Abstract 2946: Depleting hCCR8 mAb Therapy #1: Characterization of a broad collection of anti-hCCR8 mAbs

Abstract

Abstract Background: Tumor-infiltrating Tregs (TITR) constitute a sub-family of immuno-suppressive cells abundantly found in multiple solid cancers. They play a critical role in tumor progression and their specific depletion has been recently proposed as a novel therapeutic strategy to fight cancers. Based on the transcriptional analysis of tumor infiltrating immune cells, the G-protein coupled receptor CCR8 was found to be expressed on murine and human TITR, but not on proinflammatory effector T cells. The CCR8 receptor therefore represents a unique TITR target for the development of novel depletive antibody-based therapeutics. Methods: We have generated a broad collection of monoclonal antibodies (mAb) directed against the human CCR8 receptor. This collection was widely characterized using different sources of recombinant and native hCCR8 positive cell subsets. Moreover, their binding and activities in several functional assays were assessed with different approaches (BRET, Flow Cytometry, including the inhibition of recruitment of different G-proteins to the CCR8 receptor). A comprehensive molecular and pharmacological characterization of each mAb of our proprietary library was generated. mAb binding against different peptides mimicking different states of post-translational modifications of the N-terminus of CCR8 was also monitored. Finally, using two surrogate antibodies directed against the mouse receptor, we tested the role of CCR8 antagonism and Treg depletion in multiple syngeneic models. Results: A comprehensive characterization of Domain Therapeutics’ mAb library revealed distinct mAb cellular reactivity profiles, different epitope recognition patterns (based on binding to different peptides with different post-translational modifications), subnanomolar antagonist activity of downstream signaling, and insurmountable property with regards to the CCR8 ligand CCL1. Moreover, we demonstrated that treatment with a depleting anti-mCCR8 mAb translated into robust anti-tumor activity in multiple syngeneic mouse models. Conclusion: Due to its high and relatively specific expression on tumor-infiltrating Tregs, CCR8 represents an attractive novel target to derive novel immunotherapies. At Domain Therapeutics, a mAb library of several dozen antibodies with distinct and differentiated binding and pharmacological activity profile was successfully discovered and patent-protected. This collection constitutes a unique source of future clinical candidates for the development of a best-in-class well-differentiated anti-hCCR8 depleting antibody for the treatment of cancers. Citation Format: Claudine Vermot-Desroches, Iseulys Richert, Malaury Schappler, Alice Gentil Dit Maurin, Megane Jeannelle, Solene Rose, Luc Baron, Quentin Ruet, Camille Dietsch, Pauline Urquia, Safia Ayachi, Orphee Blanchard, Maria Dolores Garcia Fernandez, Christel Franchet, Nathalie Lenne, Stephan Schann. Depleting hCCR8 mAb Therapy #1: Characterization of a broad collection of anti-hCCR8 mAbs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2946.