# US 2019/0167680 A1 · Inhibition of JAK-STAT Signaling Inhibits Formation of Neutrophil Extracellular Traps (NETs)

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- Number: US 2019/0167680 A1
- Document ID: US20190167680A1
- Status: Published application
- Kind: A1
- Application number: 16/209,698
- Filed: 2018-12-04
- Published: 2019-06-06
- Earliest claimed: 2017-12-04
- Assignees: The Brigham and Women's Hospital, Inc.; Children's Medical Center Corporation
- Applicants: The Brigham and Women`s Hospital, Inc.; Children's Medical Center Corporation
- Inventors: Rob Sellar; Benjamin Ebert; Ofir Wolach; Kim Martinod; Denisa Wagner
- Web page: https://patentgrep.com/patent/US20190167680A1

## CPC

- A61K 31/506: not condensed and containing further heterocyclic rings
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C12Q 1/485: {involving kinase}
- C12Q 1/6869: Methods for sequencing
- C12Q 1/6876: Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q 1/6883: for diseases caused by alterations of genetic material
- C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
- C12Q 2600/156: Polymorphic or mutational markers
- C12Q 2600/158: Expression markers
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES

## Abstract

The methods described herein include methods for the treatment of subjects who have Clonal Hematopoiesis of Indeterminate Potential (CHIP) or a Philadelphia-negative myeloproliferative neoplasm (MPN), e.g., polycythaemia vera (PV) or essential thrombocythaemia (ET), using inhibitors of JAK-STAT signaling.

## Claims

### Claim 1

A method of reducing risk of recurrence of a cardiovascular event in a subject who has had at least one cardiovascular event, the method comprising:
identifying a subject who has had at least one cardiovascular event;
determining the JAK2 genotype of the subject;
selecting a subject who has a Jak2V617F genotype; and
administering to the subject an effective amount of an inhibitor of JAK-STAT signaling.

### Claim 2 (depends on 1)

The method of claim 1, wherein the subject has cancer, an autoimmune disease, Clonal Hematopoiesis of Indeterminate Potential (CHIP) or a Philadelphia-negative myeloproliferative neoplasm (MPN).

### Claim 3 (depends on 2)

The method of claim 2, wherein the MPN is polycythaemia vera (PV) or essential thrombocythaemia (ET).

### Claim 4 (depends on 1)

The method of claim 1, wherein the cardiovascular event is thrombosis or myocardial infarction (MI).

### Claim 5 (depends on 1)

The method of claim 1, wherein determining the JAK2 genotype of the subject comprises determining a sequence of a portion of the subject's genome comprising a sequence encoding amino acid 617 of JAK2, and determining whether the sequence encodes a valine or a phenylalanine.

### Claim 6 (depends on 5)

The method of claim 5, wherein determining a sequence of a portion of the subject's genome comprises amplifying and/or sequencing a portion of the subject's genome comprising SEQ ID NO:1, and determining the identity of the nucleotide at position 26 of SEQ ID NO:1, and/or using a probe that hybridizes to the nucleotide at position 26 of SEQ ID NO:1.

### Claim 7 (depends on 1)

The method of claim 1, wherein the inhibitor of JAK-STAT signaling is selected from the group consisting of Tofacitinib (CP690,550); Baricitinib (INCB028050);
Ruxolitinib (INCB018424); TG101348 (SAR302503); Lestaurtinib (CEP-701);
AZD1480; R348; VX-509; GLPG0634; GSK2586184; AC-430; Pacritinib (SB1518); NS-018; CHZ868; INCB039110; Filgotinib (G-146034, GLPG-0634); Cerdulatinib (PRT062070); Gandotinib (LY-2784544); Momelotinib (GS-0387, CYT-387); PF-04965842); Upadacitinib (ABT-494); Peficitinib (ASP015K, JNJ-54781532); Fedratinib (SAR302503); and BMS-911543.

