Anti-C5 monoclonal antibody therapy prevents collagen-induced arthritis and ameliorates established disease.

Abstract

Activated components of the complement system are potent mediators of inflammation that may play an important role in numerous disease states. For example, they have been implicated in the pathogenesis of inflammatory joint diseases including rheumatoid arthritis (RA). To target complement activation in immune-mediated joint inflammation, we have utilized monoclonal antibodies (mAbs) that inhibit the complement cascade at C5, blocking the generation of the major chemotactic and proinflammatory factors CSa and C5b-9. In this study, we demonstrate the efficacy of a mAb specific for murine C5 in the treatment of collagen-induced arthritis, an animal model for RA. We show that systemic administration of the anti-C5 mAb effectively inhibits terminal complement activation in vivo and prevents the onset of arthritis in immunized animals. Most important, anti-C5 mAb treatment is also highly effective in ameliorating established disease. These results demonstrate a critical role for activated terminal complement components not only in the induction but also in the progression of collagen-induced arthritis and suggest that C5 may be an attractive therapeutic target in RA.

Evaluation of classical complement pathway activation in rheumatoid arthritis: Measurement of C1q–C4 complexes as novel activation products

“…In complement-deficient mice, arthritis was reduced or completely absent, whereas normal mice were susceptible to CIA, indicating an important role of complement in the induction of dis-ease. Consistent with this observation, systemic administration of a monoclonal anti-C5 antibody prevented CIA in susceptible mice (11).…”

Requirement of activation of complement C3 and C5 for antiphospholipid antibody–mediated thrombophilia

“…However, the anti-C5 mAb (BB5.1) used in these studies has been shown to effectively block C5 activation in vitro and in vivo in mice and in humans (13,17,18). Independent of the initiator of the complement cascade, this mAb prevents C5 activation and thus prevents the generation of the potent proinflammatory factors, C5a and C5b-9.…”

Complement activation by both classical and alternative pathways is critical for the effector phase of arthritis

“…Our earlier experiments demonstrated that CII-specific monoclonal antibodies bind to normal joint cartilage in vivo and induce arthritis [14,26]. Furthermore, it has been demonstrated that the autoreactive antibodies to CII initiate inflammation by binding to articular cartilage, which leads to complement activation, C3 deposition [16] and eventual cleavage of C5 [21]. To discern the importance of complement for the effector phase of arthritis, we used monoclonal antibodies against CII to induce arthritis in C3 -/-, FB -/-and control DBA/1J mice.…”

“…Depletion of complement by cobra venom factor made mice refractory to arthritis until complement levels had recovered [17]. Both C5 deficiency and systemic administration of anti-C5 antibody ameliorated CIA despite normal cellular and antibody responses to immunization with CII [18][19][20][21][22], although some mice could still develop arthritis in the absence of C5 [19]. Progression of arthritis was prevented by soluble complement receptor I (CD35) and overexpression of complement receptor 1-related gene/protein y, both potent inhibitors of the classical and alternative pathways of Fig.…”