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CN-122005761-A - Methods of treating diseases and conditions using interleukin-10

CN122005761ACN 122005761 ACN122005761 ACN 122005761ACN-122005761-A

Abstract

The present application relates to methods of treating diseases and disorders using interleukin-10. Methods of treating a subject having a disease or disorder responsive to IL-10 are provided, including methods of administration and related dosing regimens.

Inventors

  • M. Ofter

Assignees

  • 阿尔莫生物科技股份有限公司

Dates

Publication Date
20260512
Application Date
20151020
Priority Date
20141022

Claims (20)

  1. Use of an IL-10 agent in the manufacture of a medicament for treating cancer in a human subject, the medicament comprising a therapeutically effective amount of an IL-10 agent, wherein the therapeutically effective amount of IL-10 agent is sufficient to achieve an average IL-10 serum trough concentration of at least the EC50 of the IL-10 agent in the subject, and wherein the serum trough concentration is maintained for at least 90% over a period of at least 1 week.
  2. 2. The use of claim 1, wherein the amount is sufficient to achieve an average IL-10 serum trough concentration of at least the EC60 of the IL-10 agent.
  3. 3. The use of claim 1, wherein the amount is sufficient to achieve an average IL-10 serum trough concentration of at least EC70 of the IL-10 agent.
  4. 4. The use of claim 1, wherein the IL-10 agent is mature human IL-10.
  5. 5. The use of claim 1, wherein the IL-10 agent is a variant of mature human IL-10, and wherein the variant exhibits activity comparable to that of mature human IL-10.
  6. 6. The use of claim 1, wherein the IL-10 agent is a PEG-IL-10 agent.
  7. 7. The use of claim 6, wherein the PEG-IL-10 agent comprises at least one PEG molecule covalently linked to at least one amino acid residue of at least one subunit of IL-10.
  8. 8. The use of claim 7, wherein the PEG-IL-10 agent comprises a mixture of mono-and di-pegylated IL-10.
  9. 9. The use of claim 8, wherein the PEG component of the PEG-IL-10 agent has a molecular weight of about 5kDa to about 20 kDa.
  10. 10. The use of claim 8, wherein the PEG component of the PEG-IL-10 agent has a molecular weight of greater than about 20 kDa.
  11. 11. The use of claim 8, wherein the PEG component of the PEG-IL-10 agent has a molecular weight of at least about 30 kD.
  12. 12. The use of claim 1, wherein the IL-10 agent is an Fc fusion molecule.
  13. 13. The use of claim 1, wherein the IL-10 agent comprises a fusion protein of IL-10 and serum albumin.
  14. 14. The use of claim 1, wherein the IL-10 agent is glycosylated.
  15. 15. The use of claim 7, wherein the covalent attachment of PEG to at least one amino acid residue of at least one subunit of IL-10 comprises a linker.
  16. 16. The use of claim 1, wherein the IL-10 agent is administered subcutaneously to the subject at least once daily.
  17. 17. The use of claim 1, wherein the IL-10 agent is administered subcutaneously to the subject at least every 72 hours.
  18. 18. The use of claim 1, wherein the IL-10 agent is administered subcutaneously to the subject at least once a week.
  19. 19. The use of claim 1, wherein the period of time is at least 2 weeks.
  20. 20. The use of claim 1, wherein the period of time is at least 1 month.

Description

Methods of treating diseases and conditions using interleukin-10 The application is a divisional application, the parent application number is 201580069348.9, the application date is 2015.10.20, and the application name is 'methods for treating diseases and conditions using interleukin-10'. Cross Reference to Related Applications The present application claims priority from U.S. provisional application Ser. No. 62/067,337 filed on 10/22 of 2014, the entire contents of which are incorporated herein by reference. Technical Field The present invention relates to methods of using IL-10 and related agents in the treatment or prevention of a wide variety of diseases and conditions. Background The cytokine interleukin-10 (IL-10) is a pleiotropic cytokine that regulates a variety of immune responses through actions on T cells, B cells, macrophages and Antigen Presenting Cells (APCs). IL-10 can inhibit immune responses by inhibiting the expression of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF-alpha, GM-CSF, and G-CSF in activated monocytes and activated macrophages, and also inhibit IFN-gamma production by NK cells. Although IL-10 is expressed primarily in macrophages, expression is also detected in activated T cells, B cells, mast cells and monocytes. In addition to suppressing immune responses, IL-10 also exhibits immunostimulatory properties, including stimulating proliferation of IL-2 and IL-4 treated thymocytes, enhancing B cell viability, and stimulating expression of class II MHC. Human IL-10 is a homodimer that becomes inactive upon disruption of non-covalent interactions between two monomer subunits. The data obtained from the disclosed crystal structure of IL-10 indicate that the functional dimer has some similarity to IFN-gamma (Zdanov et al, (1995) Structure (Lond) 3:591-601). Because of its pleiotropic activity, IL-10 is associated with a wide range of diseases, disorders and conditions, including inflammatory conditions, immune-related diseases, fibrotic disorders and cancers. Clinical and preclinical evaluation of many such diseases, disorders and conditions with IL-10 has consolidated its therapeutic potential. Furthermore, PEGylated IL-10 has been shown to be more effective than non-PEGylated IL-10 in certain therapeutic settings. In view of the prevalence and severity of IL-10 related diseases, disorders and conditions, optimizing new dosing regimens and parameters for efficacy, patient tolerance, etc., would be of great value for improving the therapeutic usefulness of IL-10 and pegylated IL-10 and its related agents. Disclosure of Invention The present disclosure contemplates methods of treating and/or preventing various diseases, disorders, and conditions, and/or symptoms thereof, using IL-10, modified (e.g., pegylated) IL-10, and related agents and compositions thereof described herein. More particularly, the present disclosure relates to optimized dosing parameters to achieve and maintain efficacy in treating and/or preventing various diseases, disorders, and conditions in a subject, while minimizing adverse reactions associated therewith. Such optimization of dosing parameters, as detailed below, involves evaluating pharmacokinetic and pharmacodynamic parameters related to absorption, distribution, metabolism, and excretion ("ADME"), for example, taking into account the route of administration and other factors. It is understood that terms related to ADME and other parameters are intended to have their commonly accepted meanings in the relevant scientific arts unless the context indicates otherwise. For example, the term "serum half-life" or "t ½" refers to the time to elimination half-life (i.e., half of the serum concentration of the agent to its initial or maximum value). According to the methods described herein, the disease, disorder or condition and/or symptoms thereof may be a proliferative disorder, such as cancer or a cancer-related disorder, or a fibrotic disorder, such as cirrhosis, NASH, and NAFLD. Although not limited to a particular cancer, the cancer may be a solid tumor, including those associated with colon cancer, melanoma, and squamous cell carcinoma, or it may be a hematopoietic disorder. In other embodiments, the disease, disorder, or condition is a viral disorder, including but not limited to human immunodeficiency virus, hepatitis b or c virus, or cytomegalovirus. In further embodiments, the disease, disorder or condition is an immune or inflammatory disease, which may be acute or chronic. Examples of immune and inflammatory diseases include inflammatory bowel disease, psoriasis, rheumatoid arthritis, multiple sclerosis and Alzheimer's disease. In particular embodiments, the disease, disorder or condition is a cardiovascular disorder, including atherosclerosis. Subjects with cardiovascular disorders may have elevated cholesterol. In further embodiments, the disease, disorder or condition is thrombosis or a thrombotic condition. As discussed further below, human IL-10 is a h