Abstract LB534: Development of GB2101, a novel anti-CCR8 antibody for cancer treatment

Abstract

Abstract Background: Regulatory T cells (Tregs) play a crucial role in suppressing immune response and maintaining hemostasis and immune tolerance. Tregs are enriched in the tumor microenvironment (TME) and suppress anti-tumor immunity. Therefore, specific depletion of Tregs in the TME is expected to reduce anti-tumor immune suppression without affecting hemostasis in the periphery. The C-C motif chemokine receptor 8 (CCR8), highly expressed on Tregs from TME but significantly lower expressed on Tregs from peripheral blood, provides an ideal target for preferentially deletion of Tregs within tumors. GB2101 is a novel anti-CCR8 monoclonal antibody generated from hybridoma. The data from in vitro and in vivo studies indicated that GB2101 is a good PCC molecule with great potential for clinical development. Methods: GB2101 was generated by immunization of CCR8 gene plus CCR8 over-expressing cells in mice followed by hybridoma technology. The binding of the antibody to CCR8-expressing cells was detected by flow cytometry. CCL1 ligand blocking was assessed by flow cytometry and calcium flux assay. Antibody-dependent cell-mediated cytotoxicity (ADCC) function was evaluated by Jurkat-CD16A-NFAT reporter system. In vivo anti-tumor efficacy was assessed in syngeneic model using human CCR8 knock-in mice. Results: GB2101 displayed potent binding to cells expressing CCR8. GB2101 efficiently blocked CCL1 binding and CCL1-induced signals in CCR8 expressing cells. ADCC activity against target cells was observed and afucosylated version of GB2101 improved ADCC response. GB2101 significantly inhibited tumor growth in syngeneic model. Conclusions: GB2101 is a novel monoclonal antibody specifically binding to CCR8 with high affinity, and efficiently blocked CCL1-CCR8 pathway and suppressed tumor growth in vivo. Therefore, it is a very promising preclinical candidate that may be used in the treatment of multiple tumor types. Citation Format: Qinglin Du, Yiqi Cao, Xueyan Yang, Jing Lu, Fei Peng, Wenming Zhou, Liwen Liang, James Li, Shuhua Han. Development of GB2101, a novel anti-CCR8 antibody for cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB534.