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-9931419-B2
Publication Date
2018-04-03
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 provides liposomal vaccine compositions comprising an aqueous vehicle and liposomes built from DMPC together with one or more lipids selected from DMPG and DMTAP, and at least one sterol derivative. The compositions are characterized by specified relative percentages of DMPC, the selected lipid or lipids, and the sterol derivative, and the sterol derivative includes a reactive group enabling covalent anchoring of immunogenic polypeptides or carbohydrates to the liposome formulation.
The sterol derivative is defined in terms of a steroid ring bearing a functional group at the 3-position and covalent linkage motifs of the form St-R3-X. The reactive functionality includes imidoesters, N-hydroxysuccinimidyl esters, maleimides, alkyl halides, aryl halides, alpha-haloacyls, pyridyl disulfides, carbodiimides, glyoxals, hydrazides, and arylazides, with optional linker elements and optional poly(alkylene oxide) spacers.
The document further describes use of the sterol-derivative anchored liposome approach to present HIV-1 gp41 membrane proximal region peptides, including 2F5/N-MPR, 4E10/C-MPR, and NC-MPR, within liposomes. Covalent lipid anchoring is described as affecting peptide conformation and partitioning and as being associated with anti-peptide antibody titers after immunization in mice.
Claims Coverage
The independent claim covers a liposome-based composition with an aqueous vehicle and a defined lipid composition of DMPC plus one or more of DMPG and DMTAP, together with at least one sterol derivative. Across the claims, the invention is refined by quantitative ranges and by specifying sterol-derivative structures and optional immune-stimulatory components; the core inventive features are the sterol-derivative reactive-group design and its incorporation into the defined DMPC/DMPG/DMTAP liposome formulation.
Defined liposome lipid blend with sterol derivative and reactive group
A composition comprising an aqueous vehicle and liposomes comprising DMPC, one or more lipids selected from DMPG and DMTAP, and at least one sterol derivative, with relative percentages of 50%-98% DMPC, 1%-25% selected lipid, and 1%-25% sterol derivative, wherein the sterol derivative comprises a reactive group selected from imidoesters, N-hydroxysuccinimidyl esters, maleimides, alkyl halides, aryl halides, alpha-haloacyls, pyridyl disulfides, carbodiimides, glyoxals, amines, hydrazides, and arylazides.
Additional named immune-stimulatory components in the liposomes
The composition includes additional components selected from monophosphoryl lipid A, resiquimod, flagellin, CpG, and alpha-galactosylceramide.
The claim set centers on a DMPC-based liposome formulation that includes DMPG and/or DMTAP and at least one sterol derivative bearing a selected reactive group from a defined list. Dependent coverage specifies narrower lipid and size conditions, provides detailed sterol-derivative linkage and structure requirements for reactive groups, and adds optional named immune-stimulatory components.
Stated Advantages
Covalent lipid anchoring affects peptide conformation and partitioning.
Anti-peptide antibody titers are observed after immunization in mice.
Anti-antigen antibodies and protective efficacy are generated in an H1N1 challenge model.
Documented Applications
Use of sterol-derivative anchored liposomes with HIV-1 gp41 membrane proximal region peptides, including 2F5/N-MPR, 4E10/C-MPR, and NC-MPR.
Use of maleimide-derivatized sterol conjugated antigens, including PGA and influenza A H1N1 M2eA1, with immunostimulatory components.
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