Anti-tumor activity of vobramitamab duocarmazine (MGC018), an investigational duocarmycin-based anti-B7-H3 antibody- drug conjugate (ADC), in preclinical neuroblastoma models

Abstract Introduction: MGC018 is an ADC composed of a humanized anti-B7-H3 IgG1 monoclonal antibody conjugated via a cleavable linker to vc-seco-duocarmycin-hydroxybenzamide azaindole (DUBA), a synthetic DNA alkylating agent whose cytotoxic activity is cell-cycle independent and retained in multidrug-resistant cells. MGC018 has shown preliminary clinical activity in B7-H3-expressing tumors, including castration-resistant metastatic prostate cancer. Owing to its expression in several childhood tumors, B7-H3 is a potential target for pediatric cancers, including neuroblastoma (NB). Methods: B7-H3 expression was evaluated by flow-cytometry (FCM) in a panel of human NB cell lines. Cytotoxicity was evaluated in monolayer and in multicellular tumor spheroid (MCTS) models by MTS assay and Cell Titer Glo 3D cell viability assay, respectively. Apoptotic cell death was investigated by the Annexin V staining. Pseudometastatic, orthotopic, and resected mouse NB models were developed via tumor cells tail vein injection, implantation in the adrenal gland, or implantation followed by surgical resection of the primary tumor mass, respectively, to mimic disease conditions related to circulating tumor cells and metastases, primary tumor growth, and minimal residual disease. Results: All cell lines expressed cell surface B7-H3 in a unimodal fashion, ranging between 200 and 400 in mean ratio fluorescence intensity over unstained cells. MGC018 was cytotoxic in a dose- and time-dependent manner against all NB cell lines (IC50 range 5.1-53.9 ng/mL) and NB MCTS (IC50 range 17.8-364 ng/mL). MGC018 was inactive against a murine NB cell line (NX-S2) that did not express human B7-H3; however, NX-S2 cells were killed in the presence of MGC018 when co-cultured with human B7-H3-expressing cells, demonstrating by-stander activity. In the pseudometastatic model and in five orthotopic NB mouse models, weekly iv treatments with 1 mg/kg MGC018 for 3 weeks resulted in delayed tumor growth and increased survival rates compared to animals treated with an irrelevant (anti-CD20) duocarmycin-ADC or an anti-GD2 antibody (dinutuximab beta). A 4-week course of treatment further ameliorated MGC018 antitumor effect in both the orthotopic and resected NB models and increased the survival of NB-bearing mice co-treated with TOpotecan-TEMozolomide (TOTEM), the standard-of-care therapy for relapsed disease. In the orthotopic model, tumor relapse was temporarily or completely arrested by 2 or 3 courses of MGC018, respectively. MGC018 treatment was not associated with body weight loss, hematological toxicity, or clinical chemistry abnormalities. Conclusion: MGC018 exerts relevant antitumor activity in pre-clinical NB models and may represent a potential candidate for future NB clinical translation. Citation Format: Chiara Brignole, Veronica Bensa, Enzo Calarco, Elena Giusto, Eleonora Ciampi, Patrizia Perri, Maria Valeria Corrias, Simonetta Astigiano, Michele Cilli, Deryk Loo, Ezio Bonvini, Fabio Pastorino, Mirco Ponzoni. Anti-tumor activity of vobramitamab duocarmazine (MGC018), an investigational duocarmycin-based anti-B7-H3 antibody-drug conjugate (ADC), in preclinical neuroblastoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2981.