WO2005067963A1 - Use of polyethylene glycol-modified interferon-alpha in therapeutic dosing regimens - Google Patents

Use of polyethylene glycol-modified interferon-alpha in therapeutic dosing regimens Download PDF

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WO2005067963A1
WO2005067963A1 PCT/US2004/005594 US2004005594W WO2005067963A1 WO 2005067963 A1 WO2005067963 A1 WO 2005067963A1 US 2004005594 W US2004005594 W US 2004005594W WO 2005067963 A1 WO2005067963 A1 WO 2005067963A1
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α
days
ifn
once
mg
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PCT/US2004/005594
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French (fr)
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Lawrence M. Blatt
Peter Van Vlasselaer
Curtis Ruegg
Henry H. Hsu
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Intermune, Inc.
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Publication of WO2005067963A1 publication Critical patent/WO2005067963A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19Cytokines; Lymphokines; Interferons
    • A61K38/21Interferons [IFN]
    • A61K38/217IFN-gamma
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19Cytokines; Lymphokines; Interferons
    • A61K38/21Interferons [IFN]
    • A61K38/212IFN-alpha
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol

Abstract

The present invention provides methods of treating a viral infection (e.g., methods of treating an HCV infection, methods of treating an HBV infection); and methods of treating a proliferative disorder. The methods generally involve administering a polyethylene glycol-modified IFN-α at a frequency of less than once per week, where the polyethylene glycol-modified IFN-α is a consensus IFN-α molecule conjugated to a single, linear, 30 kD poly(ethylene glycol) molecule.

Description

USE OF POLYETHYLENE GLYCOL-MODIFIED INTERFERON- ALPHA IN THERAPEUTIC DOSING REGIMENS

FIELD OF THE INVENTION

[0001] The present invention is in the field of treatment of viral infections, cancer, and proliferative disorders, and in particular in the field of use of polyethylene glycol-modified interferon-alpha in therapeutic dosing regimens to treat such disorders.

BACKGROUND OF THE INVENTION

[0002] Hepatitis C virus (HCV) infection is the most common chronic blood borne infection in the United States. Although the numbers of new infections have declined, the burden of chronic infection is substantial, with Centers for Disease Control estimates of 3.9 million (1.8%) infected persons in the United States. Clironic liver disease is the tenth leading cause of death among adults in the United States, and accounts for approximately 25,000 deaths annually, or approximately 1% of all deaths. Studies indicate that 40% of chronic liver disease is HCN-related, resulting in an estimated 8,000-10,000 deaths each year. HCN-associated end- stage liver disease is the most frequent indication for liver transplantation among adults.

[0003] The leading therapies for cancer are currently surgery, radiation and chemotherapy. Chemotherapeutic approaches such as antitumor antibiotics, alkylating agents, nitrosourea compounds, vinca alkaloids, steroid hormones, and anti-metabolites form the bulk of therapies available to oncologists. Despite advances in the field of cancer treatment, cancer remains a major health problem.

[0004] Current data indicate that fibrosis is not a static process; extracellular matrix is constantly being laid down and resorbed and the progressive accumulation of fibrous tissue is thought to represent a relative imbalance between pro-fibrotic processes and anti-fibrotic processes. If these processes are not properly regulated, the pathologic and progressive accumulation of collagen in the extracellular space as a result of a disordered wound healing process leads to replacement of normal cells by dense fibrous bands of protein, and results in fibrotic disease with disordered function in the affected organ (for example, impairment of respiratory function, impaired circulatory function via fibrotic changes in arterial walls, fibrotic degeneration of renal and liver function, degenerative musculoskeletal function, fibrotic degeneration of cardiac muscle or skeletal muscle, fibrotic degenerative changes in neuronal tissues in the central nervous system as well as the peripheral nervous system, etc.). [0005] In addition to fibrotic disorders of the lung, liver and kidney, many other organs and tissues are susceptible to fibrotic degeneration. In particular, cardiac injury from hypoxia or ischemia, toxins, infectious agents, genetic etiologies, and structural disorders can lead to an inappropriate chronic wound healing process that results in fibrosis of cardiac tissue.

