Efficacy and safety assessment of CCR8-targeting agents in preclinical humanized models

Background

CCR8 is a potential therapeutic target to treat cancer due to its role in the immunosuppression induced by regulatory T cells (Treg). The development of a physiologically relevant model to assess CCR8-targeting therapies depends, among others, on the maintenance of a proper interaction of the receptor and ligands. CCR8 has 2 ligands: CCL1 and CCL8. Mouse CCL8 induces specific calcium flux in human CCR8-transfected mouse cells, suggesting that humanization of CCL8 is not mandatory. However, in vitro studies showed that murine CCL1 was unable to interact with human CCR8. Lack of functional CCR8/CCL1 axis could have an impact on the suppressive activity of Treg cells, thus requiring the humanization of both CCR8 and CCL1. Here we describe two humanized models, genO-hCCR8/hCCL1 and genO-BRGSF-HIS suitable for the assessment of efficacy and safety of CCR8-targeting compounds.