Abstract 1904: Preclinical development of MGC026, a glycan-linked, exatecan-based antibody-drug conjugate (ADC) targeting B7-H3 for solid cancer

Abstract

Abstract Introduction: Antibody-drug conjugates (ADCs) have emerged as an important class of therapeutic agents for the treatment of cancer. A duocarmycin-based B7-H3-targeted DNA-alkylating ADC, vobramitamab duocarmazine (vobra duo), has shown encouraging clinical activity in the treatment of metastatic castration-resistant prostate cancer. Given the broad spectrum of tumor indications addressable by targeting B7-H3, we developed MGC026, an ADC incorporating a B7-H3-targeting antibody and a novel glycan-linked topoisomerase 1 inhibitor (TOP1i). With distinct mechanisms of action, vobra duo and MGC026 can address different cancers, tumor stages, or be used in combination with alternate agents to enhance their clinical utility. Methods: MGC026 is comprised of the cleavable linker-payload, bicyclononyne carbamoyl sulfamide Val-Ala-PABC exatecan (SYNtecan E™) site-specifically conjugated at asparagine 297 of the heavy chain through enzymatic glycan remodeling and metal-free click chemistry, using Synaffix’s GlycoConnect™ technology. In vivo efficacy studies were conducted in immunodeficient mice with human tumor cell-line or patient-derived xenografts to identify the spectrum of MGC026-sensitive tumors and the relationship between exposure and antitumor activity. A toxicology study was conducted in cynomolgus monkeys in which MGC026 was administered by 15-minute IV infusion once every three weeks. Pharmacokinetic (PK) analysis and detailed toxicology evaluation was performed. Results: MGC026 demonstrated specific, dose-dependent in vivo antitumor activity toward B7-H3-positive tumor xenografts representing lung, pancreatic, and prostate cancers, head and neck squamous cell carcinoma, and melanoma. Additionally, MGC026 demonstrated antitumor activity toward B7-H3-positive patient-derived xenograft models of lung and prostate cancer, with additional indications under investigation. MGC026, administered to cynomolgus monkeys at dose levels of 10, 30, and 50 mg/kg every 3 weeks for a total of 3 doses, exhibited approximate dose-proportional PK and high stability in circulation. MGC026 was well tolerated, with no lung toxicity observed, and the highest dose level tested (50 mg/kg) was declared as the highest non-severely toxic dose. Conclusions: MGC026 exhibited a favorable preclinical profile, with potent in vivo activity toward B7-H3-expressing tumor xenografts representing a range of cancer indications. MGC026 was tolerated in cynomolgus monkeys, a relevant toxicology model, at exposure levels exceeding those required for antitumor activity. These data support clinical development of MGC026 for the treatment of B7-H3-expressing solid cancers. Citation Format: Juniper A. Scribner, Jennifer G. Brown, Thomas Son, Linda Jin, Carroll McKenzie, Viktoriya Nam, Curtis Bush, Dienis Quinonez, James Tamura, Sergey Gorlatov, Hua Li, Shelley Butler, Ezio Bonvini, Deryk Loo. Preclinical development of MGC026, a glycan-linked, exatecan-based antibody-drug conjugate (ADC) targeting B7-H3 for solid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1904.