[0006] There is a need in the art for improved methods of treating viral diseases and proliferative disorders (including cancer, fibrotic disorders, and angiogenic disorders). The present invention addresses this need. Literature

[0007] U.S. Patent Nos. 6,524,570, 5,908,621, and 6,177,074; U.S. Patent No. 5,382,657; METAVIR (1994) Hepatology 20:15-20; Brunt (2000) Hepatol. 31:241-246; Alpini (1997) J Hepatol. 27:371-380; Baroni et al. (1996) Hepatol. 23:1189-1199; Czaja et al. (1989) Hepatol. 10:795-800; Grossman et al. (1998) J Gastroenterol. Hepatol. 13:1058-1060; Rockey and Chung (1994) J Invest. Med. 42:660-670; Sakaida et al. (1998) J Hepatol. 28:471-479; Shi et al. (1997) Proc. Natl. Acad. Sci. USA 94:10663-10668; Baroni et al. (1999) Liver 19:212-219; Lortat- Jacob et al. (1997) J. Hepatol. 26:894-903; Llorent et al. (1996) J. Hepatol. 24:555-563; U.S. Patent No. 5,082,659; European Patent Application EP 294,160; U.S. Patent No. 4,806,347; Balish et al. (1992) J. Infect. Diseases 166:1401-1403; Katayama et al. (2001) J. Viral Hepatitis 8:180-185; U.S. Patent No. 5,082,659; U.S. Patent No. 5,190,751; U.S. Patent No. 4,806,347; Wandl et al. (1992) Br. J. Haematol. 81:516-519; European Patent Application No. 294,160; Canadian Patent No. 1,321,348; European Patent Application No. 276,120; Wandl et al. (1992) Sem. Oncol 19:88-94; Balish et al. (1992) J. Infectious Diseases 166:1401-1403; Van Dijk et al. (1994) Int. J. Cancer 56:262-268; Sundmacher et al. (1987) Current Eye Res. 6:273-276; U.S. Patent Nos. 6,172,046; 6,245,740; 5,824,784; 5,372,808; 5,980,884; published international patent applications WO 96/21468; WO 96/11953; Torre et al. (2001) J. Med. Virol. 64:455-459; Bekkering et al. (2001) J. Hepatol. 34:435-440; Zeuzem et al. (2001) Gastroenterol. 120:1438-1447; Zeuzem (1999) J. Hepatol. 31:61-64; Keeffe and Hollinger (1997) Hepatol 26:101S-107S; Wills (1990) Clin. Pharmacokinet. 19:390-399; Heathcote et al. (2000) New Engl. J. Med. 343:1673-1680; Husa and Husova (2001) Bratisl Let Listy 102:248-252; Glue et al. (2000) Clin. Pharmacol. 68:556-567; Bailon et al. (2001) Bioconj. Chem. 12:195-202; and Neumann et al. (2001) Science 282:103; Zalipsky (1995) Adv. Drug Delivery Reviews S. 16, 157-182; Mann et al. (2001) Lancet 358:958-965; Zeuzem et al. (2000) New Engl. J. Med. 3 3 -.1666-1612; U.S. Patent Nos. 5,985,265; 5,908,121; 6,177,074; 5,985,263; 5,711,944; 5,382,657; and 5,908,121; Osborn et al. (2002) J Pharmacol Exp. Therap. 303:540-548; Sheppard et al. (2003) Nat. Immunol. 4:63-68; Chang et al. (1999) Nat. Biotechnol 17:793-797; Adolf (1995) Multiple Sclerosis 1 Suppl. LS44-S47.

SUMMARY OF THE INVENTION [0008] The present invention provides methods of treating a viral infection (e.g., methods of treating an HCV infection, methods of treating an HBV infection); and methods of treating a proliferative disorder. The methods generally involve administering a polyethylene glycol- modified IFN-α at a frequency of less than once per week, where the polyethylene glycol- modified IFN-α is a consensus IFN-α molecule conjugated to a single, linear, 30 kD poly(ethylene glycol) molecule.

FEATURES OF THE INVENTION

[0009] The present invention features methods of treating a viral infection (e.g., an HCV infection, an HBV infection, etc.) in an individual. The methods generally involve administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In some embodiments, the method • for treating a viral infection (e.g., an HCV infection, an HBV infection, etc.) in an individual involves subjecting the individual to any of the foregoing PEGylated IFN-α regimens as a mono herapy. In other embodiments, the method provides any of the foregoing PEGylated IFN-α regimens for the treatment of an HCV infection in an individual, and further provides administering to the individual an effective amount or amounts of one or more drugs selected from the group consisting of ribavirin, pirfenidone, pirfenidone analogs, NS3 inhibitors, inhibitors of HCV RNA-directed RNA polymerase, thymosin-α, 2 '-substituted ribonucleoside analogs, and immunomodulatory nucleoside analogs.

