Use of toll-like receptor 2 (TLR-2) agonist for modulating human immune response

Patent metadata

Field	Value
Publication number	US-12268739-B2
Application number	US-201917263515-A
Country	US
Kind code	B2
Filing date	Jul 26, 2019
Priority date	Jul 27, 2018
Publication date	Apr 8, 2025
Grant date	Apr 8, 2025

Abstract

Provided herein are Toll-like receptor 2 (TLR2) agonists for use in enhancing human immune response and/or as adjuvants in vaccines. The TLR2 agonists include thiophenes, imidazoles, or phenyl-containing compounds, which may be compounds of Formulae (I), (II), (III), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. The compounds described herein are used as enhancers of an immune response (e.g., innate and/or adaptive immune response), and are useful in treating and/or preventing a disease, as adjuvants in a vaccine for the disease. (e.g., proliferative disease, inflammatory disease, autoimmune disease, infectious disease, or chronic disease). Also provided in the present disclosure are pharmaceutical compositions, kits, methods, and uses including or using a compound described herein.

First claim

What is claimed is:

1. A composition comprising an antigen and a Toll-like receptor 2 (TLR2) agonist, wherein the TLR2 agonist is a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen or optionally substituted alkyl;
R 2 is hydrogen or optionally substituted alkyl; or R 1 and R 2 are joined together with the intervening atoms to form a substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclic ring, or substituted or unsubstituted heteroaryl ring;
R 3 is hydrogen, halogen, optionally substituted alkyl, —OR a1 , or —N(R a2 ) 2 , wherein R a1 is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group when attached to an oxygen atom;
wherein each occurrence of R a2 is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
R is hydrogen or optionally substituted alkyl;
X is O or S; and
R 4 is hydrogen, optionally substituted heterocyclyl, or optionally substituted aryl.

2. The composition of claim 1 , wherein the antigen comprises a protein or polypeptide.

3. The composition of claim 1 , wherein the antigen comprises a nucleic acid encoding a protein or a polypeptide.

4. The composition of claim 1 , wherein the antigen is from a microbial pathogen.

5. The composition of claim 1 , wherein the antigen is a cancer-specific antigen.

6. The composition of claim 1 , wherein the composition is a vaccine composition and the TLR2 agonist is an adjuvant.

7. The composition of claim 1 , wherein the compound is of Formula (IA):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are joined together with the intervening atoms to form a substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclic ring, or substituted or unsubstituted heteroaryl ring;
Y is —OR a1 , or —N(R a2 ) 2 , wherein R a1 is optionally substituted C 1-6 alkyl; and each occurrence of R a2 is independently hydrogen or optionally substituted C 1-6 alkyl.

8. A method of enhancing an immune response to an antigen in a subject in need thereof, the method comprising administering to the subject the composition of claim 1 .

9. The method of claim 8 , wherein the administration is prophylactic.

10. The method of claim 8 , wherein the subject is a human neonate, an infant, an adult, or an elderly.

11. The method of claim 10 , wherein the infant is less than 28 days of age at the time of administration.

12. A method of vaccinating a subject in need thereof, the method comprising administering to the subject an effective amount of the composition of claim 1 .

13. The composition of claim 7 , wherein R 1 and R 2 are joined together with the intervening atoms to form a 5-membered carbocyclic ring, 6-membered carbocyclic ring, or 7-membered carbocyclic ring.

14. The composition of claim 7 , wherein the compound is of formula:

or a pharmaceutically acceptable salt thereof, wherein:
R 4A is halogen, optionally substituted alkyl, optionally substituted acyl, —CN, —SO 2 N(R a ) 2 , —OR b , optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
each instance of R X is independently hydrogen, halogen, or optionally substituted alkyl;
R B is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
x is 0, 1, 2, 3, 4, 5, or 6;
x1 is 0, 1, 2, 3, 4, 5, or 6;
a is 0, 1, 2, 3, 4, or 5;
each instance of R a is independently hydrogen, optionally substituted alkyl, a nitrogen protecting group, or two instances of R a are joined together with the intervening atoms to form optionally substituted heterocyclyl; and
R b is hydrogen, optionally substituted alkyl, or an oxygen protecting group.

15. The composition of claim 14 , wherein the compound is of formula:

or a pharmaceutically acceptable salt thereof.

16. The composition of claim 15 , wherein at least one instance of R 4A is halogen, —CN, or —SO 2 N(R a ) 2 , wherein each instance of R a is independently optionally substituted alkyl, or two instances of R a are joined together with the intervening atoms to form an optionally substituted heterocyclyl.

17. The composition of claim 15 , wherein a is 1; and R 4A is —SO 2 N(R a ) 2 , wherein each instance of R a is independently optionally substituted alkyl, or two instances of R a are joined together with the intervening atoms to form an optionally substituted heterocyclyl.

18. The composition of claim 1 , wherein the compound is of formula:

or a pharmaceutically acceptable salt thereof.

Assignees

• Childrens Medical Center
• Dana Farber Cancer Inst Inc

Inventors

• Dowling David J
• Levy Ofer
• Borriello Francesco
• Scott David A
• Brightman Spencer E

Classifications

• A61P37/04

  Immunostimulants · CPC title

• A61K2039/55511

  Organic adjuvants · CPC title

• A61K31/4164

  1,3-Diazoles · CPC title

• A61K31/18

  Sulfonamides (compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63) · CPC title

• C12N2760/16134

  Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein · CPC title