Enhanced efficacy of recombinant FVIII in noncovalent complex with PEGylated liposome in hemophilia A mice.
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.
Pan
Junliang
J
Bayer HealthCare LLC, Richmond, CA 94806, USA.
Liu
Tongyao
T
Kim
Ji-Yun
JY
Zhu
Daguang
D
Patel
Chandra
C
Cui
Zhi-Hua
ZH
Zhang
Xin
X
Newgren
James O
JO
Reames
Aaron
A
Canivel
Dodie
D
Jesmok
Gary
G
Pierce
Glenn F
GF
Sommer
Jurg M
JM
Jiang
Haiyan
H
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
D008081:Liposomes; D046911:Macromolecular Substances; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D005169:Factor VIII