A Monoclonal Antibody to High-Molecular Weight Kininogen Is Therapeutic in a Rodent Model of Reactive Arthritis

Abstract

We reported that high-molecular weight kininogen is proangiogenic by releasing bradykinin and that a monoclonal antibody to high-molecular weight kininogen, C11C1, blocked its binding to endothelial cells. We now test if this antibody can prevent arthritis and systemic inflammation in a Lewis rat model. We studied 32 animals for 16 days. Group I (negative control) received saline intraperitoneally. Group II (disease-treated) received peptidoglycan-polysaccharide simultaneously with C11C1. Group III (disease-untreated) received peptidoglycan-polysaccharide simultaneously with isotype-matched mouse IgG. Group IV (disease-free-treated) and group V (disease-free isotype-treated) received saline and C11C1 or mouse IgG. Analysis of joint diameter changes showed a decrease in the C11C1 disease-treated group compared to the disease-untreated group. The hind paw inflammatory score showed a decrease in the intensity and extent of inflammation between the disease-untreated and the C11C1 disease-treated group. Prekallikrein, high-molecular weight kininogen, factor XI, and factor XII were decreased in the disease-untreated group compared to the C11C1 disease-treated group. T-kininogen was increased in the disease-untreated group when compared with the C11C1 disease-treated group. Disease-free groups IV and V did not show any sign of inflammation at any time. This study shows that monoclonal antibody C11C1 attenuates plasma kallikrein-kinin system activation, local and systemic inflammation, indicating therapeutic potential in reactive arthritis.

Organ Messenger Ribonucleic Acid and Plasma Proteome Changes in the Adjuvant-Induced Arthritis Model: Responses to Disease Induction and Therapy with the Estrogen Receptor-β Selective Agonist ERB-041

“…Kininogens serve as substrate for kallikrein in the biosynthesis of vasoactive and proinflammatory kinins that have been associated with edema, pain, and proinflammatory responses (43). Direct inhibition of kallikrein activity or decreasing kininogen by monoclonal antibody titration provides therapeutic benefit in a Lewis rat models of reactive arthritis (44).…”

Peptide Hormone Regulation of Angiogenesis

“…All components of the KKS have been detected in the synovial fluid of patients with rheumatoid arthritis (see review in Ref. 77) and are elevated in the peptidoglycan polysaccharide-induced rat model of arthritis and systemic inflammation (154). In this model, a BK inhibitor (105) or blockage of BK generation by an anti-HK monoclonal antibody (154) prevents joint swelling and inflammation.…”

Regulation of Angiogenesis by the Kallikrein-Kinin System

“…We have shown that mAb C11C1 may prevent the binding of HK to endothelial cells and thus subsequent generation of BK [95,96]. Recently, we showed that the same antibody is therapeutic in a rodent model of reactive arthritis [97] where angiogenesis may play a significant role in the pathogenesis of the joint disease. This mechanism is further supported by the finding of other investigators that angiogenesis is suppressed in rats with kininogen deficiency [98].…”