# US 11,439,619 B2 · Phosphaplatin compounds as immuno-modulatory agents and therapeutic uses thereof

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- Number: US 11,439,619 B2
- Document ID: US11439619B2
- Status: Granted
- Kind: B2
- Application number: 16/645,043
- Filed: 2018-09-07
- Published: 2021-04-29
- Granted: 2022-09-13
- Earliest claimed: 2017-09-08
- Assignees: Phosplatin Therapeutics LLC
- Applicants: Phosplatin Therapeutics Inc.
- Inventors: Tyler Ames; Matthew Price
- Web page: https://patentgrep.com/patent/US11439619B2

## CPC

- A61K 31/282: Platinum compounds
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 39/0011: {Cancer antigens}
- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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

Use of (pyrophosphato)platinum(II) or platinum(IV) complexes (“phosphaplatins”), especially 1,2-cyclohexanediamine(pyrophosphato) platinum(II), as immunogenic cell death (ICD) inducing agents and their combination with immune checkpoint protein inhibitors for treatment of cancers, and the mechanistic rationale for the methods thereof, are disclosed.

## Claims

### Claim 1

A method for treating a subject having cancer, comprising administering to the subject a therapeutically effective amount of a phosphaplatin compound having a structure of formula I or II:
or a pharmaceutically acceptable salt thereof, to induce immunogenic cell death (ICD) in the subject, and a therapeutically effective amount of an immune checkpoint protein inhibitor, wherein R1 and R2 are each independently selected from NH3, substituted or unsubstituted aliphatic amines, and substituted or unsubstituted aromatic amines; and wherein R3 is selected from substituted or unsubstituted aliphatic diamines, and substituted or unsubstituted aromatic diamines.

### Claim 2 (depends on 1)

The method of claim 1, wherein R1 and R2 are each independently selected from NH3, methyl amine, ethyl amine, propyl amine, isopropyl amine, butyl amine, cyclohexane amine, aniline, pyridine, and substituted pyridine; and R3 is selected from 1,2-ethylenediamine and cyclohexane-1,2-diamine.

### Claim 3 (depends on 1)

The method of claim 1, wherein the phosphaplatin compound is selected from the group consisting of:
pharmaceutically acceptable salts, and mixtures thereof.

### Claim 4 (depends on 1)

The method of claim 1, wherein the phosphaplatin compound is R,R-pyrodach-2:

### Claim 5

A method for treating a subject having cancer, comprising administering to the subject a therapeutically effective amount of a phosphaplatin compound having a structure of formula III or IV:
or a pharmaceutically acceptable salt thereof, to induce immunogenic cell death (ICD) in the subject, and a therapeutically effective amount of an immune checkpoint protein inhibitor, wherein R1 and R2 are each independently selected from NH3, substituted or unsubstituted aliphatic amines, and substituted or unsubstituted aromatic amines; and wherein R3 is selected from substituted or unsubstituted aliphatic diamines, and substituted or unsubstituted aromatic diamines.

### Claim 6 (depends on 5)

The method of claim 5, wherein R1 and R2 are each independently selected from NH3, methyl amine, ethyl amine, propyl amine, isopropyl amine, butyl amine, cyclohexylamine, aniline, pyridine, and substituted pyridine; and R3 is selected from 1,2-ethylenediamine and cyclohexane-1,2-diamine.

### Claim 7 (depends on 5)

The method of claim 5, wherein the monomeric platinum (IV) pyrophosphate complex has a formula (IV), wherein R3 is 1,2-ethylene-diamine or cyclohexane-1,2-diamine.

### Claim 8 (depends on 1)

The method of claim 1, wherein the administering comprises intravenous or intraperitoneal injection.

### Claim 9 (depends on 1)

The method of claim 1, wherein the dose of pyrophosphate platinum complex is in the range of from about 1 mg and to about 200 mg/Kg based on body weight of the subject.

