseudometastatic, resected mouse were developed mimic disease conditions related primary growth, metastases, circulating cells with minimal residual disease, Results All lines expressed surface unimodal fashion. cytotoxic dose-dependent time-dependent manner all (IC50 range 5.1–53.9 ng/mL) MCTS 17.8–364 ng/mL). inactive murine line (NX-S2) that did not express B7-H3; however, NX-S2 killed presence when co-cultured cells, demonstrating bystander activity. In orthotopic pseudometastatic models, weekly intravenous treatments 1 mg/kg 3 weeks delayed growth compared animals treated irrelevant (anti-CD20) duocarmycin-ADC. treatment 4 further increased survival both models. favorably TOpotecan-TEMozolomide (TOTEM), standard-of-care therapy relapsed relapse or arrested two three repeated 4-week treatments, Further observed mice combination TOTEM. associated body weight loss, hematological toxicity, chemistry abnormalities. Conclusion exerts relevant antitumor preclinical represents candidate translation.