Factor VIII associated with lipidic nanoparticles retains efficacy in the presence of anti‐factor VIII antibodies in hemophilia A mice

Abstract

The development of inhibitory antibodies against factor VIII (FVIII) is a major challenge in hemophilia A (HA) therapy. Such antibodies develop in nearly 30% of patients receiving replacement FVIII, abrogating therapeutic efficacy. This work evaluated whether B-domain deleted FVIII encapsulated in phosphatidylinositol containing lipid nanoparticles (PI-BDD FVIII) could serve as an efficacious FVIII replacement therapy in the presence of inhibitors. The HA mice were given clinically relevant doses of FVIII to develop inhibitors. The efficacy of free and PI-BDD FVIII was studied in inhibitor-positive HA mice using a tail clip assay. Mathematical modeling of these data was conducted to evaluate the hypothesis that lipid association sterically shields the protein from inhibitor binding. The immunization protocol resulted in a mean inhibitory titer level of 198 ± 52 BU/ml. Free BDD FVIII was ineffective at controlling blood loss in inhibitor-positive HA mice as early as 2 h post dose. In contrast, PI-BDD FVIII treated animals retained partial hemostatic efficacy as long as 18 h post dose. Mathematical modeling supports the hypotheses that a greater fraction of lipid-associated FVIII remains unbound to inhibitors and that PI-BDD FVIII has lower binding affinity to inhibitors than does the free protein. In addition, the modeling approaches extend current efforts to model the impact of immunogenicity on PK and the therapeutically meaningful endpoint of efficacy, thereby addressing an important knowledge gap, particularly in the FVIII scientific literature. Clinical translation of these findings could result in a significant improvement in the quality of care of inhibitor-positive HA patients.

Platelet–Microcapsule Hybrids Leverage Contractile Force for Targeted Delivery of Hemostatic Agents

“…The targeted “burst” release enabled by activated platelet contractile forces provides an advantage over other nanoparticle-based delivery systems for fVIII in the presence of inhibitors. While it was reported that adsorbing fVIII onto soy phosphatidylinositol (PI)-containing lipid nanoparticles decreased the ability of fVIII inhibitors to bind to the fVIII protein (fVIII antibody binding domains are thought to be protected in the lipid layer), release of full fVIII dose is reliant upon desorption of the protein and redistribution between the PI nanoparticles, vWF, inhibitor, and its free form . This prevents the full dose from being effectively available immediately after administration.…”

“…Recently, research on PEGylating fVIII , or formulating fVIII with nanoparticles , in order to prevent inhibitor interactions has been reported. However, neither strategy is ideal, as PEGylation has been shown to prevent only some inhibitor species from binding to fVIII, while association with nanoparticles limits the bioavailability of the fVIII dose.…”

Nanoparticles for hematologic diseases detection and treatment

“…Liposomes can encapsulate drugs for different medical purposes: thrombin inhibitors, able to exert an anticoagulant activity in case of arterial acute thrombosis [ 136 ], mRNA to encode erythropoietin, factor IX protein [ 137 ] and anti-factor VIII antibodies [ 138 , 139 ] for haemophilia treatment and Tmprss6 siRNA for thalassemia cure [ 140 ].…”

A Look at the Future Hemophilia A Treatment

“…The drug continues to be haemostatically partially effective up to 18 hours after injection, a net better result than that obtained after the administration of free B-domain deleted FVIII. The probable explanation is that the product encapsulated in lipid nanoparticles has lower binding affinity towards inhibitors, so that a larger proportion of the compound remains unbound to inhibitors [17].…”