Methods and compositions for liposomal formulation of antigens and uses thereof
Inventors
Fujii, Gary • Szoka, Francis C. • WATSON, Douglas S.
Assignees
Molecular Express Inc • University of California San Diego UCSD
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Publication Number
US-10369229-B2
Publication Date
2019-08-06
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
A composition is disclosed that includes an aqueous vehicle and liposomes comprising DMPC and DMPG and/or DMTAP, together with at least one reactive sterol derivative. The reactive sterol derivatives covalently link an influenza M2 antigen polypeptide sequence to the sterol derivative, and between 1% and 100% of the reactive sterol derivatives comprise an influenza M2 antigen polypeptide sequence covalently linked thereto.
The disclosure further describes sterol derivatives that are reactive and include functional moieties for covalent anchoring, including amine reactive groups, sulfhydryl reactive groups, carboxyl reactive groups, photoaffinity reactive groups, maleimide, and N-hydroxysuccinimidyl (NHS) esters. Sterol derivatives are described in terms of sterol and derivative possibilities that support antigen covalent linkage.
The liposomal vaccine compositions are described in relation to inducing immune responses, including challenge protection examples using HIV-1 gp41 membrane proximal region (MPR) lipopeptide studies and influenza A H1N1 M2eA1. The disclosure also describes additional adjuvant components that may be included, such as MPL and Toll-like receptor agonists, and further defines liposome size ranges and component relative amounts in some embodiments.
Claims Coverage
The independent claim is directed to an aqueous liposomal vaccine composition with DMPC and DMPG and/or DMTAP and reactive sterol derivatives that covalently anchor an influenza M2 antigen polypeptide sequence, with 1% to 100% of the reactive sterol derivatives bearing the antigen. Dependent claims refine the formulation with quantitative lipid ratios, liposome diameter ranges, specific sterol derivative identities, optional adjuvant components, and specific functional moieties such as maleimide.
Reactive sterol derivative covalently linked to influenza M2 antigen polypeptide sequence
A composition comprising an aqueous vehicle and liposomes including at least one reactive sterol derivative, wherein between 1% and 100% of the sterol derivatives comprise an influenza M2 antigen polypeptide sequence covalently linked thereto.
DMPC with DMPG and/or DMTAP liposome components
Liposomes comprising dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) and/or dimyristoyltrimethylammonium propane (DMTAP) as liposome constituents.
Sterol and lipid relative percentage ranges
The composition in which the liposomes have relative percentage ranges of 70%-85%, 5%-15%, and 10%-15% for the DMPC, DMPG/DMTAP, and reactive sterol derivative components.
Liposome diameter range
The composition in which the liposomes have a diameter substantially between 50 and 500 nm.
Sterol derivative identities derived from cholesterol or named sterols
The composition in which the reactive sterol derivatives comprise derivatives of cholesterol or one or more named sterols including cholesteryl chloroformate, stigmasterol, sitosterol, ergosterol, lanosterol, desmosterol, or campesterol.
Toll-like receptor agonist adjuvant
The composition further includes an adjuvant that is a Toll-like Receptor agonist.
Maleimide functional moiety for the sterol derivative linkage
The composition in which the functional moiety of the sterol derivative is maleimide.
The claimed subject matter centers on an aqueous liposomal vaccine composition in which DMPC plus DMPG and/or DMTAP liposomes include reactive sterol derivatives that covalently anchor an influenza M2 antigen polypeptide sequence, with dependent claims specifying component ranges, liposome diameter, sterol derivative identities, optional adjuvant, and linkage chemistry.
Stated Advantages
Inducing immune responses.
Challenge protection is described in association with the influenza example.
Documented Applications
Influenza A H1N1 M2eA1 challenge survival / challenge protection.
HIV-1 gp41 membrane proximal region (MPR) lipopeptide studies including epitopes N-MPR, C-MPR, and NC-MPR.
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