Rapid-onset clinical and mechanistic effects of anti-C5aR treatment in the mouse collagen-induced arthritis model

Abstract

SummaryPreclinical evidence supports targeting the C5a receptor (C5aR) in rheumatoid arthritis (RA). To support ongoing clinical development of an anti-C5aR monoclonal antibody, we have investigated for the first time the mechanism of action and the pharmacodynamics of a blocking anti-murine C5aR (antimC5aR) surrogate antibody in mouse collagen-induced arthritis (CIA). First, efficacy was demonstrated in a multiple-dose treatment study. Almost complete inhibition of clinical disease progression was obtained, including reduced bone and cartilage destruction in anti-mC5aR-treated mice. Then, the mechanism of action was examined by looking for early effects of antimC5aR treatment in single-dose treatment studies. We found that 48 h after single-dose treatment with anti-mC5aR, the neutrophil and macrophage infiltration into the paws was already reduced. In addition, several inflammatory markers, including tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-17A were reduced locally in the paws, indicating reduction of local inflammation. Furthermore, dose-setting experiments supported a beneficial clinical effect of dosing above the C5aR saturation level. In conclusion, these preclinical data demonstrated rapid onset effects of antibody blockade of C5aR. The data have translational value in supporting the Novo Nordisk clinical trials of an anti-C5aR antibody in rheumatoid arthritis patients, by identifying potential biomarkers of treatment effects as well as by providing information on pharmacodynamics and novel insights into the mechanism of action of monoclonal antibody blockade of C5aR.

Complement Receptors in Myeloid Cell Adhesion and Phagocytosis

“…Either C3aR or C5aR deficiency in mice reduced the severity of collagen-induced arthritis in mice, with C5aR appearing to play a greater role (22). Consistent with this, antibody mediated blockade of C5aR eliminates mouse collagen induced arthritis and reduces levels of multiple cytokines (23). However, attempts to treat human rheumatoid arthritis with a small molecule C5aR antagonist were not successful (24).…”

A New Approach for the Treatment of Arthritis in Mice with a Novel Conjugate of an Anti-C5aR1 Antibody and C5 Small Interfering RNA

“…Theoretically C5siRNA bound to asialo-glycoprotein receptor (ASGR) antibody should have the same effect on hepatocytes. Similarly a newly developed anti-C5aR1 inhibitory antibody by Novo Nordisk Park can be conjugated (39). Most biological activities of C5a are mediated through C5aR1 (40) and it is widely expressed in inflammatory cells and the agents that act on C5aR hold great potential as therapeutics (41).…”

MicroRNAs in neutrophils: potential next generation therapeutics for inflammatory ailments

“…Currently, many methods to reduce inflammation are being attempted to treat conditions such as non‐infectious arthritis (reviewed in ). Those targeting immune cell recruitment (allosteric antagonists to CXCR1/2 or C5a‐C5aR), neutrophil degranulation (phosphodiesterase inhibitors) and pro‐inflammatory cytokines (recombinant proteins or antibodies against IL‐6, IL1‐Beta, IL‐8, IL‐1 receptors or NF‐κB activity) and adhesion molecules all succeeded in reducing neutrophil recruitment in mice models. However, some of the discoveries are not translated in clinics, exemplified through clinical trials targeting Selectins or Integrins failing to improve rheumatoid arthritis symptoms .…”