US-12622961-B2 - Lipopolysaccharide molecules for enhancing immune responses

Abstract

The present disclosure provides compositions and methods for enhancing immune response in a subject. In an embodiment, this disclosure provides modified LPS molecules and compositions comprising the modified LPS molecules. The disclosure also provides methods for enhancing an immune response in a subject.

Inventors

• Timothy MEREDITH
• Gloria KOMAZIN
• Michael A. MAYBIN

Assignees

• THE PENN STATE RESEARCH FOUNDATION

Dates

Publication Date

20260512

Application Date

20200910

Claims (14)

1. 1 . A PEtN-modified saccharide having the following structure: where R 1 is H; R 2 is independently H or and at least one R 2 is R 3 is H, R 4 is H or and R 5 is H or
2. 2 . The PEtN-modified saccharide of claim 1 , wherein the PEtN-modified saccharide has the following structure:
3. 3 . The PEtN-modified saccharide of claim 1 , wherein the PEtN-modified saccharide has the following structure:
4. 4 . The PEtN-modified saccharide of claim 1 , wherein the PEtN-modified saccharide has the following structure:
5. 5 . A composition comprising a PEN-modified saccharide of claim 1 .
6. 6 . The composition of claim 5 , further comprising pharmaceutically acceptable carrier.
7. 7 . The composition of claim 5 , further comprising one or more antigens.
8. 8 . The composition of claim 5 , further comprising one or more adjuvants.
9. 9 . A method for generating or enhancing an immune response in an individual comprising administering to the individual an effective amount of a PEtN-modified saccharide of claim 1 or a composition comprising the PEtN-modified saccharide.
10. 10 . The method of claim 9 , further comprising administering an antigen against which an immune response is desired.
11. 11 . The method of claim 10 , wherein the PEtN-modified saccharide and the antigen are administered at the same time.
12. 12 . The method of claim 10 , wherein the PEtN-modified saccharide and the antigen are administered at different times.
13. 13 . The method of claim 10 , wherein the antigen is a peptide or protein.
14. 14 . The method of claim 10 , wherein the PEtN-modified saccharide binds to TLR4.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62/898,458, filed Sep. 10, 2019, the disclosure of which is incorporated herein by reference. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT This invention was made with government support under grant no. R21 AI138152 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND OF THE DISCLOSURE Vaccines are biological compositions that elicit an immune response against a particular diseased condition. Vaccines may be preventative (preventing or attenuating the effects of a future infection), or therapeutic (administered after onset of a condition, such as, cancer). Most vaccines are designed empirically using inactivated or attenuated pathogens. While adjuvants are commonly used to improve vaccine efficacy, associated side-effects of promising adjuvants have hindered their wide-spread use. For example, LPS, a glycolipid consisting of a lipid A anchor within the bilayer, and a set of covalently attached core saccharides, is a potent activator of immune responses. However, LPS is toxic to humans and animals due to hyper-activation of inflammatory immune responses. While modified forms of LPS (such as acetylated forms) with reduced toxicity have been reported, the less toxic variants generally also have reduced immunostimulatory properties. For example, it is known that while under-acylated forms of LPS such as lipid IVA are less toxic, they also have lower Toll-like receptor 4 (TLR4) receptor activity, lead to less cytokine production, and weaker adjuvancy. As such, there is a continuing need for development of adjuvants that enhance immune responses while being well-tolerated. SUMMARY OF THE DISCLOSURE This disclosure provides compositions and methods for enhancing immune response in a subject. In an embodiment, this disclosure provides modified LPS molecules and compositions comprising the modified LPS molecules. The disclosure also provides methods for enhancing an immune response in a subject. The human immune system can detect picogram levels of LPS through Toll-like receptor 4 signaling, which leads to induction of a proinflammatory response and secretion of cytokines and other second messengers. The cytokine/chemokine response to LPS and other TLR4 agonists in part orchestrates the production of antibodies to provide long-term humoral immunity. Co-administration of LPS and analogs with targeted antigens (from cancer cells, viruses, etc) in vaccine formulations can thus boost antibody production through adjuvancy. LPS (hexa-acylation state, with or without modifications) is generally too potent to be of use in vaccines; however, as the robust TLR4 response induces fever, vasodilation, and general toxicity. This disclosure provides modified lipopolysaccharide (LPS) molecules that act as vaccine adjuvants to enhance immune responses to an administered antigen. A modification comprises addition of phosphoethanolamine (PEtN) groups to the 1- and/or 4′ phosphates on the lipid A or lipid A-based core (e.g., lipid IVA and de-O-acyl lipid A cores) of the molecule. The PEtN groups are linked to one or both phosphate(s) of the lipid A or lipid A-based molecules (e.g., lipid IVA and de-O-acyl lipid A molecules) via a phosphoanhydride bond. In an embodiment, the PEtN-modified saccharide(s) (e.g., PEtN-LPS molecules) of this disclosure retain TLR4 binding activity resulting in production of cytokines and an enhancement in immune responses. PEtN-modified saccharide (e.g., modified LPS molecules) of the present disclosure exhibit reduced toxicity. This disclosure also provides modified lipid A and lipid A-based compounds (e.g., lipid IVA and de-O-acyl lipid A compounds) that act as vaccine adjuvants to enhance immune responses to an administered antigen. The lipid A and lipid A-based compounds (e.g., lipid IVA and de-O-acyl lipid A compounds) of this disclosure have reduced toxicity due to the addition of phosphoethanolamine (PEtN) groups to the 1- and/or 4′ phosphates on the backbone of the molecules. The PEtN groups are linked to phosphates of the lipid A and lipid A-based compounds (e.g., lipid IVA and de-O-acyl lipid A compounds) via a phosphoanhydride bond. In an embodiment, the PEtN lipid A and lipid A-based compounds (e.g., lipid IVA and de-O-acyl lipid A compounds) of this disclosure retain TLR4 binding activity resulting in production of cytokines and an enhancement in immune responses. In an aspect, the present disclosure provides PEtN-modified saccharide(s) (e.g., compound) and PEtN-LPS molecules. In an aspect, the present disclosure provides compositions. The compositions may comprise pharmaceutically acceptable carriers. The compositions may be immunogenic and/or vaccine compositions. In an aspect, the present disclosure provides methods of using compounds and compositions of the present disclosure. The methods may be used to genera