### Claim 8

A method of reducing risk of occurrence or recurrence of a cardiovascular event in a subject, optionally a subject who has Clonal Hematopoiesis of Indeterminate Potential (CHIP), the method comprising administering to the subject an effective amount of an inhibitor of JAK-STAT signaling.

### Claim 9 (depends on 8)

The method of claim 8, wherein the cardiovascular event is thrombosis or myocardial infarction (MI).

### Claim 10 (depends on 8)

The method of claim 8, further comprising determining the JAK2 genotype of the subject; and selecting a subject who has a Jak2V617F genotype.

### Claim 11 (depends on 10)

The method of claim 10, wherein determining the JAK2 genotype of the subject comprises determining a sequence of a portion of the subject's genome comprising a sequence encoding amino acid 617 of JAK2, and determining whether the sequence encodes a valine or a phenylalanine.

### Claim 12 (depends on 11)

The method of claim 11, wherein determining a sequence of a portion of the subject's genome comprises amplifying and/or sequencing a portion of the subject's genome comprising SEQ ID NO:1, and determining the identity of the nucleotide at position 26 of SEQ ID NO:1, and/or using a probe that hybridizes to the nucleotide at position 26 of SEQ ID NO:1.

### Claim 13 (depends on 8)

The method of claim 8, wherein the inhibitor of JAK-STAT signaling is selected from the group consisting of Tofacitinib (CP690,550); Baricitinib (INCB028050);
Ruxolitinib (INCB018424); TG101348 (SAR302503); Lestaurtinib (CEP-701);
AZD1480; R348; VX-509; GLPG0634; GSK2586184; AC-430; Pacritinib (SB1518); NS-018; CHZ868; INCB039110; Filgotinib (G-146034, GLPG-0634);
Cerdulatinib (PRT062070); Gandotinib (LY-2784544); Momelotinib (GS-0387, CYT-387); PF-04965842); Upadacitinib (ABT-494); Peficitinib (ASP015K, JNJ-54781532); Fedratinib (SAR302503); and BMS-911543.

### Claim 14

A method of inhibiting formation of NETs in a subject, the method comprising administering to the subject an effective amount of a JAK-STAT inhibitor.

### Claim 15 (depends on 14)

The method of claim 14, for reducing NETosis, or reducing the risk of NETosis-related conditions.

### Claim 16 (depends on 14)

The method of claim 14, wherein the subject is healthy.

### Claim 17 (depends on 14)

The method of claim 14, wherein the subject has an autoimmune disease, atherosclerosis; cancer; Clonal Hematopoiesis of Indeterminate Potential (CHIP);
or a Philadelphia-negative myeloproliferative neoplasm (MPN).

### Claim 18 (depends on 17)

The method of claim 17, wherein the autoimmune disease is Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Systemic lupus erythematosus (SLE), Rheumatoid Arthritis (RA), psoriasis, Antiphospholipid syndrome (APS), multiple sclerosis (MS), dermatomyositis (DM), polymyositis (PM), and IgG4-related autoimmune pancreatitis (AIP), or a Drug-Induced Autoimmune Disease.

### Claim 19 (depends on 17)

The method of claim 17, wherein the MPN is polycythaemia vera (PV) or essential thrombocythaemia (ET).

### Claim 20 (depends on 14)

The method of claim 14, wherein the inhibitor of JAK-STAT signaling is selected from the group consisting of Tofacitinib (CP690,550); Baricitinib (INCB028050);
Ruxolitinib (INCB018424); TG101348 (SAR302503); Lestaurtinib (CEP-701);
AZD1480; R348; VX-509; GLPG0634; GSK2586184; AC-430; Pacritinib (SB1518); NS-018; CHZ868; INCB039110; Filgotinib (G-146034, GLPG-0634);
Cerdulatinib (PRT062070); Gandotinib (LY-2784544); Momelotinib (GS-0387, CYT-387); PF-04965842); Upadacitinib (ABT-494); Peficitinib (ASP015K, JNJ-54781532); Fedratinib (SAR302503); and BMS-911543.