A recombinant factor VIII A2 domain polypeptide quantitatively neutralizes human inhibitor antibodies that bind to A2

Scandella, Dorothea; Mattingly, M; Prescott, Richard

doi:10.1182/blood.v82.6.1767.bloodjournal8261767

Cited by 30 publications

(38 citation statements)

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“…This method has been described previously. 17,18 Briefly, an inhibitor plasma diluted to 10 Bethesda units/mL is added to an equal volume of serial dilutions of individual…”

Section: Inhibitor Neutralization Assaymentioning

confidence: 99%

New Characteristics of Anti-Factor VIII Inhibitor Antibody Epitopes and Unusual Immune Responses to Factor VIII

Scandella

2002

Semin Thromb Hemost

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Treatment of individuals with severe hemophilia A by plasma-derived or recombinant factor VIII leads to the production of anti-factor VIII antibodies in approximately 30% of such patients. Because some of these antibodies inactivate factor VIII, they are considered a major factor in preventing optimal therapeutic treatment. Factor VIII is a cofactor that must bind to factors IX and X and phospholipids in order for normal blood coagulation to occur. The inhibition of factor VIII activity is due to binding by anti- factor VIII antibodies in the patient plasma to the same sites required for factors IX and X and phospholipid binding. Previously, inhibitor epitopes were localized to the A2, A3, and C2 domains and to a region of acidic amino acids between the A1 and A2 domains. Inhibitor binding to these domains prevented factor VIII binding to factor IXa (A2, A3), factor Xa (C2), and phospholipids (C2), and binding to the acidic region interfered with factor X binding. Antibody binding to a minor C2 domain epitope slowed activated factor VIII release from von Willebrand factor (vWF) and interfered with factor Xa binding to factor VIII.

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“…This method has been described previously. 17,18 Briefly, an inhibitor plasma diluted to 10 Bethesda units/mL is added to an equal volume of serial dilutions of individual…”

Section: Inhibitor Neutralization Assaymentioning

confidence: 99%

New Characteristics of Anti-Factor VIII Inhibitor Antibody Epitopes and Unusual Immune Responses to Factor VIII

Scandella

2002

Semin Thromb Hemost

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“…FVIII epitopes that are targeted by inhibitors have been mapped by immunoblotting [5,6], by immunoprecipitation of conformational epitopes expressed by recombinant fragments of FVIII [10] and by competition experiments between polyclonal preparations of affinity‐purified human anti‐FVIII antibodies and monoclonal murine antibodies for binding to FVIII [9,11]. Three major clusters of B‐cell epitopes have been delineated including the amino‐terminal segment of the A2 domain on the heavy chain (amino acids 373–740) [12,13], epitopes located in the A3 domain [9], and in the C2 domain [14–16]. The antibody response to FVIII varies greatly from one patient to another with regard to epitope specificity [5,9,17] and may change of specificity over time [18].…”

Section: Inhibitors To Factor VIII In Haemophilia Amentioning

confidence: 99%

The concept of idiotypic vaccination against factor VIII inhibitors in haemophilia A

et al. 2002

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Idiotypic vaccination has proven successful in several animal models and human trials. Here we suggest that the expression of cross-reactive idiotypes on factor VIII (FVIII) inhibitors of patients with haemophilia A, patients with anti-FVIII autoimmune disease and natural anti-FVIII antibodies of healthy individuals, together with the ability of anti-idiotypic reagents to neutralize anti-FVIII antibodies, provides a rationale for designing a vaccine strategy aimed at preventing the occurrence of or suppressing inhibitors, based on the induction of protective anti-idiotypes. Here we discuss the rationale supporting the concept of using idiotypic vaccination to prevent the occurrence of FVIII inhibitors in patients with haemophilia A.

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“…Inhibitor neutralization assays were developed to determine to which factor VIII domains inhibitory antibodies are directed. 19 This method employs plasmas diluted to 1 to 2 Bethesda units per milliliter and incubated in the presence of increasing concentrations of factor VIII domains isolated from thrombin-cleaved factor VIII or from recombinant factor VIII domains expressed from a baculoviral vector in insect cells. 20 The maximum decrease in the Bethesda units per milliliter for each factor VIII domain represents the fraction of inhibitory antibodies that bind to each domain.…”

Section: Domain Specificities Of Anti-factor VIII Inhibitor Antibodiementioning

confidence: 99%

Properties of Anti-Factor VIII Inhibitor Antibodies in Hemophilia A Patients

Scandella

2000

Semin Thromb Hemost

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Blood coagulation factor VIII functions in the intrinsic pathway of blood coagulation as a cofactor by enhancing the assembly of its complex with factors IX and X on the surface of activated platelets. This requires factor VIII interaction with these two proteins, von Willebrand factor (vWF), and phospholipids on the platelet surface. Once factor VIII and factor IX are activated by proteolytic cleavage, the complex is able to activate factor X to factor Xa by proteolysis. In hemophilia A patients with severe factor VIII deficiency, about 30% respond to factor VIII infusion therapy immunologically to produce antibodies that inactivate the infused factor VIII and others that are noninhibitory. An assay that measures only the inhibitor antibodies demonstrated that the factor VIII A2, A3, and C2 domains are the most immunogenic, and domains A1 and B are poorly immunogenic or not immunogenic. The specific antibody responses to A2, A3, and C2 vary considerably among individuals, and epitopes for inhibitor antibodies have been determined for all three. The anti-C2 inhibitors prevent factor VIII binding to phospholipids and vWF, and anti-A3 inhibitors prevent binding to factor IX (IXa). An inhibitor binding site for factor X has been localized to the A1 domain acidic region, leading to inhibition of factor VIII/factor X binding by antibodies. This inhibitor mechanism is rare. Because a second binding site for factor IX was localized to the factor VIII A2 domain, it is likely but not proven that prevention of factor IX binding to factor VIII is the inhibitor mechanism for this epitope.

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A recombinant factor VIII A2 domain polypeptide quantitatively neutralizes human inhibitor antibodies that bind to A2

Cited by 30 publications

References 0 publications

New Characteristics of Anti-Factor VIII Inhibitor Antibody Epitopes and Unusual Immune Responses to Factor VIII

New Characteristics of Anti-Factor VIII Inhibitor Antibody Epitopes and Unusual Immune Responses to Factor VIII

The concept of idiotypic vaccination against factor VIII inhibitors in haemophilia A

Properties of Anti-Factor VIII Inhibitor Antibodies in Hemophilia A Patients

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