Product‐dependent anti‐factor <scp>VIII</scp> antibodies

Butenas, Saulius; Krudysz-Amblo, Jolanta; Rivard, Georges E.; Mann, Kenneth G.

doi:10.1111/hae.12127

Cited by 10 publications

(12 citation statements)

References 47 publications

(97 reference statements)

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“…Coagulation factor replacement therapy usually starts at a very young age and requires regular intravenous dosing for the patient's lifetime. The development of inhibiting antibodies to replacement FVIII and FIX is one of the clinical concerns in treatment of hemophilia . These inhibitors block the function of the proteins and can be life‐threatening.…”

Section: Host Cell Cytokine Impuritiesmentioning

confidence: 99%

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Experience with host cell protein impurities in biopharmaceuticals

Vanderlaan¹,

Zhu-Shimoni²,

Lin³

et al. 2018

Biotechnology Progress

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In the 40-year history of biopharmaceuticals, there have been a few cases where the final products contained residual host cell protein (HCP) impurities at levels high enough to be of concern. This article summarizes the industry experience in these cases where HCP impurities have been presented in public forums and/or published. Regulatory guidance on HCP impurities is limited to advising that products be as pure as practical, with no specified numerical limit because the risk associated with HCP exposure often depends on the clinical setting (route of administration, dose, indication, patient population) and the particular impurity. While the overall safety and purity track record of the industry is excellent, these examples illustrate several important lessons learned about the kinds of HCPs that co-purify with products (e.g., product homologs, and HCPs that react with product), and the kinds of clinical consequences of HCP impurities (e.g., direct biological activity, immunogenicity, adjuvant). The literature on industry experience with HCP impurities is scattered, and this review draws in to one reference documented examples where the data have been presented in meetings, patents, product inserts, or press releases, in addition to peer-reviewed journal articles. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:828-837, 2018.

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Section: Host Cell Cytokine Impuritiesmentioning

confidence: 99%

“…The development of inhibiting antibodies to replacement FVIII and FIX is one of the clinical concerns in treatment of hemophilia. 53,54 These inhibitors block the function of the proteins and can be life-threatening.…”

Section: Hcps In Hemophilia Therapeuticsmentioning

confidence: 99%

Experience with host cell protein impurities in biopharmaceuticals

Vanderlaan¹,

Zhu-Shimoni²,

Lin³

et al. 2018

Biotechnology Progress

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“…17 Regarding nonneutralizing antibodies, it remains debated as to whether these antibodies, or at least any immune response they provoke, are of clinical significance and should be considered as well. [18][19][20] The importance of T-regulatory cells (Tregs) in the process of antibody formation has been established, and to date, different subsets of cells with suppressor activities have been defined, eg, CD4 …”

mentioning

confidence: 99%

FVIII inhibitors: pathogenesis and avoidance

Astermark

2015

Blood

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The pathogenesis of inhibitory antibodies has been the focus of major scientific interest over the last decades, and several studies on underlying immune mechanisms and risk factors for formation of these antibodies have been performed with the aim of improving the ability to both predict and prevent their appearance. It seems clear that the decisive factors for the immune response to the deficient factor are multiple and involve components of both a constitutional and therapy-related nature. A scientific concern and obstacle for research in the area of hemophilia is the relatively small cohorts available for studies and the resulting risk of confounded and biased results. Careful interpretation of data is recommended to avoid treatment decisions based on a weak scientific platform. This review will summarize current concepts of the underlying immunological mechanisms and risk factors for development of inhibitory antibodies in patients with hemophilia A and discuss how these findings may be interpreted and influence our clinical management of patients. (Blood. 2015;125(13):2045-2051 IntroductionUnderstanding of the pathophysiological mechanisms leading to the development of inhibitory anti-factor (F)VIII antibodies in patients with hemophilia A has improved considerably over the last 2 decades. It is clear that the process is multifactorial and involves cells, cytokines, and other immune regulatory molecules, the level and action of which are both genetically and nongenetically defined. Despite improvements in understanding, we remain unable to fully predict the immune response to the deficient factor and inhibitor risk at the onset of replacement therapy. There are several ongoing efforts aiming to achieve more accurate methods for prediction and others to develop nonimmunogenic hemostatic options, but these remain opportunities for the future. Findings continue to emerge regarding risk factors and potential immune mechanisms of significance for the outcome, but until new results have been sufficiently confirmed through replication and the mechanisms of action in humans better defined, the chances of withholding a beneficial treatment or administering one associated with an adverse outcome are increased. Efficacy and safety should be the guiding principles for all treaters in the environment of cost constraints in which they act. This review will summarize current data-based findings and interpretations of how and why inhibitory antibodies develop in patients with hemophilia A and explore how the findings may or may not influence our daily practice. Immune response to FVIIIThe initiation of an immune response and formation of high-affinity polyclonal antibodies toward FVIII requires endocytosis of the infused molecule by antigen presenting cells (APCs), eg, dendritic cells, macrophages, and/or B cells, processing intracellularly in the endosomes, and presentation of antigen-derived peptides via the HLA class II molecules on the cell surface to the CD4 1 T cells. In previously untreated patients, ie, patients...

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“…Non-neutralizing antibodies have been described in haemophilia patients but their significance has not been elucidated [11,12]. Studies in other diseases indicated that NNA against therapeutic proteins may alter the protein's PK profiles [13].…”

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confidence: 99%