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

Autor: 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
Přispěvatelé: 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], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Jazyk: angličtina
Rok vydání: 2021
Předmět:
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
Zdroj: Journal of Internal Medicine, 290 (1)
Journal of Internal Medicine, 290(1), 141-156. WILEY
Journal of Internal Medicine
Journal of Internal Medicine, Wiley, 2020, ⟨10.1111/joim.13234⟩
ISSN: 0954-6820
1365-2796
DOI: 10.1111/joim.13234⟩
Popis: 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
Databáze: OpenAIRE
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