title: Enhanced efficacy of recombinant FVIII in noncovalent complex with PEGylated liposome in hemophilia A mice.
abstract: Recombinant FVIII formulated in PEG-ylated liposomes (rFVIII-PEG-Lip) was reported to increase the bleed-free days from 7 to 13 days (at 35 IU/kg rFVIII) in severe hemophilia A patients. To understand the underlying mechanism, we sought to recapitulate its efficacy in hemophilia A mice. Animals treated with rFVIII-PEG-Lip achieved approximately 30% higher survival relative to rFVIII after tail vein transection inflicted 24 hours after dosing. The efficacy of rFVIII-PEG-Lip represents an approximately 2.5-fold higher "apparent" FVIII activity, which is not accounted for by its modestly increased (13%) half-life. The enhanced efficacy requires complex formation between rFVIII and PEG-Lip before the administration. Furthermore, PEG-Lip associates with the majority of platelets and monocytes in vivo, and results in increased P-selectin surface expression on platelets in response to collagen. Rotational thromboelastometry (ROTEM) analysis of whole blood from rFVIII-PEG-Lip-treated animals at 5 minutes up to 72 hours after dosing recapitulated the 2- to 3-fold higher apparent FVIII activity. The enhanced procoagulant activity is fully retained in plasma unless microparticles are removed by ultracentrifugation. Taken together, the efficacy of rFVIII-PEG-Lip is mediated mainly by its sensitization of platelets and the generation of procoagulant microparticles that may express sustained high-affinity receptors for FVIII.
authors: Bayer HealthCare LLC, Richmond, CA 94806, USA.
authors: Junliang
authors: J
authors: Pan
authors: Tongyao
authors: T
authors: Liu
authors: Ji-Yun
authors: JY
authors: Kim
authors: Daguang
authors: D
authors: Zhu
authors: Chandra
authors: C
authors: Patel
authors: Zhi-Hua
authors: ZH
authors: Cui
authors: Xin
authors: X
authors: Zhang
authors: James O
authors: JO
authors: Newgren
authors: Aaron
authors: A
authors: Reames
authors: Dodie
authors: D
authors: Canivel
authors: Gary
authors: G
authors: Jesmok
authors: Glenn F
authors: GF
authors: Pierce
authors: Jurg M
authors: JM
authors: Sommer
authors: Haiyan
authors: H
authors: Jiang
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005169:Factor VIII / Q000008:administration & dosage* / Q000378:metabolism; D006207:Half-Life; D006467:Hemophilia A / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008081:Liposomes; D046911:Macromolecular Substances / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism; D013379:Substrate Specificity; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D008081:Liposomes; D046911:Macromolecular Substances; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D005169:Factor VIII