Methods and compositions relating to adjuvants

Patent metadata

Field	Value
Publication number	US-11464854-B2
Application number	US-201816495901-A
Country	US
Kind code	B2
Filing date	Mar 23, 2018
Priority date	Mar 23, 2017
Publication date	Oct 11, 2022
Grant date	Oct 11, 2022

Abstract

The methods and compositions described herein relate to methods of immunization or stimulating an immune response, e.g., using agonists of TLR7 and/or TLR8 as antigens. The methods and compositions described herein have particular relevance to use in infants.

First claim

What is claimed herein is:

1. A method of immunizing a subject, the method comprising administering to the subject
i) an adjuvant comprising an agonist of TLR7 and/or TLR8; and
ii) at least one antigen;

wherein the adjuvant and the at least one antigen are not conjugated to each other; and
wherein the adjuvant comprises an agonist of TLR7 and/or TLR8, and the agonist of TLR7 and/or TLR8 comprises a compound selected from the group consisting of Formula IX; Formula XII; 3M-052; CRX-672; CRX-677; and CRX-748:

wherein n is a number between 0 and 20,
n1 is between 1 and 15;
R is H, C1-6alkyl, C1-6alkylamino, C1-6alkoxy, C3-6cycloalkylC1-6alkyl, C3-6cycloalkylC1-6alkylamino, C3-6cycloalkylC1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC1-6alkylamino, or C1-6alkoxyC1-6alkoxy;
wherein each of C1-6alkyl, C1-6alkylamino, C1-6alkoxy, C3-6cycloalkylC1-6alkyl, C3-6cycloalkylC1-6alkylamino, C3-6cycloalkylC1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC1-6alkylamino or C1-6alkoxyC1-6alkoxy is branched or unbranched, and optionally terminally substituted with a hydroxyl, amino, thio, hydrazino, hydrazido, azido, acetylenyl, carboxyl, or maleimido group;
R 2 is a lipid group; and
X is —CH 2 OH; —CH 2 CH 2 OH; polyunsaturated fatty acid with two or more carbon-carbon double bonds in its hydrocarbon chain; polyunsaturated fatty alcohol with two or more carbon-carbon double bonds in its hydrocarbon chain; a sterol lipid; or glycerolipid.

2. The method of claim 1 , wherein X is —CH 2 OH.

3. The method of claim 1 , wherein the agonist of TLR7 and/or TLR8 comprises a compound having the structure of CRX-649 (Formula X):

4. The method of claim 1 , wherein the agonist of TLR7 and/or TLR8 comprises a compound having the structure of Formula XI:

5. The method of claim 1 , wherein the agonist of TLR7 and/or TLR8 comprises a compound selected from the group consisting of:

6. The method of claim 1 , wherein the agonist of TLR7 and/or TLR8 comprises a hydroxyl group, and the agonist of TLR7 and/or TLR8 further comprises a lipid moiety, phosphorylation, or phospholipid moiety conjugated to the hydroxyl group.

7. The method of claim 6 , wherein the lipid moiety or phospholipid moiety is conjugated to the hydroxyl group of

8. The method of claim 1 , wherein the administration of the adjuvant and antigen provides protection at a lower dose or with fewer doses than the antigen administered without the adjuvant.

9. The method of claim 1 , wherein the antigen is comprised by a vaccine selected from the group consisting of:
a pneumococcal vaccine; a hepatitis B (HBV) vaccine; an acellular pertussis (aP) vaccine; a diphtheria tetanus acellular pertussis (DTaP) vaccine; a hepatitis A (HAV) vaccine; and a meningococcal (MV) vaccine.

