Covalently modified antigens for improved immune response and/or stability
Inventors
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12150989-B2
Publication Date
2024-11-26
Expiration Date
Abstract
Covalently modified polypeptide antigens having improved immunogenicity and/or stability, as well as compositions, cells, and methods relating thereto, are described herein. Polypeptide antigens are covalently conjugated to a one or more of steroid acid moieties to improve their stability and/or to trigger improved cellular immunity, or improved cellular and humoral immunity, against the antigen upon administration to a subject. The steroid acids include bile acids and bile acid analogs that enhance endocytosis and/or endosomal escape of endosomally trapped cargoes by potentiating enzymatic cleavage of sphingomyelin to ceramide within endosomal membranes. The steroid acid moieties may be pre-conjugated to a peptide, and the steroid acid-peptide moiety subsequently conjugated to the polypeptide antigen. The peptide may comprise one or more domains that impart an additional functionality to the modified polypeptide antigen.
Core Innovation
The invention provides a method of improving polypeptide antigen immunogenicity by covalently conjugating a polypeptide antigen to one or more steroid acid-peptide moieties. The steroid acid-peptide moieties are conjugated in a sufficient number such that the modified polypeptide antigen triggers an improved adaptive immune response to the polypeptide antigen upon administration, relative to a corresponding unmodified polypeptide antigen. The peptide comprised in the steroid acid-peptide moiety comprises a nuclear localization signal (NLS).
The steroid acid in the conjugate is described as mediating endosomal escape of the modified polypeptide antigen. The described mechanism is that bile acids increase endocytosis and trigger acid sphingomyelinase-mediated sphingomyelin cleavage to ceramide, promoting endosomal escape. Increased cytosolic/endosomal escape is described as enhancing proteasomal processing and MHC-I presentation.
In addition, the disclosure describes immunogenic compositions and use contexts in which the modified polypeptide antigen is administered to a subject to induce improved adaptive immunity. The compositions include a polypeptide antigen and pharmaceutically acceptable excipients and/or adjuvants, with mention of dendritic cells including bone marrow-derived dendritic cells and intracellular delivery. The document also describes examples involving ovalbumin (OVA) and SARS-CoV-2 Spike glycoprotein, including S1-RBD and S2.
Claims Coverage
The document includes one independent claim. It centers on improving polypeptide antigen immunogenicity by covalently conjugating the antigen to steroid acid-peptide moieties that include a nuclear localization signal (NLS) and mediate endosomal escape, with the conjugate configured in a sufficient number to improve adaptive immune response upon administration.
Covalent conjugation to steroid acid-peptide moieties with NLS
Conjugating a polypeptide antigen to one or more steroid acid-peptide moieties to produce a modified polypeptide antigen, where the peptide in the steroid acid-peptide moiety comprises a nuclear localization signal (NLS).
Sufficient number of steroid acid-peptide moieties for improved adaptive immunity
Conjugating the modified polypeptide antigen to a sufficient number of steroid acid-peptide moieties to trigger an improved adaptive immune response to the polypeptide antigen upon administration to a subject as compared to a corresponding unmodified polypeptide antigen.
Steroid acid-mediated endosomal escape
Using a steroid acid that mediates endosomal escape of the modified polypeptide antigen.
Improved adaptive immune response via immunogenic composition administration
Inducing an enhanced adaptive immune response in a subject against an unmodified polypeptide antigen by administering an immunogenic composition.
Overall, claim coverage centers on covalently conjugating a polypeptide antigen to steroid acid-peptide moieties containing an NLS, with the conjugate configured by number to improve adaptive immune response upon administration and with steroid acid described as mediating endosomal escape. Additional scope includes inducing enhanced adaptive immunity via administration of an immunogenic composition.
Stated Advantages
Improved adaptive immune response to the polypeptide antigen upon administration, as compared to a corresponding unmodified polypeptide antigen.
Steroid acid is described as mediating endosomal escape of the modified polypeptide antigen.
Enhanced antigen presentation and adaptive immune responses are described in the disclosure context.
Greater thermal stability is described as an additional benefit relative to an unmodified polypeptide antigen.
Documented Applications
Vaccination/therapeutic administration to induce or enhance adaptive immune responses to a polypeptide antigen in a subject.
Cancer treatment is described as an application context for the methods/compositions.
Infectious disease is described as an application context, with examples including SARS-CoV-2 Spike glycoprotein (S1-RBD and S2).
Use with an exemplary model antigen, ovalbumin (OVA), is described in the disclosure context.
Interested in licensing this patent?