[0010] In another aspect, the present invention features methods of treating a viral infection (e.g., an HCV infection, an HBV infection, etc.) in an individual, the methods generally involving administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more; and administering an effective amount of a Type II interferon receptor agonist, e.g., IFN-γ. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In some embodiments, the method provides any of the foregoing PEGylated IFN-α and Type II interferon receptor agonist combination regimens for the treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.) in an individual, and further provides administering to the individual an effective amount or amounts of one or more additional therapeutic agents. In some embodiments, the methods provide any of the foregoing PEGylated IFN-α and Type II interferon receptor agonist combination regimens for the treatment of HCV infection in an individual, and further provide administering to the individual an effective amount of one or more drugs selected from the group consisting of ribavirin, pirfenidone, pirfenidone analogs, NS3 inhibitors, inhibitors of HCV RNA-directed RNA polymerase, thymosin-α, 2 '-substituted ribonucleoside analogs, and immunomodulatory nucleoside analogs. In another aspect, the present invention features methods of treating a viral infection

(e.g., an HCV infection, an HBV infection, etc.) in an individual, the methods generally involving administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more; administering an effective amount of a Type II interferon receptor agonist, e.g., IFN-γ; and administering a TNF-α antagonist. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In some embodiments, the method provides any of the foregoing PEGylated IFN-α, Type II interferon receptor agonist, and TNF-α antagonist combination regimens for the treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.) in an individual, and further provides administering an effective amount or amounts of one or more additional therapeutic agents. In some embodiments, the methods provide any of the foregoing PEGylated IFN-α, Type II interferon receptor agonist, and TNF-α antagonist combination regimens for the treatment of an HCV infection in an individual, and further provide administering to the individual an effective amount or amounts of one or more drugs selected from the group of ribavirin, pirfenidone, pirfenidone analogs, NS3 inhibitors, inhibitors of HCV RNA-directed RNA polymerase, thymosin-α, 2 '-substituted ribonucleoside analogs, and immunomodulatory nucleoside analogs. [0012] In another aspect, the present invention features methods of treating a viral infection (e.g., an HCV infection, an HBV infection, etc.) in an individual, the methods generally involving administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more; and administering an effective amount of ribavirin. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In some embodiments, the method provides any of the foregoing PEGylated IFN-α and ribavirin combination regimens for the treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.) in an individual, and further provides administering to the individual an effective amount of one or more additional therapeutic agents. In some embodiments, the methods provide any of the foregoing PEGylated IFN-α and ribavirin combination regimens for the treatment of an HCV infection in an individual, and further provide administering to the individual an effective amount or amounts of one or more drugs selected from the group of pirfenidone, pirfenidone analogs, NS3 inhibitors, inhibitors of HCV RNA-directed RNA polymerase, thymosin-α, 2 '-substituted ribonucleoside analogs, and immunomodulatory nucleoside analogs.

[0013] In another aspect, the present invention features methods of treating a viral infection (e.g., an HCV infection, an HBV infection, etc.) in an individual, the methods generally involving administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more; and administering an effective amount of pirfenidone or a pirfenidone analog. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In some embodiments, the method provides any of the foregoing PEGylated IFN-α and pirfenidone or pirfenidone analog combination regimens for the treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.) in an individual, and further provides administering to the individual an effective amount or amounts of one or more additional therapeutic agents. In some embodiments, the methods provide any of the foregoing PEGylated IFN-α and pirfenidone or pirfenidone analog combination regimens for the treatment of an HCV infection in an individual, and further provides administering to the individual an effective amount or amounts of one or more drugs selected from the group of ribavirin, NS3 inhibitors, inhibitors of HCV RNA-directed RNA polymerase, thymosin-α, 2 '-substituted ribonucleoside analogs, and immunomodulatory nucleoside analogs.

[0014] In another aspect, the present invention features methods of treating cancer in an individual, the methods generally involving administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In some embodiments, the method for treating cancer in an individual involves subjecting the individual to any of the foergoing PEGylated IFN-α regimens as a monotherapy. In other embodiments, the method provides any of the foregoing PEGylated IFN-α regimens for the treatment of cancer in an individual, and further providing administering to the individual an effective amount or amounts of one or more additional anti-cancer agents.

