Abstract 15644: A Fully Human Monoclonal IgG Phosphorylcholine Antibody Prevents Accelerated Atherosclerosis in Mice
Background: Serum contains natural IgM antibodies against the phosphorylcholine headgroup of phosphatidylcholine (anti-PC). Low levels are associated with an increased risk for cardiovascular disease and a poor prognosis following acute coronary syndrome. The prototypic anti-PC, the murine IgM T15/E06 antibody has anti-atherosclerotic effects. We showed that human polyclonal IgM anti-PC (unlike IgG) prevented uptake of oxLDL into macrophages (MO) and that both IgM and IgG anti-PC blocked UPR (unfolded protein response; ER stress) in cultured endothelium and MO. UPR is linked to vascular intervention, inflammation and accelerated atherosclerosis.
Hypothesis: A monoclonal IgG PC antibody resembling natural IgM anti-PC will target vascular inflammation and exert anti-inflammatory effects, thus preventing accelerated atherosclerosis development following revascularization procedures.
Methods and results: Two phage display libraries for binders to PC were screened, and binders converted to full IgG1 antibodies. Clone M99-B05 (Athera Biotechnologies) was more effective than IgM anti-PC in inhibiting oxLDL uptake. A tissue array of human aortas with lesions was stained with antibodies against cell types, UPR markers (Grp78 and CHOP) and biotinylated M99-B05. UPR increased with lesion severity, was most prominent in MO, positive endothelial cells were seen. M99-B05 bound to lesions in a pattern similar to that of ER stress, binding to MO was common. M99-B05 was then tested in a femoral artery cuff model of accelerated, inflammation driven, vascular injury in hypercholesterolemic ApoE3*Leiden mice. Antibody was given as a single (3d protocol) or twice weekly (14d protocol) injections. At 3d, accumulation of leukocytes in the cuffed arteries was significantly inhibited by M99-B05. At 14d, intimal thickening was almost completely prevented by PC-mAb, even in doses as low as 0.5 mg/kg.
Conclusion: The PC epitope is a promising target for drugs to prevent vascular inflammation. The fully human PC-mAb M99-B05 bound to inflammatory cells in human lesions, and had beneficial effects in an animal model of vascular disease. M99-B05 has a potential in secondary prevention in ACS patients with low anti-PC, possibly by inhibiting vascular inflammation.
- © 2011 by American Heart Association, Inc.