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bioRxiv · 10.1101/2024.03.04.582839

LDL-Binding IL-10 Reduces Vascular Inflammation in Atherosclerotic Mice

Volpatti, L. R.·Norton de Matos, S.·Borjas, G.·Reda, J.·Watkins, E. A.·Zhou, Z.·Nguyen, M.·Solanki, A.·Fang, Y.·Hubbell, J. A.
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Abstract

Atherosclerosis is a chronic inflammatory disease associated with the accumulation of low-density lipoprotein (LDL) in arterial walls. Higher levels of the anti-inflammatory cytokine IL-10 in serum are correlated with reduced plaque burden. However, cytokine therapies have not translated well to the clinic, partially due to their rapid clearance and pleiotropic nature. Here, we engineered IL-10 to overcome these challenges by hitchhiking on LDL to atherosclerotic plaques. Specifically, we constructed fusion proteins in which one domain is IL-10 and the other is an antibody fragment (Fab) that binds to protein epitopes of LDL. In murine models of atherosclerosis, we show that systemically administered Fab-IL-10 constructs bind circulating LDL and traffic to atherosclerotic plaques. One such construct, 2D03-IL-10, significantly reduces aortic immune cell infiltration to levels comparable to healthy mice, whereas non-targeted IL-10 has no therapeutic effect. Mechanistically, we demonstrate that 2D03-IL-10 preferentially associates with foamy macrophages and reduces pro-inflammatory activation markers. This platform technology can be applied to a variety of therapeutics and shows promise as a potential targeted anti-inflammatory therapy in atherosclerosis.

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Volpatti, L. R., Norton de Matos, S., Borjas, G., Reda, J., Watkins, E. A., Zhou, Z., Nguyen, M., Solanki, A., Fang, Y., Hubbell, J. A.. 2024-03-06. LDL-Binding IL-10 Reduces Vascular Inflammation in Atherosclerotic Mice. https://doi.org/10.1101/2024.03.04.582839

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