[0015] In another aspect, the present invention features methods of treating a cancer in an individual, the methods generally involving administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more; and administering an effective amount of pirfenidone or a pirfenidone analog. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In other embodiments, the method provides any of the foregoing PEGylated IFN-α and pirfenidone or pirfenidone analog combination regimens for the treatment of a cancer in an individual, and further provides administering to the individual an effective amount or amounts of one or more additional anti-cancer agents.

[0016] In another aspect, the present invention features methods of treating a proliferative disorder (e.g., cancer, a fibrotic disorder, an angiogenic disorder) in an individual, the methods generally involving administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more; and administering an effective amount of a Type II interferon receptor agonist, e.g., IFN-γ. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In some embodiments, the method provides any of the foregoing PEGylated IFN-α and Type II interferon receptor agonist combination regimens for the treatment of a proliferative disorder in an individual, and further provides administering to the individual an effective amount or amounts of one or more additional anti-cancer, anti-fibrotic or anti-angiogenic agents. In some embodiments, the methods provide any of the foregoing PEGylated IFN-α and Type II interferon receptor agonist combination regimens for the treatment of a proliferative disorder in an individual, and further provides administering to the individual an effective amount of pirfenidone or a pirfenidone analog.

[0017] In another aspect, the present invention features methods of treating a fibrotic disorder in an individual, the methods generally involving administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more; administering an effective amount of a Type II interferon receptor agonist, e.g., IFN-γ; and administering an effective amount of a TNF antagonist. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In some embodiments, the method provides any of the foregoing PEGylated IFN-α, Type II interferon receptor agonist, and TNF antagonist combination regimens for the treatment of a fibrotic disorder in an individual, and further provides administering to the individual an effective amount or amounts of one or more additional anti-fibrotic agents. In some embodiments, the methods provide any of the foregoing PEGylated IFN-α, Type II interferon receptor agonist, and TNF antagonist combination regimens for the treatment of a fibrotic disorder in an individual, and further provides administering to the individual an effective amount of pirfenidone or a pirfenidone analog.

[0018] In another aspect, the invention features any of the above-described methods in which the PEGylated IFN-α is a conjugate wherein the PEG moiety is linked to either the alpha- amino group of the N-terminal residue in the CIFN polypeptide or the epsilon-amino group of a lysine residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon-amino group of the lysine residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon-amino group of the lysine residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon- amino group of the lysine residue in the CIFN polypeptide, thereby forming a hydrolytically stable linkage between the PEG moiety and the CIFN polypeptide.

[0019] In another aspect, the invention features any of the above-described methods in which the PEGylated IFN-α is a conjugate wherein the PEG moiety is linked to the N-terminal residue in the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the alpha- amino group of the N-terminal residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the alpha-amino group of the N-terminal residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the alpha-amino group of the N-terminal residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the alpha-amino group of the N-terminal residue of the CIFN polypeptide.

[0020] In another aspect, the invention features any of the above-described methods in which the PEGylated IFN-α is a conjugate wherein the PEG moiety is linked to a lysine residue in the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the epsilon-amino group of a lysine residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the lysine group in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the lysine group in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon-amino group of the lysine residue in the CIFN polypeptide.

[0021] In another aspect, the invention features any of the above-described methods in which the PEGylated IFN-α is a conjugate wherein the PEG moiety is linked to a surface-exposed lysine residue in the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the epsilon-amino group of a surface-exposed lysine residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon- amino group of the surface-exposed lysine residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the surface-exposed lysine residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon- amino group of the surface-exposed lysine residue in the CIFN polypeptide.

[0022] In another aspect, the invention features any of the above-described methods in which the PEGylated IFN-α is a conjugate wherein the PEG moiety is linked to a lysine chosen from lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165 of the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the epsilon-amino group of a lysine chosen from lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165 of the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide.

[0023] In another aspect, the invention features any of the above-described methods in which the PEGylated IFN-α is a conjugate wherein the PEG moiety is linked to a lysine chosen from lys50, lys71, lys134, lys135, and lys165 of the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the epsilon-amino group of a lysine chosen from lys , lys , lys , lys , and lys165 of the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide.

