Development of a Transgenic Mouse Model Immune Tolerant for Human Interferon Beta

Hermeling, Suzanne; Jiskoot, Wim; Crommelin, Daan J.A.; Bornæs, Claus; Schellekens, Huub

doi:10.1007/s11095-005-4578-z

Cited by 67 publications

(79 citation statements)

References 18 publications

(21 reference statements)

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“…22 Transgenic mouse models for human IFN␣2b (hIFN␣2b) and human IFN␤ (hIFN␤) 19,20 were shown to be predictive of the human immune response, because commercially available hIFN␤ drugs that were found to induce antibodies in a large number of patients were shown to break immune tolerance in these mice. 19 Submitted October 30, 2010; accepted June 6, 2011. Prepublished online as Blood First Edition paper, June 24, 2011; DOI 10.1182 DOI 10.…”

Section: Introductionmentioning

confidence: 99%

“…15,16 Expression of human FVIII during this period should therefore lead to the depletion of high-avidity human FVIII-specific T cells and result in specific immune tolerance toward human FVIII. Similar genetically engineered mouse models were described for human insulin analogs, 17 modified human tissue plasminogen activator variants, 18 human IFNs, 19,20 human Fas ligand inhibitory protein (decoy receptor 3, DcR3), 21 and a mutant of human FVIII. 22 Transgenic mouse models for human IFN␣2b (hIFN␣2b) and human IFN␤ (hIFN␤) 19,20 were shown to be predictive of the human immune response, because commercially available hIFN␤ drugs that were found to induce antibodies in a large number of patients were shown to break immune tolerance in these mice.…”

Section: Introductionmentioning

confidence: 99%

“…Similar genetically engineered mouse models were described for human insulin analogs, 17 modified human tissue plasminogen activator variants, 18 human IFNs, 19,20 human Fas ligand inhibitory protein (decoy receptor 3, DcR3), 21 and a mutant of human FVIII. 22 Transgenic mouse models for human IFN␣2b (hIFN␣2b) and human IFN␤ (hIFN␤) 19,20 were shown to be predictive of the human immune response, because commercially available hIFN␤ drugs that were found to induce antibodies in a large number of patients were shown to break immune tolerance in these mice. 19 In the present study, we describe the selection and characterization of a transgenic mouse line that is immunologically tolerant to native human FVIII but is still able to mount an antibody response to human FVIII when challenged with a modified FVIII protein that possesses increased immunogenicity.…”

Section: Introductionmentioning

confidence: 99%

“…39 Therefore, the difference in the levels of human F8 cDNA and human F8 mRNA found after successful gene-therapy approaches and after transgenic expression of human F8 cDNA are likely to be substantial. There are several other examples of transgenic mouse models that are immunologically tolerant to specific human proteins such as insulin, 17 IFNs,19,20 or factor IX, 48 but lack detectable human protein in the circulation. Moreover, Connely et al 49 demonstrated that the lack of circulating FVIII protein observed after gene therapy using a vector containing a human F8 cDNA driven by an albumin promoter was not necessarily associated with a lack of the production of functional human FVIII protein.…”

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confidence: 99%

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Maintenance and break of immune tolerance against human factor VIII in a new transgenic hemophilic mouse model

