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<p>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 engineer IL-10 to overcome these challenges by hitchhiking on LDL to atherosclerotic plaques. Specifically, we construct Fab-IL-10 by fusing IL-10 to the antibody fragment (Fab) of four different oxidized LDL-binding antibodies. We show that systemically administered Fab-IL-10 constructs bind circulating LDL and traffic to atherosclerotic plaques in atherosclerosis mouse models. Among them, 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 modular technology may be applied to a variety of protein therapeutics and shows promise as a potential targeted anti-inflammatory therapy in atherosclerosis.</p>

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LDL-binding IL-10 reduces vascular inflammation in atherosclerotic mice

  • 期刊论文

  • 发表日期：

    2026年1月2日

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  • Lisa R. Volpatti,
  • Salvador Norton de Matos,
  • Gustavo Borjas,
  • Taryn N. Beckman,
  • Joseph W. Reda,
  • Elyse A. Watkins,
  • Zhengjie Zhou,
  • Mindy Nguyen,
  • Ani Solanki,
  • Yun Fang,
  • Jeffrey A. Hubbell

摘要

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 engineer IL-10 to overcome these challenges by hitchhiking on LDL to atherosclerotic plaques. Specifically, we construct Fab-IL-10 by fusing IL-10 to the antibody fragment (Fab) of four different oxidized LDL-binding antibodies. We show that systemically administered Fab-IL-10 constructs bind circulating LDL and traffic to atherosclerotic plaques in atherosclerosis mouse models. Among them, 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 modular technology may be applied to a variety of protein therapeutics and shows promise as a potential targeted anti-inflammatory therapy in atherosclerosis.