1. Identification of IgG1 isotype phosphorylcholine antibodies for the treatment of inflammatory cardiovascular diseases
- Author
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Ewa Ninio, J.W. Jukema, Erna Peters, James R. Mitchell, S.A.P. Karabina, Johan Frostegård, R.C.M. Jong, A. Bergman, Margreet R. de Vries, I. Dahlbom, Michael R MacArthur, M.M. Ewing, M. Nordzell, D.J. Sexton, J.C. Karper, Paul H.A. Quax, Knut Pettersson, J. Kuiper, Einthoven Laboratory for Experimental Vascular Medicine (ELEVM - LEIDEN), Leiden University Medical Center (LUMC), Harvard T.H. Chan School of Public Health, Athera Biotechnologies, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Takeda Pharmaceuticals International GmbH, Karolina Institutet, Partenaires INRAE, Karolinska Institutet [Stockholm], Leiden Academic Centre for Drug Research (LACDR), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
- Subjects
0301 basic medicine ,Male ,Phosphorylcholine ,Anti-Inflammatory Agents ,Inflammation ,030204 cardiovascular system & hematology ,CCL2 ,Epitope ,Choline ,03 medical and health sciences ,restenosis ,0302 clinical medicine ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,In vivo ,Internal Medicine ,medicine ,therapeutics ,Macrophage ,Animals ,Atherosclerosis ,Restenosis ,Therapeutics ,Vascular disease ,biology ,business.industry ,Chimera ,Macrophages ,Antibodies, Monoclonal ,vascular disease ,Cholesterol, LDL ,Original Articles ,3. Good health ,Rats ,Mice, Inbred C57BL ,Disease Models, Animal ,Macaca fascicularis ,030104 developmental biology ,Cardiovascular Diseases ,inflammation ,Immunoglobulin G ,Monoclonal ,biology.protein ,Cancer research ,Female ,Original Article ,medicine.symptom ,Antibody ,atherosclerosis ,business ,Oxidation-Reduction - Abstract
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. ISSN:0954-6820 ISSN:1365-2796
- Published
- 2021