Methods and compositions for liposomal formulation of antigens and uses thereof
Inventors
Fujii, Gary • Szoka, Jr., Francis C. • WATSON, Douglas S.
Assignees
Molecular Express Inc • University of California San Diego UCSD
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Publication Number
US-8765171-B2
Publication Date
2014-07-01
Expiration Date
Abstract
The present invention relates to liposomal vaccine compositions, methods for the manufacture thereof, and methods for the use thereof to stimulate an immune response in an animal. These compositions comprise dimyristoylphosphatidylcholine (“DMPC”); either dimyristoylphosphatidylglycerol (“DMPG”) or dimyristoyltrimethylammonium propane (“DMTAP”) or both DMPC and DMTAP; and at least one sterol derivative providing a covalent anchor for one or more immunogenic polypeptide(s) or carbohydrate(s).
Core Innovation
The invention relates to liposomal vaccine compositions comprising an aqueous vehicle, liposomes, and one or more immunogenic polypeptides covalently linked to sterol derivatives. The liposomes include DMPC and one or more lipids selected from DMPG and DMTAP, together with at least one sterol derivative, and the liposome components are defined by relative percentages for DMPC, the selected DMPG/DMTAP lipid(s), and the sterol derivative.
A central feature is that the immunogenic polypeptide(s) are covalently linked to between 1% and 100% of the at least one sterol derivative, enabling presentation of membrane-anchored immunogenic polypeptides. The sterol derivative is functionalized with linkage-bearing moieties, including covalent linkage architectures described with reactive groups and spacers such as (alkylene oxide)n, and the attachment structure and linkage positioning are presented as capable of modulating immunological behavior.
The disclosure further specifies preferred liposome size ranges and immunization concepts, including prime/boost regimens and parenteral or enteral routes. The compositions may optionally include immunostimulatory adjuvants and/or additional immune activators, and example content indicates that differences in lipid anchor structure and attachment location on HIV-1 gp41 membrane-proximal region epitopes affect secondary structure, membrane partitioning, and anti-peptide antibody titers.
Claims Coverage
The independent claim coverage focuses on an immunogenic polypeptide liposomal vaccine composition in which the polypeptide is covalently linked to a sterol derivative incorporated into liposomes, with the liposome lipid composition and the polypeptide-to-sterol linkage percentage defined by relative ranges. The independent claim identified below is clm-00001; dependent claims refine inventive features by tightening quantitative ranges and specifying linkage attachment and optional components.
Covalently sterol-anchored immunogenic polypeptide in DMPC/DMPG/DMTAP liposomes
An aqueous vehicle with liposomes comprising DMPC, one or more lipids selected from DMPG and DMTAP, and at least one sterol derivative, using relative percentages of 50%-98% (i): 1%-25% (ii): 1%-25% (iii), and one or more immunogenic polypeptide(s) covalently linked to between 1% and 100% of said at least one sterol derivative.
Sterol-derivatized polypeptide covalent linkage level
One or more immunogenic polypeptides covalently linked to between about 5% and about 10% of at least one sterol derivative.
Optional immunostimulatory liposome components
Liposomes including one or more components selected from monophosphoryl lipid A, resiquimod, flagellin, CpG, and α-galactosylceramide.
Covalent attachment via lysine residue on the polypeptide
At least one immunogenic polypeptide covalently linked to one or more sterol derivatives via a lysine residue on the immunogenic polypeptide.
(Alkylene oxide)n spacer-length constraint for the covalent linkage
The covalent linkage to an immunogenic polypeptide includes an (alkylene oxide)n moiety with an average length n between 40 and 1000.
Liposome diameter substantially between 50 and 500 nm
Liposomes having a diameter substantially between 50 and 500 nm.
Overall claim coverage centers on a liposomal vaccine composition where immunogenic polypeptides are covalently linked to sterol derivatives that are incorporated into DMPC-containing liposomes with optional DMPG/DMTAP, with quantitative ranges for lipid percentages and polypeptide-to-sterol linkage, and further refinements specifying linkage attachment details, spacer length, optional immunostimulatory components, and liposome size.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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