Tregitope Peptides: The Active Pharmaceutical Ingredient of IVIG?

Groot, Anne S. De; Cousens, Leslie P.; Mingozzi, Federico; Martin, W.

doi:10.1155/2013/493138

Cited by 23 publications

(21 citation statements)

References 46 publications

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“…It has been proposed that Tregitopes represent an evolutionary mechanism by which to suppress autoreactivity to the wide array of different immunoglobulin molecules that are created during immune development,107 and may be the mechanism underlying the efficacy of intravenous immunoglobulin in the treatment of IMIDs 108. Tregitopes can ameliorate inflammation in several murine models of autoimmunity, and are in preclinical stages of development for the treatment of IMIDs 107…”

Section: Targeting Specific Cellular Subsetsmentioning

confidence: 99%

Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis?

2017

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The past three decades have witnessed remarkable advances in our ability to target specific elements of the immune and inflammatory response, fuelled by advances in both biotechnology and disease knowledge. As well as providing superior treatments for immune-mediated inflammatory diseases (IMIDs), such therapies also offer unrivalled opportunities to study the underlying immunopathological basis of these conditions.In this review, we explore recent approaches to the treatment of IMIDs and the insights to pathobiology that they provide. We review novel biologic agents targeting the T-helper 17 axis, including therapies directed towards interleukin (IL)-17 (secukinumab, ixekizumab, bimekizumab), IL-17R (brodalumab), IL-12/23p40 (ustekinumab, briakinumab) and IL-23p19 (guselkumab, tildrakizumab, brazikumab, risankizumab, mirikizumab). We also present an overview of biologics active against type I and II interferons, including sifalumumab, rontalizumab, anifrolumab and fontolizumab. Emerging strategies to interfere with cellular adhesion processes involved in lymphocyte recruitment are discussed, including both integrin blockade (natalizumab, vedolizumab, etrolizumab) and sphingosine-1-phosphate receptor inhibition (fingolimod, ozanimod). We summarise the development and recent application of Janus kinase (JAK) inhibitors in the treatment of IMIDs, including first-generation pan-JAK inhibitors (tofacitinib, baricitinib, ruxolitinib, peficitinib) and second-generation selective JAK inhibitors (decernotinib, filgotinib, upadacitinib). New biologics targeting B-cells (including ocrelizumab, veltuzumab, tabalumab and atacicept) and the development of novel strategies for regulatory T-cell modulation (including low-dose IL-2 therapy and Tregitopes) are also discussed. Finally, we explore recent biotechnological advances such as the development of bispecific antibodies (ABT-122, COVA322), and their application to the treatment of IMIDs.

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Section: Targeting Specific Cellular Subsetsmentioning

confidence: 99%

Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis?

2017

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“…Tolerance through regulatory T cell epitopes. The C H 2 domain of the IgG Fc fragment contains atypical T cell epitopes, which during co-presentation of Fc with associated antigen, has been shown to expand antigen-specific CD4 + CD25 high Foxp3 + regulatory T cells (Tregs) [20]. Fc-derived regulatory T cell epitopes, referred to as Tregitopes, were also found to confer tolerance to recombinant adeno-associated virus gene transfer vectors [21].…”

Section: Indeed Fcriib Is the Only Fc Receptor That Is Constitutivementioning

confidence: 99%

Immunogenicity of long-lasting recombinant factor VIII products

Ing

Gupta

Teyssandier

et al. 2016

Cellular Immunology

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Replacement therapy for patients with hemophilia A using plasma-derived or recombinant factor VIII (FVIII) is complicated by the short half-life of the FVIII products and by the occurrence of neutralizing antibodies in a substantial number of patients. In the recent years, enormous efforts have been invested to develop new generations of coagulation factors with extended half-lives. Presumably, the use of long-lasting FVIII products should reduce the frequency of administration to the patients and drastically improve their quality of life. The question of their immunogenicity remains however unanswered as yet. The present review proposes a summary of the different strategies developed to enhance the half-life of FVIII, including fusion of FVIII to the Fc fragment of the human IgG1 or to human serum albumin, or attachment of polyethylene glycol. Based on the available literature, we hypothesize on the potential benefits or risks associated with each of the latter strategies in terms of immunogenicity of the newly derived hemostatic drugs.

