Hemophilia A is an X-linked
bleeding disorder caused by the deficiency of
factor VIII (FVIII). Exogenous FVIII is administered therapeutically, and due to a short half-life, frequent infusions are often required. Fifteen to thirty-five percent of severe
hemophilia A patients develop inhibitory
antibodies toward FVIII that complicate clinical management of the disease. Previously, we used
phosphatidylinositol (PI) containing lipidic nanoparticles to improve the therapeutic efficacy of recombinant FVIII by reducing immunogenicity and prolonging the circulating half-life. The objective of this study is to investigate further improvements in the FVIII-PI formulation resulting from the addition of
polyethylene glycol (PEG) to the particle. PEGylation was achieved by passive transfer of PEG conjugated
lipid into the FVIII-PI complex. PEGylated FVIII-PI (FVIII-PI/PEG) was generated with high association efficiency. Reduced activity in vitro and improved retention of activity in the presence of
antibodies suggested strong shielding of FVIII by the particle; thus, in vivo studies were conducted in
hemophilia A mice. Following
intravenous administration, the apparent terminal half-life was improved versus both free FVIII and FVIII-PI, but exposure determined by area under the curve was reduced. The formation of inhibitory
antibodies after subcutaneous immunization with FVIII-PI/PEG was lower than free FVIII but resulted in a significant increase in inhibitors following
intravenous administration. Passive transfer of PEG onto the FVIII-PI complex does not provide any therapeutic benefit.