Annals of Nuclear Medicine

, Volume 19, Issue 4, pp 261–266 | Cite as

Imaging of lesions in a murine rheumatoid arthritis model with a humanized anti-interleukin-6 receptor antibody

  • Kanji Sugimoto
  • Norihiro Nishimoto
  • Tadamitsu Kishimoto
  • Kazuyuki Yoshizaki
  • Tsunehiko Nishimura
Original Artical


Rheumatoid arthritis (RA) has been attributed to the abnormal production of cytokine interleukin-6 (IL-6), which has a variety of physiological activities.In vivo IL-6-receptor imaging provides useful suggestions regarding the mechanism of anti-IL-6-receptor antibody action and indicates a basic therapeutic strategy for treating RA. Therefore, this study was designed to establish a method for radiolabeling anti-IL-6-receptor antibodies and to investigate the feasibility of using radi-olabeled anti-IL-6-receptor antibodies in the scintigraphic imaging of lesions in an animal RA model. Anti-IL-6-receptor antibodies were conjugated with a bifunctional chelating agent, hydorazinonicotinamide (HYNIC), and radiolabeled with technetium-99m (99mTc) using the ligand exchange reaction of99mTc-tricine complex. The binding affinity was estimated using the U266 cell line. Whole body scintigraphy, biodistribution and autoradiography were undertaken in mice containing synovial cells that had been transplanted from an RA patient. Our findings showed that the antibodies accumulated in the implanted tissue. When radiolabeled anti-IL-6-receptor antibodies are used in scintigraphic imaging, the distribution of the IL-6-receptors is associated with the inflammatory cell infiltration that is seen in the early stage of RA. Accordingly, imaging with humanized anti-IL-6-receptor antibodies appears to be useful for detecting early pathophysiological conditions and assessing the efficacy of antibody treatment as well as the prognosis of patients with RA.

Key words

rheumatoid arthritis interleukin-6 HYNIC technetium-99m scintigraphic imaging 


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  1. 1.
    Arend WP, Dayer JM. Inhibition of the production and effects of interleukin-1 and tumor necrosis factor alpha in rheumatoid arthritis.Arthritis Rheum 1995; 38 (2): 151–160.PubMedCrossRefGoogle Scholar
  2. 2.
    Hirano T, Taga T, Nakano N, Yasukawa K, Kashiwamura S, Shimizu K, et al. Purification to homogeneity and characterization of human B-cell differentiation factor (BCDF or BSFp-2).Proc Natl Acad Sci USA 1985; 82: 5490–5494.PubMedCrossRefGoogle Scholar
  3. 3.
    Takagi Y, Wong GG, Clark SC, Burakoff SJ, Herrmann SH. B cell stimulatory factor-2 is involved in the differentiation of cytotoxic T lymphocytes.J Immunol 1988; 140: 508–512.Google Scholar
  4. 4.
    Asano S, Okano A, Ozawa K, Nakahata T, Ishibashi T, Koike K, et al.In vivo effects of recombinant human interleukin-6 in primates: stimulated production of platelets.Blood 1990; 75: 1602–1605.PubMedGoogle Scholar
  5. 5.
    Kishimoto T. The biology of interleukin-6.Blood 1989; 74: 1–10.PubMedGoogle Scholar
  6. 6.
    Tamura T, Udagawa N, Takahashi N, Miyaura C, Tanaka S, Yamada Y, et al. Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6.Proc Natl Acad Sci USA 1993; 90: 11924–11928.PubMedCrossRefGoogle Scholar
  7. 7.
    Houssiau FA, Devogelaer JP, van Damme J, de Deuxchaisnes CN, van Snick J. Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides.Arthritis Rheum 1988; 31: 784–788.PubMedCrossRefGoogle Scholar
  8. 8.
    Swaak AJ, van Rooyen A, Nieuwenhuis E, Aarden LA. Interleukin-6 (IL-6) in synovial fluid and serum of patients with rheumatic diseases.Scand J Rheumatol 1988; 17: 469–474.PubMedCrossRefGoogle Scholar
  9. 9.
    Sato K, Tsuchiya M, Saldanha J, Koishihara Y, Ohsugi Y, Kishimoto T, et al. Reshaping a human antibody to inhibit the interleukin 6-dependent tumor cell growth.Cancer Res 1993; 53 (4): 851–856.PubMedGoogle Scholar
  10. 10.
    Hagihara K, Nishimoto N, Yoshizaki K. A humanized anti-IL-6 receptor antibody (MRA) in RA therapy.Nippon Rinsho 2002; 60 (12): 2401–2407.PubMedGoogle Scholar
  11. 11.
    Yoshizaki K, Nishimoto N, Mihara M, Kishimoto T. Therapy of rheumatoid arthritis by blocking IL-6 signal transduction with a humanized anti-IL-6 receptor antibody.Springer Semin Immunopathol 1998; 20: 247–259.PubMedCrossRefGoogle Scholar
  12. 12.
    Nishimoto N, Kishimoto T, Yoshizaki K. Anti-interleukin 6 receptor antibody treatment in rheumatic disease.Ann Rheum Dis 2000; 59 Suppl 1: i21–27.PubMedCrossRefGoogle Scholar
  13. 13.
    Abrams MJ, Juweid M, tenKate CI, Schwartz DA, Häuser MM, Gaul FE, et al. Technetium-99m-human polyclonal IgG radiolabeled via the hydrazino nicotinamide derivative for imaging focal sites of infection in rats.J Nucl Med 1990; 31:2022–2028.PubMedGoogle Scholar
  14. 14.
    Larsen SK, Solomon HF, Caldwell G, Abrams MJ. [99m-Tc]tricine: a useful precursor complex for the radiolabeling of hydrazinonicotinate protein conjugates.Bioconjugate Chem. 1995; 6: 635–638.CrossRefGoogle Scholar
  15. 15.
    Matsuno H, SawaiT, NezukaT, Uzuki M, Tsuji H, Nishimoto N, et al. Treatment of rheumatoid synovitis with anti-reshaping human interleukin-6 receptor monoclonal antibody: use of rheumatoid arthritis tissue implants in the SCID mouse model.Arthritis Rheum 1998; 41 (11): 2014–2021.PubMedCrossRefGoogle Scholar
  16. 16.
    Taga T, Kawanishi Y, Hardy RR, Hirano T, Kishimoto T. Receptors for B cell stimulatory factor 2: Quantitation, specificity, distribution, and regulation of their expression.J Exp Med 1987; 166: 967–981.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  • Kanji Sugimoto
    • 1
  • Norihiro Nishimoto
    • 2
  • Tadamitsu Kishimoto
    • 3
  • Kazuyuki Yoshizaki
    • 2
  • Tsunehiko Nishimura
    • 4
  1. 1.Division of Tracer KineticsOsaka University Graduate School of MedicineJapan
  2. 2.Department of Medical Science I, School of Health and Sport SciencesOsaka UniversityJapan
  3. 3.Department of Molecular MedicineOsaka University Graduate School of MedicineJapan
  4. 4.Department of Radiology, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan

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