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“…These Tregitopes protect the FVIIIFc molecules from the deleterious anti-FVIII immune response by inducing the expansion of Tregs. 9 Krishnamoorthy et al showed, in FVIII-deficient mice, a decreased immune response to FVIIIFc products. 10 As this is a fairly newly approved product, we do not have enough clinical data or randomized trials on its use in ITI.…”

Section: Evidence Of Immunogenicity Of Fviii Products Coupled To Humamentioning

confidence: 99%

What is the role of an extended half-life product in immune tolerance induction in a patient with severe hemophilia A and high-titer inhibitors?

Janbain¹,

Pipe

2016

Hematology

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A 10-year-old boy presents with a history of severe hemophilia A and high-titer inhibitor that had failed high-dose immune tolerance induction (ITI) with a recombinant factor VIII (rFVIII) product and a plasma-derived FVIII product. You are asked by his mother whether he should be tried on ITI with an extended half-life product, in particular, consideration of a rFVIIIFc concentrate. Learning Objective• To understand the role of immune tolerance induction in the new era of extended half-life products Hemophilia A is an X-linked recessive disease characterized by decreased levels of factor VIII (FVIII) that predispose to bleeding, and especially spontaneous bleeding, in patients with severe disease where FVIII levels are ,1% (0.01 IU/mL). Up to 30% of patients with severe hemophilia develop inhibitors or alloantibodies that neutralize the activity of FVIII, resulting in difficult-to-control bleeding.1 The current management of these patients is to treat acute bleeding with agents that bypass the need for FVIII, activated prothrombin complex concentrate, or activated recombinant factor FVII, along with immune tolerance induction (ITI) in order to eradicate the inhibitor. Several protocols of ITI have been published worldwide with approximately a 70% overall success rate.2 Although different factors were studied as possible predictors of ITI success, 3 we will focus here on the type of FVIII product and the role of extended half-life product (EHL), especially rFVIIIFc in ITI.We conducted a search in Embase and Medline, using as keywords "immune tolerance induction in hemophilia" (791 and 416, respectively) and "recombinant FVIIIFc" (112 and 32, respectively). We found a total of 4 articles combined, from which 1 additional reference, covering immunogenicity of EHLs, was taken from the bibliography 4 : 1 was cited as an abstract with no available full article, 2 were series of case reports, and 1 focused on immunogenicity in hemophilia A mice.The development of alloantibodies or inhibitors in patients with hemophilia receiving FVIII products is a very complex process. It involves several components of the immune system as well as the FVIII molecule itself and its immunogenicity. What is well known is that T cells drive the inhibitor development that is secreted by B cells as FVIII-specific alloantibodies. ITI with regular prolonged exposure to clotting factor concentrate is the mainstay of treatment of patients with inhibitors in order to induce tolerance and therefore eradicate the alloantibodies. The choice of the product to be used remains challenging with conflicting data about superiority of plasma-derived products over recombinant products. A meta-analysis of 13 studies failed to clarify this matter as most of these studies did not control for other confounding factors, especially pre-ITI risk. 5 We are left with the lack of randomized trials comparing these 2 classes of products and the emergence of the new EHLs that offer a prolonged half-life of FVIII in the blood along with speculative theories about reduc...

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Tregitope Peptides: The Active Pharmaceutical Ingredient of IVIG?

Cited by 23 publications

References 46 publications

Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis?

Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis?

Immunogenicity of long-lasting recombinant factor VIII products

What is the role of an extended half-life product in immune tolerance induction in a patient with severe hemophilia A and high-titer inhibitors?

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