Immune checkpoint blockade therapy for treating staphylococcus aureus infections

Abstract

This disclosure provides a method reducing the number of Staphylococcus aureus bacterial cells in a subject and a method of treating or preventing diseases or disorders caused by S. aureus. This disclosure also provides a method of diagnosis or prognosis of a disease or disorder caused by S. aureus.

Description

Abstract: This invention provides a method for reducing the number of Staphylococcus aureus cells in a subject, and a method for treating or preventing diseases or conditions caused by Staphylococcus aureus. This invention also provides a method for diagnosing or prognosing diseases or conditions caused by Staphylococcus aureus.

Claims

CLAIMSWhat is claimed is:

1. A method for reducing the number of cells of a pathogenic bacterium or a pathogenic fungus in a subject in need thereof, comprising administering to the subject an effective amount of an inhibitor of an inhibitory immune checkpoint molecule.

2. The method of claim 1, wherein the administered inhibitor inhibits an inhibitory immune checkpoint molecule selected from the group consisting of LAG-3, TIM-3, CTLA-4, PD-1, and PD-L1.

3. The method of claim 1 or 2, wherein the administered inhibitor comprises an antibody or antigen-binding fragment thereof, a small molecule, a protein, a polypeptide, a peptide, a peptide mimetic, a nucleic acid, an antisense molecule, a ribozyme, a RNAi molecule, a lipid, a lipopeptide, a carbohydrate, or a combination thereof.

4. The method of any one claims 1-3, wherein the administered inhibitor comprises an anti- LAG-3 antibody, an anti-TIM-3 antibody, an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-PD-Ll antibody, an antigen-binding fragment thereof, or a combination thereof.

5. The method of any one of claims 1-4, wherein the administered inhibitor comprises (i) an anti-LAG-3 antibody or an antigen-binding fragment thereof, (ii) a combination of an anti- PD-1 antibody or an antigen-binding fragment thereof and an anti-LAG-3 antibody or an antigen-binding fragment thereof, or (iii) a bispecific antibody that binds PD-1 and LAG-3.

6. The method of claim 5, wherein the administered anti-PD-1 antibody is nivolumab, the anti-LAG-3 antibody is relatlimab, or the bispecific antibody comprises an antigen binding fragment of nivolumab and an antigen binding fragment of relatlimab.

7. A method of diagnosis or prognosis of a disease or disorder caused by a pathogenic bacterium or a pathogenic fungus in a subject in need thereof, comprising: determining a level of each of a set of biomarkers in a sample from the subject, wherein the set of biomarkers comprises an inhibitory immune checkpoint molecule or a cytokine;determining a change in the level of each of the set of biomarkers as compared to a reference level for each of the set of biomarkers; and assessing the presence of the disease or disorder or a status of the disease or disorder based on the change in the level of each of the set of biomarkers as compared to the reference level for each of the set of biomarkers.

8. The method of claim 7, wherein the set of biomarkers comprises one or more of(a) LAG-3, PD-1, CTLA-4, TIM-3, IFNy, IL-2, TNFa, and IL-17; or(b) LAG-3 , TIM-3 , and CXCL 13.

9. The method of claim 7 or 8, wherein the set of biomarkers comprises: (a) TIM-3; (b) TIM-3 and LAG-3; (c) TIM-3 and CTLA-4; (d) TIM-3 and PD-1; (e) TIM-3 and IL- 17; (f) TIM-3, LAG-3, and PD-1; (g) TIM-3, LAG-3, and CTLA-4; (h) TIM-3, CTLA-4, and PD-1; (i) TIM-3, LAG-3, CTLA-4, and PD-1; (j) TIM-3, LAG-3, and IL- 17; (k) TIM-3, CTLA-4, and IL- 17; (1) TIM-3, PD-1, and IL- 17; (m) TIM-3, LAG-3, PD-1, and IL- 17; (n) TIM-3, LAG-3, CTLA-4, and IL- 17; (o) TIM-3, CTLA-4, PD-1, and IL- 17; or (p) TIM-3, LAG-3, CTLA-4, PD-1, and IL- 17.

