Hypothesis for the Control of Clotting Factor VIII Inhibitory Antibodies by Decreasing Potency of Helper T‐Cell‐Recognized Epitopes in Factor VIII

Tiarks, Cheryl Y.; Humphreys, Robert E.; Anderson, John; Mole, John E.; Pechet, Liberto

doi:10.1111/j.1365-3083.1992.tb03125.x

Cited by 3 publications

(3 citation statements)

References 43 publications

(16 reference statements)

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“…A strategy has been outlined (Tiarks et al 1992) for the reduction of immune response to Factor VIII by replacing epitopes associated with activity‐inhibiting antibodies. Porcine/human chimeric Factor VIII retained activity in the presence of inhibiting antibodies to the epitope replaced by the porcine sequence (Lubin et al 1994).…”

Section: Discussionmentioning

confidence: 99%

“…Neutralizing antibody production developed in 47% of patients treated with SakSTAR variants compared with 81% of patients treated with wild-type SakStar, demonstrating that despite successful reduction in antigenicity there is the problem of individuals showing varying degrees of responses to particular epitopes through the inherent flexibility of the immune response. A strategy has been outlined (Tiarks et al 1992) for the reduction of immune response to Factor VIII by replacing epitopes associated with activity-inhibiting antibodies. Porcine/human chimeric Factor VIII retained activity in the presence of inhibiting antibodies to the epitope replaced by the porcine sequence (Lubin et al 1994).…”

Section: Discussionmentioning

confidence: 99%

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Reduced antibody response to streptavidin through site‐directed mutagenesis

Meyer¹,

Schultz²,

Lin³

et al. 2001

Protein Science

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Streptavidin provides an effective receptor for biotinylated tumoricidal molecules, including radionuclides, when conjugated to an antitumor antibody and administered systemically. Ideally, one would like to administer this bacterial protein to patients repeatedly, so as to maximize the antitumor effect without eliciting an immune response. Therefore, we attempted to reduce the antigenicity of streptavidin by mutating surface residues capable of forming high energy ionic or hydrophobic interactions. A crystallographic image of streptavidin was examined to identify residues with solvent-exposed side chains and residues critical to streptavidin's structure or function, and to define loops. Mutations were incorporated cumulatively into the protein sequence. Mutants were screened for tetramer formation, biotin dissociation, and reduced immunoreactivity with pooled patient sera. Patient antisera recognized one minor continuous epitope with binding locus at residue E101 and one major discontinuous epitope involving amino acid residues E51 and Y83. Mutation of residues E51, Y83, R53, and E116 reduced reactivity with patient sera to <10% that of streptavidin, but these mutations were no less antigenic in rabbits. Mutant 37, with 10 amino acid substitutions, was only 20% as antigenic as streptavidin. Rabbits immunized with either streptavidin or mutant 37 failed to recognize the alternative antigen. Biotin dissociated from mutant 37 four to five times faster than from streptavidin. Residues were identified with previously undescribed impact on biotin binding and protein folding. Thus, substitution of charged, aromatic, or large hydrophobic residues on the surface of streptavidin with smaller neutral residues reduced the molecule's ability to elicit an immune response in rabbits.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Reduced antibody response to streptavidin through site‐directed mutagenesis

Meyer¹,

Schultz²,

Lin³

et al. 2001

Protein Science

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“…The isolation of FVIII-specific T cell lines and clones will be required for determin ing the extent to which these T cell responses result from the antigenspecific recognition of FVIII and the type of cytokines involved in this immunologic response. Clarifying the role of FVIII-reactive T cells in health and disease is essential for understanding the pathogenesis of the inhibitor antibody response and for devising alternative inhibitor anti body suppression therapies centered around inhibition of specific T cell function (45,46).…”

Section: Discussionmentioning

confidence: 99%

T Lymphocyte Proliferative Responses Induced by Recombinant Factor VIII in Hemophilia A Patients with Inhibitors

Singer¹,

Addiego²,

Reason³

et al. 1996

Thromb Haemost

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SummaryIn this study we sought to determine whether factor VUI-reactive T lymphocytes were present in hemophilia A patients with inhibitor antibodies. Peripheral blood mononuclear cells (MNC) were obtained from 12 severe hemophilia A patients having high titer inhibitors, 4 severe hemophilia A patients without inhibitors and 5 normal male subjects. B cell-depleted MNC were cultured in serum-free medium in the absence or presence of 2 µg of recombinant human factor VIII (rFVIII) per ml, and cellular proliferation was assessed after 5 days of culture by measuring 3H-thymidine incorporation. rFVIII induced marked cellular proliferation in cultures of 4 of 12 inhibitor-positive hemophilia patients: fold increase over background (stimulation index, SI) of 7.8 to 23.3. The remaining 8 inhibitor-positive patients, the 4 hemophilia patients without inhibitors and the 5 normal subjects, all had lower proliferative responses to rFVIII, SI range = 1.6 to 6.0. As a group, the inhibitor-positive subjects had significantly higher proliferative responses to rFVIII than did the inhibitor-negative and normal subjects (p < 0.05 by t-test). Cell fractionation experiments showed that T lymphocytes were the rFVIII-responsive cell type, and that monocytes were required for T cell proliferation. Thus, rFVIII-reactive T lymphocytes are present in the peripheral circulation of some inhibitor-positive hemophilia A patients. These T cells may recognize FVIII in an antigen-specific manner and play a central role in the regulation of inhibitor antibody production

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