Antibody-mediated inhibition of ADAMTS-7 reduces experimental atherosclerosis

Sharifi, M. A.; Riechel, J.; Winkler, M. J.; Dang, T. A.; Graesser, C.; Müller, P.; Abrahamian, C.; Panyam, N.; Briquez, P. S.; Spiegel, H.; Sager, H. B.; Raven, N.; Schunkert, H.; Kessler, T.

doi:10.64898/2026.08.11.744317

bioRxiv · 10.64898/2026.08.11.744317

Antibody-mediated inhibition of ADAMTS-7 reduces experimental atherosclerosis

Sharifi, M. A.·Riechel, J.·Winkler, M. J.·Dang, T. A.·Graesser, C.·Müller, P.·Abrahamian, C.·Panyam, N.·Briquez, P. S.·Spiegel, H.·Sager, H. B.·Raven, N.·Schunkert, H.·Kessler, T.

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Abstract

Objective: One of the strongest genetic associations with coronary artery disease (CAD) risk maps to the metalloproteinase 'a disintegrin and metalloproteinase with thrombospondin motifs 7' (ADAMTS-7) locus. The protein was shown to promote plaque formation and instability. We aimed to generate and evaluate an antibody-based strategy targeting ADAMTS-7 therapeutically to reduce atherosclerotic plaque formation. Approach and Results: A truncated form of human ADAMTS-7 was produced in Nicotiana benthamiana and used as antigen for antibody generation by hybridoma technology. Eight monoclonal antibodies (mAbs) were screened, among which ADAMTS-7-mAb32 (mAb32) demonstrated the highest affinity, as confirmed by surface plasmon resonance analyses and immunoblotting against full-length ADAMTS-7. In vitro, mAb32 inhibited interactions of ADAMTS-7 with its substrates TIMP-1 and SVEP1 in a dose- and time-dependent manner, as assessed by time-resolved Forster resonance energy transfer assays. To assess therapeutic efficacy in vivo, Apoe-/- mice were fed a Western diet for ten weeks and treated with weekly injections of mAb32 or control IgG over the last six weeks. En face aortic Oil Red O staining revealed significantly reduced plaque area in the treatment group, without changes in plasma cholesterol levels or body weight. No evidence of liver or kidney toxicity was observed. Conclusion: Monoclonal antibody-based inhibition of ADAMTS-7 reduced atherosclerotic burden in vivo without affecting lipid metabolism, supporting ADAMTS-7 as a viable therapeutic target in CAD. Further development of mAb32 may provide a cholesterol-independent treatment strategy for atherosclerosis.

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Sharifi, M. A., Riechel, J., Winkler, M. J., Dang, T. A., Graesser, C., Müller, P., Abrahamian, C., Panyam, N., Briquez, P. S., Spiegel, H., Sager, H. B., Raven, N., Schunkert, H., Kessler, T.. 2026-08-19. Antibody-mediated inhibition of ADAMTS-7 reduces experimental atherosclerosis. https://doi.org/10.64898/2026.08.11.744317

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