Endocytic receptor for pro-coagulant factor VIII: Relevance to inhibitor formation

Navarrete, Ana-Maria; Dasgupta, Suryasarathi; Teyssandier, Maud; Repessé, Yohann; Delignat, Sandrine; André, Sébastien; Bayry, Jagadeesh; Kaveri, Srini V.; Lacroix‐Desmazes, Sébastien

doi:10.1160/th10-05-0294

Cited by 8 publications

(6 citation statements)

References 77 publications

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“…Although controversial, the endocytosis of FVIII implicates mannose-ending sugars and charged amino-acid residues in the C1 and C2 domains of FVIII [25][26][27]. Studies have ruled out a role for LRP and related receptors in the endocytic process by MO-DCs and implicated mannose-sensitive receptors such as CD206 [28,29]. In our hands, Neureight was endocytosed with a dose-dependency identical to that of Advate and Helixate, suggesting that the moieties implicated in FVIII internalization are identical irrespective of the method used to produce FVIII (fed-batch or perfusion approaches).…”

Section: Discussionmentioning

confidence: 99%

Biochemical characterization and immunogenicity of Neureight, a recombinant full-length factor VIII produced by fed-batch process in disposable bioreactors

Delignat

Peyron

Ghazaly³

et al. 2018

Cellular Immunology

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Hemophilia A is a X-linked recessive bleeding disorder consecutive to the lack of circulating pro-coagulant factor VIII (FVIII). The most efficient strategy to treat or prevent bleeding in patients with hemophilia A relies on replacement therapy using exogenous FVIII. Commercially available recombinant FVIII are produced using an expensive perfusion technology in stainless steel fermenters. A fed-batch fermentation technology was recently developed to produce 'Neureight', a full-length recombinant human FVIII, in Chinese hamster ovary (CHO) cells. Here, we investigated the structural and functional integrity and lack of increased immunogenicity of Neureight, as compared to two commercially available full-length FVIII products, Helixate and Advate, produced in baby hamster kidney or CHO cells, respectively. Our results demonstrate the purity, stability and functional integrity of Neureight with a standard specific activity of 4235 ± 556 IU/mg. The glycosylation and sulfation profiles of Neureight were similar to that of Advate, with the absence of the antigenic carbohydrate epitopes α-Gal and Neu5Gc, and with sulfation of Y1680, that is critical for FVIII binding to von Willebrand factor (VWF). The endocytosis of Neureight by human immature dendritic cells was inhibited by VWF, and its half-life in FVIII-deficient mice was similar to that of Advate, confirming unaltered binding to VWF. In vitro and in vivo assays indicated a similar immunogenicity for Neureight, Advate and Helixate. In conclusion, the production of full-length FVIII in a fed-batch fermentation mode generates a product that presents similar biochemical, functional and immunogenic properties as products developed using the classical perfusion technology.

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Section: Discussionmentioning

confidence: 99%

Biochemical characterization and immunogenicity of Neureight, a recombinant full-length factor VIII produced by fed-batch process in disposable bioreactors

Delignat

Peyron

Ghazaly³

et al. 2018

Cellular Immunology

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“…Over the years, several receptors have been identified for FVIII 5,6,20,21 that have mostly been implicated in FVIII catabolism. 8,22 To date, the only receptor incriminated in FVIII internalization by APCs is the C-type lectin receptor CD206, that binds mannose-ending glycans linked to Asn239 in the A1 domain of FVIII, and Asn2118 in the C1 domain. 7 The importance of the C1 domain of FVIII in binding to phospholipids and participating in FVIII endocytosis has recently been proposed.…”

Section: Discussionmentioning

confidence: 99%

The C1 and C2 domains of blood coagulation factor VIII mediate its endocytosis by dendritic cells

et al. 2016

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T he development of inhibitory antibodies to therapeutic factor VIII is the major complication of replacement therapy in patients with hemophilia A. The first step in the initiation of the anti-factor VIII immune response is factor VIII interaction with receptor(s) on antigenpresenting cells, followed by endocytosis and presentation to naïve CD4 + T cells. Recent studies indicate a role for the C1 domain in factor VIII uptake. We investigated whether charged residues in the C2 domain participate in immunogenic factor VIII uptake. Co-incubation of factor VIII with BO2C11, a monoclonal C2-specific immunoglobulin G, reduced factor VIII endocytosis by dendritic cells and presentation to CD4 + T cells, and diminished factor VIII immunogenicity in factor VIII-deficient mice. The mutation of basic residues within the BO2C11 epitope of C2 replicated reduced in vitro immunogenic uptake, but failed to prevent factor VIII immunogenicity in mice. BO2C11 prevents factor VIII binding to von Willebrand factor, thus potentially biasing factor VIII immunogenicity by perturbing its half-life. Interestingly, a factor VIII Y1680C mutant, that does not bind von Willebrand factor, demonstrated unaltered endocytosis by dendritic cells as well as immunogenicity in factor VIII-deficient mice. Co-incubation of factor VIII Y1680C with BO2C11, however, resulted in decreased factor VIII immunogenicity in vivo. In addition, a previously described triple C1 mutant showed decreased uptake in vitro, and reduced immunogenicity in vivo, but only in the absence of endogenous von Willebrand factor. Taken together, the results indicate that residues in the C1 and/or C2 domains of factor VIII are implicated in immunogenic factor VIII uptake, at least in vitro. Conversely, in vivo, the binding to endogenous von Willebrand factor masks the reducing effect of mutations in the C domains on factor VIII immunogenicity.

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“…To date, the only endocytic receptor that has been shown to lead to FVIII processing and presentation to CD4 T cells is the macrophage mannose receptor (MMR) also known as CD206. 54 Pre-incubation of MO-DCs with mannan, an antagonist of mannose-sensitive receptors, inhibits more than 50% of FVIII endocytosis, and abrogates the activation of a FVIII-specific T-cell line. 29,55 CD206 is a divalent ion-dependent endocytic receptor that belongs to the C-type lectin receptor family.…”

Section: The Macrophage Mannose Receptor or Cd206mentioning

confidence: 99%

Inhibitor Formation in Congenital Hemophilia A: an Immunological Perspective

Delignat

Rayes

Russick

et al. 2018

Semin Thromb Hemost

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The immunogenicity of therapeutic factor VIII (FVIII) in patients with hemophilia A has been puzzling scientific and clinical communities for more than 3 decades. Indeed, the development of inhibitory antibodies to FVIII remains a major clinical challenge and is associated with enormous societal costs. Thus, the reasons for which a presumably innocuous, short-lived, intravenously administered glycoprotein triggers such a deleterious, long-lasting neutralizing immune response is an enigma. This review does not pretend to bring an answer to this challenging question. It will however summarize the latest findings regarding the molecular interactions at play in the recognition of FVIII by the immune cells, the validity of the proposed risk factors for FVIII alloimmunization, and the different solutions that allow induction of FVIII-specific tolerance in preclinical models of hemophilia A.

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Endocytic receptor for pro-coagulant factor VIII: Relevance to inhibitor formation

Cited by 8 publications

References 77 publications

Biochemical characterization and immunogenicity of Neureight, a recombinant full-length factor VIII produced by fed-batch process in disposable bioreactors

Biochemical characterization and immunogenicity of Neureight, a recombinant full-length factor VIII produced by fed-batch process in disposable bioreactors

The C1 and C2 domains of blood coagulation factor VIII mediate its endocytosis by dendritic cells

Inhibitor Formation in Congenital Hemophilia A: an Immunological Perspective

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