Mono- and di-PEG IL-10 production; and uses

• US 10,639,353 B2
• Filed: 12/28/2016
• Issued: 05/05/2020
• Est. Priority Date: 12/17/2008
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Blaisdell, Steven J., Cutler, Collette M., Paporello, Brittany C., Ambrogelly, Alexandre
• Primary Examiner(s): Hama, Joanne
• Assistant Examiner(s): Seharaseyon, Jegatheesan
• Application Number:
  US15/393,013
• Publication Number:
  US 20170202923A1
• Time in Patent Office: 1,224 Days
• Field of Search: None
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61K 38/2066 IL-10
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

Provided are methods of producing mono- and di-pegylated IL-10.

Claims

1. A method of treating a patient having a proliferative condition or disorder, the method comprising:

administering to a patient having a proliferative condition or disorder an effective amount of a composition comprising a mixture of about 50% mono-pegylated human interleukin-10 (IL-10) and about 50% di-pegylated human IL-10;

wherein the administering is effective to treat the proliferative condition or disorder in the patient and wherein the proliferative condition or disorder is cancer; and

wherein the PEG component of the mono-pegylated human IL-10 and di-pegylated human IL-10 is covalently attached to the alpha amino group of the amino acid residue at the N-terminus of IL-10.

2. The method of claim 1, wherein the composition is administered in an amount of from about 0.01 μ

g to about 100 μ

g per kg of body weight per day.

3. The method of claim 2, wherein the composition is administered in an amount of from about 20 μ

g to about 100 μ

g per kg of body weight per day.

4. The method of claim 2, wherein the composition is administered in an amount of from about 20 μ

g to about 50 μ

g per kg of body weight per day.

5. The method of claim 1, wherein the cancer is cancer of the uterus, cervix, breast, prostate, testes, penis, gastrointestinal tract, kidney, renal cell, bladder, bone, bone marrow, skin, head, neck, skin, liver, gall bladder, lung, pancreas, salivary gland, adrenal gland, thyroid, brain, or immune system.

6. The method of claim 5, wherein the cancer is cancer of the pancreas.

7. The method of claim 5, wherein the cancer is renal cell cancer.

8. The method of claim 5, wherein the cancer of the gastrointestinal tract is cancer of the esophagus, oropharynx, stomach, small intestine, large intestine, colon, or rectum.

9. The method of claim 8, wherein the cancer of the gastrointestinal tract is cancer of the colon or rectum.

10. The method of claim 5, wherein the cancer of the immune system is a cancer of the spleen or thymus.

11. The method of claim 1, wherein the proliferative condition or disorder is a cancer of the central nervous system (CNS) or peripheral nervous system (PNS).

12. The method of claim 11, wherein the proliferative condition or disorder is a glioma or cancer of a ganglia.

13. The method of claim 1, wherein the cancer is an epithelial cell cancer, an endothelial cell cancer, or a squamous cell carcinoma.

14. The method of claim 1, wherein the cancer is an adenocarcinoma, a lymphoma, a carcinoma, a melanoma, a leukemia, a myeloma, or a sarcoma.

15. The method of claim 1, wherein the mono-pegylated IL-10 and di-pegylated IL-10 comprise a PEG-linker selected from the group consisting of succinimidylcarbonate-PEG, PEG-butyraldehyde, PEG-pentaldehyde, PEG-amido-propionaldehyde, PEG-urethano-propioaldehyde, and PEG-propylaldehyde.

16. The method of claim 15, wherein the PEG-linker is PEG-propylaldehyde.

17. The method of claim 1, wherein the mono-pegylated IL-10 and di-pegylated IL-10 comprise a polyethylene glycol (PEG) having a molecular mass of from about 5,000 daltons to about 20,000 daltons.

18. The method of claim 1, wherein the PEG has a molecular mass of about 5,000 daltons.

19. The method of claim 1, wherein the method comprises administering at least one additional therapeutic agent.

20. The method of claim 19, wherein the at least one additional therapeutic agent is selected from the group consisting of doxorubicin, epirubicin, an anti-folate agent, irinotecan, cyclophosphamide, androgen, estrogen, anti-estrogen, flutamide, diethylstilbestrol, tamoxifen, ifosfamide, mitolactol, an alkylating agent, etoposide, vinorelbine, vinblastine, vindesine, a glucocorticoid, a histamine receptor antagonist, an angiogenesis inhibitor, radiation, a radiation sensitizer, anthracycline, a vinca alkaloid, a taxane, paclitaxel, docetaxel, a cell cycle inhibitor, or a monoclonal antibody against a tumor antigen.

21. The method of claim 20, wherein the anti-folate agent is methotrexate or fluorouracil.

22. The method of claim 20, wherein the alkylating agent is melphalan or cis-platin.

23. The method of claim 20, wherein the cell cycle inhibitor is a cyclin-dependent kinase inhibitor.