Immunogenicity of long-lasting recombinant factor VIII products

Ing, Mathieu; Gupta, Nimesh; Teyssandier, Maud; Maillère, Bernard; Pallardy, Marc; Delignat, Sandrine; Lacroix‐Desmazes, Sébastien

doi:10.1016/j.cellimm.2015.12.006

Cited by 38 publications

(27 citation statements)

References 79 publications

(84 reference statements)

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“…In 2015, PEGylated anti-hemophilic factor VIII (ADYNOVATE) was approved for treatment of hemophilia A, both in terms of preventing bleeding episodes, or treating acute bleeding. Based on the increased half-life of this drug in comparison to non-PEGylated factor VIII, there is also hope that the need for less frequent administration may reduce the incidence of anti-factor VIII antibody generation, which affects up to 30% of patients (for most biologics, antidrug antibody generation occurs in <5% of patients) and leads to reduced drug efficacy (35). There are also a large number of polymer-immobilized nanomedicines that are under Phase II or III investigation in clinical trials.…”

Section: Polymeric Nanoparticlesmentioning

confidence: 99%

Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date

et al. 2016

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In this review we provide an up to date snapshot of nanomedicines either currently approved by the US FDA, or in the FDA clinical trials process. We define nanomedicines as therapeutic or imaging agents which comprise a nanoparticle in order to control the biodistribution, enhance the efficacy, or otherwise reduce toxicity of a drug or biologic. We identified 51 FDA-approved nanomedicines that met this definition and 77 products in clinical trials, with ~40% of trials listed in clinicaltrials.gov started in 2014 or 2015. While FDA approved materials are heavily weighted to polymeric, liposomal, and nanocrystal formulations, there is a trend towards the development of more complex materials comprising micelles, protein-based NPs, and also the emergence of a variety of inorganic and metallic particles in clinical trials. We then provide an overview of the different material categories represented in our search, highlighting nanomedicines that have either been recently approved, or are already in clinical trials. We conclude with some comments on future perspectives for nanomedicines, which we expect to include more actively-targeted materials, multi-functional materials ("theranostics") and more complicated materials that blur the boundaries of traditional material categories. A key challenge for researchers, industry, and regulators is how to classify new materials and what additional testing (e.g. safety and toxicity) is required before products become available.

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Section: Polymeric Nanoparticlesmentioning

confidence: 99%

Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date

et al. 2016

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“…Careful attention is required when considering bispecific antibodies, antibody drug conjugates, and other products lacking an endogenous analog since they are more likely to elicit ADA formation [49]. For instance, Hemophilia A is a life-threatening genetic disease in which patients lack an essential clotting factor and is treated with Factor VIII replacement therapy [50]. Unfortunately this therapy triggers ADA response in up to a third of patients and often worsens the condition in patients with high ADA titers.…”

Section: Immunotoxicitymentioning

confidence: 99%

Unraveling the Effect of Immunogenicity on the PK/PD, Efficacy, and Safety of Therapeutic Proteins

Smith

Manoli

Jaw

et al. 2016

Journal of Immunology Research

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Biologics have emerged as a powerful and diverse class of molecular and cell-based therapies that are capable of replacing enzymes, editing genomes, targeting tumors, and more. As this complex array of tools arises a distinct set of challenges is rarely encountered in the development of small molecule therapies. Biotherapeutics tend to be big, bulky, polar molecules comprised of protein and/or nucleic acids. Compared to their small molecule counterparts, they are fragile, labile, and heterogeneous. Their biodistribution is often limited by hydrophobic barriers which often restrict their administration to either intravenous or subcutaneous entry routes. Additionally, their potential for immunogenicity has proven to be a challenge to developing safe and reliably efficacious drugs. Our discussion will emphasize immunogenicity in the context of therapeutic proteins, a well-known class of biologics. We set out to describe what is known and unknown about the mechanisms underlying the interplay between antigenicity and immune response and their effect on the safety, efficacy, pharmacokinetics, and pharmacodynamics of these therapeutic agents.

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“…Both Fc and albumin conjugations can potentially decrease the immunogenicity of FVIII by what is called antigen shielding, where the fusion moiety inhibits uptake of the FVIII product by the antigen-presenting cells needed to generate an immune response 38. Conjugation of PEG to a molecule not only prolongs the half-life but also is thought to make it less immunogenic by inhibiting the binding of protein to endocytic receptors on antigen-presenting cells 39. This strategy has been utilized to increase the half-life of multiple drugs now.…”

Section: Inhibitor Development and Immunogenicity Of New Ehl Fviiimentioning

confidence: 99%

Many factor VIII products available in the treatment of hemophilia A: an embarrassment of riches?

Lieuw¹

2017

JBM

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Hemophilia A (HA) is a common bleeding disorder caused by the deficiency of factor VIII (FVIII) with an incidence of ~1 in 5000 male births. Replacement of FVIII is necessary to prevent and treat bleeding episodes. However, with multiple new drugs in addition to old standards, choosing among the different FVIII treatment options is harder than ever. There are FVIII products that are plasma derived or recombinant, FVIII products designed to extend the half-life of FVIII, and the first single-chain FVIII product, recombinant factor VIII single chain (rFVIII-SC). As development of inhibitors to FVIII continues to be a major problem in the care of HA patients, recent studies showing lower rates of inhibitor development with plasma-derived FVIIII products versus recombinant FVIII products have made choosing among the many options now available even more complex. Although still unproven, extended half-life (EHL) products may provide the hope of decreased immunogenicity but need further testing in previously untreated patients (PUPs). This review highlights some of the differences between FVIII products currently available and hopefully assists the clinician to decide which FVIII product to choose for their patients.

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Immunogenicity of long-lasting recombinant factor VIII products

Cited by 38 publications

References 79 publications

Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date

Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date

Unraveling the Effect of Immunogenicity on the PK/PD, Efficacy, and Safety of Therapeutic Proteins

Many factor VIII products available in the treatment of hemophilia A: an embarrassment of riches?

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