genO-hCCR8/hCCL1/hFcγR preclinical mouse model for efficacy assessment of CCR8-targeting agents

Background

CCR8 is an emerging therapeutic target in oncology due to its role in Treg-mediated immunosuppression. The development of physiologically relevant preclinical models to evaluate CCR8-targeting therapies requires preservation of functional interactions between the receptor and its ligands. CCR8 has two known ligands, CCL1 and CCL8. Previous studies have shown that mouse CCL8 can induce calcium flux in human CCR8-transfected murine cells [1], suggesting that humanization of CCL8 may not be required. In contrast, murine CCL1 does not interact with human CCR8 in vitro, indicating that disruption of the CCR8/CCL1 axis may impair Treg suppressive function and thereby necessitate humanization of both CCR8 and CCL1.

In addition, depletion of CCR8+ Tregs by therapeutic agents has been shown to depend on Fcγ receptor (FcγR) engagement [2]. However, significant interspecies differences in FcγR repertoire and expression pattern between mice and humans limit the translational relevance of mouse models expressing mouse FcγR. A previously described humanized FcγR mouse model expressing human FcγRI, FcγRIIA, FcγRIIB, FcγRIIIA and FcγRIIIB in a human-like distribution enables more accurate evaluation of Fc-mediated responses [3]. Building on this, we developed a novel humanized model expressing humanized CCR8, CCL1 and FcγRs (genO-hCCR8/hCCL1/hFcγR).