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Updated: Jul 11, 2025
Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
Identification of effective CCR2 inhibitors for cancer therapy using humanized mice
Shigeaki Sugiyama1, Kanae Yumimoto1, Shun Fujinuma1
1Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.
Abstract:
C-C chemokine receptor type 2 (CCR2) is the receptor for C-C motif chemokine 2 (CCL2) and is associated with various inflammatory diseases and cancer metastasis. Although many inhibitors for CCR2 have been developed, it remains unresolved which inhibitors are the most effective in the clinical setting. In the present study, we compared 10 existing human CCR2 antagonists in a calcium influx assay using human monocytic leukemia cells. Among them, MK0812 was found to be the most potent inhibitor of human CCR2. Furthermore, we generated a human CCR2B knock-in mouse model to test the efficacy of MK0812 against a lung metastasis model of breast cancer. Oral administration of MK0812 to humanized mice did indeed reduce the number of monocytic myeloid-derived suppressor cells and the rate of lung metastasis. These results suggest that MK0812 is the most promising candidate among the commercially available CCR2 inhibitors. We propose that combining these two screening methods may provide an excellent experimental method for identifying effective drugs that inhibit human CCR2.
Insights
MK0812 is the most effective C-C chemokine receptor type 2 (CCR2) inhibitor, significantly reducing breast cancer lung metastasis in a humanized mouse model. This study highlights MK0812 as a promising therapeutic candidate for CCR2-related diseases.
Area of Science:
- Immunology
- Pharmacology
- Oncology
Background:
- C-C chemokine receptor type 2 (CCR2) plays a role in inflammatory diseases and cancer metastasis.
- Numerous CCR2 inhibitors exist, but their clinical efficacy remains unclear.
- Identifying potent and effective CCR2 antagonists is crucial for therapeutic development.
Purpose of the Study:
- To compare the efficacy of 10 human CCR2 antagonists.
- To evaluate the therapeutic potential of the most potent antagonist, MK0812, in a preclinical cancer metastasis model.
Main Methods:
- A calcium influx assay was used to screen 10 CCR2 antagonists in human monocytic leukemia cells.
- A human CCR2B knock-in mouse model was generated to assess MK0812's efficacy in a breast cancer lung metastasis model.
Main Results:
- MK0812 demonstrated the highest potency in inhibiting human CCR2 in vitro.
- Oral administration of MK0812 in humanized mice reduced monocytic myeloid-derived suppressor cells and lung metastasis rates.
- These findings support MK0812 as a leading CCR2 inhibitor candidate.
Conclusions:
- MK0812 is the most promising CCR2 inhibitor among those tested.
- The combination of in vitro screening and a humanized mouse model offers a robust method for identifying effective CCR2 inhibitors.
- MK0812 warrants further investigation for treating CCR2-mediated inflammatory diseases and cancer metastasis.
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