Humanized Ccr8 Mouse Model Provides A Translational Tool For Anti-Human Ccr8 Antibody Drug Development.

Abstract CCR8 is reported as an important chemokine receptor expressed on intra-tumoral Tregs and plays a critical role in CCR8+Treg-mediated immunosuppression via inducing STAT3-dependent overexpression of FOXP3, CD39, IL-10, and granzyme B on Tregs with interaction of CCL1 (CCR8 ligand). CCR8 becomes a promising target in the anticancer drug development. Generation of humanized CCR8 mouse model can greatly improve translation and accelerate CCR8-related drug development. To evaluate the anti-tumor efficacy of human CCR8 blockade in tumor mouse models, Biocytogen has successfully generated a novel CCR8 humanized knock-in mouse strain to support anti-human CCR8 antibody drug development. In this mouse model, the full length of encoding sequences of mouse CCR8 gene were replaced by the full length of encoding sequences of human CCR8 (hCCR8) gene. CCR8 gene expression in WT and B-hCCR8 mice were tested by RT-PCR. Human CCR8 mRNA was detected in hCCR8 mice model but not in wild-type mice. Protein expression of human CCR8 in hCCR8 mice was evaluated by flow cytometer in a colon cancer cell line MC38 tumor bearing mouse model. The human CCR8 protein were successfully detected in tumor-infiltrating Tregs in B-hCCR8 mice bearing MC38 tumor, but not in Treg cells from spleen. An anti-tumor efficacy study showed significant tumor growth inhibition of hCCR8 antibodies in B-hCCR8 mice bearing MC38 tumors, suggesting that the B-hCCR8 mouse model is an effective tool for in vivo efficacy evaluation of therapeutic hCCR8 antibodies to support anti-human CCR8 antibody clinical development. Citation Format: Linlin Wang, Chengzhang Shang, Jing Zhang, Yichao Chen, Leila Kokabee, Qingcong Lin. Humanized CCR8 mouse model provides a translational tool for anti-human CCR8 antibody drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2954.