Tlr8 agonist for modulating immune response

Patent metadata

Field	Value
Publication number	US-2025041278-A1
Application number	US-202218696547-A
Country	US
Kind code	A1
Filing date	Sep 29, 2022
Priority date	Sep 30, 2021
Publication date	Feb 6, 2025
Grant date	—

Abstract

Provided herein are uses for an immunostimulatory compound for stimulating an immune response when administered either alone or as an adjuvant in a vaccine. Also provided herein are kits, compositions, and methods of administration for the compound described for proliferative disease, inflammatory disease, autoimmune disease, infectious disease, or chronic disease, in a subject in need thereof. Using the compound as a vaccine adjuvant enables effective immunization in vulnerable populations.

First claim

What is claimed is:

1 . A method of enhancing an immune response in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I):

2 . A method of treating a disease or reducing the risk of a disease, the method comprising administering to a subject in need thereof an effective amount of a compound of Formula (I):

3 . The method of claim 1 , wherein the immune response is an innate immune response.

4 . The method of claim 1 , wherein the immune response is an adaptive immune response.

5 . The method of any one of claims 1, 3, or 4 , wherein the immune response is a cell-mediated immune response.

6 . The method of any one of claims 1, 3, 4, or 5 , wherein the immune response is a heterologous immune response.

7 . The method of any one of claims 1-4 , wherein the compound is adsorbed onto alum.

8 . The method of any one of claims 1-7 , wherein the compound is lipidated.

9 . The method of any one of claims 1-8 , wherein the compound is in an aqueous formulation.

10 . The method of any one of claims 1-8 , wherein the compound is in an emulsion formulation and/or a nanoparticle formulation.

11 . The method of any one of claims 1-9 , wherein the compound is administered to the subject more than once.

12 . The method of any one of claims 1-11 , wherein the subject has or is at risk of developing an infectious disease.

13 . The method of claim 12 , wherein the infectious disease is caused by a bacterium, a mycobacterium, a fungus, a virus, a parasite, or a prion.

14 . The method of claim 11 or claim 13 , wherein the infectious disease is sepsis.

15 . The method of any one of claims 1-11 , wherein the subject has or is at risk of developing cancer.

16 . The method of claim 15 , wherein the cancer is metastatic cancer.

17 . The method of claim 15 or claim 16 , wherein the cancer is a hematological cancer, lung cancer, breast cancer, brain cancer, gastrointestinal cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, ovarian cancer, testicular cancer, prostate cancer, endometrial cancer, muscle cancer, bone cancer, neuroendocrine cancer, connective tissue cancer, head and neck cancer, or skin cancer.

18 . The method of any one of claims 1-11 , wherein the subject has or is at risk of developing an allergy.

19 . The method of any one of claims 1-11 , wherein the subject has a radiation injury.

20 . The method of any one of claims 1-19 , wherein the subject is immune-senescent, immune-compromised, is infected with human immunodeficiency virus (HIV), has chronic lung disease, asthma, cardiovascular disease, cancer, a metabolic disorder, chronic kidney disease, liver disease, is malnourished, or is frail.

21 . The method of any one of claims 1-20 , wherein the administration is systemic or local.

22 . The method of any one of claims 1-21 , wherein the administration is intramuscular, intradermal, oral, intravenous, topical, intranasal, intravaginal, or sublingual.

23 . The method of any one of claims 1-22 , wherein the administration is prophylactic.

24 . The method of any one of claims 1-23 , wherein the subject is a human neonate, an infant, an adult, or an elderly individual.

25 . The method of claim 24 , wherein the subject is a human adult.

26 . The method of claim 24 , wherein the subject is an elderly human.

27 . The method of claim 26 , wherein the administration occurs when the subject is more than 65 years of age.

28 . The method of any one of claims 1-23 , wherein the subject is a companion animal or a research animal.

29 . The method of claim 28 , wherein the subject is an adult or elderly companion animal.

30 . The method of any one of claims 1-29 , wherein the compound activates peripheral blood mononuclear cells (PBMCs).

31 . The method of claim 30 , wherein the PBMCs are macrophages or dendritic cells.

32 . The method of any one of claims 1-31 , wherein the compound induces a T helper type 1 (Th1) immune response.

33 . The method of any one of claims 1-32 , wherein the compound induces the production of a signaling molecule selected from a proinflammatory or Th-polarizing cytokine or chemokine in the subject.

34 . The method of claim 33 , wherein the signaling molecule is a cytokine selected from TNF, IL-6, IL-10, IL-12 p40, IL-12 p70, GM-CSF, IFN-7, IFN-α2, IL1-β and/or IP-10, a chemokine selected from CCL2 (MCP1), CCL3, CCL5, and/or CXCL8 (IL-8), or a combination thereof.

35 . The method of any one of claims 1-34 , wherein the compound of enhances humoral immunity.

36 . The method of any one of claims 1-35 , wherein the compound induces the production of an immunoglobulin in the subject.

37 . The method of claim 36 , wherein the immunoglobulin is an immunoglobulin G (IgG), immunoglobulin A (IgA), or immunoglobulin M (IgM).

38 . The method of claim 37 , wherein the IgG is a subclass 1 IgG (IgG1) or a subclass 2 IgG (IgG2).

39 . A composition comprising an antigen and a compound of Formula (I):

40 . The composition of claim 39 , wherein the antigen comprises a protein or polypeptide.

41 . The composition of claim 39 or claim 40 , wherein the antigen comprises a nucleic acid encoding a protein or a polypeptide.

42 . The composition of claim 41 , wherein the nucleic acid is DNA or RNA.

43 . The composition of any one of claims 39-42 , wherein the antigen is from a microbial pathogen.

44 . The composition of claim 43 , wherein the microbial pathogen is a bacterium, mycobacterium, fungus, virus, parasite, or prion.

45 . The composition of claim 44 , wherein the bacterium is Bacillus anthracis, Bordetella pertussis, Corynebacterium diphtheriae, Clostridium tetani, Haemophilus influenzae type b, pneumococcus, Staphylococci spp., Streptococcus spp., Mycobacterium spp., Neiserria spp., Salmonella typhi, Vibrio cholerae , or Yersinia pestis.

46 . The composition of claim 44 , wherein the virus is an adenovirus, a coronavirus, an enterovirus such as polio virus, dengue virus, Ebola virus, a herpes viruses such as herpes simplex virus, cytomegalovirus and varicella-zoster, measles, mumps, rubella, hepatitis A virus, hepatitis B virus, hepatitis C virus, human papilloma virus, Influenza virus, rabies, Japanese encephalitis, rotavirus, human immunodeficiency virus (HIV), respiratory syncytial virus (RSV), smallpox, yellow fever, dengue virus, or Zika virus.

47 . The composition of claim 46 , wherein the coronavirus virus is Middle East Respiratory Syndrome coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome (SARS)-associated coronavirus (SARS-CoV)-1, or SARS-CoV-2.

48 . The composi

Assignees

• Childrens Medical Ct Corp

Inventors

• Dowling David J
• Levy Ofer
• Van Haren Simon D
• Chew Katherine
• Soni Dheeraj
• De Leon Maria

Classifications

• A61K2039/55572

  Lipopolysaccharides; Lipid A; Monophosphoryl lipid A · CPC title

• A61K2039/55511

  Organic adjuvants · CPC title

• A61K39/39 Primary

  characterised by the immunostimulating additives, e.g. chemical adjuvants · CPC title

• A61P31/14

  for RNA viruses · CPC title

• A61P37/04

  Immunostimulants · CPC title