Tolerogenic form of Factor VIII to prevent inhibitor development in the treatment of Hemophilia A

Abstract

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.

Hemophilia a patients with inhibitors: Mechanistic insights and novel therapeutic implications

“…In murine HA models, researchers found that phosphatidylserine (PS) induced immune tolerance and reduced the production of inhibitors by affecting the maturation of DCs, inducing the generation of Tregs, and inhibiting the generation of memory B cells ( 68 – 70 ). More recently, studies have demonstrated that the binding of FVIII to lysophosphatidylserine (Lyso-PS) to form the Lyso-PS-rFVIII Fc complex significantly reduced inhibitor development in HA mice after either intravenous or oral administration of Lyso-PS ( 71 , 72 ). In addition, researchers found that site N2118, containing high-mannose glycans, have a significant impact on FVIII immunogenicity in the murine HA model ( 73 ).…”

Structural insights into blood coagulation factor VIII: Procoagulant complexes, membrane binding, and antibody inhibition

“…2 Furthermore, healthy individuals with no genetic disruption to FVIII may also spontaneously develop FVIII inhibitory antibodies resulting in acquired hemophilia. 3 Guided by structural studies of FVIII, recent bioengineering efforts have inspired the development of new molecules to bypass or replace extant FVIII therapeutic products, including bispecific antibodies that form active tenase complexes, 4,5 FVIII molecules that are either deimmunized or do not cross-react with anti-human FVIII antibodies, [6][7][8][9] and FVIII preparations with extended plasma half-lives. [10][11][12]…”