# US 2022/0031776 A1 · Bacteriophage for modulating inflammatory bowel disease

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- Number: US 2022/0031776 A1
- Document ID: US20220031776A1
- Status: Published application
- Kind: A1
- Application number: 16/644,641
- Filed: 2018-09-07
- Published: 2022-02-03
- Earliest claimed: 2017-09-08
- Assignees: Keio University; Biomx Ltd.; Yeda Research and Development Co. Ltd. at the Weizmann Institute of Science
- Applicants: Keio University; BiomX Ltd.; Yeda Research and Development Co. Ltd. at the Weizmann Institute of Science
- Inventors: Kenya Honda; Koji Atarashi; Seiko Narushima; Eran Elinav; Rotem Sorek; Efrat Khabra; Hava Ben David; Eyal Weinstock; Sarah Pollock; Yulia Matiuhin; Naomi Zak
- Web page: https://patentgrep.com/patent/US20220031776A1

## CPC

- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 35/76: Viruses; Subviral particles; Bacteriophages
- C12N 7/00: Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00)
- C12N 2795/10021: Viruses as such, e.g. new isolates, mutants or their genomic sequences
- C12N 2795/10032: Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

Disclosed herein are bacteriophage compositions and therapeutic uses thereof. The disclosure also relates to bacteriophage that are capable of lysing Klebsiella bacterial strains, e.g., strains that are associated with inflammatory bowel disease, and thereby capable of modulating disease.

## Claims

### Claim 1

1) A pharmaceutical composition comprising at least two different lytic bacteriophage each selected from a different group, wherein the groups consist of:
a) KP2W-P0101, KP2W-P0102, KP2W-P0103, KP2W-P0104, KP2W-P0105, KP2W-P0106, KP2W-P0107, KP2W-P0108, KP2W-P0109, and any other lytic bacteriophage that has at least 83% homology as determined by BLAST to any of the foregoing bacteriophage in a) and is capable of lytic infection of KP2 or a KP2 mutant,
b) KP2M-P0201, KP2W-P0202, KP2M-P0203, KP2M-P0204, KP2M-P0205, KP2M-P0206, KP2M-P0207, KP2M-P0208, KP2M-P0209, KP2M-P0210, KP2M-P0211, KP2M-P0212, and any other lytic bacteriophage that has at least 85% homology as determined by BLAST to any of the foregoing bacteriophage in b) and is capable of lytic infection of KP2 or a KP2 mutant, and
c) KP2W-M0102, KP2W-M0103, KP2W-M0104, KP2M-M0105, KP2W-M0106, KP2W-M0107, KP2M-M0108, KP2M-M0109, KP2M-M0110, KP2M-M0111, KP2M-M0112, and any other lytic bacteriophage that has at least 86% homology as determined by BLAST to any of the foregoing bacteriophage in c) and is capable of lytic infection of KP2 or a KP2 mutant,
wherein the pharmaceutical composition is formulated for delivery to a mammalian intestine or formulated for delivery to a mammalian mouth.

### Claim 2 (depends on 1)

2) The composition of claim 1, comprising at least one bacteriophage selected from a)-c).

### Claim 3 (depends on 1)

3) The composition of claim 1, comprising:
a) KP2W-P0105 and KP2M-P0203,
b) KP2M-P0203 and KP2W-M0104,
c) KP2W-P0105 and KP2W-M0104,
d) KP2W-P0102 and KP2M-P0209,
e) KP2M-P0209 and KP2W-M0107,
f) KP2W-P0102 and KP2W-M0107,
g) KP2W-P0109 and KP2M-P0211,
h) KP2M-P0211 and KP2M-M0112,
i) KP2W-P0109 and KP2M-M0112,
j) KP2W-P0105 and KP2M-P0203 and KP2W-M0104,
k) KP2W-P0102 and KP2M-P0209 and KP2W-M0107,
l) KP2W-P0109 and KP2M-P0211 and KP2M-M0112,
m) KP2W-P0105 and KP2M-P0209 and KP2M-M0112,
n) KP2W-P0102 and KP2M-P0211 and KP2W-M0104, or
o) KP2W-P0109 and KP2M-P0203 and KP2W-M0107.

### Claim 4 (depends on 1)

4) The composition of claim 1, wherein the composition is formulated for delivery to the mammalian intestine.

### Claim 5 (depends on 1)

5) The composition of claim 1, formulated for delivery to the mammalian mouth.

### Claim 6 (depends on 1)

6) The composition of claim 1, wherein the composition is free of lytic bacteriophage that lyse any of Klebsiella pneumoniae strain ATCC BAA-2552 (KP1), KP3, ATCC 13882 (KP5), ATCC BAA-1705 (KP6), ATCC 700603 (KP7), and ATCC 700721 (KP8).

### Claim 7 (depends on 1)

7) The composition of claim 1, wherein the composition is free of lytic bacteriophage that lyse any of Klebsiella pneumoniae strain ATCC BAA-2552 (KP1), KP3, ATCC 23356 (KP4), ATCC 13882 (KP5), ATCC BAA-1705 (KP6), ATCC 700603 (KP7), and ATCC 700721 (KP8).