10. The method of any one of claims 7-9, wherein the set of biomarkers comprises TIM-3, LAG-3, and CXCL13.

11. The method of any one of claims 7-10, wherein the sample is a bone marrow or PBMC sample.

12. The method of any one of claims 7-11, wherein the sample is a serum sample.

13. The method of any one of claims 7-12, wherein the change in the level of a set of biomarkers is an increase of an expression level of each of the biomarkers in the set.

14. A method of preventing, treating or ameliorating a disease or disorder caused by a pathogenic bacterium or a pathogenic fungus in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an inhibitor of an inhibitory immune checkpoint molecule.

15. A method of preventing, treating or ameliorating a disease or disorder caused by a pathogenic bacterium or a pathogenic fungus in a subject in need thereof, comprising administering a therapeutically effective amount of an inhibitor of an inhibitory immune checkpoint molecule, wherein the subject is determined to have a disease or disorder caused by the pathogenic bacterium or pathogenic fungus according to the method of any one of claims 7-10.

16. The method of any one of claims 7-15, wherein the disease or disorder comprises an infection.

17. The method of claim 16, wherein the infection is bacteremia, a bone infection, bone loss, osteomyelitis, biofilm formation, antimicrobial resistant infection, or sepsis.

18. The method of claim 16, wherein the infection is a prosthetic joint infection, a fracture related infection, a diabetic foot infection, a hematogenous osteomyelitis, or a spine infection.

19. The method of any one of claims 14-18, wherein the administered inhibitor inhibits an inhibitory immune checkpoint molecule selected from the group consisting of LAG-3, TIM-3, CTLA-4, PD-1, and PD-L1.

20. The method of any one of claims 14-19, wherein the administered inhibitor comprises an antibody or antigen-binding fragment thereof, a small molecule, a protein, a polypeptide, a peptide, a peptide mimetic, a nucleic acid, an antisense molecule, a ribozyme, a RNAi molecule, a lipid, a lipopeptide, a carbohydrate, or a combination thereof.

21. The method of any one of claims 14-20, wherein the administered inhibitor comprises an anti-LAG-3 antibody, an anti-TIM-3 antibody, an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-PD-Ll antibody, an antigen-binding fragment thereof, or a combination thereof.

22. The method of any one of claims 14-21, wherein the administered inhibitor comprises (i) an anti-LAG-3 antibody or an antigen-binding fragment thereof, (ii) a combination of an anti- PD-1 antibody or an antigen-binding fragment thereof and an anti-LAG-3 antibody or an antigen-binding fragment thereof, or (iii) a bispecific antibody that binds PD-1 and LAG-3.

23. The method of claim 22, wherein the anti-PD-1 antibody is nivolumab, the anti -LAG-3 antibody is relatlimab, or the bispecific antibody is an anti-PD-1 and anti-LAG-3 bispecific antibody (e.g., a bispecific antibody comprising an antigen binding fragment of nivolumab and an antigen binding fragment of relatlimab).

24. The method of any one of claims 1-6 and 14-23, which further comprises administering to the subject an additional therapeutic agent.

25. The method of claim 24, wherein the additional therapeutic agent comprises a second inhibitor of a second inhibitory immune checkpoint molecule, an antibiotic, an antipathogen antibody specific for the pathogenic bacterium or pathogenic fungus, or a combination thereof.

26. The method of claim 25, wherein the additional administered therapeutic agent is one selected from the group consisting of (1) an antipathogen antibody that specifically binds to Staphylococcus aureus,' (2) a second inhibitory immune checkpoint molecule selected from the group consisting of LAG-3, TIM-3, CTLA-4, PD-1, and PD-L1; and (3) an antibiotic having an anti-bacterial activity against Staphylococcus aureus,' or a combination thereof.

