Low risk of inhibitor formation in haemophilia patients after a change in treatment from Chinese hamster ovary cell-produced to baby hamster kidney cell-produced recombinant factor VIII

Singleton, Evelyn; Smith, Jude; Kavanagh, Mary; Nolan, Beatrice; White, Barry

doi:10.1160/th07-06-0408

Cited by 13 publications

(4 citation statements)

References 9 publications

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Section: Discussionsupporting

confidence: 84%

“…These findings provide an important support to results from earlier studies, showing that switching to a different FVIII product is not associated with increased immunogenicity and the risk of inhibitor formation. [10][11][12][13]22,25 Highly debated in this regard is the role of the FVIII product type, that is, pdFVIII versus rFVIII and rFVIII-Fc. In this study a sub-analysis was performed to evaluate if the change in immunoregulatory parameters was different according to the product type and type of switch.…”

Section: Shl Fviii → Shl Fviii (Nmentioning

confidence: 99%

“…Since reports of increased inhibitor in previously treated patients (PTPs) after exposure to an intermediate-purity pasteurized concentrate and to a double virus-inactivated pdFVIII concentrate in the 1990s, 8,9 subsequent studies failed to confirm FVIII product switching concerns. [8][9][10][11][12][13] However, many patients and physicians are reported to believe that switching product raises the probability of inhibitor development in PTPs. 14,15 To unequivocally address this issue, we performed a cohort study in patients with haemophilia A (PWHA) who switched FVIII products as a result of national contracting.…”

Section: Introductionmentioning

confidence: 99%

“…In light of this discussion, we asked whether switching to a different FVIII product should be considered a risk factor for inhibitor development. Since reports of increased inhibitor in previously treated patients (PTPs) after exposure to an intermediate‐purity pasteurized concentrate and to a double virus‐inactivated pdFVIII concentrate in the 1990s, 8,9 subsequent studies failed to confirm FVIII product switching concerns 8–13 . However, many patients and physicians are reported to believe that switching product raises the probability of inhibitor development in PTPs 14,15 .…”

Section: Introductionmentioning

confidence: 99%

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No immunological changes after factor VIII product switch: An in depth analysis in haemophilia A patients

et al. 2023

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Background: A challenging complication in the treatment of haemophilia A is the formation of neutralizing anti-FVIII antibodies (inhibitors). There is ongoing debate on the effect of FVIII product and inhibitor risk, rendering patients and physicians reluctant to switch FVIII-products.Aim: This study aimed to evaluate changes in the immune profile of haemophilia A patients after switching FVIII products and their possible relation to inhibitor development. Secondary, FVIII efficacy after switching were assessed.Methods: Patients, who switched FVIII-products between 2017-2019, were included in this single centre cohort study. Prospective comparison of immunoregulatory cells and markers by flow-cytometry before and after the switch was performed in a subgroup. For the total cohort clinical data regarding inhibitor development and FVIII efficacy 1 year before and after switching were retrospectively collected.Results: One-hundred patients (including 39 with prospective immunological assessment) were analyzed, of which 31% switched from plasma-derived (pdFVIII) to recombinant standard half-life FVIII (SHL-rFVIII), 47% between different SHL-rFVIII, and 22% from pdFVIII/SHL-rFVIII to rFVIII-Fc. No remarkable changes in immunoregulatory cell functions were observed after switching, regardless the type of switch. None of the patients developed an inhibitor. FVIII efficacy, that is, FVIII usage, half-life and annual bleeding rate (ABR), was similar before and after switch for the SHL products, whereas rFVIII-Fc associated with a longer half-life (13.1 vs. 15.0 h) and lower ABR (3.0 vs. 1.0). Conclusions:Switching to a different FVIII product was not associated with inhibitor development, nor with differences in the immune profile. Switching to rFVIII-Fc lead to lower ABR.

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Section: Discussionsupporting

confidence: 84%

Section: Shl Fviii → Shl Fviii (Nmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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No immunological changes after factor VIII product switch: An in depth analysis in haemophilia A patients

et al. 2023

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Evolution of recombinant factor VIII safety: KOGENATE® and Kogenate® FS/Bayer

Lusher

Scharrer

2009

Int J Hematol

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The use of factor VIII (FVIII) concentrates in the treatment of hemophilia A has raised important safety issues, historically of pathogen transmission and increasingly of inhibitor development to FVIII treatment. While manufacturing processes of current recombinant FVIII products have been shaped entirely around preventing pathogen transmission, the same modifications that afford a greater margin of safety could affect immunogenicity of the product, consequences of which could only be seen through long-term clinical experience. This review summarizes pathogen safety and inhibitor reports from clinical trials, post-marketing surveillance studies, and study reports on KOGENATE and its successor, Kogenate FS/Bayer. Although KOGENATE and Kogenate FS/Bayer are nearly identical products, subtle manufacturing improvements to address the need for greater margins of safety from a pathogen transmission perspective have also led to a potentially improved immunogenicity profile (15% in previously untreated/minimally treated patients with severe hemophilia A for Kogenate FS/Bayer). Notably, there has been no occurrence of pathogen contamination, and minimal de novo inhibitor formation in previously treated patients throughout the use of both products. Overall, KOGENATE and Kogenate FS/Bayer have a long history of safety in a variety of clinical settings, including treatment of bleeding, surgical management, and prophylaxis therapy.

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Murine leukemia virus-derived retroviral vector has differential integration patterns in human cell lines used to produce recombinant factor VIII

Freitas

Fontes

Fernandes

et al. 2014

Revista Brasileira de Hematologia e Hemoterapia

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ObjectiveNowadays recombinant factor VIII is produced in murine cells including in Chinese hamster ovary (CHO) and baby hamster kidney cells (BHK). Previous studies, using the murine leukemia virus-derived retroviral vector pMFG-FVIII-P140K, modified two recombinant human cell lines, HepG2 and Hek293 to produce recombinant factor VIII. In order to characterize these cells, the present study aimed to analyze the integration pattern of retroviral vector pMFG-FVIII-P140K.MethodsThis study used ligation-mediated polymerase chain reaction to locate the site of viral vector integration by sequencing polymerase chain reaction products. The sequences were compared to genomic databases to characterize respective clones.ResultsThe retroviral vector presented different and non-random profiles of integration between cells lines. A preference of integration for chromosomes 19, 17 and 11 was observed for HepG2FVIIIdB/P140K and chromosome 9 for Hek293FVIIIdB/P140K. In genomic regions such as CpG islands and transcription factor binding sites, there was no difference in the integration profiles for both cell lines. Integration in intronic regions of encoding protein genes (RefSeq genes) was also observed in both cell lines. Twenty percent of integrations occurred at fragile sites in the genome of the HepG2 cell line and 17% in Hek293.ConclusionThe results suggest that the cell type can affect the profile of chromosomal integration of the retroviral vector used; these differences may interfere in the level of expression of recombinant proteins.

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Low risk of inhibitor formation in haemophilia patients after a change in treatment from Chinese hamster ovary cell-produced to baby hamster kidney cell-produced recombinant factor VIII

Cited by 13 publications

References 9 publications

No immunological changes after factor VIII product switch: An in depth analysis in haemophilia A patients

No immunological changes after factor VIII product switch: An in depth analysis in haemophilia A patients

Evolution of recombinant factor VIII safety: KOGENATE® and Kogenate® FS/Bayer

Murine leukemia virus-derived retroviral vector has differential integration patterns in human cell lines used to produce recombinant factor VIII

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