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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

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Abstract

Purpose

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.

Materials and Methods

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

Results

After intravenous administration of 125I-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 125I-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.

Conclusion

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.

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Abbreviations

125I-PBI:

N-Succinimidyl 4-125I-iodobenzoate

HRPO:

horseradish peroxidase

SCID:

severe combined immunodeficiency

TMB:

3,3′,5,5′tetramethylbenzidine

TNF:

tumor necrosis factor

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Acknowledgments

We thank Dr. Katsumi Sato (Tohoku Rosai Hospital) for providing synovial tissues.

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Authors and Affiliations

  1. Drug Metabolism and Pharmacokinetics Research Laboratories, Tokyo, Japan

    Motoko Saito, Yasushi Yoshigae, Atsushi Kurihara & Toshihiko Ikeda

  2. Biological Research Laboratories, Tokyo, Japan

    Junichi Nakayama

  3. R&D Project Management Department, Sankyo Co., Ltd., Tokyo, Japan

    Yukie Ogawa

  4. Global Project Management, Daiichi Sankyo Pharma Development, Daiichi Sankyo Pharma Inc., Edison, NJ, USA

    Masahiko Ohtsuki

  5. 1-2-58, Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan

    Toshihiko Ikeda

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  1. Motoko Saito
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  2. Yasushi Yoshigae
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  3. Junichi Nakayama
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  4. Yukie Ogawa
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  5. Masahiko Ohtsuki
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  6. Atsushi Kurihara
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  7. Toshihiko Ikeda
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Correspondence to Toshihiko Ikeda.

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Saito, M., Yoshigae, Y., Nakayama, J. et al. 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. Pharm Res 24, 310–317 (2007). https://doi.org/10.1007/s11095-006-9148-5

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  • DOI: https://doi.org/10.1007/s11095-006-9148-5

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