27. The method of claim 26, wherein the additional administered therapeutic agent comprises an anti-LAG-3 antibody, an anti-TIM-3 antibody, an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-PD-Ll antibody, or a combination thereof.

28. The method of any one of claims 24-27, wherein the additional therapeutic agent is administered concurrently, or before, or after with the inhibitor.

29. The method of claim 24 or 28, wherein the inhibitor and the additional therapeutic agent are contained in the same composition.

30. The method of any one of claims 24-29, wherein the inhibitor and / or the additional therapeutic agent is administered to the subject intratumorally, intravenously, subcutaneously, intraosseously, orally, transdermally, in sustained release, in controlled release, in delayed release, as a suppository, or sublingually.

31. The method of any one of claims 7-30, wherein the subject has received or is about to receive a surgery or an implant.

32. The method of any one of claims 7-31, wherein the subject has received surgery.

33. The method of any one of claims 7-31, wherein the subject is about to receive surgery.

34. The method of any one of claims 31-33, wherein the surgery is selected from the group consisting of orthopedic surgery, cardiothoracic surgery, plastic surgery, neurosurgery, oral surgery, total joint replacement, open reduction internal fixation (ORIF), debridement for open fracture, spine surgery, median sternotomy, revision total joint, revision ORIF, drainage of soft tissue abscess, and organ transplantation surgery.

35. The method of any one of claims 31, 32 or 34, wherein the subject has received an implant.

36. The method of any one of claims 31, or 33, wherein the subject is about to receive an implant.

37. The method of any one of claims 31-36, wherein the subject has received or is about to receive an orthopedic implant.38 The method of any one of claims 1-37, wherein the bacterium is selected from the group consisting of Staphylococcus aureus, S. epidermidis, S. lugdunensis, Cutibacterium acnes, Group B Streptococcus, and Enterobacteria.

39. The method of claim 38, wherein the Staphylococcus aureus is methicillin-resistant Staphylococcus aureus (MRS A) or methicillin-susceptible Staphylococcus aureus (MS SA).

40. The method of any one of claims 1-39, wherein the subject is a mammal.

41. The method of any one of claims 1-40, wherein the mammal is a human.

42. The method of any one of claims 1-6 and 14-41, wherein prior to the administration of the inhibitor, the subject is determined to have:(i) an elevated serum titer of soluble TIM-3 compared to a previously measured TIM-3 serum titer for the subject,(ii) a serum titer of soluble TIM-3 higher than that in healthy control subjects, or(iii) a serum titer of soluble TIM-3 is at least 2100, 2200, 2300, 2400, 2500, or 3000 pg / ml.

43. The method of claim 42, wherein the subject is administered the inhibitor prior to surgery or receiving an implant.

44. The method of claim 42, wherein the subject is administered the inhibitor after a surgery or receiving an implant.

45. The method of claim 43 or 44, wherein the subject has received surgery or implant within 1 week, 2 weeks, 3 weeks, 1 month 3 months, 6 months, 12 months, or 18 months after the administration of the inhibitor of the inhibitory immune checkpoint molecule.

46. The method of any one of claims 43-45, wherein the surgery is selected from the group consisting of orthopedic surgery, cardiothoracic surgery, plastic surgery, neurosurgery, oral surgery, total joint replacement, open reduction internal fixation (ORIF), debridement for open fracture, spine surgery, median sternotomy, revision total joint, revision ORIF, drainage of soft tissue abscess, or organ transplantation surgery.

47. The method of any one of claims 42-46, wherein the serum titer of soluble TIM-3 in the subject is determined to be at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% (2 fold) higher in the subject than that in healthy control subjects.

48. The method of any one of claims 1-6 and 14-41, wherein prior to the administration of the inhibitor, the subject is determined to have:(i) an elevated serum titer of soluble LAG-3 compared to a previously measured LAG- 3 serum titer for the subject,(ii) a serum titer of soluble LAG-3 higher than that in healthy control subjects, or(iii) a serum titer of soluble LAG-3 at least 80000, 85000, 90000, 95000, or 100000 pg / ml.

