Effect of Route of Administration of Human Recombinant Factor VIII on Its Immunogenicity in Hemophilia A Mice

Peng, Aaron; Gaitonde, Puneet; Kosloski, Matthew P.; Miclea, Razvan D.; Varma, Prashant; Balu‐Iyer, Sathy V.

doi:10.1002/jps.21765

Cited by 34 publications

(26 citation statements)

References 13 publications

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“…There are several examples from preclinical relative immunogenicity studies that show the sc route is more immunogenic than the iv route. The sc administration of FVIII showed significantly higher total antibody titers compared to hemophilia A mice that were given FVIII via the iv route (12). A similar observation has been made for other therapeutic proteins such as interferon alpha and human growth hormone (3,13,14).…”

Section: Immunogenicity Of Proteins Given Via Sc Routesupporting

confidence: 60%

Immunogenicity of Subcutaneously Administered Therapeutic Proteins—a Mechanistic Perspective

Fathallah

Bankert

Balu‐Iyer

2013

AAPS J

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Abstract. The administration of therapeutic proteins via the subcutaneous route (sc) is desired for compliance and convenience, but could be challenging due to perceived immunogenic potential or unwanted immune responses. There are clinical and preclinical data supporting as well as refuting the generalized notion that sc is more immunogenic. We provide a mechanistic perspective of immunogenicity of therapeutic proteins administered via the sc route and discuss strategies and opportunities for novel therapeutic approaches to mitigate immunogenicity.KEY WORDS: biotechnology; immunogenicity; mitigation of immunogenicity; protein therapeutics; subcutaneous administration. IMMUNOGENICITY OF PROTEINS GIVEN VIA SC ROUTEThe subcutaneous (sc) route of administration of therapeutic proteins is desired over the intravenous (iv) route due to patient comfort and compliance. In addition, it could also prolong half-life of the therapeutic in circulation (1,2). However, this route of administration could be problematic due to a perceived potential for unwanted immunogenicity (3). As most of the vaccines are given via the sc route, it is expected that the sc route is more immunogenic than the iv route. However, a recent comparative clinical study of sc vs iv administration of abatacept, a fusion protein of Fc of human IgG and extracellular domain of CTLA-4, showed that the efficacy and immunogenicity are comparable between the two routes of administration (4,5). However, the immunogenic potential of chronic administration and long-term effects are not often adequately addressed during clinical trials (6). Few preclinical studies have shown that the sc route of administration does not increase immunogenicity (7-9). For example, the relative immunogenicity of Betaseron, interferon beta, is less for sc administration compared to iv administration (9). Based on clinical experience of head-to-head comparison and a few preclinical studies, one could argue that the generalization that the sc route is more immunogenic than the iv route is not universally valid.A comparative immunogenicity study of three brands of insulin in type 1 diabetics showed an increase in incidence of anti-insulin titer development, across brands, in patients selfadministering via sc route as compared to iv administration in hospital in the same cohort (10). In the therapeutic use of erythropoietin-α, incidence of immunogenicity increased with the change from iv to sc. It is appropriate to mention here that elimination of human serum albumin from the formulation as well as stopper material change (11) coincided with changes in route of administration, and thus, the effect of the sc route of administration on immunogenicity is not unambiguous for erythropoietin. There are several examples from preclinical relative immunogenicity studies that show the sc route is more immunogenic than the iv route. The sc administration of FVIII showed significantly higher total antibody titers compared to hemophilia A mice that were given FVIII via the iv route (12). A similar ob...

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Section: Immunogenicity Of Proteins Given Via Sc Routesupporting

confidence: 60%

Immunogenicity of Subcutaneously Administered Therapeutic Proteins—a Mechanistic Perspective

Fathallah

Bankert

Balu‐Iyer

2013

AAPS J

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“…Several reports have indicated that the intravenous application route for proteins is associated with a less immunogenic response than the subcutaneous or intramuscular application routes. 40,41 Therefore, we expected to see a higher incidence of antibodies against FVIII after subcutaneous application if mice were able to respond to FVIII. Our data confirmed this assumption.…”

Section: Discussionmentioning

confidence: 99%

CD4+ T-cell epitopes associated with antibody responses after intravenously and subcutaneously applied human FVIII in humanized hemophilic E17 HLA-DRB1*1501 mice

