Abstract ND08: M3554, a novel anti-GD2 antibody drug conjugate

Abstract The glycosphingolipid GD2 is a cell membrane component of a limited number of normal tissues including nerve cells, melanocytes or lymphocytes. However, in some tumor types as neuroblastoma, osteosarcoma, glioma, or soft tissue sarcoma, GD2 is found on cell membranes with high levels. This tumor associated expression pattern makes GD2 an attractive target for therapeutic antibodies like dinutuximab (ch14.18) and naxitamab, which have been approved for neuroblastoma. M3554 is designed a be novel anti-GD2 ADC based on the humanized ch14.18 anti-GD2 antibody. The payload linker consists of the Topoisomerase I inhibitor (TOP1i) payload exatecan and a cleavable beta-glucuronide linker structure, which demonstrated higher potency, better bystander effects and improved activity in multidrug resistant cancer cells compared to other TOP1i payloads. While the antitumor effect of approved anti-GD2 antibodies is presumably related to Antibody-Dependent Cellular Cytotoxicity (ADCC) and Complement- Dependent Cytotoxicity (CDC), M3554 will exploit the high antigen density for direct tumor cytotoxicity by the payload. As the ADCC and CDC effector functions are believed to cause side effects for the approved GD2 antibodies, we have modified the M3554 antibody moiety with mutations in the Fc-region to reduce or eliminate these Fcγ receptor mediated functions. The cytotoxicity of M3554 was in the subnanomolar IC50 range for the GD2-positive neuroblastoma cell line CHP134. M3554 showed strong in vivo antitumor activity with tumor regressions in the CHP134 xenograft model and in patient-derived xenografts from neuroblastoma, osteosarcoma or glioma at doses ranging from 3 to 10 mg/kg. In addition, M3554 showed favorable pharmacokinetics in rats and monkeys, indicating a very stable linker-payload, and a favorable safety profile. In conclusion, M3554 represents a novel therapeutic approach for oncology indications with a high unmet medical need and high GD2 prevalence. Disclosures: Christiane Amendt, Christine Knuehl, Willem Sloot, Stanley Sweeney-Lasch, Joao NS Pereira, Julia Dotterweich, Hans-Henning Boehm and Jan Anderl are employees of the healthcare business of Merck KGaA, Darmstadt, Germany. Timothy Crandall is an employee of EMD Serono. Mira Toister-Achituv is an employee of Inter-Lab Ltd., Yavne, Israel, an affiliate of Merck KGaA, Darmstadt, Germany.Sponsor: This study was sponsored by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945). Citation Format: Christiane Amendt, Christine Knuehl, Timothy Crandall, Willem Sloot, Mira Toister-Achituv, Stanley Sweeney-Lasch, Joao NS Pereira, Julia Dotterweich, Hans_Henning Boehm, Jianguo Ma, Jan Anderl. M3554, a novel anti-GD2 antibody drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr ND08.