Abstract P052: Functional ADORA2A antibodies demonstrates the antagonistic and tumor suppression activities

Abstract

Abstract G protein-coupled receptors (GPCRs), a family of seven-transmembrane receptor proteins function as sensors transmitting extracellular signals into the cell and mediate a diverse range of ligand signaling, are proven to be successful drug targets. GPCRs and the associated downstream signaling pathways have been linked to a wide range of disease types such as cancer, inflammatory and immune disorders, as well as metabolic and neurological diseases. Antibodies are becoming an increasingly promising modality to target these receptors due to their unique properties, such as exquisite specificity, long half-life, and fewer side effects, and their improved pharmacokinetic and pharmacodynamic profiles compared to peptides and small molecules, which results from their more favorable biodistribution. To date, there are only two US Food and Drug Administration-approved GPCR antibody drugs, namely erenumab and mogamulizumab, and this highlights the challenges encountered in identifying functional antibodies against GPCRs. ADORA2A operates as an adenosine receptor and immune checkpoint protein that prevents the inappropriate activation of T-cells and is an immuno-oncology target. Immune checkpoint blockades are one of the newest pillars of cancer therapeutic development. Current examples for targeting ADORA2A involve small molecule antagonists. Selective antibody binders of ADORA2A are therefore a largely untapped immunotherapeutic candidate. Using our proprietary biologics discovery and optimization platform, Twist Biopharma identified a potent high-affinity antibody, TB206-001, amongst other promising leads. Initial in vitro assays showed that TB206-001 binds with high affinity to both human and mouse ADORA2A. TB206-001 showed antagonistic activity by suppressing cAMP level stimulated by NECA, a high affinity adenosine receptor agonist. Primary T cell assays demonstrated that TB206-001 restored T cell activity which was inhibited by NECA which suppresses T cell activation. Subsequent in vivo testing also showed the efficacy in animal models of cancer, indicating its activity in tumor suppression. TB206-001 is a high-affinity antagonistic anti-ADORA2A antibody demonstrating preclinical activity. Citation Format: Linya Wang, Ana Lujan, Eric Kwan, Crystal Safavi, Mouna Villalta, Tom Yuan, Melina Mathur, Joyce Lai, Hoa Giang, Qiang Liu, Fumiko Axelrod, Aaron Sato. Functional ADORA2A antibodies demonstrates the antagonistic and tumor suppression activities [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P052.