Methods for treating multidrug-resistant bacterial infections

Abstract

This disclosure relates to methods for treating multidrug-resistant bacterial infection disorders. In particular, this disclosure provides a BTN3A-activated antibody and the use of the antibody in the treatment of multidrug-resistant bacterial infection disorders in human subjects requiring treatment, such as disorders caused by multidrug-resistant Mycobacterium tuberculosis infection.

Claims

1. A BTN3A-activated antibody for use in treating multidrug-resistant bacterial infection disorders, preferably selected from multidrug-resistant Mycobacterium tuberculosis infections, in human subjects requiring treatment.

2. (i) When measured by flow cytometry assay, human PBMCs should contain 50 μg / ml or less, preferably 10 μg / ml or less EC ５０ Properties that are bonded together; (ii) When measured in vitro using a degranulation assay, the activation of γδ T cells, typically Vγ9Vδ2 T cells, in co-culture with BTN3A-expressing cells is less than 5 μg / ml, preferably 1 μg / ml or less EC ５０ The properties induced by; (iii) In vitro, as measured by a CFU (colony-forming unit) assay, the properties that induce activation of γδ T cells, typically Vγ9Vδ2 T cells, in co-culture with Mtb-infected macrophages or Mtb bacterial suspension; or (iv) Properties that induce activation of circulating γδ T cells, typically Vγ9Vδ2 T cells, in vivo. A BTN3A activating antibody for use according to claim 1, comprising one or more of the following:

3. A BTN3A activating antibody for use according to claim 1 or 2, comprising HCDR1 of SEQ ID NO: 5, HCDR2 of SEQ ID NO: 6 or 35-38 and HCDR3 of SEQ ID NO: 7, and LCDR1 of SEQ ID NO: 8, 39-40, LCDR2 of SEQ ID NO: 9 and LCDR3 of SEQ ID NO: 10, preferably comprising HCDR1-3 of SEQ ID NOs: 5-7 and LCDR1-3 of SEQ ID NOs: 8-10.

4. (i) Does it include HCDR1-3 of SEQ ID NOs. 11-13 and LCDR1-3 of SEQ ID NOs. 14-16? (ii) comprising a variable heavy chain (VH) polypeptide containing an amino acid sequence that is at least about 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1, and a variable light chain (VL) polypeptide containing an amino acid sequence that is at least about 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 2; (iii) A variable heavy chain (VH) polypeptide comprising an amino acid sequence that is at least approximately 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 3, and a variable light chain (VL) polypeptide comprising an amino acid sequence that is at least approximately 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:

4. A BTN3A activating antibody for use according to any one of claims 1 to 3, which is one of the following:

5. A BTN3A activating antibody for use according to any one of claims 1 to 4, comprising the variable heavy chain VH of SEQ ID NO: 1 and the variable light chain VL of SEQ ID NO:

2.

6. The BTN3A activating antibody for use according to any one of claims 1 to 5, wherein the BTN3A activating antibody comprises a mutant IgG1 constant region or a chemically modified IgG1 constant region, and the mutant IgG1 constant region or chemically modified IgG1 constant region completely eliminates or reduces binding to the Fcγ receptor compared to a corresponding antibody having a wild-type IgG1 isotype constant region, preferably the BTN3A activating antibody comprises a mutant IgG1 constant region which is an IgG1 triple mutant Fc having mutants L247F, L248E and P350S.

7. A BTN3A activating antibody for use according to any one of claims 1 to 6, comprising the heavy chain of SEQ ID NO: 23 and the light chain of SEQ ID NO:

24.

8. A BTN3A activating antibody for use according to any one of claims 1 to 7, administered in combination with at least one second therapeutic substance selected from antiviral agents, antibacterial agents, anti-inflammatory agents, cytokines, therapeutic cells and / or immune checkpoint inhibitors, either concurrently or sequentially.

9. A BTN3A-activated antibody for use according to any one of claims 1 to 8, preferably administered concurrently or separately with rifampicin, isoniazid, ethambutol, and pyrazinamide, for the treatment of disorders caused by multidrug-resistant bacterial infection by Mycobacterium tuberculosis.

10. A BTN3A activating antibody for use according to any one of claims 1 to 9, wherein the treatment reduces Vγ9Vδ2 T cells in the blood of the subject to treatment.

11. A BTN3A activated antibody for use according to any one of claims 1 to 10, for treating disorders caused by multidrug-resistant Mycobacterium tuberculosis infection, wherein the treatment (i) reduces the risk of relapse after discontinuation of treatment, (ii) enhances the effectiveness of standard treatment, (iii) shortens the duration of standard treatment, and / or (iv) prevents progression from latent tuberculosis to active tuberculosis.

12. A BTN3A-activated antibody for use according to any one of claims 1 to 11, for treating disorders caused by multidrug-resistant Mycobacterium tuberculosis infection, wherein the subject is a human subject having active tuberculosis disease.

13. A BTN3A-activated antibody for use according to any one of claims 1 to 12, for treating disorders caused by Mycobacterium tuberculosis infection that is resistant to at least isoniazid and rifampin.

14. A BTN3A activated antibody for use according to any one of claims 1 to 13, for treating disorders caused by methicillin-resistant Staphylococcus aureus, MDR Escherichia coli, MDR Pseudomonas aeruginosa, carbapenem-resistant Klebsiella pneumoniae, MDR Streptococcus pneumoniae, vancomycin-resistant Enterococci (Entrococcus faecium and Enterococcus faecalis).

15. A BTN3A-activated antibody for use according to any one of claims 1 to 14, preferably administered by intravenous infusion to a subject requiring treatment, preferably in a unit dose containing 0.1 mg to 1 g, for example, a dose containing 1 mg to 200 mg, preferably 2 to 6 times every 2 to 4 weeks.

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