Rationale: Previous studies have indicated an important role for
complement in
atherosclerosis, a
lipid-driven chronic inflammatory disease associated to oxidative stress in the vessel wall. However, it remains unclear how
complement is activated in the process of
atherogenesis. An accepted general model for complement activation in the context of
ischemia reperfusion injury is that
ischemia induces the exposure of neoepitopes that are recognized by natural self-reactive
IgM antibodies, and that in turn activate
complement. Objective: We investigated whether a similar phenomenon may be involved in the pathogenesis of
atherosclerosis, and whether interfering with this activation event, together with inhibition of subsequent amplification of the cascade at the C3 activation step, can provide protection against
atherogenesis. Methods and Results: We utilized C2scFv-Crry, a novel construct consisting of a single chain antibody (scFv) linked to Crry, a
complement inhibitor that functions at C3 activation. The scFv moiety was derived from C2
IgM mAb that specifically recognizes
phospholipid neoepitopes known to be expressed after
ischemia. C2scFv-Crry targeted to the
atherosclerotic plaque of
Apoe -/- mice, demonstrating expression of the C2 neoepitope. C2scFv-Crry administered twice per week significantly attenuated
atherosclerotic plaque in the aorta and aortic root of
Apoe -/- mice fed with a high-fat diet (HFD) for either 2 or 4 months, and treatment reduced C3 deposition and
membrane attack complex formation as compared to vehicle treated mice. C2scFv-Crry also inhibited the uptake of
oxidized low-density-lipoprotein (
oxLDL) by peritoneal macrophages, which has been shown to play a role in pathogenesis, and C2scFv-Crry-treated mice had decreased
lipid content in the lesion with reduced
oxLDL levels in serum compared to vehicle-treated mice. Furthermore, C2scFv-Crry reduced the deposition of endogenous total
IgM in the plaque, although it did not alter serum
IgM levels, further indicating a role for natural
IgM in initiating complement activation. Conclusion: Neoepitope targeted
complement inhibitors represent a novel therapeutic approach for
atherosclerosis.