Abstract 3737: Molecular and early clinical characterization of the anti-CD73 antibody S095024 (Sym024)

Abstract Background: Adenosine signaling is a central immunosuppressive mechanism affecting a broad set of immune cell types. Adenosine is generated from extracellular ATP by a group of ectonucleotidases including CD39 and CD73. Suppressing the adenosine pathway via CD73 blockade may enhance the potential of checkpoint inhibitor therapies. S095024 (Sym024) is a fully human, effector-function attenuated antibody that binds to human and cynomolgus CD73 with sub-nM affinity. Methods: Preclinically, the stoichiometry and conformational structure of the binding interaction between CD73 and S095024 was assessed by SEC-MALS and cryo-EM and the ability of S095024 to inhibit CD73 activity was done in vitro covering 3-, 6- and 24-hour incubation periods. The clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of S095024 alone or in combination with Sym021, an anti-PD1 antibody, was investigated in a first-in-human study (NCT04672434) in patients with selected types of advanced solid tumors. Following assessment of single agent S095024 (100 to 1500 mg IV Q2W) in part I, the safety and tolerability of S095024 (300 to 1500 mg IV Q2W) was assessed in combination with Sym021 (200 mg IV Q2W) in part II. A part IIa was added: patients received 3000 mg IV Q2W of S095024 in Cycle 1, followed by 3000 mg S095024 + 200 mg Sym021 from Cycle 2 onwards. Results: Structural data indicate that S095024 binds to CD73 in a unique configuration by bridging the two monomers of the molecule, interacting in a 1: 1 stoichiometry and effectively preventing the conformational state cycling required for catalysis. Functional data using a 20x cell line panel harboring a broad range of CD73 expression levels demonstrates that this interaction modus results in deep enzymatic inhibition. As of 12 Oct 2023, 43 patients have been treated with, S095024 in the FIH study. S095024, as a single agent (N=18) and in combination with PD-1 blockade (N=25) was well tolerated across all dose levels. The most frequent treatment emergent adverse events (≥15% patients) were fatigue, nausea, diarrhea, dyspnea, and vomiting. A dose proportional increase in drug exposure, both in monotherapy and combination, was observed starting at 900 mg. Target engagement assessed both peripherally (free soluble CD73) and intra-tumorally (enzymatic activity), showed a sustained decrease in free soluble CD73 in blood at dose levels ≥1500 mg and dose-dependent CD73 modulation, with 80% inhibition reached at ≥1500 mg in tumor biopsies. Conclusions: These findings reveal the potential of S095024 (Sym024) to prevent adenosine-mediated tumor evasion and support further clinical investigation. Citation Format: Anna Spreafico, Jordi R. Ahnert, David Sommerhalder, Maria Almena-Carrasco, Najah Harouki Crochemore, Xenophon Ianopulos, Janus S. Jakobsen, Emily Armbruster, Audrey Delmas, Amédée des Georges, Camilla Fröhlich, Julia Geronimi, Michael M. Grandal, Randi W. Hansen, Johan Lantto, Julie Legrand, Franck Levasseur, Matteo Riva, Christelle Rodrigues, Vanessa Seif, Vasileios Askoxylakis, Nehal Lakhani. Molecular and early clinical characterization of the anti-CD73 antibody S095024 (Sym024) 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 (6Suppl): Abstract nr 3737.