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

• Published in: Journal of thrombosis and haemostasis 2023-08
• Main Authors: Hillarp, Andreas, Holme, Pål A, Wåland, Erik P, Le, Marie S, Henriksson, Carola E, Tjønnfjord, Geir E, Måseide, Ragnhild J
• Format: Article
• Language: English
• ISSN: 1538-7836

The immunogenicity, safety and efficacy of recombinant FVIII (rFVIII) have gained increasing interest after the introduction of extended half-life (EHL) 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. Routinely switch from standard half-life to PEGylated EHL rFVIII products in patients with haemophilia A (HA). From December 2022 until May 2023, 83 adults with HA attending Oslo Haemophilia Comprehensive Care Centre received a test dose with a PEGylated rFVIII product in order to switch treatment. Four patients presented with decreased recovery without the presence of FVIII inhibitor. Accordingly, we performed a variant inhibitor test utilizing different rFVIII concentrates as source of FVIII and enzyme-linked immunosorbent assay (ELISA) to search for anti-PEG antibodies. We demonstrated inhibitory anti-PEG/anti-PEGylated rFVIII antibodies in four patients (5%), both persistent and transient, which explain the impaired recovery. The patients had neutralizing anti-PEG antibodies prior to the first dosing of PEGylated rFVIII. We demonstrated neutralizing antibodies (mainly IgG) specific for PEG and all three commercially available PEGylated rFVIII products. 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.