Therapeutic choices for patients with hemophilia and high‐titer inhibitors

Kulkarni, Raghav; Aledort, LM; Berntorp, Erik; Brackman, H. H.; Brown, Dee; Cohen, A; Ewing, Nadia P.; Gringeri, A.; Gruppo, Ralph A.; Hoots, Keith; Leissenger, Cindy A.; Peerlinck, Kathelijne; Mc, Poon; Wong, WS

doi:10.1002/ajh.1192

Cited by 39 publications

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“…20 On the other hand, the management of hemophilia with inhibitors is particularly expensive, both in absolute terms and in comparison with the treatment of hemophilia without inhibitors. 21 Available studies on costs and quality of life are retrospective, often carried out in single centers on very small numbers of patients, and focused mainly on drug costs. 4,5 No prospective study has specifically focused on patients with hemophilia and inhibitors with the objective of assessing the global socioeconomic and cultural impact of management.…”

Section: Introductionmentioning

confidence: 99%

Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS Study Group

Gringeri

Mantovani

Scalone

et al. 2003

Blood

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339

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Inhibitors in patients with hemophilia are a rare complication of a rare disease causing pain and disability in patients and impairment to the quality of their lives. Recent advances in treatment have brought improvements, but they have done so by absorbing larger amounts of financial resources. This study involved 52 Italian patients with hemophilia with high-responding inhibitors who were longitudinally observed for 18 months to evaluate concomitantly cost of care and quality of life. Overall, 0.6 bleeding episodes per patient per month were recorded. This frequency of events was lower than that reported in other cohorts of patients with hemophilia who were not taking inhibitors. The average monthly cost of care was, in euros, €18 000 (US $18 000) per patient, mainly because of treatment products. Recombinant activated factor VII, mostly used for orthopedic surgery, represented 50% of the expenses. Quality of life, measured through validated questionnaires, was similar to that of patients with severe hemophilia without inhibitors. In particular, physical quality of life was similar to that in patients with diabetes and on dialysis, whereas mental quality of life was comparable to that in the general population. This study shows that hemophilia complicated by inhibitors, a prototype of rare disease, requires high amounts of resources for management that provides a satisfactory quality of life. (Blood. 2003;

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Section: Introductionmentioning

confidence: 99%

Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS Study Group

Gringeri

Mantovani

Scalone

et al. 2003

Blood

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339

358

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“…Interestingly, porcine FVIII has been used effectively in the clinic as a "bypass" therapy; that is, a therapeutic protein that can evade neutralization by anti-FVIII antibodies in many allo-and autoimmune inhibitor patients. [5][6][7] However, some patients have or could develop antibodies that neutralize porcine FVIII as well, 8 because of antigenic cross-reactivity 9 or because regions in which the porcine sequence differs from the human FVIII sequence stimulate effector T cells, leading to antibody production. Identification of the binding sites (B-cell epitopes) on FVIII that are recognized by inhibitors would allow rational design of novel therapeutic FVIII proteins that are more similar to human FVIII and, hence, likely to be less immunogenic.…”

Section: Introductionmentioning

confidence: 99%

High-resolution mapping of epitopes on the C2 domain of factor VIII by analysis of point mutants using surface plasmon resonance

