# US 2018/0021294 A1 · Ephrin Receptor A2 (EPHA2)-Targeted Docetaxel-Generating Nano-Liposome Compositions

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- Number: US 2018/0021294 A1
- Document ID: US20180021294A1
- Status: Published application
- Kind: A1
- Application number: 15/460,280
- Filed: 2017-03-16
- Published: 2018-01-25
- Earliest claimed: 2016-03-16
- Assignees: Merrimack Pharmaceuticals, Inc.
- Applicants: Merrimack Pharmaceuticals, Inc.
- Inventors: Daryl C. Drummond; Dmitri B. Kirpotin; Zhaohua R. Huang; Suresh K. Tipparaju; Charles Noble
- Web page: https://patentgrep.com/patent/US20180021294A1

## CPC

- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 9/1272: comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers (lipids as modifying agents {A61K47/543})
- A61K 47/6913: {the liposome being modified on its surface by an antibody}
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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

## Abstract

EphA2-targeted immunoliposomes for delivering docetaxel are useful in the treatment of certain types of cancer. The immunoliposomes can include an EphA2 targeting moiety (e.g., a scFv) and encapsulate a docetaxel prodrug in a stable salt form within a liposome having an average size of about 100 nm. Novel docetaxel prodrugs suitable for loading into nanoliposomes (including immunoliposomes) are provided, along with novel and other useful EphA2 targeting moieties for preparation of EphA2-targeted doxorubicin-generating immunoliposome therapies. Pharmaceutical compositions can be prepared that include nanoliposomes encapsulating one or more docetaxel prodrugs, and/or immunoliposomes or nanoparticles comprising an EphA2 binding moiety and encapsulating one or more docetaxel prodrugs. The pharmaceutical compositions are useful for administration to a patient for the treatment of cancer.

## Claims

### Claim 1

An EphA2-targeted docetaxel-generating liposome comprising a docetaxel-generating prodrug encapsulated within a lipid vesicle comprising one or more lipids, a PEG lipid derivative and an EphA2 binding moiety on the outside of the lipid vesicle.

### Claim 2 (depends on 1)

The liposome of claim 1, wherein the EphA2 binding moiety is a scFv moiety covalently bound to a lipid within the lipid vesicle.

### Claim 3 (depends on 1)

The liposome of claim 1, wherein the docetaxel generating prodrug is a compound of Formula (I)
where R1 and R2 are each independently H or lower alkyl, and n is an integer 2-3.

### Claim 4 (depends on 1)

The liposome of claim 1, wherein the EphA2 binding moiety is a scFv moiety comprising the CDRs of SEQ ID NO:40 or SEQ ID NO:41.

### Claim 5 (depends on 4)

The liposome of claim 4, wherein the EphA2 binding moiety is a scFv moiety comprising the sequence of SEQ ID NO:41.

### Claim 6 (depends on 1)

The liposome of claim 1, wherein the lipid vesicle comprises sphingomyelin, cholesterol and PEG-DSG.

### Claim 7 (depends on 6)

The liposome of claim 6, wherein the lipid vesicle comprises sphingomyelin, cholesterol and PEG-DSG in a weight ratio of about 4.4:1.6:1.

### Claim 8 (depends on 1)

The liposome of claim 1, wherein the liposome encapsulates a docetaxel-generating prodrug of formula (I)
where R1 and R2 are each C1-C3 alkyl, and n is 2 or 3.

### Claim 9 (depends on 1)

The liposome of claim 1, wherein the docetaxel-generating prodrug encapsulates the compound of formula (I) with sucrose octasulfate.

### Claim 10 (depends on 1)

The liposome of claim 1, wherein the docetaxel-generating prodrug is a sucrose octasulfate salt of any one of Compounds 1-3 encapsulated in a liposome.

### Claim 11 (depends on 1)

The liposome of claim 1, wherein the liposome further comprises the scFv moiety covalently bound to PEG-DSPE as scFv-PEG-DSPE in a ratio of about 1:142 by weight with respect to the total sphingomyelin in the liposome.

### Claim 12 (depends on 1)

The liposome of claim 1 where the liposome has a drug-to-phospholipid ratio in the liposome greater than 250 g docetaxel equivalents/mol phospholipid, and preferably between 250-350 g/mol when the drug loading is based on docetaxel equivalents.

### Claim 13 (depends on 1)

The liposome of claim 1 where the pH of the storage buffer is below neutral, preferably between 4-6.5, and more preferably between 5-6.

### Claim 14 (depends on 1)

The liposome of claim 1, wherein the EphA2 binding moiety binds to the same epitope on EphA2 as an scFv consisting of SEQ ID NO:41.

### Claim 15 (depends on 1)

The liposome of claim 1, wherein the EphA2 binding moiety competes for binding to EphA2 with an scFv consisting of SEQ ID NO:41.

### Claim 16 (depends on 1)

A method of treating cancer in a human patient need thereof, the method comprising administering to the human patient a therapeutically effective amount of the liposome of claim 1 in a pharmaceutical composition.

### Claim 17 (depends on 16)

The method of claim 16, wherein the cancer is selected from the group consisting of breast, solid tumors, gastric, esophageal, lung, prostate and ovarian cancer.

### Claim 18 (depends on 16)

The method of claim 16, wherein the cancer is triple negative breast cancer (TNBC).

### Claim 19 (depends on 16)

The method of claim 16, wherein the cancer is gastric, gastroesophageal junction or esophageal carcimona.

### Claim 20 (depends on 16)

The method of claim 16, wherein the cancer is small cell lung cancer or non-small cell lung cancer.

### Claim 21 (depends on 16)

The method of claim 16, wherein the cancer is ovarian cancer, endometrial carcinoma or urothelial carcinoma.

### Claim 22 (depends on 16)

The method of claim 16, wherein the cancer is prostate adenocarcinoma.

### Claim 23 (depends on 16)

The method of claim 16, wherein the cancer is soft tissue carcinoma or squamous cell carcinoma of the head and neck (SCCHN).

### Claim 24 (depends on 16)

The method of claim 16, wherein the cancer is Pancreatic ductal adenocarcinoma (PDAC).

### Claim 25 (depends on 16)

The method of claim 16, wherein the liposome comprises an EphA2 binding scFv moiety comprising the sequence of SEQ ID NO:41.

### Claim 26 (depends on 16)

The method of claim 16, wherein the liposome comprises the docetaxel-generating prodrug selected from the group consisting of: Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, and Compound 6.

### Claim 27 (depends on 26)

The method of claim 26, wherein the docetaxel prodrug is Compound 3.

### Claim 28 (depends on 26)

The method of claim 26, wherein the docetaxel prodrug is Compound 6.

### Claim 29 (depends on 1)

The liposomes of claim 1 where the hematologic toxicity is less than that of free docetaxel.

### Claim 30 (depends on 14)

The method of claim 14, where the hematologic toxicity of the dose of docetaxel delivered in the liposome is less than that of the same dose of free docetaxel.