# US 11,077,133 B2 · Methods and compositions for treating cancers and enhancing therapeutic immunity by selectively reducing immunomodulatory M2 monocytes

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- Number: US 11,077,133 B2
- Document ID: US11077133B2
- Status: Granted
- Kind: B2
- Application number: 16/711,470
- Filed: 2019-12-12
- Published: 2020-06-25
- Granted: 2021-08-03
- Earliest claimed: 2015-04-10
- Assignees: Thomas Jefferson University
- Applicants: Thomas Jefferson University
- Inventors: David W. Andrews; Douglas C. Hooper
- Web page: https://patentgrep.com/patent/US11077133B2

## CPC

- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 31/7125: Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 35/00: Antineoplastic agents
- A61P 37/04: Immunostimulants
- C12N 15/1138: {against receptors or cell surface proteins}
- C12N 2310/11: Antisense
- C12N 2310/315: Phosphorothioates
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The present disclosure provides pharmaceutical compositions comprising nucleic acids capable of targeting IGF-1R expression in M2 cells. The present disclosure also provides methods for the selective reduction of M2 cells by targeting expression of IGF-1R in these cells. The present disclosure further provides methods for treating cancer and enhancing therapeutic by targeting expression of IGF-1R in M2 cells in patients. The pharmaceutical composition of the present invention is effective when administered systemically to subjects in need thereof. The ease of administration of the pharmaceutical composition facilitates treatment and enhances patient compliance.

## Claims

### Claim 1

A method for treating cancer in a subject in need thereof, the method comprising:
systemically administering to the subject an effective amount of a pharmaceutical composition comprising a first Insulin-like Growth Factor-1 Receptor antisense oligonucleotide (IGF-1R AS ODN), wherein the sequence of the first IGF-1R AS ODN is SEQ ID NO: 1, and wherein the first IGF-1R AS ODN has a modified phosphate backbone; and
administering to the subject at least one biodiffusion chamber, the chamber comprising tumor cells and a second IGF-1R AS ODN, wherein the sequence of the second IGF-1R AS ODN is SEQ ID NO:1, and wherein the second IGF-1R AS ODN has a modified phosphate backbone.

### Claim 2 (depends on 1)

The method of claim 1, wherein the biodiffusion chamber is administered to the subject prior to systemically administering the pharmaceutical composition.

### Claim 3 (depends on 1)

The method of claim 1, wherein the biodiffusion chamber is administered to the subject subsequent to systemically administering the pharmaceutical composition.

### Claim 4 (depends on 1)

The method of claim 1, wherein the tumor cells and the second IGF-1R AS ODN are each irradiated.

### Claim 5 (depends on 1)

The method of claim 1, wherein the biodiffusion chamber is surgically implanted into the rectus sheath of the subject for a therapeutically effective time.

### Claim 6 (depends on 1)

The method of claim 1, wherein the modified phosphate backbone of the first IGF-1R AS ODN renders the first IGF-1R AS ODN resistant to nuclease degradation.

### Claim 7 (depends on 6)

The method of claim 6, wherein the modified phosphate backbone of the first IGF-1R AS ODN comprises at least one phosphorothioate linkage.

### Claim 8 (depends on 6)

The method of claim 6, wherein the modified phosphate backbone of the first IGF-1R AS ODN comprises up to about 50% phosphorothioate-linkages.

### Claim 9 (depends on 6)

The method of claim 6, wherein the modified phosphate backbone of the first IGF-1R AS ODN is fully phosphorothioate-linked.

### Claim 10 (depends on 5)

The method of claim 5, wherein the first IGF-1R AS ODN has at least one terminal modification.

### Claim 11 (depends on 10)

The method of claim 10, wherein the at least one terminal modification is a phosphorothioate monophosphate.

### Claim 12 (depends on 10)

The method of claim 10, the at least one terminal modification comprises a 5′ cap structure and/or a 3′ cap structure.

### Claim 13 (depends on 1)

The method of claim 1, wherein the modified phosphate backbone of the second IGF-1R AS ODN renders the second IGF-1R AS ODN resistant to nuclease degradation.

### Claim 14 (depends on 13)

The method of claim 13, wherein the modified phosphate backbone of the second IGF-1R AS ODN comprises at least one phosphorothioate linkage.

### Claim 15 (depends on 14)

The method of claim 14, wherein the modified phosphate backbone of the second IGF-1R AS ODN comprises up to about 50% phosphorothioate linkages.

### Claim 16 (depends on 14)

The method of claim 14, wherein the modified phosphate backbone of the second IGF-1R AS ODN is fully phosphorothioate-linked.

### Claim 17 (depends on 13)

The method of claim 13, wherein the second IGF-1R AS ODN has at least one terminal modification.

### Claim 18 (depends on 17)

The method of claim 17, wherein the at least one terminal modification is a phosphorothioate monophosphate.

### Claim 19 (depends on 17)

The method of claim 17, the at least one terminal modification comprises a 5′ cap structure and/or a 3′ cap structure.

### Claim 20 (depends on 1)

The method of claim 1, wherein the modified phosphate backbone of the first IGF-1R AS ODN and the modified phosphate backbone of the second IGF-1R AS ODN are the same.

### Claim 21 (depends on 1)

The method of claim 1, wherein the modified phosphate backbone of the first IGF-1R AS ODN and the modified phosphate backbone of the second IGF-1R AS ODN are different.

### Claim 22 (depends on 1)

The method of claim 1, wherein the cancer is selected from the group consisting of glioma, astrocytoma, breast cancer, head and neck squamous cell cancer, papillary renal cell carcinoma Type II, lung cancer, pancreatic cancer, gall bladder cancer, rectal cancer, classical Hodgkin's lymphoma, ovarian cancer, and colorectal cancer.

### Claim 23 (depends on 22)

The method of claim 22, wherein the cancer is glioma.