[0024] In connection with the above-described monopegylated CIFN molecules, the invention contemplates embodiments of each such molecule where the CIFN polypeptide is chosen from interferon alpha-coni, interferon alpha-con2, and interferon alpha-con3, the amino acid sequences of which CIFN polypeptides are disclosed in U.S. Pat. No. 4,695,623.

[0025] In another aspect, the invention also features any of the above-described methods in which the PEGylated IFN-α is a composition comprising a population of monopegylated consensus interferon (CIFN) molecules, where the population consists of one or more species of molecules, and where each species is comprised of a single CIFN polypeptide and a single PEG moiety, where the PEG moiety is linear and about 30 kD in molecular weight and is directly or indirectly attached through a covalent linkage to either the N-terminal residue or a lysine residue in the CIFN polypeptide. In further embodiments, in each such species in the population the linkage comprises an amide bond between the PEG moiety and either the alpha- amino group of the N-terminal residue or the epsilon-amino group of the lysine residue in the CIFN polypeptide. In still further embodiments, in each such species in the population the linkage comprises an amide bond between a propionyl group of the PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon-amino group of the lysine residue in the CIFN polypeptide. In additional embodiments, in each such species in the population the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon-amino group of the lysine residue in the CIFN polypeptide.

[0026] In another aspect, the invention features any of the above-described methods in which the PEGylated IFN-α is a population consisting of one or more species of molecules, where each species is comprised of a single CIFN polypeptide and a single PEG moiety, and where the PEG moiety is linear and about 30 kD in molecular weight and is directly or indirectly attached through a covalent linkage to either the N-terminal residue or a surface-exposed lysine residue in the CIFN polypeptide. In further embodiments, in each such species in the population the linkage comprises an amide bond between the PEG moiety and either the alpha- amino group of the N-terminal residue or the epsilon-amino group of the surface-exposed lysine residue in the CIFN polypeptide. In still further embodiments, in each such species in the population the linkage comprises an amide bond between a propionyl group of the PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon-amino group of the surface-exposed lysine residue in the CIFN polypeptide. In additional embodiments, in each such species in the population the amide bond is formed by condensation of an alpha- methoxy, omega-propanoic acid activated ester of the PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon-amino group of the surface-exposed lysine residue in the CIFN polypeptide.

[0027] In another aspect, the invention features any of the above-described methods in which the PEGylated IFN-α is a population consisting of one or more species of molecules, where each species is comprised of a single CIFN polypeptide and a single PEG moiety, and where the PEG moiety is linear and about 30 kD in molecular weight and is directly or indirectly attached through a covalent linkage to either the N-terminal residue or a lysine residue chosen from lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165 of the CIFN polypeptide. In further embodiments, in each such species in the population the linkage comprises an amide bond between the PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon-amino group of the lysine residue in the CIFN polypeptide. In still further embodiments, in each such species in the population the linkage comprises an amide bond between a propionyl group of the PEG moiety and either the alpha-amino group of the N- terminal residue or the epsilon-amino group of the lysine residue in the CIFN polypeptide. In additional embodiments, in each such species in the population the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon-amino group of the lysine residue in the CIFN polypeptide.

[0028] In another aspect, the invention features any of the above-described methods in which the PEGylated IFN-α is a population consisting of one or more species of molecules, where each species is comprised of a single CIFN polypeptide and a single PEG moiety, and where the PEG moiety is linear and about 30 kD in molecular weight and is directly or indirectly attached through a covalent linkage to either the N-terminal residue or a lysine residue chosen from lys121, lys134, lys135, and lys165 of the CIFN polypeptide. In further embodiments, in each such species in the population the linkage comprises an amide bond between the PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon-amino group of the lysine residue in the CIFN polypeptide. In still further embodiments, in each such species in the population the linkage comprises an amide bond between a propionyl group of the PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon-amino group of the lysine residue in the CIFN polypeptide. In additional embodiments, in each such species in the population the amide bond is formed by condensation of an alpha-methoxy, omega- propanoic acid activated ester of the PEG moiety and either the alpha-amino group of the N- terminal residue or the epsilon-amino group of the lysine residue in the CIFN polypeptide.

