Transgenic mouse expressing human CCR5 as a model for in vivo assessments of human selective CCR5 antagonists.
The species selectivity of receptor antagonists often hinders their preclinical assessment in vivo. In order to evaluate human selective CC chemokine receptor type 5 (CCR5) antagonists in vivo, we generated human CCR5 transgenic mice that expressed the transgene on both peripheral blood leukocytes as well as thymocytes. The selective CCR5 ligand CC chemokine ligand 4 (CCL4)/macrophage inflammatory protein (MIP)-1beta induced the chemotaxis of thymocytes that had been derived from the transgenic mice, but not from littermate mice, suggesting that the human CCR5 expressed in the transgenic mice were functional. The binding of the human CCR5 specific antibody 45531 to peripheral blood granulocytes from the transgenic mice was inhibited by human selective CCR5 antagonist SCH-351125. Using this antibody, we developed an ex vivo assay system that is suitable for the evaluation of a test compound's ability to occupy the human CCR5 receptor on mouse peripheral blood leukocytes. This transgenic mouse model is useful for estimating the pharmacodynamics of human selective CCR5 antagonists in vivo.
Saita
Yuji
Y
Inflammation Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. yuuji.saita@jp.astellas.com
Kondo
Mitsuhiro
M
Miyazaki
Takahiro
T
Yamaji
Noboru
N
Shimizu
Yasuaki
Y
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001667:Binding, Competitive / Q000187:drug effects; D002460:Cell Line; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC / Q000378:metabolism / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D007457:Iodine Radioisotopes; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D010091:Oximes; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D000911:Antibodies, Monoclonal; C491541:Ccl25 protein, mouse; C496534:Ccl3 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC; D003497:Cyclic N-Oxides; D007457:Iodine Radioisotopes; D019402:Macrophage Inflammatory Proteins; D010091:Oximes; D010880:Piperidines; D011725:Pyridines; D019713:Receptors, CCR5; C438583:Ancriviroc