Factor VIII: Perspectives on Immunogenicity and Tolerogenic Strategies

Scott, David W.; Pratt, Kathleen P.

doi:10.3389/fimmu.2019.03078

Cited by 14 publications

(13 citation statements)

References 92 publications

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“…3 ), and subsequently we used the trained classifier algorithms to predict the chromogenic activities of hypothetical alanine mutations at residues from the A1, A3 and C1 domains (Supplementary Table 2 ). Interestingly, we found that amino acids at binding sites were not particularly central, creating the tempting hypothesis that they can be substituted in therapeutic proteins to increase the FVIII binding affinity and to modulate its immunogenic profile 61 .…”

Section: Discussionmentioning

confidence: 99%

Protein residue network analysis reveals fundamental properties of the human coagulation factor VIII

Lopes

Rios

Nogueira

et al. 2021

Sci Rep

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Hemophilia A is an X-linked inherited blood coagulation disorder caused by the production and circulation of defective coagulation factor VIII protein. People living with this condition receive either prophylaxis or on-demand treatment, and approximately 30% of patients develop inhibitor antibodies, a serious complication that limits treatment options. Although previous studies performed targeted mutations to identify important residues of FVIII, a detailed understanding of the role of each amino acid and their neighboring residues is still lacking. Here, we addressed this issue by creating a residue interaction network (RIN) where the nodes are the FVIII residues, and two nodes are connected if their corresponding residues are in close proximity in the FVIII protein structure. We studied the characteristics of all residues in this network and found important properties related to disease severity, interaction to other proteins and structural stability. Importantly, we found that the RIN-derived properties were in close agreement with in vitro and clinical reports, corroborating the observation that the patterns derived from this detailed map of the FVIII protein architecture accurately capture the biological properties of FVIII.

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Section: Discussionmentioning

confidence: 99%

Protein residue network analysis reveals fundamental properties of the human coagulation factor VIII

Lopes

Rios

Nogueira

et al. 2021

Sci Rep

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“…However, the generation of neutralizing antibodies renders treatment ineffective in up to 30% of the severe patients. 1 , 2 Emicizumab is a humanized bispecific antibody that binds simultaneously to activated factor IX (FIXa) and factor X (FX), thereby mimicking the cofactor function of activated factor VIII (FVIIIa), even in the presence of FVIII inhibitors. 3 , 4 Once-weekly subcutaneous administration of emicizumab markedly decreased the bleeding rate in patients who had hemophilia A with or without FVIII inhibitors.…”

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confidence: 99%

Non-inhibitory antibodies inducing increased emicizumab clearance in a severe haemophilia A inhibitor patient

et al. 2021

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“…Challenges with the incorporation of these therapeutics into clinical care include the lack of standardisation of coagulation assays and the limited long‐term safety data with regard to the theoretical risk of PEG exposure for routine prophylaxis indications 16,17 . Data on EHL factor concentrates remains limited in the paediatric population, particularly in previously untreated patients (PUPs), with a preclinical model supporting potential for increased induction of tolerance 18 . Table III 1–8 includes key data from studies in children, with even more sparse data on EHL product use in PUPs summarised in Table IV.…”

Section: Factor Concentratesmentioning

confidence: 99%

“…16,17 Data on EHL factor concentrates remains limited in the paediatric population, particularly in previously untreated patients (PUPs), with a preclinical model supporting potential for increased induction of tolerance. 18 Table III [1][2][3][4][5][6][7][8] includes key data from studies in children, with even more sparse data on EHL product use in PUPs summarised in Table IV.…”

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confidence: 99%

Haemophilia: factoring in new therapies

Fassel

McGuinn

2021

Br J Haematol

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Haemophilia is an inherited bleeding disorder in which the haemostatic defect results from deficiency of coagulation factor VIII (FVIII) in haemophilia A or factor IX (FIX) in haemophilia B. Traditional treatments for haemophilia have largely worked by directly replacing the missing coagulation factor, but face challenges due to the short half-life of FVIII and FIX, the need for frequent intravenous access and development of neutralising antibodies to coagulation factors (inhibitors). Recent advances in haemophilia therapy have worked to eliminate these challenges. Half-life extension of factor concentrates has lengthened the time needed between infusions, enhancing quality of life. Subcutaneous administration of therapeutics utilising alternative mechanisms to overcome inhibitors have expanded the options to prevent bleeding. Finally, initial successes with gene therapy offer a cautious hope for durable cure. In the present review, we will discuss currently available treatments, as well as highlight therapeutics in various stages of clinical development for the treatment of haemophilia A and B. In this review, we present therapies that are currently clinically available and highlight therapeutics that are in various stages of clinical development for the treatment of haemophilia A and B.

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Factor VIII: Perspectives on Immunogenicity and Tolerogenic Strategies

Abstract: Therapeutic treatment of bleeds with FVIII can lead to an antibody response that effectively inhibits its function. Herein, we review the factors that contribute to this immunogenicity and possible ways to overcome it.

Cited by 14 publications

References 92 publications

Protein residue network analysis reveals fundamental properties of the human coagulation factor VIII

Protein residue network analysis reveals fundamental properties of the human coagulation factor VIII

Non-inhibitory antibodies inducing increased emicizumab clearance in a severe haemophilia A inhibitor patient

Haemophilia: factoring in new therapies

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