Peptide Vaccine Against ADAMTS-7 Ameliorates Atherosclerosis and Postinjury Neointima Hyperplasia

Abstract

BACKGROUND: The metalloprotease ADAMTS-7 (a disintegrin and metalloproteinase with thrombospondin type 1 motif 7) is a novel locus associated with human coronary atherosclerosis. ADAMTS-7 deletion protects against atherosclerosis and vascular restenosis in rodents. METHODS: We designed 3 potential vaccines consisting of distinct B cell epitopic peptides derived from ADAMTS-7 and conjugated with the carrier protein KLH (keyhole limpet hemocyanin) as well as aluminum hydroxide as an adjuvant. Arterial ligation or wire injury was used to induce neointima in mice, whereas ApoE -/ - and LDLR -/ - (LDLR [low-density lipoprotein receptor]) mice fed a high-fat diet were applied to assess atherosclerosis. In addition, coronary stent implantation was performed on vaccine-immunized Bama miniature pigs, followed by optical coherence tomography to evaluate coronary intimal hyperplasia. RESULTS: A vaccine, ATS7vac, was screened out from 3 candidates to effectively inhibit intimal thickening in murine carotid artery ligation models after vaccination. As well, immunization with ATS7vac alleviated neointima formation in murine wire injury models and mitigated atherosclerotic lesions in both hyperlipidemic ApoE -/ - and LDLR -/ - mice without lowering lipid levels. Preclinically, ATS7vac markedly impeded intimal hyperplasia in swine stented coronary arteries, but without significant immune-related organ injuries. Mechanistically, ATS7vac vaccination produced specific antibodies against ADAMTS-7, which markedly repressed ADAMTS-7–mediated COMP (cartilage oligomeric matrix protein) and TSP-1 (thrombospondin-1) degradation and subsequently inhibited vascular smooth muscle cell migration but promoted re-endothelialization. CONCLUSIONS: ATS7vac is a novel atherosclerosis vaccine that also alleviates in-stent restenosis. The application of ATS7vac would be a complementary therapeutic avenue to the current lipid-lowering strategy for atherosclerotic disease.

BAY-9835: Discovery of the First Orally Bioavailable ADAMTS7 Inhibitor

“…Consequently, ADAMTS7 antibodies raised against the ADAMTS7 catalytic domain protected against stent-induced restenosis in a preclinical swine model. 24,25 Furthermore, high ADAMTS7 levels were identified in heart tissue 20 and injured vessels, 18 which is in line with the CAD protection conferred by the low risk allele and the intimal thickening induced by the high risk allele as detailed above. Collectively, the data suggest that ADAMTS7 inhibition might be a new way to treat CAD and restenosis.…”

Targeting ADAMTS-7: A Vaccination Against Atherosclerosis—and Its Complications?

“…9,10 Ma et al 4 generated a vaccine targeting ADAMTS-7 using 3 epitopes of its secondary structure at the catalytic domain as well as the C-terminal thrombospondin (the "TS" in ADAMTS) repeats. 4 This is important because the catalytic domain was recently identified to be critical for the role of ADAMTS-7 in atherosclerosis, 10 and the thrombospondin repeats are known to bind its targets COMP and thrombospondin-1. 7,8 The authors were able to induce an immune response against these epitopes and subsequently studied the efficacy in vascular diseases.…”

“…8 Assuming that the mechanisms affected by vaccination against ADAMTS-7 are better understood, such treatment needs to demonstrate an excellent safety profile, as novel strategies for prevention of atherosclerosis or treatment of its complications might be of relevance for large patient groups. Ma et al 4 observed no safety issues of ATS7vac, which nevertheless needs to be complemented by robust testing in other models before treatment of patients can be considered.…”

“…7,8 The authors were able to induce an immune response against these epitopes and subsequently studied the efficacy in vascular diseases. 4 Only antibodies against the catalytic domain were efficient in a screening, which focused on remodeling after carotid artery ligation as a functional readout. The resulting vaccine, ATS7vac, was then evaluated for efficacy in wire-injury models of neointima proliferation and models of atherosclerotic plaque formation.…”

ADAMTS-7 Modulates Atherosclerotic Plaque Formation by Degradation of TIMP-1

“…9 Recently, in an experimental study, vaccination against ADAMTS-7 successfully reduced atherosclerotic plaque formation under proatherogenic conditions and prevented neointima formation and in-stent restenosis. 10 The effects of ADAMTS-7 on vascular remodeling can be explained by degradation of the substrate COMP (cartilage oligomeric matrix protein), 11 which was also found to mediate ADAMTS-7-related effects in rheumatoid arthritis and represents its first known substrate. Another binding partner of ADAMTS-7 is THBS1 (thrombospondin-1 or TSP1).…”