Report on 4 cases with decreased recovery due to neutralizing antibodies specific for PEGylated recombinant factor VIII

Andreas Hillarp; Pål A Holme; Erik P Wåland; Marie S Le; Carola E Henriksson; Geir E Tjønnfjord; Ragnhild J Måseide

doi:10.1016/j.jtha.2023.07.019

Report on 4 cases with decreased recovery due to neutralizing antibodies specific for PEGylated recombinant factor VIII

J Thromb Haemost. 2023 Oct;21(10):2771-2775. doi: 10.1016/j.jtha.2023.07.019. Epub 2023 Aug 3.

Authors

Andreas Hillarp¹, Pål A Holme², Erik P Wåland³, Marie S Le³, Carola E Henriksson⁴, Geir E Tjønnfjord⁵, Ragnhild J Måseide⁶

Affiliations

¹ Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway; Department of Translational Medicine, Lund University, Lund, Sweden.
² Department of Haematology, Oslo University Hospital, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
³ Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.
⁴ Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁵ Department of Haematology, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁶ Department of Haematology, Oslo University Hospital, Oslo, Norway. Electronic address: ragmas@ous-hf.no.

PMID: 37543216
DOI: 10.1016/j.jtha.2023.07.019

Abstract

Background: The immunogenicity, safety, and efficacy of recombinant factor VIII (rFVIII) have gained increasing interest after the introduction of extended half-life products with various modifications of the rFVIII molecule, such as covalent attachment of polyethylene glycol (PEG). Anti-PEG antibodies may be associated with a temporary reduction of FVIII recovery, but according to previous studies, they usually disappear after continuous dosing. Anti-PEG antibodies with an inhibitory capacity have never been demonstrated in patients treated with PEGylated rFVIII products.

Objectives: To routinely switch from standard half-life to PEGylated extended half-life rFVIII products in patients with hemophilia A.

Methods: From December 2022 until May 2023, 83 adults with hemophilia A attending Oslo Haemophilia Comprehensive Care Centre received a test dose with a PEGylated rFVIII product to switch treatment. Four patients presented with decreased recovery without the presence of an FVIII inhibitor. Accordingly, we performed a variant inhibitor test utilizing different rFVIII concentrates as a source of FVIII and enzyme-linked immunosorbent assay to search for anti-PEG antibodies.

Results: We found inhibitory anti-PEG/anti-PEGylated rFVIII antibodies in 4 patients (5%), both persistent and transient, explaining the impaired recovery. The patients had neutralizing anti-PEG antibodies prior to the first dosing of PEGylated rFVIII. We demonstrated neutralizing antibodies (mainly immunoglobuline G) specific for PEG and all 3 commercially available PEGylated rFVIII products.

Conclusion: The number of patients with inhibitory anti-PEG antibodies was significant, and the presence of inhibitors against PEGylated rFVIII emphasizes the importance of individual monitoring when switching FVIII concentrates to ensure safety and efficacy of the treatment.

Keywords: FVIII recovery; PEGylated recombinant FVIII products; extended half-life FVIII products; hemophilia A; neutralizing anti-PEG antibodies.

MeSH terms

Adult
Antibodies, Neutralizing
Factor VIII* / adverse effects
Half-Life
Hemophilia A* / diagnosis
Hemophilia A* / drug therapy
Humans
Polyethylene Glycols / therapeutic use
Recombinant Proteins / therapeutic use

Substances

Factor VIII
Antibodies, Neutralizing
Recombinant Proteins
Polyethylene Glycols