### Claim 10 (depends on 1)

The method of claim 1, wherein the cancer is selected from the group consisting of colon cancer, pancreatic cancer, gastric cancer, liver cancer, breast cancer, prostate cancer, lung cancer, and melanoma, osteosarcoma, chondrosarcoma, Ewing tumor, malignant fibrous histiocytoma (MFH), mibrosarcoma, giant cell tumor, chordoma, spindle cell sarcomas, multiple myeloma, non-Hodgkin lymphoma, Hodgkin lymphoma, leukemia, childhood acute myelogenous leukemia (AML), chronic myelomonocytic leukaemia (CMML), hairy cell leukaemia, juvenile myelomonocytic leukaemia (JIVIML), myelodysplastic syndromes, myelofibrosis, myeloproliferative neoplasms, polycythaemia vera, thrombocythaemiaosteosarcoma, chondrosarcoma, Ewing tumor, malignant fibrous histiocytoma (MFH), mibrosarcoma, giant cell tumor, chordoma, spindle cell sarcomas, multiple myeloma, non-Hodgkin lymphoma, Hodgkin lymphoma and leukemia.

### Claim 11 (depends on 1)

The method of claim 1, in conjunction with administering to the subject an additional anti-cancer agent.

### Claim 12 (depends on 11)

The method of claim 11, wherein the additional anti-cancer agent is selected from the group consisting of alkylating agents, glucocorticoids, immunomodulatory drugs (IMiDs) and proteasome inhibitors, cyclocreatine, a RNAi agent, a nucleic acid, a vector, 5-fluorouracil, Oxaliplatin, Irinotecan, Capecitabine, Gemcitabine, Cetuximab, Paclitaxel, Bevacizumab, folinic acid (leucovorin), Regorafenib, Aflibercept, topoisomerase I inhibitors, NKTR-102, Tivantinib, PX-866, Sorafenib, Linifanib, kinase inhibitors, Telatinib, XL281 (BMS), Robatumumab, and IGF1-R Inhibitors.

### Claim 13 (depends on 3)

The method of claim 3, wherein the phosphaplatin compound is administered to the subject prior to administration of the immune checkpoint protein inhibitor or at the same time as administration of the immune checkpoint protein inhibitor.

### Claim 14 (depends on 3)

The method of claim 3, wherein the subject is a patient having a cancer having low or no response to treatment with an immune checkpoint protein inhibitor alone.

### Claim 15 (depends on 3)

The method of claim 3, wherein the immune checkpoint protein inhibitor is selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, B7-1/B7-2 inhibitors, CTLA-4 inhibitors, and combinations thereof.

### Claim 16 (depends on 3)

The method of claim 3, wherein the immune checkpoint protein inhibitor is an antibody selected from the group consisting of Pembrolizumab, Nivolumab, Pidilizumab (CT-011), Atezolizumab, Avelumab, Durvalumab, Ipilimumab, and combinations thereof.

### Claim 17 (depends on 3)

The method of claim 3, wherein the cancer is selected from the group consisting of colon cancer, pancreatic cancer, gastric cancer, liver cancer, breast cancer, prostate cancer, lung cancer, bladder cancer, urothelial carcinoma, thymic epithelial tumors, head and neck cancer, skin cancers, osteosarcoma, chondrosarcoma, Ewing tumor, malignant fibrous histiocytoma (MFH), mibrosarcoma, giant cell tumor, chordoma, spindle cell sarcomas, multiple myeloma, non-Hodgkin lymphoma, Hodgkin lymphoma, leukemia, childhood acute myelogenous leukemia (AML), chronic myelomonocytic leukaemia (CMML), hairy cell leukaemia, juvenile myelomonocytic leukaemia (JIVIML), myelodysplastic syndromes, myelofibrosis, myeloproliferative neoplasms, polycythaemia vera, thrombocythaemiaosteosarcoma, chondrosarcoma, Ewing tumor, malignant fibrous histiocytoma (MFH), mibrosarcoma, giant cell tumor, chordoma, spindle cell sarcomas, multiple myeloma, non-Hodgkin lymphoma, Hodgkin lymphoma and leukemia.

### Claim 18 (depends on 3)

The method of claim 3, wherein the cancer is characterized with a low level of tumor-infiltrating lymphocytes (TILs).

### Claim 19 (depends on 1)

The method of claim 1, wherein induction of the immunogenic cell death by the phosphaplatin compound is characterized by release of damage associated molecular patterns (DAMPs), high mobility group box 1 (HMGB1), calreticulin (CRT), and DAMP adenosine triphosphate (ATP) from cells of the subject treated with the phosphaplatin compound.