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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