Steinitz

Helden

Binder

et al. 2012

Blood

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Today it is generally accepted that B cells require cognate interactions with CD4 IntroductionThe most serious complication in replacement therapy with FVIII products is the development of neutralizing antibodies against FVIII (FVIII inhibitors), which is observed in approximately 25% to 30% of patients with severe hemophilia A. 1 Although several genetic 2 and nongenetic 3 factors that contribute to the risk for patients to develop these antibodies have been identified, why some patients develop antibodies while others do not remains largely unknown.Today it is generally accepted that B cells require cognate interactions with CD4 ϩ T cells to develop high-affinity antibodies against protein antigens. 4,5 In line with this perception, several lines of evidence have supported the involvement of CD4 ϩ T cells in the generation of antibody responses against FVIII in patients with hemophilia A and in murine hemophilia models. 6,7 CD4 ϩ T cells express T-cell receptors that recognize antigen-derived peptides (CD4 ϩ T-cell epitopes) presented by MHC class II molecules, which are expressed on specialized antigen-presenting cells. 8 Structural features of both the MHC class II molecule and the peptide determine the specificity of CD4 ϩ T cells that can bind to the MHC class II-peptide complex. 8,9 The conditions under which CD4 ϩ T cells interact with this complex determine whether the immune system reacts with nonresponsiveness, is activated to develop specific antibodies, or is tolerized to suppress antibody responses. 9,10 Therefore, it is crucial to understand which FVIII peptides are presented by MHC class II complexes under conditions of FVIII replacement therapy and how CD4 ϩ T cells interact with MHC class II-FVIII peptide complexes expressed by antigenpresenting cells. The available information on FVIII peptides presented in the context of specific human MHC class II molecules is limited. Several studies used peripheral blood cells of patients and healthy controls 11 to identify CD4 ϩ T-cell epitopes in the A2 domain, 12 A3 domain, 13 and C2 domain of FVIII. 14 However, these studies lack information on the specific MHC class II molecules associated with the FVIII peptides identified. Jacquemin et al identified T-cell epitopes of FVIII using CD4 ϩ T-cell clones isolated from a mild hemophilia A patient carrying an Arg2150His mutation in the C1 domain of FVIII. 15 All clones recognized FVIII peptides encompassing residue Arg2150. Peptides were presented by HLA-DRB1*0401/HLA-DRB4*01 or HLA-DRDRB1*1501/ HLA-DRB5*0101. One of the peptides identified was a promiscuous epitope that bound to several different HLA-DR proteins. James et al used MHC class II tetramers to analyze FVIII-specific CD4 ϩ T cells obtained from a mild hemophilia A patient carrying an Ala2201Pro mutation in the C2 domain of FVIII. 16 Responses of CD4 ϩ T cells to sequences containing Ala2201 (wild-type), Pro2201 (hemophilic), and other predicted T-cell epitopes were evaluated and resulted in the identification of an HLA-DRB1*0101 restricted T-ce...

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“…Animals were sacrificed at week 6 and plasma was collected. Total anti‐FVIII titers were determined using an ELISA as previously described . Inhibitory anti‐FVIII titers were quantified with the Bethesda assay.…”

Section: Methodsmentioning

confidence: 99%

Soy Phosphatidylinositol Containing Nanoparticle Prolongs Hemostatic Activity of B-Domain Deleted Factor VIII in Hemophilia A Mice

Shetty

Kosloski

Mager

et al. 2015

Journal of Pharmaceutical Sciences

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Factor VIII (FVIII) replacement therapy in Hemophilia A (HA) is complicated by a short half-life and high incidence of inhibitory antibody response against the protein. Phosphatidylinositol (PI) containing lipidic nanoparticles have previously been shown to reduce the immunogenicity and prolong the half-life of full length FVIII. It has not been established whether this prolongation in half-life improves hemostatic efficacy and whether this approach could be extended to the B-domain deleted form of FVIII (BDD FVIII). In the current study, we evaluated the pharmacokinetics (PK), hemostatic efficacy and immunogenicity of BDD FVIII associated with PI nanoparticles (PI-BDD FVIII) in HA mice. Comparative human PK was predicted using an ‘informed scaling’ approach. PI-BDD FVIII showed a ~ 1.5-fold increase in terminal half-life compared to free BDD FVIII following i.v. bolus doses of 40 IU/kg. PI-BDD FVIII treated animals retained hemostatic efficacy longer than the free FVIII treated group in a tail vein transection model of hemostasis. PI association reduced the development of inhibitory and binding antibodies against BDD FVIII after a series of i.v. injections. The combined improvements in circulating half-life and hemostatic efficacy could significantly prolong the time above clinically established therapeutic thresholds of prophylactic FVIII replacement therapy in humans.

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Effect of Route of Administration of Human Recombinant Factor VIII on Its Immunogenicity in Hemophilia A Mice

Cited by 34 publications

References 13 publications

Immunogenicity of Subcutaneously Administered Therapeutic Proteins—a Mechanistic Perspective

Immunogenicity of Subcutaneously Administered Therapeutic Proteins—a Mechanistic Perspective

CD4+ T-cell epitopes associated with antibody responses after intravenously and subcutaneously applied human FVIII in humanized hemophilic E17 HLA-DRB1*1501 mice

Soy Phosphatidylinositol Containing Nanoparticle Prolongs Hemostatic Activity of B-Domain Deleted Factor VIII in Hemophilia A Mice

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