[0029] In another aspect, the invention features any of the above-described methods in which the PEGylated IFN-α is a population consisting of one or more species of monopegylated CIFN in which the PEG moiety is linked to the N-terminal residue of the CIFN polypeptide. In other embodiments, in each such species in the population the PEG moiety is linked to the alpha-amino group of the N-terminal residue in the CIFN polypeptide. In further embodiments, in each such species in the population the linkage comprises an amide bond between the PEG moiety and the alpha-amino group of the N-terminal residue in the CIFN polypeptide. In still further embodiments, in each such species in the population the linkage comprises an amide bond between a propionyl group of the PEG moiety and the alpha-amino group of the N-terminal residue in the CIFN polypeptide. In additional embodiments, in each such species in the population the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the alpha-amino group of the N- terminal residue of the CIFN polypeptide.

[0030] In another aspect, the invention features any of the above-described methods in which the PEGylated IFN-α is a population consisting of one or more species of monopegylated CIFN in which the PEG moiety is linked to a lysine residue in the CIFN polypeptide. In other embodiments, in each such species in the population the PEG moiety is linked to the epsilon- amino group of a lysine residue in the CIFN polypeptide. In further embodiments, in each such species in the population the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the lysine group in the CIFN polypeptide. In still further embodiments, in each such species in the population the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the lysine group in the CIFN polypeptide. In additional embodiments, in each such species in the population the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon-amino group of the lysine residue in the CIFN polypeptide.

[0031] In another aspect, the invention features any of the above-described methods in which the PEGylated IFN-α is a population consisting of one or more species of monopegylated CIFN in which the PEG moiety is linked to a surface-exposed lysine residue in the CIFN polypeptide. In further embodiments, in each such species in the population the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the surface- exposed lysine residue in the CIFN polypeptide. In still further embodiments, in each such species in the population the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the surface-exposed lysine residue in the CIFN polypeptide. In additional embodiments, in each such species in the population the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon-amino group of the surface-exposed lysine residue in the CIFN polypeptide.

[0032] In another aspect, the invention features any of the above-described methods in which the PEGylated IFN-α is a population consisting of one or more species of monopegylated CIFN in which the PEG moiety is linked to a lysine residue chosen from lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165 of the CIFN polypeptide. In other embodiments, in each such species in the population the PEG moiety is linked to the epsilon-amino group of a lysine chosen from lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165 ofthe CIFN polypeptide. In further embodiments, in each such species in the population the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group ofthe chosen lysine residue in the CIFN polypeptide. In still further embodiments, in each such species in the population the linkage comprises an amide bond between a propionyl group ofthe PEG moiety and the epsilon-amino group ofthe chosen lysine residue in the CIFN polypeptide. In additional embodiments, in each such species in the population the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester ofthe PEG moiety and the epsilon-amino group ofthe chosen lysine residue in the CIFN polypeptide.

[0033] In another aspect, the invention features any ofthe above-described methods in which the PEGylated IFN-α is a population consisting of one or more species of monopegylated CIFN in which the PEG moiety is linked to a lysine residue chosen from lys121, lys134, lys135, and lys 65 ofthe CIFN polypeptide. In other embodiments, in each such species in the population the PEG moiety is linked to the epsilon-amino group of a lysine chosen from lys121, lys134, lys135, and lys165 ofthe CIFN polypeptide. In further embodiments, in each such species in the population the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group ofthe chosen lysine residue in the CIFN polypeptide. In still further embodiments, in each such species in the population the linkage comprises an amide bond between a propionyl group ofthe PEG moiety and the epsilon-amino group ofthe chosen lysine residue in the CIFN polypeptide. In additional embodiments, in each such species in the population the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester ofthe PEG moiety and the epsilon-amino group ofthe chosen lysine residue in the CIFN polypeptide.

[0034] In connection with each ofthe above-described populations of monopegylated CIFN molecules where such monopegylated CIFN molecules can comprise a PEG moiety linked to a lysine residue of a CIFN polypeptide, it will be understood that the invention contemplates embodiments characterized by a plurality of species of monopegylated, lysine-derivatized CIFN molecules, where each such species is characterized by a site of linkage that is not the same as the site of linkage in another species.

