Enhancement of the efficacy of therapeutic proteins by formulation with PEGylated liposomes; a case of FVIII, FVIIa and G-CSF.
BACKGROUND
Improving the pharmacodynamics of protein drugs has the potential to improve the care and the quality of life of patients suffering from a variety of diseases.


METHODS
Four approaches to improve protein drugs are described: PEGylation, amino acid substitution, fusion to carrier proteins and encapsulation. A new platform technology based on the binding of proteins/peptides to the outer surface of PEGylated liposomes (PEGLip) is then presented. Binding of proteins to PEGLip is non-covalent, highly specific and dependent on an amino acid consensus sequence within the proteins. Association of proteins with PEGLip results in substantial enhancement of the pharmacodynamic properties of proteins following administration. This has been demonstrated in preclinical studies and clinical trials with coagulation factors VIII and VIIa. It has also been demonstrated in preclinical studies with granulocyte colony-stimulating factor. A mechanism is presented that explains the improvements in hemostatic efficacy of PEGLip-formulated coagulation factors VIII and VIIa.


RESULTS
The reader will gain an understanding of the advantages and disadvantages of each of the approaches discussed.


CONCLUSIONS
PEGLip formulation is an important new approach to improve the pharmacodynamics of protein drugs. This approach may be applied to further therapeutic proteins in the future.
Yatuv
Rivka
R
Omri Laboratories Ltd, Building 22, Weizmann Science Park, PO Box 4015, Nes-Ziona 74140, Israel.
Robinson
Micah
M
Dayan
Inbal
I
Baru
Moshe
M
D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004341:Drug Evaluation; D004353:Drug Evaluation, Preclinical; D005169:Factor VIII / Q000008:administration & dosage*; D015942:Factor VIIa / Q000008:administration & dosage*; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage*; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage / Q000138:chemical synthesis*; D008954:Models, Biological; D008958:Models, Molecular; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry; D011506:Proteins / Q000008:administration & dosage* / Q000737:chemistry
D000925:Anticoagulants; D008081:Liposomes; D011506:Proteins; D016179:Granulocyte Colony-Stimulating Factor; D011092:Polyethylene Glycols; D005169:Factor VIII; D015942:Factor VIIa