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SAT0076 Comparison of anti-interleukin-6 and anti-interleukin-6 receptor antibodies using in vivo functional systems
  1. S. Shaw,
  2. D. Marshall,
  3. H. Neale,
  4. K. Kretsos,
  5. T. Bourne,
  6. A. Lawson
  1. UCB Pharma, Slough, United Kingdom

Abstract

Background The multi-step assembly of the interleukin-6 (IL-6) signaling complex offers the potential for several therapeutic points of intervention in the treatment of rheumatoid arthritis; for example, targeting the cytokine IL-6, the IL-6 receptor (IL-6R; gp80), or gp130.

Objectives The objective of this study was to compare affinity-matched anti-murine monoclonal antibodies (mAbs) that target either the IL-6 cytokine or the IL-6 receptor in a range of in vivo assays.

Methods Affinity-matched anti-murine reagents 54E07 mAb (anti-IL-6) and 440-1 mAb (anti-IL-6R; gp80) were evaluated for their ability to inhibit either murine IL-6 or CFA-induced serum amyloid A (SAA). IL-6 is also known to have a significant role in B-cell function; therefore, these antibodies (Abs) were evaluated for their ability to inhibit dinitrophenyl (DNP)-specific Ab production. Furthermore, these Abs were dosed to steady state and their capacity to inhibit collagen-induced arthritis (CIA) in DBA-1 mice was evaluated.

Results 54E07 mAb produced a ≥90% reduction in the SAA response to both IL-6 and CFA at a dose of 0.1 mg/kg (p<0.01 and p<0.001, respectively). In contrast, doses of at least 1 mg/kg and 3 mg/kg of 440-1 mAb were required to significantly reduce the SAA response (p<0.001 for both doses). In vivo inhibition of IL-6 by 54E07 mAb significantly reduced the DNP-specific IgG response by 72% at doses as low as 0.3 mg/kg s.c. (p<0.05), whereas 440-1 mAb only achieved a significant reduction (80%) in DNP-specific Ab titer at a dose of 10 mg/kg s.c. (p<0.05). In the murine CIA model, both 54E07 mAb and 440-1 mAb achieved a similar reduction (≥97%) in the clinical arthritis score at the same high dose exposure; however, at the same low dose exposure, only 54E07 mAb caused a significant reduction (67%) in clinical score versus controls.

Conclusions These murine in vivo studies strongly suggest that targeting IL-6 cytokine rather than the IL-6 receptor is the more efficient therapeutic approach for the treatment of autoimmune diseases such as rheumatoid arthritis.

Disclosure of Interest None Declared

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