# US 9,518,300 B2 · Composition and method for treating a hematological malignancy

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- Number: US 9,518,300 B2
- Document ID: US9518300B2
- Status: Granted
- Kind: B2
- Application number: 14/686,036
- Filed: 2015-04-14
- Published: 2015-11-05
- Granted: 2016-12-13
- Earliest claimed: 2014-04-14
- Assignees: Dana-Farber Cancer Institute, Inc.
- Applicants: Dana-Farber Cancer Institute, Inc.
- Inventors: Ruben Carrasco; Jianjun Zhao
- Web page: https://patentgrep.com/patent/US9518300B2

## CPC

- C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575)
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/145: {with organic compounds}
- A61K 31/663: Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
- A61K 31/7105: Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
- A61K 31/711: Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- C12N 15/1135: {against oncogenes or tumor suppressor genes}
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/141: MicroRNAs, miRNAs
- C12N 2310/321: 2'-O-R Modification
- C12N 2320/31: Combination therapy
- C12Q 2600/118: Prognosis of disease development
- C12Q 2600/178: miRNA, siRNA or ncRNA
- 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
- 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

Provided are compositions and methods for treating hematological malignancies, such as multiple myeloma, in a subject by increasing levels or activity of miR-30 RNA in plasma cells of the subject.

## Claims

### Claim 1

A method for inhibiting BCL9 expression in a population of B cells in a first subject, the method comprising administering to the first subject a therapeutically effective amount of an agent comprising an miR-30 polynucleotide, wherein the population of B cells have a higher amount of BCL9 RNA or protein than a corresponding population of B cells from a second subject and wherein the second subject does not have multiple myeloma.

### Claim 2 (depends on 1)

The method of claim 1, wherein the administration of the agent decreases the amount of BCL9 RNA or protein in the population of B cells.

### Claim 3 (depends on 1)

The method of claim 1, wherein the population of B cells are sensitive to inhibition of a Wnt signaling pathway.

### Claim 4 (depends on 1)

The method of claim 1, wherein the miR-30 polynucleotide comprises a ribonucleic acid.

### Claim 5 (depends on 1)

The method of claim 1, wherein the miR-30 polynucleotide comprises a deoxyribonucleic acid.

### Claim 6 (depends on 1)

The method of claim 1, wherein the miR-30 polynucleotide comprises one or more non-naturally occurring polynucleotides.

### Claim 7 (depends on 6)

The method of claim 6, wherein the non-naturally occurring nucleotide is a 2′-O-methyl oligoribonucleotide.

### Claim 8 (depends on 1)

The method of claim 1, wherein the miR-30 polynucleotide comprises a polynucleotide that hybridizes specifically to one or more sequence motifs selected from the group consisting of SEQ ID NOs: 33 and 34.

### Claim 9 (depends on 1)

The method of claim 1, wherein the miR-30 polynucleotide comprises a motif having the nucleic acid sequence of SEQ ID NO: 36.

### Claim 10 (depends on 1)

The method of claim 1, wherein the miR-30 polynucleotide comprises a polynucleotide comprising one or more sequences selected from the group consisting of SEQ ID NOs: 1-5.

### Claim 11 (depends on 1)

The method of claim 1, wherein the agent further comprises a nanoparticle.

### Claim 12 (depends on 1)

The method of claim 1, wherein the agent further comprises a lipid.

### Claim 13 (depends on 11)

The method of claim 11, wherein the nanoparticle is a lipid nanoparticle.

### Claim 14 (depends on 1)

The method of claim 1, wherein the agent further comprises a viral vector.

### Claim 15 (depends on 14)

The method of claim 14, wherein the viral vector is a lentiviral vector, an adenoviral vector, an adeno-associated viral vector, or a retroviral vector.

### Claim 16 (depends on 1)

The method of claim 1, wherein the agent further comprises a plasmid.

### Claim 17 (depends on 1)

The method of claim 1, wherein the agent is administered intravenously or subcutaneously.

### Claim 18 (depends on 1)

The method of claim 1, wherein the subject has or is at risk for monoclonal Gammopathy of Undetermined Significance (MGUS), smoldering myeloma, asymptomatic MM, or symptomatic MM.

### Claim 19 (depends on 18)

The method of claim 18, wherein the symptomatic MM is newly diagnosed MM.

### Claim 20 (depends on 18)

The method of claim 18, wherein the symptomatic MM is late stage relapsed/refractory MM.

### Claim 21 (depends on 1)

The method of claim 1, further comprising administering an additional anti-cancer therapy to the subject.

### Claim 22 (depends on 21)

The method of claim 21, wherein the additional anti-cancer therapy is selected from the group consisting of surgery, chemotherapy, radiation, hormone therapy, immunotherapy, and a combination thereof.

### Claim 23 (depends on 21)

The method of claim 21, wherein the additional anti-cancer therapy reduces bone absorption.

### Claim 24 (depends on 21)

The method of claim 21, wherein the additional anti-cancer therapy reduces osteoclast mediated bone resorption.

### Claim 25 (depends on 23)

The method of claim 23, wherein the additional anti-cancer therapy is a bisphosphonate.

### Claim 26 (depends on 1)

The method of claim 1, wherein the subject is a human.

### Claim 27

A method of reducing proliferation, survival, migration, or colony formation ability of multiple myeloma cells in a subject with multiple myeloma, the method comprising administering to the subject a therapeutically effective amount of an agent comprising an miR-30 polynucleotide, wherein the multiple myeloma cells have a higher amount of BCL9 RNA or protein than normal plasma cells.

### Claim 28

A method of inhibiting metastasis of multiple myeloma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising an miR-30 polynucleotide, wherein the multiple myeloma cells have a higher amount of BCL9 RNA or protein than normal plasma cells.

### Claim 29

A method of treating a hematological malignancy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent comprising an miR-30 polynucleotide, wherein the hematological malignant cells have a higher amount of BCL9 RNA or protein than normal hematological cells.

### Claim 30 (depends on 29)

The method of claim 29, wherein the hematological malignancy is selected from the group consisting of myelodysplastic syndrome, Hodgkin's lymphoma, chronic lymphocytic leukemia, and B cell lymphoma.

### Claim 31 (depends on 9)

The method of claim 9, wherein the miR-30 polynucleotide comprises insertion, deletion or substitution of one or more nucleotides in a sequence selected from the group consisting of SEQ ID NOs: 1-5.