Abstract
Abstract An often rate-limiting step for cancer immunotherapy is drug development. The generation of humanized mouse models can be used to assess the clinical utility of new drugs earlier in the discovery process. Tumor-associated macrophages (TAMs) represent an emerging therapeutic target, specifically high expression of the colony-stimulating factor 1 receptor (CSF1R) protein on tumors and TAMs facilitate a tumor permissive environment. Previous reports have demonstrated that blockade of the CSF1/CSF1R pathway reduced and reprogrammed intra-tumoral CSF1R+ TAMs, altogether alleviating immune suppression. To evaluate preclinical efficacy and toxicity of CSF1R targeted therapeutic candidates, Biocytogen has successfully generated a double humanized B-hCSF1/hCSF1R mouse model. The full-length encoding sequence of mouse Csf1 and the extracellular domain of Csf1r were replaced by human CSF1 and CSF1R genes, respectively. Evaluation of CSF1 and CSF1R protein expression in homozygous B-hCSF1/hCSF1R mice (H/H) was confirmed by ELISA and flow cytometry analysis. We next performed an in vivo efficacy screening study using genetically modified hCSF1 or wild-type MC38 cells inoculated into B-hCSF1/hCSF1R (H/H) mice and observed that anti-human CSF1R antibodies or combination therapy of anti-mouse PD-L1 and anti-human CSF1R antibodies were effective in controlling tumor growth. Our combined studies illustrate that Biocytogen’s novel B-hCSF1/hCSF1R mice offer a promising model for in vivo validation of CSF1 and CSF1R antibody therapeutics. Citation Format: Ruili Lyu, Shujin Zhang, Rebecca Soto, Suman Zhao, Chonghui Liu, Luke (Zhaoxue) Yu. Evaluation of therapeutic drug candidates using a novel humanized B-hCSF1/hCSF1R mouse model [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 1648.
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