Passive transfer of polyethylene glycol to liposomal-recombinant human FVIII enhances its efficacy in a murine model for hemophilia A.
The replacement therapy using recombinant human FVIII (rFVIII) is the first line of therapy for hemophilia A. Approximately 15-30% of the patients develop inhibitory antibodies. Recently, we reported that liposomes composed of phosphatidylserine (PS) could reduce the immunogenicity of rFVIII. However, PS containing liposomal-rFVIII is likely to reduce the systemic exposure and efficacy of FVIII due to rapid uptake of the PS containing liposomes by the reticuloendothelial system (RES). Here, we investigated whether phosphatidylserine (PS) liposomes containing Polyethylene glycol (PEG) (PEGylated), could reduce the immunogenicity of rFVIII and reverse the reduction in systemic exposure of rFVIII. Animals given PEGylated liposomal-rFVIII had lower total and inhibitory anti-rFVIII antibody titers, compared to animals treated with rFVIII alone. The mean stimulation index of CD4+ T-cells from animals given PEGylated liposomal-rFVIII also was lower than for animals that were given rFVIII alone. Pharmacokinetic studies following intravenous dosing indicated that the systemic exposure (area under the activity curve, AUAC(0-24h)) of PEGylated liposomal-rFVIII was approximately 59 IU/mL x h and significantly higher than that of non-PEGylated liposomal-rFVIII (AUAC(0-24h) approximately 36 IU/mL x h). Based on these studies, we speculate that PEGylated PS-containing liposomal rFVIII may improve efficacy of rFVIII.
Ramani
Karthik
K
Department of Pharmaceutical Sciences, 521 Hochstetter Hall, University at Buffalo, State University of New York, Amherst, New York 14260, USA.
Purohit
Vivek
V
Miclea
Razvan
R
Gaitonde
Puneet
P
Straubinger
Robert M
RM
Balu-Iyer
Sathy V
SV
D000818:Animals; D000906:Antibodies / Q000276:immunology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005169:Factor VIII / Q000737:chemistry / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006467:Hemophilia A / Q000188:drug therapy*; D008081:Liposomes; D008297:Male; D051379:Mice; D008823:Micelles; D011092:Polyethylene Glycols / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000166:cytology
D000906:Antibodies; D008081:Liposomes; D008823:Micelles; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D005169:Factor VIII