10. The method of claim 9 , wherein the vaccine is pneumococcal conjugate vaccine (PCV)13.

11. The method of claim 1 , wherein the subject is a human infant at the time of administration.

12. A method of stimulating an immune response of a subject, the method comprising administering to the human an adjuvant comprising an agonist of TLR7 and/or TLR8; and wherein the adjuvant comprises an agonist of TLR7 and/or TLR8, and the agonist of TLR7 and/or TLR8 comprises a compound selected from the group consisting of Formula IX; Formula XII; 3M-052; CRX-672; CRX-677; and CRX-748:

wherein n is a number between 0 and 20,
n1 is a number between 1 and 15;
R is H, C1-6alkyl, C1-6alkylamino, C1-6alkoxy, C3-6cycloalkylC1-6alkyl, C3-6cycloalkylC1-6alkylamino, C3-6cycloalkylC1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC1-6alkylamino, or C1-6alkoxyC1-6alkoxy;
wherein each of the C1-6alkyl, C1-6alkylamino, C1-6alkoxy, C3-6cycloalkylC1-6alkyl, C3-6cycloalkylC1-6alkylamino, C3-6cycloalkylC1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC1-6alkylamino or C1-6alkoxyC1-6alkoxy is branched or unbranched, and optionally terminally substituted with a hydroxyl, amino, thio, hydrazino, hydrazido, azido, acetylenyl, carboxyl, or maleimido group;
R 2 is a lipid group; and
X is —CH 2 OH; —CH 2 CH 2 OH; polyunsaturated fatty acid with two or more carbon-carbon double bonds in its hydrocarbon chain; polyunsaturated fatty alcohol with two or more carbon-carbon double bonds in its hydrocarbon chain; a sterol lipid; or glycerolipid.

13. A kit comprising an adjuvant comprising an agonist of TLR7 and/or TLR8; and wherein the adjuvant comprises an agonist of TLR7 and/or TLR8, and the agonist of TLR7 and/or TLR8 comprises a compound selected from the group consisting of Formula IX; Formula XII; 3M-052; CRX-672; CRX-677; and CRX-748:

wherein n is a number between 0 and 20,
n1 is a number between 1 and 15;
R is H, C1-6alkyl, C1-6alkylamino, C1-6alkoxy, C3-6cycloalkylC1-6alkyl, C3-6cycloalkylC1-6alkylamino, C3-6cycloalkylC1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC1-6alkylamino, or C1-6alkoxyC1-6alkoxy;
wherein each of the C1-6alkyl, C1-6alkylamino, C1-6alkoxy, C3-6cycloalkylC1-6alkyl, C3-6cycloalkylC1-6alkylamino, C3-6cycloalkylC1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC1-6alkylamino or C1-6alkoxyC1-6alkoxy is branched or unbranched, and optionally terminally substituted with a hydroxyl, amino, thio, hydrazino, hydrazido, azido, acetylenyl, carboxyl, or maleimido group;
R 2 is a lipid group; and
X is —CH 2 OH; —CH 2 CH 2 OH; polyunsaturated fatty acid with two or more carbon-carbon double bonds in its hydrocarbon chain; polyunsaturated fatty alcohol with two or more carbon-carbon double bonds in its hydrocarbon chain; a sterol lipid; or glycerolipid.

14. The kit of claim 13 , further comprising at least one antigen.

15. The method of claim 1 , wherein the agonist of TLR7 and/or TLR8 is a compound of formula:

16. The method of claim 1 , wherein R is C1-6alkyl.

17. The method of claim 1 , wherein R is C1-6alkoxyC1-6alkyl.

18. The method of claim 1 , wherein R 2 is

19. The method of claim 1 , wherein the agonist of TLR7 and/or TLR8 is a compound of formula:

Assignees

• Childrens Medical Center
• Univ Of Montana

Inventors

• Levy Ofer
• Dowling David
• Bazin-Lee Helene
• Burkhart David
• Evans Jay
• Smith Alyson Jessica

Classifications

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• A61K47/543

  Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine · CPC title

• A61K31/4745

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title

• A61K31/685

  one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin · CPC title

• A61K9/107

  Emulsions {; Emulsion preconcentrates; Micelles (composition of emulsions A61K47/00)} · CPC title