49. The method of any one of claim 47, wherein the serum titer of soluble LAG-3 in the subject is determined to be at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% (2 fold) higher in the subject than that in healthy control subjects.

50. The method of any one of claims 1-6 and 14-41, wherein prior to the administration of the inhibitor, the subject is determined to have:(i) an elevated serum titer of CXCL13 compared to a previously measured CXCL13 serum titer for the subject,(ii) a serum titer of CXCL13 higher than that in healthy control subjects, or(iii) a serum titer of CXCL13 is at least 50, 55, 60, 65, 70, or 75 pg / ml.

51. The method of any one of claims 1-6 and 14-41, wherein prior to the administration of the inhibitor the subject is determined to have:(a)(i) an elevated serum titer of CXCL13 compared to a previously measured CXCL13 serum titer for the subject,(ii) a serum titer of CXCL13 higher than that in healthy control subjects, or(iii) a serum titer of CXCL13 is at least 50, 55, 60, 65, 70, or 75 pg / ml; and / or(b) (i) an elevated serum titer of soluble TIM-3 compared to a previously measured TIM-3 serum titer for the subject,(ii) a serum titer of soluble TIM-3 higher than that in healthy control subjects, or(iii) a serum titer of soluble TIM-3 is at least 2100, 2200, 2300, 2400, 2500, or 3000 pg / ml; and / or(c) (i) an elevated serum titer of soluble LAG-3 compared to a previously measured LAG-3 serum titer for the subject,(ii) a serum titer of soluble LAG-3 higher than that in healthy control subjects, or(iii) a serum titer of soluble LAG-3 is at least 80000, 85000, 90000, 95000, or 100000 pg / ml; or any combination of (a)-(c).

52. The method of any one of claims 48-51 wherein the subject is administered the inhibitor prior to surgery or receiving an implant.

53. The method of any one of the previous claims, wherein the administered LAG-3 antibody or antigen-binding fragment thereof is an antibody or antigen-binding fragment of an antibody selected from the group consisting of BMS 986016, MK-4280 (28G-10),REGN3767, GSK2831781, IMP731 (H5L7BW), BAP050, IMP-701 (LAG-5250), TSR-033, LAG525, BI754111, and FS-118.

54. The method of any one of the previous claims, wherein the administered TIM- inhibitor is an antibody or antigen-binding fragment of an antibody selected from the group consisting of TSR-022, LY3321367, EPZ005687, and DZNep.

55. The method of any one of the previous claims, wherein the administered inhibitor further comprises a TIGIT inhibitor.

56. The method of claim 55, wherein the administered inhibitor is a TIGIT antibody or an antigen-binding fragment thereof.

57. The method of claim 56, wherein the administered TIGIT inhibitor is an antibody or antigen-binding fragment of an antibody selected from the group consisting of BMS-986207, AB154, COM902 (CGEN-15137), or OMP-313M32.

58. The method of any one of the previous claims, wherein the administered PD-1 inhibitor is an antibody or antigen-binding fragment of an antibody selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, nivolumab, PDR001, MEDI0680 (AMP-514), TSR-042, REGN2810, JSOOI, AMP-224 (GSK-2661380), PF- 06801591, BGB-A317, BI754091, and SHR-1210.

59. The method of any one of the previous claims, wherein the administered PD-L1 inhibitor is an antibody or antigen-binding fragment of an antibody selected from the group consisting of atezolizumab, durvalumab, BMS-936559, avelumab, LY3300054, CX-072 (Proclaim-CX-072), FAZ053, KN035, MPDL3280A, MEDI4736, MSB0010718C and MDX-1105.

60. The method of any one of the previous claims, wherein the administered inhibitor is a small molecule selected from the group consisting of BMS-8, BMS-37, BMS-202, BMS-230, BMS-242, BMS-1001, BMS-1166, SB415286, JQI, and I-BET151.

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