Abstract A140: MGC026, a glycan-linked, exatecan-based antibody-drug conjugate (ADC) targeting B7-H3, is efficacious toward prostate cancer patient-derived xenografts

Abstract Introduction: Prostate cancer (PC) is the second most common cancer among men in the United States. Although multiple treatment options are available to treat prostate cancer, the development of resistance commonly leads to the recurrence of a castration-resistant form of the disease, with 35,770 men expected to die in 2025. B7-H3, a member of the B7 superfamily, is highly expressed in PC and associated with disease severity and increased risk of cancer progression after surgery. MGC026, an ADC incorporating a B7-H3-targeting antibody and a novel glycan-linked topoisomerase 1 inhibitor (TOP1i), is currently being evaluated in clinical studies. The therapeutic potential of MGC026 was explored in preclinical patient-derived xenograft models of advanced castration-resistant prostate cancer (CRPC) as a proof of concept for targeting B7-H3 in PC. 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. B7-H3 expression in the LuCaP patient-derived xenograft (PDX) series [Prostate 77(6):654-671, 2017] was assessed by immunohistochemistry and compared with B7-H3 expression in primary and metastatic PC samples. In vivo efficacy studies were conducted with the LuCaP PDX models representing the major genomic and phenotypic features of the disease. Results: B7-H3 was found to be frequently overexpressed in PC. >90% of primary prostate tumor samples and >85% of metastatic prostate tumor samples expressed B7-H3, with an immunohistochemical H-score > 100, while 52% and 58% exhibited H-scores >200, respectively. Importantly, the LuCaP PDX models demonstrated a similar range of B7-H3 expression as the clinical PC specimens, underscoring their clinical relevance to evaluate the therapeutic potential of MGC026. MGC026 (10 mg/kg IV Q2Wx2) demonstrated in vivo antitumor activity toward B7-H3-positive LuCaP PDX models (H-score range of 82-264), including both adenocarcinoma and neuroendocrine subtypes. MGC026 was active toward 14 of 20 models, based on the National Cancer Institute standards, with 9 of 20 models exhibiting partial or complete responses relative to the tumor volume at baseline. Conclusions: MGC026 demonstrated strong efficacy in CRPC LuCaP PDX models, supporting its clinical development for the treatment of B7-H3-expressing advanced PC. With their extensive characterization, these models also provide future opportunities to assess potential biomarkers of response in this indication. Citation Format: Juniper A. Scribner, Monirath Hav, Antwanette Summers, Holly Nguyen, Jennifer Conner, Eva Corey, Deryk T. Loo. MGC026, a glycan-linked, exatecan-based antibody-drug conjugate (ADC) targeting B7-H3, is efficacious toward prostate cancer patient-derived xenografts [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A140.