Nguyen

Lewis

Ettinger

et al. 2014

Blood

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• Amino acid residues comprising B-cell epitopes recognized by neutralizing antifactor VIII antibodies (inhibitors) have been identified. • Amino acids contributing significant antigen-antibody binding avidity are candidates for mutagenesis in the design of less antigenic proteins.Neutralizing anti-factor VIII (FVIII) antibodies that develop in patients with hemophilia A and in murine hemophilia A models, clinically termed "inhibitors," bind to several distinct surfaces on the FVIII-C2 domain. To map these epitopes at high resolution, 60 recombinant FVIII-C2 proteins were generated, each having a single surface-exposed residue mutated to alanine or a conservative substitution. The binding kinetics of these muteins to 11 monoclonal, inhibitory anti-FVIII-C2 antibodies were evaluated by surface plasmon resonance and the results compared with those obtained for wild-type FVIII-C2. Clusters of residues with significantly altered binding kinetics identified "functional" B-cell epitopes, defined as those residues contributing appreciable antigen-antibody avidity. These antibodies were previously shown to neutralize FVIII activity by interfering with proteolytic activation of FVIII by thrombin or factor Xa, or with its binding to phospholipid surfaces, von Willebrand factor, or other components of the intrinsic tenase complex. Fine mapping of epitopes by surface plasmon resonance also indicated surfaces through which FVIII interacts with proteins and phospholipids as it participates in coagulation. Mutations that significantly altered the dissociation times/half-lives identified functionally important interactions within antigenantibody interfaces and suggested specific sequence modifications to generate novel, less antigenic FVIII proteins with possible therapeutic potential for treatment of inhibitor patients. (Blood. 2014;123(17):2732-2739 IntroductionThe development of neutralizing anti-factor VIII (FVIII) antibodies is a serious complication that may be encountered when FVIII replacement therapy is administered to patients with hemophilia A (HA). It affects 25% to 30% of the treated HA population, with a peak occurrence after ;14 FVIII infusions.1-3 Autoimmune responses to FVIII can also occur, 4 and although this happens only rarely, the resulting bleeding phenotype can be severe. Inhibitors can be difficult and extremely expensive to manage clinically. Interestingly, porcine FVIII has been used effectively in the clinic as a "bypass" therapy; that is, a therapeutic protein that can evade neutralization by anti-FVIII antibodies in many allo-and autoimmune inhibitor patients. [5][6][7] However, some patients have or could develop antibodies that neutralize porcine FVIII as well, 8 because of antigenic cross-reactivity 9 or because regions in which the porcine sequence differs from the human FVIII sequence stimulate effector T cells, leading to antibody production. Identification of the binding sites (B-cell epitopes) on FVIII that are recognized by inhibitors would allow rational design of novel therapeutic FVIII...

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“…Of particular concern are Abs that may render the drugs less effective; examples include the development of Abs against factor VIII in hemophiliacs (1,2), calcitonin in patients treated for osteoporosis (3,4), erythropoietin (Epo) 2 in patients undergoing therapy for chronic renal failure (5,6), and IFN-␤ in individuals undergoing treatment for multiple sclerosis (7).…”

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confidence: 99%

Rationally Engineered Therapeutic Proteins with Reduced Immunogenicity

Tangri¹,

Mothé

Eisenbraun³

et al. 2005

The Journal of Immunology

160

169

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Chronic administration of protein therapeutics may elicit unacceptable immune responses to the specific protein. Our hypothesis is that the immunogenicity of protein drugs can be ascribed to a few immunodominant helper T lymphocyte (HTL) epitopes, and that reducing the MHC binding affinity of these HTL epitopes contained within these proteins can generate drugs with lower immunogenicity. To test this hypothesis, we studied the protein therapeutic erythropoietin (Epo). Two regions within Epo, designated Epo 91–120 and Epo 126–155, contained HTL epitopes that were recognized by individuals with numerous HLA-DR types, a property common to immunodominant HTL epitopes. We then engineered analog epitopes with reduced HLA binding affinity. These analog epitopes were associated with reduced in vitro immunogenicity. Two modified forms of Epo containing these substitutions were shown to be bioactive and nonimmunogenic in vitro. These findings support our hypothesis and demonstrate that immunogenicity of protein drugs can be reduced in a systematic and predictable manner.

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Therapeutic choices for patients with hemophilia and high‐titer inhibitors

Cited by 39 publications

References 0 publications

Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS Study Group

Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS Study Group

High-resolution mapping of epitopes on the C2 domain of factor VIII by analysis of point mutants using surface plasmon resonance

Rationally Engineered Therapeutic Proteins with Reduced Immunogenicity

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