Atherosclerosis plus · 2026
Passive E06 IgG reduces lesional PC-OxPL and macrophage accumulation in cholesterol-fed Ldlr-/- mice.
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Trausch-Quiróz Brian, Normand Alexandre, Que Xuchu, Alekseeva Elena, Yang Xiaohong, Resch Craig, Ravandi Amir, Witztum Joseph L, Tsimikas Sotirios
Аннотация
BACKGROUND: Oxidized phospholipids (OxPL) promote vascular inflammation and atherosclerosis. Although transgenic expression of the E06 single-chain antibody reduces atherosclerosis in mice, the therapeutic potential and mechanism of passive immunization with full-length recombinant E06 IgG remain unknown.
METHODS: Male Ldl r-/- mice fed a cholesterol-enriched diet received placebo or recombinant E06 IgG (5 or 25 mg/kg subcutaneously twice weekly) for 12 weeks. Plasma lipids, oxidation-specific biomarkers, atherosclerosis, lesional phosphocholine-containing OxPL (PC-OxPL), macrophage content, collagen, and necrotic core were quantified. To assess whether E06 IgG depletes circulating OxPL, apo(a)- and lipoprotein(a)-transgenic mice received a single intravenous injection of E06 IgG followed by serial measurements of oxidation-specific biomarkers and total plasma OxPL by targeted LC-MS/MS.
RESULTS: Terminal plasma E06 IgG concentrations confirmed dose-dependent systemic exposure. Compared with placebo, E06 IgG significantly reduced lesional macrophage content (47.6 ± 14.5% vs 34.4 ± 9.2% vs 34.3 ± 9.1% of lesion area; P = 0.013) and lesional PC-OxPL (28.5 ± 8.8% vs 18.2 ± 7.5% vs 20.1 ± 7.0%; P = 0.010) in placebo, 5 mg/kg, and 25 mg/kg groups, respectively. No significant differences were observed in plasma cholesterol, triglycerides, circulating OxPL-related biomarkers, aortic root lesion area, plaque collagen, or necrotic core. Acute E06 IgG administration demonstrated target engagement in apo(a)- and Lp(a)-transgenic mice but produced only transient, non-significant changes in circulating OxPL measured by ELISA and LC-MS/MS.
CONCLUSIONS: These findings provide proof-of-concept that passive E06 IgG selectively neutralizes lesional PC-OxPL and reduces plaque macrophage accumulation despite minimal sustained effects on circulating OxPL, supporting further investigation of OxPL-targeted therapies and suggesting that circulating OxPL may not adequately reflect vascular target engagement.
METHODS: Male Ldl r-/- mice fed a cholesterol-enriched diet received placebo or recombinant E06 IgG (5 or 25 mg/kg subcutaneously twice weekly) for 12 weeks. Plasma lipids, oxidation-specific biomarkers, atherosclerosis, lesional phosphocholine-containing OxPL (PC-OxPL), macrophage content, collagen, and necrotic core were quantified. To assess whether E06 IgG depletes circulating OxPL, apo(a)- and lipoprotein(a)-transgenic mice received a single intravenous injection of E06 IgG followed by serial measurements of oxidation-specific biomarkers and total plasma OxPL by targeted LC-MS/MS.
RESULTS: Terminal plasma E06 IgG concentrations confirmed dose-dependent systemic exposure. Compared with placebo, E06 IgG significantly reduced lesional macrophage content (47.6 ± 14.5% vs 34.4 ± 9.2% vs 34.3 ± 9.1% of lesion area; P = 0.013) and lesional PC-OxPL (28.5 ± 8.8% vs 18.2 ± 7.5% vs 20.1 ± 7.0%; P = 0.010) in placebo, 5 mg/kg, and 25 mg/kg groups, respectively. No significant differences were observed in plasma cholesterol, triglycerides, circulating OxPL-related biomarkers, aortic root lesion area, plaque collagen, or necrotic core. Acute E06 IgG administration demonstrated target engagement in apo(a)- and Lp(a)-transgenic mice but produced only transient, non-significant changes in circulating OxPL measured by ELISA and LC-MS/MS.
CONCLUSIONS: These findings provide proof-of-concept that passive E06 IgG selectively neutralizes lesional PC-OxPL and reduces plaque macrophage accumulation despite minimal sustained effects on circulating OxPL, supporting further investigation of OxPL-targeted therapies and suggesting that circulating OxPL may not adequately reflect vascular target engagement.