# US 12,214,045 B2 · Multi-arm polymer conjugates of TLR agonist compounds and related immunotherapeutic treatment methods

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- Number: US 12,214,045 B2
- Document ID: US12214045B2
- Status: Granted
- Kind: B2
- Application number: 18/221,300
- Filed: 2023-07-12
- Published: 2023-11-23
- Granted: 2025-02-04
- Earliest claimed: 2017-01-10
- Assignees: Nektar Therapeutics
- Applicants: Nektar Therapeutics
- Inventors: Zhongxu Ren; Neel K. Anand; Haiying Cai; Bo-Liang Deng; Bhalchandra V. Joshi; Jonathan Zalevsky; Takahiro Miyazaki; Saul Kivimae
- Web page: https://patentgrep.com/patent/US12214045B2

## CPC

- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61K 9/0029: {Parenteral nutrition; Parenteral nutrition compositions as drug carriers}
- A61K 47/54: the modifying agent being an organic compound
- A61K 47/642: {the peptide or protein in the drug conjugate being a cytokine, e.g. IL2, chemokine, growth factors or interferons being the inactive part of the conjugate}
- A61P 35/00: Antineoplastic agents
- 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

Provided are multi-arm polymer conjugates of Toll-Like Receptor (“TLR”) agonists such as TLR 7/8 agonists, as well as related compositions, and methods of making and using such conjugates. Exemplary conjugates are encompassed by Formula I: or a pharmaceutically acceptable salt form thereof, where R, taken together with each Q, is a residue of a polyol, polythiol, or polyamine bearing from 3 to about 50 hydroxyl, thiol, or amino groups; each Q is a linker selected from oxygen, sulfur and —NH; each POLY is independently a water-soluble, non-peptidic polymer; each Xr is independently a linkage-containing spacer moiety; q is a positive integer from 3 to about 50; and each TLR 7/8 AG is a Toll-like receptor 7/8 agonist. Also provided is a method of administering to a patient having cancer (a) an IL-2Rβ-activating amount of a long-acting, IL-2Rβ-selective agonist; and (b) a Toll-like receptor agonist such as a conjugate as described above, as well as related compositions, kits and methods.

## Claims

### Claim 1

A method of treating cancer comprising administering a conjugate comprising a Toll-like Receptor (TLR) 7/8 agonist covalently attached, via a linkage-containing spacer moiety, to a multi-arm, water-soluble, non-peptidic polymer having a formula in accordance with Formula III:
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: L is —(CH2)m—, —(CH2)m—NH—C(O)—(CH2)m—, —CHF—(CH2)m—NH—C(O)—(CH2)m—, —CH(CH3)—NH—C(O)—(CH2)m—, —CH(CH(CH3)2)—NH—C(O)—(CH2)m—, —CH(CH2CH(CH3)2)—NH—C(O)—(CH2)m—, —C(CH3)2—NH—C(O)—(CH2)m—, a single bond, or —NH—(CH2)m—,
each m is independently an integer from 1 to 5, inclusive;
each n is independently an integer from 40 to 350, inclusive;
R1 is hydrogen or —CH2—O—CH2—CH3; and
R2 is hydrogen or hydroxyl
to a subject in need thereof.

### Claim 2

A method of administration comprising administering to a subject having cancer (i) a conjugate comprising a Toll-like receptor (TLR) 7/8 activating amount of a TLR 7/8 agonist covalently attached, via a linkage-containing spacer moiety, to a multi-arm, water-soluble, non-peptidic polymer having a formula in accordance with
Formula III:
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: L is —(CH2)m—, —(CH2)m—NH—C(O)—(CH2)m—, —CHF—(CH2)m—NH—C(O)—(CH2)m—, —CH(CH3)—NH—C(O)—(CH2)m—, —CH(CH(CH3)2)—NH—C(O)—(CH2)m—, —CH(CH2CH(CH3)2)—NH—C(O)—(CH2)m—, —C(CH3)2—NH—C(O)—(CH2)m—, a single bond, or —NH—(CH2)m—,
each m is independently an integer from 1 to 5, inclusive;
each n is independently an integer from 40 to 350, inclusive;
R1 is hydrogen or —CH2—O—CH2—CH3; and
R2 is hydrogen or hydroxyl, and (ii) am IL-2Rβ-activating amount of a long acting interleukin-2 receptor beta (IL-2Rβ)-biased agonist.

### Claim 3 (depends on 2)

The method of claim 2, wherein the conjugate and the long acting IL-2Rβ-biased agonist are administered concurrently or sequentially and in any order, and via the same and/or different routes of administration, each in an immunomodulating amount.

### Claim 4 (depends on 3)

The method of claim 3, wherein the method comprises a single cycle of administering.

### Claim 5 (depends on 3)

The method of claim 3, wherein the method comprises two or more cycles of administering.

