A longitudinal evaluation of anti‐<scp>FVIII</scp> antibodies demonstrated IgG4 subclass is mainly correlated with high‐titre inhibitor in haemophilia A patients

Montalvão, Silmara Aparecida de Lima; Tucunduva, A. C.; Siqueira, Lúcia H.; Sambo, Antonella; Medina, Samuel Souza; Ozelo, Margareth C.

doi:10.1111/hae.12646

Cited by 30 publications

(31 citation statements)

References 26 publications

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“…However, patients who achieve ITI success demonstrate a shift from IgG4 to IgG1 or absence of immunoglobulin (data in submission). Regarding IgG subclasses, we also observed a close correlation between high‐titre inhibitors and the presence of IgG4 anti‐FVIII . Similarly, Whelan et al .…”

Section: Quality Issues In Fviii Inhibitor Testingsupporting

confidence: 86%

Quality laboratory issues in bleeding disorders

et al. 2016

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Selected quality issues pertinent to the determination of accurate results in the haemostasis laboratory are discussed. Specifically, the implementation of a successful external quality-assessment scheme is described, including its impact on result accuracy as well as the programme's unique challenges and opportunities. Errors in the preanalytical phase of laboratory testing represent the greatest source for reporting incorrect test results. Some of the most common preanalytical errors are described including those that necessitate sample rejection. Analytical means to identify potential sources of error and analytical means to overcome particular interferences are described. Representing the most important clinical complication in the treatment of patients with haemophilia, quality issues related to determination of the presence of inhibitory antibodies against factor VIII (FVIII) are reviewed. Heat treatment of patient plasma prior to testing, particularly in patients receiving replacement FVIII concentrate or during induction of immune tolerance to achieve more accurate results is recommended, while screening activated partial thromboplastin time-based mixing tests to rule out inhibitor presence is discouraged. The initiatives presented in this review can be implemented in robust and resource restricted settings to improve the quality of laboratory testing in patients with bleeding disorders.

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Section: Quality Issues In Fviii Inhibitor Testingsupporting

confidence: 86%

Quality laboratory issues in bleeding disorders

et al. 2016

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“…Here, an IgG2 response to the FVII transgene product was seen in dog N24, which expressed supraphysiological levels of FVII. The canine IgG2 corresponds to human IgG4, a subclass with a strong association with high-titer FVIII inhibitors in hemophilia 33 that is also reported predominant in the anti-rhFVIIa antibody response in FVII deficiency. 34 The reasons for the observed immune response here remain unclear.…”

Section: Discussionmentioning

confidence: 83%

Sustained correction of FVII deficiency in dogs using AAV-mediated expression of zymogen FVII

Marcos‐Contreras

Smith

Bellinger³

et al. 2016

Blood

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• Dogs with an FVII G96E mutation (FVII-G96E) represent the most common human FVII mutation type and are ideal for testing new therapies.• cFVII gene delivery in FVII-G96E dogs via AAV at a dose effective in humans showed stable and clinically therapeutic FVII expression.Factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder treated by infusion of fresh-frozen plasma, plasma-derived FVII concentrates and low-dose recombinant activated FVII. Clinical data suggest that a mild elevation of plasma FVII levels (>10% normal) results in improved hemostasis. Research dogs with a G96E missense FVII mutation (FVII-G96E) have <1% FVII activity. By western blot, we show that they have undetectable plasmatic antigen, thus representing the most prevalent type of human FVII deficiency (low antigen/activity). In these dogs, we determine the feasibility of a gene therapy approach using liver-directed, adeno-associated viral (AAV) serotype 8 vector delivery of a canine FVII (cFVII) zymogen transgene. FVII-G96E dogs received escalating AAV doses (2E11 to 4.95E13 vector genomes [vg] per kg). Clinically therapeutic expression (15% normal) was attained with as low as 6E11 vg/kg of AAV and has been stable for >1 year (ongoing) without antibody formation to the cFVII transgene. Sustained and supraphysiological expression of 770% normal was observed using 4.95E13 vg/kg of AAV (2.6 years, ongoing). No evidence of pathological activation of coagulation or detrimental animal physiology was observed as platelet counts, D-dimer, fibrinogen levels, and serum chemistries remained normal in all dogs (cumulative 6.4 years). We observed a transient and noninhibitory immunoglobulin G class 2 response against cFVII only in the dog receiving the highest AAV dose. In conclusion, in the only largeanimal model representing the majority of FVII mutation types, our data are first to demonstrate the feasibility, safety, and long-term duration of AAV-mediated correction of FVII deficiency. (Blood. 2016;127(5):565-571)

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“…Differently from ERT in hemophilia A, where detection of IgG4 is typically associated with presence of inhibitor234849, the presence of increased levels of non-neutralizing IgG4 antibodies, in the absence of IgE antibodies, in treated LOPD subjects compared with HD and untreated LOPD subjects possibly reflects the desensitization to the immunogen24505152. Alternatively, the production of GAA-specific IgG4 may simply reflect the chronic exposure to antigen53.…”

Section: Discussionmentioning

confidence: 96%

Long-term exposure to Myozyme results in a decrease of anti-drug antibodies in late-onset Pompe disease patients

Masat

Pascal

Antonio

et al. 2016

Sci Rep

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Immunogenicity of recombinant human acid-alpha glucosidase (rhGAA) in enzyme replacement therapy (ERT) is a safety and efficacy concern in the management of late-onset Pompe disease (LOPD). However, long-term effects of ERT on humoral and cellular responses to rhGAA are still poorly understood. To better understand the impact of immunogenicity of rhGAA on the efficacy of ERT, clinical data and blood samples from LOPD patients undergoing ERT for >4 years (n = 28) or untreated (n = 10) were collected and analyzed. In treated LOPD patients, anti-rhGAA antibodies peaked within the first 1000 days of ERT, while long-term exposure to rhGAA resulted in clearance of antibodies with residual production of non-neutralizing IgG. Analysis of T cell responses to rhGAA showed detectable T cell reactivity only after in vitro restimulation. Upregulation of several cytokines and chemokines was detectable in both treated and untreated LOPD subjects, while IL2 secretion was detectable only in subjects who received ERT. These results indicate that long-term ERT in LOPD patients results in a decrease in antibody titers and residual production of non-inhibitory IgGs. Immune responses to GAA following long-term ERT do not seem to affect efficacy of ERT and are consistent with an immunomodulatory effect possibly mediated by regulatory T cells.

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A longitudinal evaluation of anti‐FVIII antibodies demonstrated IgG4 subclass is mainly correlated with high‐titre inhibitor in haemophilia A patients

Cited by 30 publications

References 26 publications

Quality laboratory issues in bleeding disorders

Quality laboratory issues in bleeding disorders

Sustained correction of FVII deficiency in dogs using AAV-mediated expression of zymogen FVII

Long-term exposure to Myozyme results in a decrease of anti-drug antibodies in late-onset Pompe disease patients

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