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The safety and efficacy of several life-saving therapeutic proteins are compromised due to their immunogenicity. Once a sustained immune response against a protein-based therapy is established, clinical options that are safe and cost-effective become limited. Prevention of immunogenicity of therapeutic proteins prior to their initial use is critical as it is often difficult to reverse an established immune response. Here, we discuss a rational design and testing of a phosphatidylserine-containing nanoparticle platform for novel oral prophylactic reverse vaccination approach, i.e., pre-treatment of a therapeutic protein in the presence of nanoparticles to prevent immunogenicity of protein therapies.
Background:The development of antidrug antibodies, also termed inhibitors, against administered factor VIII (FVIII) is one of the major complications in the clinical management of hemophilia A. Once formed, these inhibitory antibodies abrogate the activity of FVIII, resulting in loss of hemostatic efficacy and patients are subjected to increased risk of bleeding tendencies. Current treatment options after inhibitor development are expensive and ineffective in some cases. Therefore, treatment strategies that can prevent inhibitor formation is an effective approach in the management of hemophilia A.
Objectives:We aimed to evaluate and discuss the use of a tolerogenic form of FVIII as an immunotherapy strategy to prevent inhibitor risk.Methods: FVIII was associated with nanoparticles containing lysophosphatidylserine (Lyso-PS) and administered to hemophilia A mice via intravenous route. These animals then received weekly rechallenge injections with free FVIII, and plasma was collected at the end of the study to evaluate for inhibitor development. To investigate whether Lyso-PS nanoparticles influence the plasma survival of FVIII, a pharmacokinetic study following a single intravenous administration of FVIII in the presence and absence of Lyso-PS nanoparticles was performed. For dosing convenience, the tolerogenic effect of Lyso-PS nanoparticles following oral administration was also examined.
Results and conclusions:The results demonstrated that FVIII associated with Lyso-PS nanoparticles significantly reduced inhibitor development while improving plasma survival of FVIII following intravenous administration, suggesting a multifunctional FVIII form to improve clinical utility. Additionally, reduction in inhibitor formation can also be achieved using Lyso-PS nanoparticles through the user-friendly oral route of administration.
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