Immune Responses to Plasma-Derived Versus Recombinant FVIII Products

Abstract

The most severe side effect of hemophilia treatment is the inhibitor development occurring in 30% of patients, during the earliest stages of treatment with factor (F)VIII concentrates. These catastrophic immune responses rapidly inactivate the infused FVIII, rendering the treatment ineffective. This complication is associated with a substantial morbidity and mortality. The risk factors involved in the onset of the inhibitors are both genetic and environmental. The source of FVIII products, i.e. plasma-derived or recombinant FVIII products, is considered one of the most relevant factors for inhibitor development. Numerous studies in the literature report conflicting data on the different immunogenicity of the products. The SIPPET randomized trial showed an increased in the inhibitor rate in patients using recombinant FVIII products than those receiving plasma-derived products in the first exposure days. The SIPPET randomized trial showed an increase in the inhibitor rate in patients using recombinant FVIII products compared to those treated with plasma-derived products in the first days of exposure. The potential increase in the immunogenicity of recombinant products can be attributed to several factors such as: the different post-translational modification in different cell lines, the presence of protein aggregates, and the role played by the chaperon protein of FVIII, the von Willebrand factor, which modulates the uptake of FVIII by antigen presenting cells (APCs). Furthermore, the presence of non-neutralizing antibodies against FVIII has shown to be in increased inhibitor development as demonstrated in a sub-analysis of the SIPPET study. In addition, the presence of the specific subclasses of the immunoglobulins may also be an important biomarker to indicate whether the inhibitor will evolve into a persistent neutralizing antibody or a transient one that would disappear without any specific treatment. Recently, the availability of novel non-replacement therapies as well as emicizumab, administered by weekly subcutaneous infusion, have significantly changed the quality of life of patients with inhibitors showing a considerable reduction of the annual bleeding rate and in most patients the absence of bleeding. Although, these novel drugs improve patients' quality of life, they do not abolish the need to infuse FVIII during acute bleeding or surgery. Therefore, the issue of immunogenicity against FVIII still remains an important side effect of hemophilia treatment.

The Impact of Recombinant Versus Plasma-Derived Factor VIII Concentrates on Inhibitor Development in Previously Untreated Patients With Hemophilia A: A 2021 Update of a Systematic Review and Meta-Analysis

“…As the usual immune response mechanism, this process will require the second trigger to produce more. The main neutralizing antibodies are IgG1 and IgG4 subtypes [ 36 ].…”

From a bispecific monoclonal antibody to gene therapy: A new era in the treatment of hemophilia A

“…Emicizumab has significantly changed the quality of life of hemophilia patients, including those with inhibitors, the direct consequence of the important decrease of the annual bleeding rate and, in most of them, the absence of bleeding. The association of FVIII products is necessary, however, during acute bleeding or surgery 11 . The quality of life of 241 adults with hemophilia A after 24 weeks of prophylactic treatment with emicizumab was assessed using the Haem-A-QoL questionnaire.…”

“…The disadvantages of therapy with FVIII products are intravenous administration (even to those with difficult venous access), frequent injections (especially in the case of standard FVIII products) and the risk of the appearance of anti-FVIII antibodies (inhibitors) (ref. 10 ) in about 30% of patients, especially at the beginning of substitution treatment with FVIII concentrates 11 . These limitations contribute to the decrease of patients' compliance and quality of life 10 .…”

“…Porcine FVIII could be used to obtain hemostasis in patients with hemophilia A with inhibitors in whom human FVIII products have proven to be ineffective. A recombinant porcine factor VIII (rpFVIII) product can be an option in these patients as on-demand therapy, including in those undergoing prophylaxis with emicizumab 11 . Patients with inhibitors use by-passing agents (aPCC or rFVIIa) for the treatment of hemorrhagic episodes and immune tolerance induction therapy -the last with the purpose of eradicating the inhibitors, which is very expensive.…”

Immunogenicity of Current and New Therapies for Hemophilia A

“…Nevertheless, there are some potential explanations for the observed results. The higher immunogenicity of rFVIII could be related to different post-translational modifications, production in different cell lines, and the absence of other proteins, such as von Willebrand factor (VWF) [ 30 ].…”