### Claim 8

8) A pharmaceutical composition comprising at least two different lytic bacteriophage, each selected from a different group, wherein the groups consist of:
a) KP3W-P0101, KP3W-P0102, KP3W-P0103, KP3W-P0104, KP3W-P0105, KP3W-P0106, KP3W-P0107, KP3W-P0108, KP3W-P0109, KP3W-P0110, KP3W-P0111, KP3W-P0112, KP3W-P0113, KP3W-P0114, and any other lytic bacteriophage that has at least 78% homology as determined by BLAST to any of the foregoing bacteriophage in a) and is capable of lytic infection of KP3 or a KP3 mutant,
b) KP3W-P0201, KP3W-P0202, KP3W-P0203, and any other lytic bacteriophage that has at least 96% homology as determined by BLAST to any of the foregoing bacteriophage in b) and is capable of lytic infection of KP3 or a KP3 mutant, and
c) KP3W-S0101, KP3W-S0102, and any other lytic bacteriophage that has at least 88% homology as determined by BLAST to any of the foregoing bacteriophage in c) and is capable of lytic infection of KP3 or a KP3 mutant,
wherein the pharmaceutical composition is formulated for delivery to a mammalian intestine or formulated for delivery to a mammalian mouth.

### Claim 9 (depends on 8)

9) The composition of claim 8, wherein the composition is formulated for delivery to the mammalian intestine.

### Claim 10 (depends on 8)

10) The composition of claim 8, formulated for delivery to the mammalian mouth.

### Claim 11 (depends on 8)

11) The composition of claim 8, wherein the composition is free of lytic bacteriophage that lyses any of Klebsiella pneumoniae strain ATCC BAA-2552 (KP1), KP2, ATCC 23356 (KP4), ATCC 13882 (KP5), ATCC BAA-1705 (KP6), ATCC 700603 (KP7), and ATCC 700721 (KP8).

### Claim 12

12) A pharmaceutical composition comprising at least two different lytic bacteriophage, wherein
a) at least one bacteriophage is selected from:
i) KP2W-P0101, KP2W-P0102, KP2W-P0103, KP2W-P0104, KP2W-P0105, KP2W-P0106, KP2W-P0107, KP2W-P0108, KP2W-P0109, any other lytic bacteriophage that has at least 83% homology to the foregoing bacteriophage of i) and is capable of lytic infection of KP2 or a KP2 mutant,
ii) KP2M-P0201, KP2W-P0202, KP2M-P0203, KP2M-P0204, KP2M-P0205, KP2M-P0206, KP2M-P0207, KP2M-P0208, KP2M-P0209, KP2M-P0210, KP2M-P0211, KP2M-P0212, and any other lytic bacteriophage that has at least 85% homology as determined by BLAST to any of the foregoing bacteriophage of ii) and is capable of lytic infection of KP2 or a KP2 mutant, and
iii) KP2W-M0102, KP2W-M0103, KP2W-M0104, KP2M-M0105, KP2W-M0106, KP2W-M0107, KP2M-M0108, KP2M-M0109, KP2M-M0110, KP2M-M0111, KP2M-M0112, any other lytic bacteriophage that has at least 86% homology as determined by BLAST to any of the foregoing bacteriophage of ii) and is capable of lytic infection of KP2 or a KP2 mutant, and
b) at least one bacteriophage is selected from:
i) KP3W-P0101, KP3W-P0102, KP3W-P0103, KP3W-P0104, KP3W-P0105, KP3W-P0106, KP3W-P0107, KP3W-P0108, KP3W-P0109, KP3W-P0110, KP3W-P0111, KP3W-P0112, KP3W-P0113, KP3W-P0114, and any other lytic bacteriophage that has at least 78% homology as determined by BLAST to any of the foregoing bacteriophage of i) and is capable of lytic infection of KP3 or a KP3 mutant,
ii) KP3W-P0201, KP3W-P0202, KP3W-P0203, and any other lytic bacteriophage that has at least 96% homology as determined by BLAST to any of the foregoing bacteriophage of ii) and is capable of lytic infection of KP3 or a KP3 mutant,
iii) KP3W-S0101, KP3W-S0102, and any other lytic bacteriophage that has at least 88% homology as determined by BLAST to any of the foregoing bacteriophage of iii) and is capable of lytic infection of KP3 or a KP3 mutant,
wherein the pharmaceutical composition is formulated for delivery to a mammalian intestine or formulated for delivery to a mammalian mouth.

### Claim 13 (depends on 12)

13) The composition of claim 12, wherein the composition is formulated for delivery to the mammalian intestine.

### Claim 14 (depends on 12)

14) The composition of claim 12, formulated for delivery to the mammalian mouth.

### Claim 15 (depends on 12)

15) The composition of claim 12, wherein the composition is free of lytic bacteriophage that lyses any of Klebsiella pneumoniae strain ATCC BAA-2552 (KP1), ATCC 13882 (KP5), ATCC BAA-1705 (KP6), ATCC 700603 (KP7), and ATCC 700721 (KP8).

