Abstract 6537: A novel CCR4 antagonist induces potent anti-tumor response through inhibition of Treg migration into the tumor microenvironment
Authors: Rashmi Nair, Chandrasekhar Abbineni, Krishna Chaitanya Talluri, Amit A Dhudashiya, Aravind AB, Naveen Kumar R, Ramya R, D Balasubramanyam, Pathur Obanna, Rabin Madhaiyan, DS Samiulla, Girish Daginakatte, Kishore Narayanan, Kavitha Nellore, Shekar Chelur, Susanta Samajdar, Murali Ramachandra
Journal: Cancer Research (2024)

Abstract Regulatory T cells (Tregs), an immunosuppressive subset of CD4+ T cells, play a vital role in maintaining immune homeostasis by regulating response to self antigens and maintaining tolerance. On the contrary, Tregs infiltrating the tumor microenvironment (TME) impede effective anti-tumor immunity by inhibiting tumor-specific T cell responses and generating a suppressive TME, thus promoting tumor progression. Clinically, Tregs have been proven to play a significant role in resistance to immune checkpoint inhibitors (ICIs) leading to lower response rates. Hence, targeting Tregs would lead to activation of tumor-specific effector T cells and improved long-term anti-tumor immune responses with ICI treatment. CCR4, a chemokine receptor highly expressed on Tregs, spearhead the migration of Tregs and their accumulation in the TME, by responding to the chemokines CCL22 and CCL17 secreted by the inflamed cells in the tumor. CCR4 expression is associated with poor prognosis in various solid tumors. This warrants the therapeutic targeting of CCR4-expressing Tregs to enable effective and durable anti-tumor immune responses. We sought to discover and develop novel small molecule antagonists of CCR4 for use in cancer therapy. Multiple series of CCR4 antagonists were identified by iterative medicinal chemistry efforts and SAR based approach. These compounds were optimized towards attaining required potency, acceptable physicochemical properties, high selectivity and desirable pharmacokinetic profile to achieve anti-tumor activity. Aurigene’s CCR4 antagonists exhibited potent inhibition of CCR4 activity in the reporter-based β-arrestin recruitment assay. This translated well into potent inhibition of CCL22-mediated chemotaxis of CCR4-expressing Tregs in an in vitro cell migration assay. Furthemore, the lead compounds showed desirable drug-like properties and excellent pharmacokinetic exposure in rodents. In an ongoing study in a syngeneic mice tumor model, one of the lead compounds is being evaluated for impact on Treg infiltration, CD8:Treg ratio in the tumor and efficacy. In summary, we have identified novel CCR4 antagonists with desirable drug-like properties that are being evaluated further to identify a clinical candidate. Citation Format: Rashmi Nair, Chandrasekhar Abbineni, Krishna Chaitanya Talluri, Amit A Dhudashiya, Aravind AB, NaveenR Kumar, Ramya R, D Balasubramanyam, Pathur Obanna, Rabin Madhaiyan, DS Samiulla, Girish Daginakatte, Kishore Narayanan, Kavitha Nellore, Shekar Chelur, Susanta Samajdar, Murali Ramachandra. A novel CCR4 antagonist induces potent anti-tumor response through inhibition of Treg migration into the tumor microenvironment [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(6_Suppl):Abstract nr 6537.