On September 23, 2020 MacroGenics, Inc. (NASDAQ: MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, reported the publication of a manuscript in Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), highlighting the development of MGC018, the Company’s investigational antibody-drug conjugate (ADC) targeting B7-H3 for the treatment of solid tumors (Press release, MacroGenics, SEP 23, 2020, View Source [SID1234565512]).
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B7-H3 has been identified as a cell surface protein with limited expression on normal tissues but over-expressed on the epithelium and tumor-associated vasculature in solid tumors. Overexpression of this molecule has been shown to be associated with cancer disease severity, risk of recurrence and reduced survival. The Company’s early studies showed that ligation of B7-H3 by select monoclonal antibodies (mAbs) led to mAb internalization and antitumor activity toward B7-H3-expressing tumor cells when conjugated to a toxic payload. Based on these results, MacroGenics selected a lead candidate mAb and developed MGC018, an ADC targeting B7-H3 for the treatment of cancer.
As described in the paper "Preclinical Development of MGC018, a Duocarmycin-based Antibody-drug Conjugate Targeting B7-H3 for Solid Cancer," the authors report on preclinical studies that showed that MGC018 mediated specific in vitro killing across a range of B7-H3-expressing solid tumor cell types. Furthermore, the preclinical studies showed that MGC018 mediated bystander in vitro killing of B7-H3-negative tumor cells in the presence of B7-H3-positive tumor cells.
MGC018 displayed potent antitumor activity in preclinical tumor xenograft models of breast, ovarian and lung cancer, as well as melanoma. Additionally, antitumor activity was observed toward patient-derived tumor xenograft models of breast, prostate and head and neck cancer displaying heterogeneous expression of B7-H3. Importantly, MGC018 exhibited an acceptable pharmacokinetic and safety profile in cynomolgus monkeys following repeat-dose administration.
"With its overexpression on a wide range of solid cancers but limited presence on normal tissues, B7-H3 is an attractive candidate for an ADC-targeting approach," said Deryk Loo, Ph.D., Senior Director of Research at MacroGenics and the lead author of the paper. "The published preclinical antitumor activity data and safety profile provided evidence of a potentially favorable therapeutic index to support the development of MGC018 for the treatment of solid tumors."
Scott Koenig, M.D., Ph.D., President and CEO of MacroGenics, further commented: "Encouraged by the MGC018 interim clinical dose escalation data presented at ASCO (Free ASCO Whitepaper) in May, we have recently initiated recruitment of patients with metastatic castration-resistant prostate, triple negative breast and non-small cell lung cancers in the dose expansion portion of the Phase 1 clinical study. We expect to provide an update on this study next year."
About MGC018
MGC018 is comprised of an anti-B7-H3 humanized IgG1/kappa monoclonal antibody conjugated via a cleavable linker to the prodrug seco-DUocarmycin hydroxyBenzamide Azaindole (DUBA; licensed from Byondis, B.V.), with an average drug-to-antibody ratio (DAR) of ~2.7. DUBA is an alkylating agent that can damage DNA in both dividing and non-dividing cells, causing cell death. MGC018 is being evaluated in a Phase 1 study (NCT03729596). Preliminary clinical results from the dose escalation portion of this study were presented at the 2020 American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) Scientific Program. MacroGenics retains full worldwide rights to MGC018.