Review articleImmunogenicity of long-lasting recombinant factor VIII products
Introduction
The past decades have witnessed extraordinary improvement in the treatment of bleeding disorders. Progressing from the Stone Age, with the use of whole blood and cryoprecipitate infusion, we have evolved to a modern time where recombinant coagulation factors are administered. Congenital disorders such as hemophilia A, that display life-threatening bleeding manifestations, have benefitted utmost from the development of new generation therapeutic factor VIII (FVIII), owing to the implication and commitment of the pharmaceutical field. Simultaneously, clinical studies as well as the implication of clinicians and basic researchers have promoted new treatment regimens (prophylaxis rather than “on-demand” treatment) that reduce the risks for hemarthrosis and arthropathy episodes and have improved the quality of life of hemophilic patients.
Despite the quality of FVIII in terms of efficacy and viral safety, the short half-life of FVIII imposes frequent administrations to provide an optimal protection of the patients from bleeding episodes. This is understandably associated with a limited adherence of the patients to prophylaxis regimen, thereby resulting in a lack of complete protection and higher treatment costs. Accordingly, the most recent developments for therapeutic coagulation factors have focused on extending their half-life in the blood: recombinant factors with longer residual time in circulation would cumulate the benefice of reducing the frequency of administration, thus improving the compliance of patients, and increasing the bleed-free time-span of the patients, thus reducing the risks for minor arthropathy-prone joint bleeds. In this context, several strategies are being exploited to optimize the pharmacokinetics of therapeutic FVIII, that include coupling of the effector protein to dimeric Fc fragments of human immunoglobulin G, to polyethylene glycol (PEG) or to human serum albumin (HSA).
The treatment of patients with hemophilia A using exogenous FVIII is complicated by the immunogenicity of the infused FVIII. Indeed, up to 30% of patients with severe hemophilia A, and up to 5% of patients with mild/moderate forms of the disease, develop anti-FVIII IgG antibodies following replacement therapy. The induced anti-FVIII IgG presumably affect the pharmacokinetics of the exogenously administered coagulation factors but, more critically, inhibit their pro-coagulant activity. The development of inhibitory anti-FVIII IgG, or ‘FVIII inhibitors’, represents a major clinical burden as well as a major societal concern owing to the additional costs that are associated with inhibitor management. To our knowledge, there is no available study that clearly establishes a correlation between the residual time of a molecule and its immunogenicity in humans. It is thus hazardous to predict the immunogenicity of long-acting FVIII products. Besides, FVIII exhibits a degree of immunogenicity that is unexpected given the fact that FVIII has no known pro-inflammatory role. In this review, we summarize the rationale for the different strategies developed to enhance the half-life of FVIII. Based on the available evidence, we further anticipate the consequences and limitations of coupling FVIII to ‘half-life enhancers’ for its immunogenicity in hemophilia A patients.
Section snippets
Coupling therapeutic FVIII to human Fc fragments
The interaction of the Fc domain of immunoglobulins with the neonatal Fc receptor (FcRn) has been known for years as a physiological mechanism that protects IgGs from catabolism and confers them a long half-life in the blood [1]. Therefore, IgGs of the IgG1, IgG2 and IgG4 sub-classes are known to circulate in the body with a half-life of 3 weeks. The FcRn is expressed at many sites and by different cell types in mammals, where it mediates IgG transcytosis and IgG recycling in a pH-dependent
Coupling therapeutic FVIII to human albumin
Accounting for 50% of total plasma proteins, albumin is the most prominent protein circulating in the blood. Serum albumin is a natural carrier for several endogenous hydrophobic molecules, such as fatty acids or thyroid hormones; it is also involved in scavenging free radical species that may be released in the blood. Albumin displays a long half-life of 20 days in vivo. This persistence is attributed to both a high hydrodynamic size, which prevents glomerular filtration by kidneys, and
PEGylation of therapeutic FVIII
PEGylation consists in a covalent conjugation of polymers of ethylene glycol (PEG) to a carrier. PEGylation was found to extend the residence time of derivatized proteins [39], [40], and was therefore considered as an efficient strategy to improve drug delivery and has been applied to enhance the lifespan of a large number of drugs over the last decades. PEG conjugation affects the physicochemical features of the target protein, without altering its structure. In particular, the hydrophilic
Conclusions
The development of a new generation of therapeutic coagulation factors is revolutionizing the treatment of patients with hemophilia. Specifically, novel products with extended half-lives should facilitate patient management, resulting in a drastically improved quality of life. Indeed, the reduced frequency of drug administration and the prolonged circulation time of the hemostatic drugs should provide a longer protection of the patients from micro-bleeds in joints, thus minimizing co-morbidity.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgments
This work was supported by Institut national de la santé et de la recherche médicale (Inserm), Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie (UPMC) Paris 6, and the Innovative Medicines Initiative Joint Undertaking under grant agreement n. 115303, with resources from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. Mathieu Ing is the recipient of a fellowship from Ministère de l’enseignement
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2019, Journal of Pharmaceutical SciencesCitation Excerpt :In an experiment by Krishnamoorthy et al.121, they compared the relative immunogenicity of several types of FVIII products to determine if their new FVIII fc fusion was less immunogenic than the currently used products. It was found that mice treated with rFVIII-Fc had significantly lower antibody response as compared to B-domain–deleted FVIII or full-length FVIII, which is confirmed by clinical observation of Eloctate (rFVIII-Fc) having much lower immunogenicity.122-124 In a study by Wang et al.,125 BALC/c mice were used to compare the relative immunogenicity of DNA vaccines by different routes of administration and showed that intramuscular administration was the least immunogenic.