In SCID mice with transplanted joint tissues from rheumatism patients, a model mice of human rheumatoid arthritis, anti-human fas antibody (R-125224) distributes specifically to human synovium.
OBJECTIVE
We investigated the tissue distribution of a humanized anti-human Fas monoclonal antibody, R-125224, in SCID mice transplanted with synovial tissues from patients with rheumatoid arthritis (SCID-HuRAg mice). The binding kinetics of R-125224 was also determined, using isolated human synovial cells.


METHODS
Tissue distribution was assessed at 1, 24 and 168 h after intravenous administration of (125)I-R-125224 to SCID-HuRAg mice (0.4 mg/kg). The in vitro binding of (125)I-R-125224 to isolated human synovial cells was investigated.


RESULTS
After intravenous administration of (125)I-R-125224 to SCID-HuRAg mice, the radioactivity distributed to various tissues at 1 h. Thereafter, the radioactivity in the tissues gradually decreased except for the transplanted synovial tissues, in which the radioactivity increased in a time-dependent manner, and at 168 h, the tissue/plasma concentration ratio was about 1. The in vitro binding affinity of (125)I-R-125224 to human synovial cells was high with a dissociation constant of 1.32 +/- 0.62 nM and the binding was inhibited by non-labeled R-125224 in a concentration-dependent manner.


CONCLUSIONS
R-125224, a candidate compound for treating rheumatoid arthritis, specifically distributed to the pharmacological target site, human synovium transplanted in SCID mice, with high affinity.
Saito
Motoko
M
Drug Metabolism and Pharmacokinetics Research Laboratories, Tokyo, Japan.
Yoshigae
Yasushi
Y
Nakayama
Junichi
J
Ogawa
Yukie
Y
Ohtsuki
Masahiko
M
Kurihara
Atsushi
A
Ikeda
Toshihiko
T
D000818:Animals; D000906:Antibodies / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000601:surgery*; D002469:Cell Separation; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes; D007596:Joints / Q000637:transplantation*; D051379:Mice; D016513:Mice, SCID; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism*; D014018:Tissue Distribution; D019014:fas Receptor / Q000276:immunology*
D000906:Antibodies; D007457:Iodine Radioisotopes; D019014:fas Receptor