PEGylated Domain I of Beta-2-Glycoprotein I inhibits the binding coagulopathic, and thrombogenic properties of IgG From patients with the antiphospholipid syndrome

Thomas C.R. McDonnell, Rohan Willis, Charis Pericleous, Vera M. Ripoll, Ian P. Giles, David A. Isenberg, Allan Brasier, Emilio B. Gonzalez, Elizabeth Papalardo, Zurina Romay-Penabad, Mohammad Jamaluddin, Yiannis Ioannou, Anisur Rahman

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

APS is an autoimmune disease in which antiphospholipid antibodies (aPL) cause vascular thrombosis and pregnancy morbidity. In patients with APS, aPL exert pathogenic actions by binding serum beta-2-glycoprotein I (β2GPI) via its N-terminal domain I (DI). We previously showed that bacterially-expressed recombinant DI inhibits biological actions of IgG derived from serum of patients with APS (APS-IgG). DI is too small (7 kDa) to be a viable therapeutic agent. Addition of polyethylene glycol (PEGylation) to small molecules enhances the serum half-life, reduces proteolytic targeting and can decrease immunogenicity. It is a common method of tailoring pharmacokinetic parameters and has been used in the production of many therapies in the clinic. However, PEGylation of molecules may reduce their biological activity, and the size of the PEG group can alter the balance between activity and half-life extension. Here we achieve production of site-specific PEGylation of recombinant DI (PEG-DI) and describe the activities in vitro and in vivo of three variants with different size PEG groups. All variants were able to inhibit APS-IgG from: binding to whole β2GPI in ELISA, altering the clotting properties of human plasma and promoting thrombosis and tissue factor expression in mice. These findings provide an important step on the path to developing DI into a first-in-class therapeutic in APS.

Original languageEnglish (US)
Article number2413
JournalFrontiers in immunology
Volume9
Issue numberOCT
DOIs
StatePublished - Oct 22 2018

Keywords

  • Antiphospholipid syndrome
  • Biologics
  • Domain I
  • PEGylation
  • Therapeutics

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    McDonnell, T. C. R., Willis, R., Pericleous, C., Ripoll, V. M., Giles, I. P., Isenberg, D. A., Brasier, A., Gonzalez, E. B., Papalardo, E., Romay-Penabad, Z., Jamaluddin, M., Ioannou, Y., & Rahman, A. (2018). PEGylated Domain I of Beta-2-Glycoprotein I inhibits the binding coagulopathic, and thrombogenic properties of IgG From patients with the antiphospholipid syndrome. Frontiers in immunology, 9(OCT), [2413]. https://doi.org/10.3389/fimmu.2018.02413