Antidrug antibodies against the polyethylene glycol moiety inhibit the procoagulant activity of therapeutic polyethylene glycolated factor VIII

Behnaz Pezeshkpoor; Nadja Sereda; Ann-Cristin Berkemeier; Isabell Matuschek; Nadine Schwarz; Peter L Turecek; Silvia Horneff; Claudia Klein; Georg Goldmann; Natascha Marquardt; Thilo Albert; Jens Müller; Johannes Oldenburg

doi:10.1016/j.jtha.2023.03.011

Antidrug antibodies against the polyethylene glycol moiety inhibit the procoagulant activity of therapeutic polyethylene glycolated factor VIII

J Thromb Haemost. 2023 Jun;21(6):1503-1514. doi: 10.1016/j.jtha.2023.03.011. Epub 2023 Mar 18.

Affiliations

¹ Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Medical Faculty, University of Bonn, Germany. Electronic address: behnaz.pezeshkpoor@ukbonn.de.
² Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Medical Faculty, University of Bonn, Germany.
³ Baxalta Innovations Gesellschaft mit beschränkter Haftung (GmbH), Global Medical Affairs, Vienna, Austria.
⁴ Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Medical Faculty, University of Bonn, Germany; Center for Rare Diseases Bonn, University Clinic Bonn, Bonn, Germany.

PMID: 36934798
DOI: 10.1016/j.jtha.2023.03.011

Abstract

Background: The standard therapy for patients with hemophilia A (HA) is the replacement with factor VIII (FVIII) therapeutics. To overcome the limitation of short half-life of wild-type FVIII protein, polyethylene glycol (PEG) can be coupled to therapeutic FVIII to improve pharmacokinetics.

Objectives: We aimed to characterize antibodies developed against a FVIII therapeutic PEGylated with a 40-kDa PEG (40PEG-BDD_FVIII) in 2 patients with mild HA.

Methods: An inhouse bead-based immunoassay was developed to characterize and confirm the specificity of the detected antibodies. The neutralizing nature of the antibodies toward PEGylated therapeutics was determined by a modified Nijmegen-Bethesda assay.

Results: Two out of 46 patients treated with 40PEG-BDD_FVIII developed inhibitory antibodies toward the drug. Switching to a non-PEGylated FVIII successfully increased the FVIII activity in both patients. In patient 1, antibodies were raised against FVIII and PEG. Anti-FVIII antibodies were of the immunoglobulin (Ig)G isotype, whereas anti-PEG antibodies were of IgG, IgM, and IgA isotypes. In patient 2, antibodies of IgG and IgA isotypes were directed only against the PEG moiety. Competitive assays confirmed the specificity of the antibodies against PEG. The applied Nijmegen-Bethesda assay revealed that patients' anti-PEG antibodies and AGP3, an antibody against the backbone of PEG, can inhibit all currently available PEGylated therapeutics but to different degrees. No inhibitory FVIII antibodies were detected.

Conclusion: Antibodies against the PEG moiety of 40PEG-BDD_FVIII abolished the efficacy of the drug. This is the first report on real-world experiences with the development of neutralizing anti-PEG antibodies after treatment with PEGylated FVIII therapeutics in mild HA.

Keywords: adaptive immunity; hemophilia A; innate immunity; neutralizing antibodies; polyethylene glycol.

MeSH terms

Factor VIII
Hemophilia A* / drug therapy
Hemostatics* / therapeutic use
Humans
Immunoglobulin A
Immunoglobulin G
Polyethylene / therapeutic use
Polyethylene Glycols / therapeutic use

Substances

Factor VIII
Polyethylene Glycols
Polyethylene
Hemostatics
Immunoglobulin G
Immunoglobulin A