### Claim 16 (depends on 12)

16) The composition of claim 12, formulated for oral or rectal dosing.

### Claim 17 (depends on 1)

17) A method of treating an inflammatory bowel disease comprising administering to a subject in need thereof a composition of claim 1.

### Claim 18 (depends on 17)

18) The method of claim 17, wherein the inflammatory bowel disease is ulcerative colitis.

### Claim 19 (depends on 17)

19) The method of claim 17, wherein the inflammatory bowel disease is Crohn's disease.

### Claim 20 (depends on 17)

20) The method of claim 17, wherein the inflammatory bowel disease is associated with proton pump inhibitor therapy.

### Claim 21 (depends on 17)

21) The method of claim 17, wherein the inflammatory bowel disease is associated with primary sclerosing cholangitis.

### Claim 22 (depends on 17)

22) The method of claim 17, wherein the subject is infected with a bacterium selected from KP2 and KP3.

### Claim 23 (depends on 17)

23) The method of claim 17, wherein the subject has been determined to be infected with a bacterium selected from KP2 and KP3.

### Claim 24 (depends on 23)

24) The method of claim 23, wherein the determination of the KP2 and/or KP3 infection is assayed by PCR.

### Claim 25 (depends on 1)

25) A method of treating an inflammatory bowel disease in a subject, comprising administrating the composition of claim 1 to a subject infected with a bacterium selected from KP2 and KP3, thereby treating the subject.

### Claim 26 (depends on 15)

26) The method of claim 15, wherein the composition is orally or rectally administered.

### Claim 27

27) A method of determining a subject to be treated with a KP2 bacteriophage, comprising the steps of:
a) obtaining a biological sample from the subject;
b) culturing bacteria obtained from the biological sample;
c) inoculating the cultured bacteria with a bacteriophage selected from one or more of:
i) KP2W-P0101, KP2W-P0102, KP2W-P0103, KP2W-P0104, KP2W-P0105, KP2W-P0106, KP2W-P0107, KP2W-P0108, KP2W-P0109, and any other lytic bacteriophage that has at least 83% homology as determined by BLAST to any of the foregoing bacteriophage of i) and is capable of lytic infection of KP2 or a KP2 mutant,
ii) KP2M-P0201, KP2W-P0202, KP2M-P0203, KP2M-P0204, KP2M-P0205, KP2M-P0206, KP2M-P0207, KP2M-P0208, KP2M-P0209, KP2M-P0210, KP2M-P0211, KP2M-P0212, and any other lytic bacteriophage that has at least 85% homology as determined by BLAST to any of the foregoing bacteriophage of ii) and is capable of lytic infection of KP2 or a KP2 mutant, and
iii) KP2W-M0102, KP2W-M0103, KP2W-M0104, KP2M-M0105, KP2W-M0106, KP2W-M0107, KP2M-M0108, KP2M-M0109, KP2M-M0110, KP2M-M0111, KP2M-M0112, and any other lytic bacteriophage that has at least 86% homology as determined by BLAST to any of the foregoing bacteriophage of iii) and is capable of lytic infection of KP2 or a KP2 mutant, and
d) determining whether the cultured bacteria are lysed by the bacteriophage,
wherein when any of the cultured bacteria are lysed by the bacteriophage, the subject is determined to be infected by KP2.

### Claim 28 (depends on 27)

28) The method of claim 27, wherein the determination of the KP2 infection is assayed by PCR.

### Claim 29

29) A method of determining a subject to be treated with a KP3 bacteriophage, comprising the steps of:
a) obtaining a biological sample from the subject;
b) culturing bacteria obtained from the biological sample;
c) inoculating the cultured bacteria with a bacteriophage selected from one or more of:
i) KP3W-P0101, KP3W-P0102, KP3W-P0103, KP3W-P0104, KP3W-P0105, KP3W-P0106, KP3W-P0107, KP3W-P0108, KP3W-P0109, KP3W-P0110, KP3W-P0111, KP3W-P0112, KP3W-P0113, KP3W-P0114, and any other lytic bacteriophage that has at least 78% homology as determined by BLAST to any of the foregoing bacteriophage of i) and is capable of lytic infection of KP3 or a KP3 mutant,
ii) KP3W-P0201, KP3W-P0202, KP3W-P0203, and any other lytic bacteriophage that has at least 96% homology as determined by BLAST to any of the foregoing bacteriophage of ii) and is capable of lytic infection of KP3 or a KP3 mutant, and
iii) KP3W-S0101, KP3W-S0102, and any other lytic bacteriophage that has at least 88% homology as determined by BLAST to any of the foregoing bacteriophage of iii) and is capable of lytic infection of KP3 or a KP3 mutant, d) determining whether the cultured bacteria are lysed by the bacteriophage, wherein when any of the cultured bacteria are lysed by the bacteriophage, the subject is determined to be infected by KP3.

### Claim 30 (depends on 29)

30) The method of claim 29, wherein the determination of the KP3 infection is assayed by PCR.