# US 11,298,376 B2 · Method of treating cancer

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- Number: US 11,298,376 B2
- Document ID: US11298376B2
- Status: Granted
- Kind: B2
- Application number: 16/296,117
- Filed: 2019-03-07
- Published: 2019-08-29
- Granted: 2022-04-12
- Earliest claimed: 2014-05-14
- Assignees: Targimmune Therapeutics AG
- Applicants: Targimmune Therapeutics AG
- Inventors: Alex Levitzki; Salim Joubran; Alexei Shir; Maya Zigler; Alaa Talhami; Yael Langut
- Web page: https://patentgrep.com/patent/US11298376B2

## CPC

- A61K 35/14: Blood; Artificial blood (perfluorocarbons A61K31/02; umbilical cord blood A61K35/51; haemoglobin A61K38/42)
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/59: obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61P 35/00: Antineoplastic agents
- C12N 15/117: Nucleic acids having immunomodulatory properties, e.g. containing CpG-motifs
- A61K 35/17: Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes (when activated by a specific antigen A61K39/00)
- C12N 2310/17: Immunomodulatory nucleic acids
- C12N 2310/351: Conjugate
- C12N 2310/53: partially self-complementary or closed
- 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

A method of treating cancer can include administering a polyplex of a double stranded RNA and a polymeric conjugate. The polymeric conjugate can consist of a linear polyethyleneimine covalently linked to one or more polyethylene glycol (PEG) moieties. Each PEG moiety can be conjugated via a linker to a targeting moiety capable of binding to a cancer antigen.

## Claims

### Claim 1

A method for treating a cancer selected from the group consisting of a cancer characterized by EGFR-overexpressing cells, a cancer characterized by HER2-overexpressing cells and prostate cancer,
said method comprising administering to a subject in need thereof a polyplex of a double stranded RNA (dsRNA) and a polymeric conjugate, wherein said polymeric conjugate
is selected from the group consisting of formulas (i)-(viii):
(iii) X-(NH—(CH2)7—CO)-Phe-Phe-(NH—CH2—CH(NH2)—CO)-Asp-Cys-PEG2k-LPEI;
(iv) X-(NH—(CH2)7—CO)-Phe-Gly-Trp-Trp-Gly-Cys-PEG2k-LPEI;
wherein R6 is
wherein R7 is
and wherein m and n are ≥1 and X is a targeting moiety capable of binding to a cancer antigen.

### Claim 2 (depends on 1)

The method of claim 1, wherein said cancer is a cancer characterized by EGFR-overexpressing cells selected from non-small-cell-lung-carcinoma, breast cancer, glioblastoma, head and neck squamous cell carcinoma, colorectal cancer, adenocarcinoma, ovary cancer, bladder cancer or prostate cancer, and metastases thereof.

### Claim 3 (depends on 2)

The method of claim 2, wherein said polyplex is selected from the group consisting of a polyplex in which:
(a) said targeting moiety is EGFR affibody, and said polymeric conjugate is of the formula (i), and the EGFR affibody is linked via a mercapto group thereof;
(b) said targeting moiety is EGFR affibody, and said polymeric conjugate is of the formula (v), and the EGFR affibody is linked via a mercapto group thereof;
(c) said targeting moiety is hEGF, and said polymeric conjugate is of the formula (ii), wherein the hEGF is linked via an amino group thereof;
(d) said targeting moiety is hEGF, and said polymeric conjugate is of the formula (vi), wherein the hEGF is linked via an amino group thereof.

### Claim 4 (depends on 1)

The method of claim 1, wherein said cancer is a cancer characterized by HER2-overexpressing cells selected from breast cancer, ovarian cancer, stomach cancer, and aggressive forms of uterine cancer, such as uterine serous endometrial carcinoma.

### Claim 5 (depends on 4)

The method of claim 4, wherein said cancer characterized by HER2-overexpressing cells is Herceptin/trastuzumab resistant cancer.

### Claim 6 (depends on 4)

The method of claim 4, wherein said polyplex is selected from the group consisting of a polyplex in which:
(a) said targeting moiety is HER2 affibody, and said polymeric conjugate is of the formula (i), and the HER2 affibody is linked via a mercapto group thereof;
(b) said targeting moiety is HER2 affibody, and said polymeric conjugate is of the formula (v), and the HER2 affibody is linked via a mercapto group thereof;
(c) said targeting moiety is hEGF, and said polymeric conjugate is of the formula (ii), wherein the hEGF is linked via an amino group thereof;
(d) said targeting moiety is hEGF, and said polymeric conjugate is of the formula (vi), wherein the hEGF is linked via an amino group thereof.

### Claim 7 (depends on 1)

The method of claim 1, wherein said cancer is prostate cancer.

