Prevention of Arthritis by Locally Synthesized Recombinant Antibody Neutralizing Complement Component C5

Abstract

Treatment of patients suffering from chronic diseases such as rheumatoid arthritis with recombinant antibodies is time consuming and fairly expensive and can be associated with side effects due to generalized depletion of the target molecule. We have addressed these issues by developing an alternative approach consisting of the intraarticular injection of a DNA vector encoding for the anti-C5 neutralizing recombinant miniantibody MB12/22. This method allows local production of the antibody in sufficient amount to be effective in preventing joint inflammation in a rat model of antigen-induced arthritis. Injection of the DNA vector in a right knee of normal rats resulted in the production of the minibody detected in the synovial washes by western blot with a strong signal peaking at 3 days after administration. DNA encoding for the minibody was shown for 14 days in the synovial tissue and was undetectable in the controlateral knee and in other organs. The preventive effect of this approach was evaluated in rats receiving a single injection of the vector 3 days before the induction of antigen-induced arthritis and analyzed 3 days later. The treated rats exhibited a lower increase in swelling, associated with a lower number of PMN in the articular washes and reduced deposition of C9 in synovial tissue compared to control rats. These results suggest that treating the inflamed joints with a vector that induces a local production of a neutralizing anti-C5 antibody may represent a useful strategy to inhibit in situ complement activation and to treat patients with monoarthritis. Moreover, this approach may be adopted as a novel therapeutic strategy to prevent monoarthritis as an alternative to local treatment with antibodies commonly used in this form of arthritis, with the advantages of the lower cost and the longer persistence of antibody production.

Critical Role and Therapeutic Control of the Lectin Pathway of Complement Activation in an Abortion-Prone Mouse Mating

“…This recombinant Ab was previously found to prevent C5 activation in several animal models developed in mice (17,18) and rats (16,(19)(20)(21)). An essentially similar procedure was followed for the production of a recombinant Ab to human CD20 reported in a previous publication (22) and used in this study as an unrelated Ab.…”

The Role of Innate Immunity in Osteoarthritis: When Our First Line of Defense Goes On the Offensive

“…Another new strategy involved intra-articular injection of a DNA vector encoding an anti-C5 recombinant mini-antibody (MB12/22). This treatment lead to in situ production of this neutralizing antibody, which resulted in a statistically significant reduction in joint inflammation in a rat model of inflammatory arthritis (92). A human anti-DR5 antibody (TRA-8) was able to selectively induce apoptosis in a subset of inflammatory macrophages in a transgenic mouse model that led to less synovial hyperplasia and cellular infiltrates as well as improved clinical scores (93).…”

Lack of Long-Lasting Hydrosalpinx in A/J Mice Correlates with Rapid but Transient Chlamydial Ascension and Neutrophil Recruitment in the Oviduct following Intravaginal Inoculation with Chlamydia muridarum

“…Interestingly, A/J mice are known to be deficient in complement component 5 (C5) (36,37). Since C5 has been found to play significant roles in various inflammatory pathologies and anti-C5 therapy has been shown to reduce the severity of autoimmune pathologies (38,39), it is possible that A/J mice are not able to develop long-lasting hydrosalpinx if C5 is required for the conversion of early hydrosalpinx into long-lasting hydrosalpinx. Although complement component 3 (C3) has been shown to be protective in controlling C. muridarum lung infection (40), the role of C5 in either chlamydial infection or pathogenesis has not been evaluated.…”