[0035] In connection with each ofthe above-described populations of monopegylated CIFN molecules, the invention contemplates embodiments where the molecules in each such population comprise a CIFN polypeptide chosen from interferon alpha-coni, interferon alpha- con2, and interferon alpha-con3. [0036] The invention further features any ofthe above-described methods in which the PEGylated IFN-α is a product that is produced by the process of reacting CIFN polypeptide with a succinimidyl ester of alpha-methoxy, omega-propionylpoly(ethylene glycol) (mPEGspa) that is linear and about 30 kD in molecular weight, where the reactants are initially present at a molar ratio of about 1 : 1 to about 1 :5 CIFN:mPEGspa, and where the reaction is conducted at a pH of about 7 to about 9, followed by recovery ofthe monopegylated CIFN product ofthe reaction. In one embodiment, the reactants are initially present at a molar ratio of about 1 :3 CIFN:mPEGspa and the reaction is conducted at a pH of about 8. In another embodiment where the PEGylated IFN-α is generated by a scaled-up procedure needed for toxicological and clinical investigations, the reactants are initially present in a molar ratio of 1 :2 CIFN:mPEGspa and the reaction is conducted at a pH of about 8.0.

[0037] In connection with the each ofthe above-described methods in which the PEGylated IFN-α is a product ofthe process of reacting CIFN polypeptide with mPEGspa, the invention contemplates embodiments where the CIFN reactant is chosen from interferon alpha-conl5 interferon alpha-con2, and interferon alpha-con3.

BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 is a graph depicting mean PEG-alfacon serum pharmacokmetic profiles from six subjects/group.

[0039] Figures 2A and 2B depict dose corrected Cmax (pg/mL; Figure 2A) and AUC0.iast (pg*h mL; Figure 2B) vs. body mass index (BMI) values by dose group.

[0040] Figure 3 depicts mean serum pharmacokmetic profiles for 4-6 subjects and corresponding fitted curves using a 1-compartment model.

[0041] Figures 4A-4G depict simulated serum pharmacokmetic profiles for various dosing regimens. Each panel in Figures 4A-4G uses different datasets that are fitted to a 1- compartment model. Figure 4A depicts simulated serum pharmacokmetic profiles for a dosing regimen with dosing every 10 days with 60 μg. Figure 4B depicts simulated serum pharmacokmetic profiles for a dosing regimen with dosing every 10 days with 100 μg. Figure 4C depicts simulated serum pharmacokmetic profiles for a dosing regimen with dosing every 10 days with 150 μg. Figure 4D depicts simulated serum pharmacokmetic profiles for a dosing regimen with dosing every 10 days with 200 μg. Figure 4E depicts simulated serum pharmacokmetic profiles for a dosing regimen with dosing every 7 days with 100 μg. Figure 4F depicts simulated serum pharmacokmetic profiles for a dosing regimen with dosing every 7 days with 150 μg. Figure 4G depicts simulated serum pharmacokmetic profiles for a dosing regimen with dosing every 7 days with 200 μg. [0042] Figure 5 depicts mean percent (%) change in serum 2',5'-oligoadenylate synthetase (OAS) for 6 subjects/dose group. The dosage of subcutaneous PEG-alfacon received in each dosage group is identified in the figure legend. The group treated with 15 μg subcutaneous Infergen® interferon alfacon-1 is identified as "Control" in the figure legend. [0043] Figure 6 depicts measured and predicted percent (%) change in OAS serum values expressed as percent of baseline (pretreatment) values, from pharmacokinetic/pharmacodynamic (PK-PD) modeling of mean serum profiles using an Emax model with minimum response fixed at 0. [0044] Figure 7 depicts the amino acid sequence ofthe consensus interferon IFN-alpha conl (SEQ ID NO:l).

DEFINITIONS

[0045] As used herein, the terms "treatment," "treating," and the like, refer to obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse affect attributable to the disease. "Treatment," as used herein, covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease or a symptom of a disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it (e.g., including diseases that may be associated with or caused by a primary disease (as in liver fibrosis that can result in the context of chronic HCV infection); (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression ofthe disease.

[0046] The terms "individual," "host," "subject," and "patient" are used interchangeably herein, and refer to a mammal, including, but not limited to, primates, including simians and humans.

[0047] The term "treatment failure patients" (or "treatment failures") as used herein generally refers to HCV-infected patients who failed to respond to previous therapy for HCV (referred to as "non-responders") or who initially responded to previous therapy, but in whom the therapeutic response was not maintained (referred to as "relapsers"). The previous therapy generally can include treatment with IFN-α monotherapy or IFN-α combination therapy, where the combination therapy may include administration of IFN-α and an antiviral agent such as ribavirin.