### Claim 6 (depends on 2)

The method of claim 2, wherein the conjugate is administered locally and the long acting IL-2Rβ-biased agonist is administered parenterally.

### Claim 7 (depends on 6)

The method of claim 6, wherein the conjugate is administered intratumorally directly to the site of a cancerous tumor.

### Claim 8 (depends on 2)

The method of claim 2, where the conjugate is administered to the subject separately from the long acting IL-2Rβ-biased agonist.

### Claim 9 (depends on 2)

The method of claim 2, wherein the conjugate is administered to the subject prior to administering the long acting IL-2Rβ-biased agonist.

### Claim 10 (depends on 2)

The method of claim 2, wherein the conjugate and the long acting IL-2Rβ-biased agonist are both administered on day 1 of treatment.

### Claim 11 (depends on 2)

The method of claim 2, wherein the conjugate is administered on day 1 of treatment and the long acting IL-2Rβ-biased agonist is administered on any one of days 1 to 4 of treatment.

### Claim 12 (depends on 2)

The method of claim 2, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, colon cancer, prostate cancer, bone cancer, colorectal cancer, gastric cancer, lymphoma, malignant melanoma, liver cancer, small cell lung cancer, non-small cell lung cancer, pancreatic cancer, thyroid cancers, kidney cancer, cancer of the bile duct, brain cancer, cervical cancer, maxillary sinus cancer, bladder cancer, esophageal cancer, Hodgkin's disease and adrenocortical cancer.

### Claim 13 (depends on 2)

The method of claim 2, wherein the long acting IL-2Rβ-biased agonist comprises compounds encompassed by the following formula:
wherein IL-2 is an interleukin-2, where “n” is an integer from about 3 to about 4000, or pharmaceutically acceptable salts thereof.

### Claim 14 (depends on 2)

The method of claim 2, wherein the conjugate has the following formula:
wherein each n is independently an integer from 40 to 350.

### Claim 15 (depends on 14)

The method of claim 14, wherein the value of n in each of the polymer arms is about 113.

### Claim 16 (depends on 2)

The method of claim 2, wherein the administering is effective to provide a percent survival rate, when evaluated in a suitable animal model, such as a mouse CT-26 colon tumor model, at a day after start of treatment that is after a day by which all subjects in the vehicle only group have reached 0% survival that is greater than that observed for administration of either of the long-acting IL-2Rβ-biased agonist or the conjugate alone, when administered at therapeutically equivalent doses to those used in the combination.

### Claim 17

A combination for use in treating a subject having cancer, the combination comprising an IL-2Rβ-activating amount of a long acting IL-2Rβ-biased agonist and an innate immunity activating amount of a conjugate comprising a Toll-like Receptor (TLR) 7/8 agonist covalently attached, via a linkage-containing spacer moiety, to a multi-arm, water-soluble, non-peptidic polymer having a formula in accordance with Formula III:
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: L is —(CH2)m—, —(CH2)m—NH—C(O)—(CH2)m—, —CHF—(CH2)m—NH—C(O)—(CH2)m—, —CH(CH3)—NH—C(O)—(CH2)m—, —CH(CH(CH3)2)—NH—C(O)—(CH2)m—, —CH(CH2CH(CH3)2)—NH—C(O)—(CH2)m—, —C(CH3)2—NH—C(O)—(CH2)m—, a single bond, or —NH—(CH2)m—,
each m is independently an integer from 1 to 5, inclusive;
each n is independently an integer from 40 to 350, inclusive;
R1 is hydrogen or —CH2—O—CH2—CH3; and
R2 is hydrogen or hydroxyl, accompanied by instructions for use in treating a subject having cancer.

### Claim 18 (depends on 17)

The combination of claim 17, wherein the long acting IL-2Rβ-biased agonist comprises compounds encompassed by the following formula:
wherein IL-2 is interleukin-2, where “n” is an integer from about 3 to about 4000, or pharmaceutically acceptable salts thereof.

### Claim 19 (depends on 17)

The combination of claim 17, wherein the conjugate has the following formula:
wherein each n is independently an integer from 40 to 350.

### Claim 20 (depends on 19)

The combination of claim 19, wherein the value of n in each of the polymer arms is about 113.

### Claim 21 (depends on 1)

The method of claim 1, wherein the conjugate is selected from the group consisting of Compounds 1-10 and 12-15:
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each n is independently an integer from 40 to 350.

### Claim 22 (depends on 1)

The method of claim 1, wherein the conjugate is administered locally.

### Claim 23 (depends on 1)

The method of claim 1, wherein the conjugate is administered directly to the site of a cancerous tumor.

### Claim 24 (depends on 1)

The method of claim 1, wherein said administering comprises administering 0.01 mg to 750 mg of the conjugate per day.