Identification of IgG1 isotype phosphorylcholine antibodies for the treatment of inflammatory cardiovascular diseases

Background Phosphorylcholine (PC) is an important pro‐inflammatory damage‐associated molecular pattern. Previous data have shown that natural IgM anti‐PC protects against cardiovascular disease. We aimed to develop a monoclonal PC IgG antibody with anti‐inflammatory and anti‐atherosclerotic properti...

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Published in:	Journal of internal medicine Vol. 290; no. 1; pp. 141 - 156
Main Authors:	Vries, M. R., Ewing, M. M., Jong, R. C. M., MacArthur, M. R., Karper, J. C., Peters, E. A. B., Nordzell, M., Karabina, S. A. P., Sexton, D., Dahlbom, I., Bergman, A., Mitchell, J. R., Frostegård, J., Kuiper, J., Ninio, E., Jukema, J. W., Pettersson, K., Quax, P. H. A.
Format:	Journal Article
Language:	English
Published:	England Blackwell Publishing Ltd 01-07-2021 Wiley John Wiley and Sons Inc
Subjects:	Animals Anti-Inflammatory Agents - therapeutic use Antibodies Antibodies, Monoclonal - therapeutic use Antibodies, Monoclonal - toxicity Apoptosis Arteriosclerosis Atherosclerosis Atherosclerosis - prevention & control Biomedical materials Cardiology and cardiovascular system Cardiovascular disease Cardiovascular diseases Cardiovascular Diseases - immunology Cardiovascular Diseases - therapy Chimera Cholesterol, LDL - antagonists & inhibitors Cholesterol, LDL - metabolism Choline Choline - metabolism Damage patterns Disease Models, Animal Endoplasmic reticulum Epitopes Fab Female Femoral artery Gene expression Genes Health services Human health and pathology IgG antibody Immunoglobulin G Immunoglobulin G - immunology Immunoglobulin M In vivo methods and tests Inflammation Lesions Life Sciences Macaca fascicularis Macrophages Macrophages - metabolism Male Medicin och hälsovetenskap Metabolism Mice Mice, Inbred C57BL Monkeys Monoclonal antibodies Monocyte chemoattractant protein 1 Optimization Original Oxidation-Reduction Phage display Phages Phosphorylcholine Phosphorylcholine - immunology Rats restenosis Safety therapeutics vascular disease atherosclerosis restenosis therapeutics vascular disease inflammation Vascular disease
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Summary:	Background Phosphorylcholine (PC) is an important pro‐inflammatory damage‐associated molecular pattern. Previous data have shown that natural IgM anti‐PC protects against cardiovascular disease. We aimed to develop a monoclonal PC IgG antibody with anti‐inflammatory and anti‐atherosclerotic properties. Methods Using various techniques PC antibodies were validated and optimized. In vivo testing was performed in a femoral artery cuff model in ApoE3*Leiden mice. Safety studies are performed in rats and cynomolgus monkeys. Results A chimeric anti‐PC (PC‐mAb(T15), consisting of a human IgG1 Fc and a mouse T15/E06 Fab) was produced, and this was shown to bind specifically to epitopes in human atherosclerotic tissues. The cuff model results in rapid induction of inflammatory genes and altered expression of genes associated with ER stress and choline metabolism in the lesions. Treatment with PC‐mAb(T15) reduced accelerated atherosclerosis via reduced expression of endoplasmic reticulum stress markers and CCL2 production. Recombinant anti‐PC Fab fragments were identified by phage display and cloned into fully human IgG1 backbones creating a human monoclonal IgG1 anti‐PC (PC‐mAbs) that specifically bind PC, apoptotic cells and oxLDL. Based on preventing macrophage oxLDL uptake and CCL2 production, four monoclonal PC‐mAbs were selected, which to various extent reduced vascular inflammation and lesion development. Additional optimization and validation of two PC‐mAb antibodies resulted in selection of PC‐mAb X19‐A05, which inhibited accelerated atherosclerosis. Clinical grade production of this antibody (ATH3G10) significantly attenuated vascular inflammation and accelerated atherosclerosis and was tolerated in safety studies in rats and cynomolgus monkeys. Conclusions Chimeric anti‐PCs can prevent accelerated atherosclerosis by inhibiting vascular inflammation directly and through reduced macrophage oxLDL uptake resulting in decreased lesions. PC‐mAb represents a novel strategy for cardiovascular disease prevention.
Bibliography:	PMCID: PMC8359267 Our beloved colleague, the esteemed and highly appreciated Prof. Dr. Mitchell suddenly passed away in November 2020.
ISSN:	0954-6820 1365-2796 1365-2796
DOI:	10.1111/joim.13234