Helden

Unterthurner

Hermann

et al. 2011

Blood

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Replacement of the missing factor VIII (FVIII) is the current standard of care for patients with hemophilia A. However, the short half-life of FVIII makes frequent treatment necessary. Current efforts focus on the development of longer-acting FVIII concentrates by introducing chemical and genetic modifications to the protein. Any modification of the FVIII protein, however, risks increasing its immunogenic potential to induce neutralizing antibodies (FVIII inhibitors), and this is one of the major complications in current therapy. It would be highly desirable to identify candidates with a high risk for increased immunogenicity before entering clinical development to minimize the risk of exposing patients to such altered FVIII proteins. In the present study, we describe a transgenic mouse line that expresses a human F8 cDNA. This mouse is immunologically tolerant to therapeutic doses of native human FVIII but is able to mount an antibody response when challenged with a modified FVIII protein that possesses altered immunogenic properties. In this situation, immunologic tolerance breaks down and antibodies develop that recognize both the modified and the native human FVIII. The applicability of this new model for preclinical immunogenicity assessment of new FVIII molecules and its potential use for basic research are discussed. (Blood. 2011; 118(13):3698-3707) IntroductionHemophilia A is an X-linked bleeding disorder that is caused by reduced function or lack of clotting factor VIII (FVIII). 1 Replacement of the missing protein is the current standard of care for patients. However, the short half-life of FVIII, ϳ 7-17 hours, 2 makes frequent treatment necessary. Current efforts focus on the development of longer-acting FVIII concentrates, which should decrease the required treatment frequency and therefore improve the quality of life for patients. Recently described approaches in the development of longer-acting concentrates are based on strategies that have been successfully applied to other therapeutic proteins: chemical modifications such as the addition of polyethylene glycol (PEG) polymers, polysialic acids, or hydroxyethyl starch 3,4 ; alternative formulations with PEG-modified liposomes 3 ; and fusion to the Fc part of human IgG. 5 In addition, molecular modifications of the FVIII protein aimed at increasing the duration of its cofactor activity or reducing its clearance in vivo have been reported. 3 Any chemical or molecular modification of the FVIII protein can potentially increase its immunogenic potential. Modifications could generate neo-epitopes for both B and T cells or may induce altered structures that could bind and trigger receptors expressed on cells of the innate immune system, thereby amplifying potential anti-FVIII antibody responses. 6 Finally, modifications could generate repetitive epitopes for B cells that might cause the activation and differentiation of B cells and the subsequent production of antibodies without the requirement for T-cell help. 7,8 Therefore, the potential impact that any...

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Maintenance and break of immune tolerance against human factor VIII in a new transgenic hemophilic mouse model

Helden

Unterthurner

Hermann

et al. 2011

Blood

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“…IFNβ-1a (Avonex®) followed in 1996 in the market. The glycosylated IFNβ-1a is produced in CHO cells and has the identical amino acid sequences of natural human IFNβ (2). The non-glycosylated IFNβ-1b has an apparent molecular weight of 18.5 kDa.…”

Section: Introductionmentioning

confidence: 99%

Effect of Arginine on Pre-nucleus Stage of Interferon Beta-1b Aggregation

et al. 2014

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Abstract. Understanding the mechanism of aggregation of a therapeutic protein would not only ease the manufacturing processing but could also lead to a more stable finished product. Aggregation of recombinant interferon (IFNβ-1b) was studied by heating, oxidizing, or seeding of unformulated monomeric solution. The formation of aggregates was monitored by dynamic light scattering (DLS) and UV spectroscopy. The autocatalytic monomer loss model was used to fit the data on aggregation rates. The influence of pre-nucleation on aggregation step was demonstrated by inducing the liquid samples containing a monomer form of folded IFNβ-1b by heat and also an oxidizing agent. Results tend to suggest that the nucleus includes a single protein molecule which has been probably deformed. Seeding tests showed that aggregation of IFNβ-1b was probably initiated when 1.0% (w/w) of monomers converted to nucleus form. Chemiluminescence spectroscopy analysis of the sample indicated the generation of 3.0 μM of hydrogen peroxide (H 2 O 2 ) during nucleation stage of IFNβ-1b aggregation. Arginine with a concentration of 200 mM was sufficient to suppress aggregation of IFNβ-1b by decreasing the rate of prenucleation step. We proposed the formation of pre-nucleus structures prior to nucleation as the mechanism of aggregation of IFNβ-1b. Furthermore, we have showed the positive anti-aggregation effect of arginine on pre-nucleation step.

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Immunogenicity of Therapeutic Proteins and the Assessment of Risk

Schellekens¹,

Jiskoot²

2010

Pharmaceutical Sciences Encyclopedia

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Nearly all therapeutic proteins induce an immune response. The immunogenic response may lead to complications such as skin reactions, anaphylaxis‐like reaction, transfusion reactions, and serum sickness due to immunogenic response to impurities and contaminants. This article focuses on risk analysis and management program for new therapeutic proteins and the factors influencing the probability of an antibody response.

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Development of a Transgenic Mouse Model Immune Tolerant for Human Interferon Beta

Cited by 67 publications

References 18 publications

Maintenance and break of immune tolerance against human factor VIII in a new transgenic hemophilic mouse model

Maintenance and break of immune tolerance against human factor VIII in a new transgenic hemophilic mouse model

Effect of Arginine on Pre-nucleus Stage of Interferon Beta-1b Aggregation

Immunogenicity of Therapeutic Proteins and the Assessment of Risk

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