### Claim 8 (depends on 7)

The method of claim 7, wherein said polyplex is selected from the group consisting of a polyplex in which:
(a) said targeting moiety is HOOC(CH2)2—CH(COOH)—NH—CO—NH—CH(COOH)—(CH2)2—CO-(DUPA residue), and said polymeric conjugate is of the formula (iii);
(b) said targeting moiety is HOOC(CH2)2—CH(COOH)—NH—CO—NH—CH(COOH)—(CH2)2—CO-(DUPA residue), and said polymeric conjugate is of the formula (vii);
(c) said targeting moiety is HOOC(CH2)2—CH(COOH)—NH—CO—NH—CH(COOH)—(CH2)2—CO-(DUPA residue), and said polymeric conjugate is of the formula (iv); or
(d) said targeting moiety is HOOC(CH2)2—CH(COOH)—NH—CO—NH—CH(COOH)—(CH2)2—CO-(DUPA residue), and said polymeric conjugate is of the formula (viii).

### Claim 9 (depends on 1)

The method of claim 1, wherein the polyplex is administered in combination with immune cells.

### Claim 10 (depends on 9)

The method of claim 9, wherein said immune cells are tumor-infiltrating T-cells (T-TILs), tumor specific engineered T-cells, or peripheral blood mononuclear cells (PBMCs).

### Claim 11 (depends on 1)

The method of claim 1, wherein the dsRNA is polyinosinic-polycytidylic acid double stranded RNA (poly I:C).

### Claim 12 (depends on 1)

The method of claim 1, wherein the cancer antigen is epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2) or prostate surface membrane antigen (PSMA).

### Claim 13 (depends on 1)

The method of claim 1, wherein said targeting moiety is hEGF, and the hEGF is linked via an amino group thereof.

### Claim 14 (depends on 13)

The method of claim 13, wherein said dsRNA is polyinosinic-polycytidylic acid double stranded RNA (poly I:C).

### Claim 15 (depends on 14)

The method of claim 14, wherein said polymeric conjugate is of the formula (ii).

### Claim 16 (depends on 15)

The method of claim 15, wherein the cancer antigen is epidermal growth factor receptor (EGFR).

### Claim 17 (depends on 14)

The method of claim 14, wherein said polymeric conjugate is of the formula (vi).

### Claim 18 (depends on 1)

The method of claim 1, wherein said targeting moiety is HOOC(CH2)2—CH(COOH)—NH—CO—NH—CH(COOH)—(CH2)2—CO-(DUPA residue).

### Claim 19 (depends on 18)

The method of claim 18, wherein said dsRNA is polyinosinic-polycytidylic acid double stranded RNA (poly I:C).

### Claim 20 (depends on 19)

The method of claim 19, wherein said polymeric conjugate is of the formula (iv).

### Claim 21 (depends on 20)

The method of claim 20, wherein the cancer antigen is prostate surface membrane antigen (PSMA).

### Claim 22

A method for treating a cancer selected from the group consisting of a cancer characterized by EGFR-overexpressing cells, a cancer characterized by HER2-overexpressing cells and prostate cancer,
said method comprising administering to a subject in need thereof a polyplex of a double stranded RNA (dsRNA) and a polymeric conjugate, wherein said polymeric conjugate consists of a linear polyethyleneimine (LPEI) covalently linked to one or more polyethylene glycol (PEG) moieties, each PEG moiety being conjugated via a linker to a targeting moiety capable of binding to a cancer antigen,
wherein said linker forms an —S—S—, NH—CO—, —CO—NH—, —S—C—, O—CO—, —CO—O— or urea (—NH—CO—NH) bond with said targeting moiety, and
wherein said linker is a peptide moiety; wherein said peptide moiety is —(NH—(CH2)7—CO)-Phe-Gly-Trp-Trp-Gly-Cys- (SEQ ID NO: 2) or —(NH—(CH2)7—CO)-Phe-Phe-(NH—CH2—CH(NH2)—CO)-Asp-Cys- (SEQ ID NO: 3).

### Claim 23 (depends on 22)

The method of claim 22, wherein said peptide moiety is —(NH—(CH2)7—CO)-Phe-Gly-Trp-Trp-Gly-Cys- (SEQ ID NO: 2).

### Claim 24 (depends on 23)

The method of claim 23, wherein said linker forms an NH—CO— or —CO—NH— bond with said targeting moiety.

### Claim 25 (depends on 24)

The method of claim 24, wherein the polymeric conjugate consists of LPEI covalently linked to one PEG moiety.

### Claim 26 (depends on 25)

The method of claim 25, wherein said dsRNA is polyinosinic-polycytidylic acid double stranded RNA (poly I:C).

### Claim 27 (depends on 26)

The method of claim 26, wherein said cancer is prostate cancer.

### Claim 28 (depends on 27)

The method of claim 27, wherein the cancer antigen is prostate surface membrane antigen (PSMA).

### Claim 29 (depends on 28)

The method of claim 28, wherein said targeting moiety is HOOC(CH2)2—CH(COOH)—NH—CO—NH—CH(COOH)—(CH2)2—CO-(DUPA residue).

### Claim 30 (depends on 24)

The method of claim 24, wherein the polymeric conjugate consists of LPEI covalently linked to three PEG moieties.