[0048] The term "pharmacokmetic profile," as used herein, refers to the profile ofthe curve defined by a patient's serum concentration of PEGylated IFN-α as a function of time, following the administration of PEGylated IFN-α to the patient. "Area under the curve," or "AUC," refers to the integrated area under the curve defined by a patient's serum concentration of PEGylated IFN-α as a function of time, following the administration of PEGylated IFN-α to the patient.

[0049] As used herein, the term "pirfenidone" refers to 5-methyl-l-phenyl-2-(lH)-pyridone. As used herein, the term "pirfenidone analog" refers to any compound of Formula I, IIA or IIB below. A "specific pirfenidone analog," and all grammatical variants thereof, refers to, and is limited to, each and every pirfenidone analog shown in Table 1.

[0050] As used herein, the term "a Type II interferon receptor agonist" refers to any naturally- occurring or non-naturally-occurring ligand of a human Type II interferon receptor which binds to and causes signal transduction via the receptor. Type II interferon receptor agonists include interferons, including naturally-occurring interferons, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising an interferon and a heterologous protein, shuffled interferons; antibody specific for an interferon receptor; non-peptide chemical agonists; and the like.

[0051] As used herein, the term "a Type III interferon receptor agonist" refers to any naturally occurring or non-naturally occurring ligand of human IL-28 receptor α ("IL-28R"), the amino acid sequence of which is described by Sheppard, et al., infra., that binds to and causes signal transduction via the receptor.

[0052] The term "antineoplastic" agent, drug or compound is meant to refer to any agent, including any chemotherapeutic agent, biological response modifier (including without limitation (i) proteinaceous, i.e. peptidic, molecules capable of elaborating or altering biological responses and (ii) non-proteinaceous, i.e. non-peptidic, molecules capable of elaborating or altering biological responses), cytotoxic agent, or cytostatic agent, that reduces proliferation of a neoplastic cell.

[0053] The term "chemotherapeutic agent" or "chemotherapeutic" (or "chemotherapy", in the case of treatment with a chemotherapeutic agent) is meant to encompass any non- proteinaceous (i.e., non-peptidic) chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as tliiotepa and cyclophosphamide (CYTOXAN™); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CBI-TMI); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, foremustine, lomustine, nimustine, ranimustine; antibiotics such as the enediyne antibiotics (e.g. calicheamicin, especially calicheamicin gammall and calicheamicin hill, see, e.g., Agnew, Chem. Intl. Ed. Engl., 33: 183-186 (1994); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromomophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L- norleucine, doxorubincin (Adramycin™) (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as demopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti- adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replinisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxanfrone; podophyllinic acid; 2- ethylhydrazide; procarbazine; PSK®; razoxane; rliizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiopeta; taxoids, e.g. paclitaxel (TAXOL®, Bristol Meyers Squibb Oncology, Princeton, NJ) and docetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine (Gemzar™); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitroxantrone; vancristine; vinorelbine (Navelbine™); novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeoloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluromethylornifhine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any ofthe above. Also included in the definition of "chemotherapeutic agent" are anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including Nolvadex™), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston™); inhibitors ofthe enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutetl imide, megestrol acetate (Megace™), exemestane, formestane, fadrozole, vorozole (Rivisor™), letrozole (Femara™), and anastrozole (Arimidex™); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any ofthe above.

[0054] The term "anti-inflammatory" agent, drug or compound is meant to include agents prevent or reduce inflammation and include, for example, and IL-1 antagonists, such as IL- lRa.

[0055] The term "anti-fibrotic agent," as used herein, includes any agent that reduces or treats fibrosis, including, but not limited to, a steroidal anti-inflammatory agent; and a TNF antagonist.

[0056] The term "hepatitis virus infection" refers to infection with one or more of hepatitis A, B, C, D, or E virus, with blood-borne hepatitis viral infection being of particular interest, particularly hepatitis C virus infection.

[0057] The term "sustained viral response" (SVR; also referred to as a "sustained response" or a "durable response"), as used herein, refers to the response of an individual to a treatment regimen for HCV infection, in terms of serum HCV titer. Generally, a "sustained viral response" refers to no detectable HCV RNA (e.g., less than about 500, less than about 200, or less than about 100 genome copies per milliliter serum) found in the patient's serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of treatment.

[0058] The term "proliferative disorder" and "proliferative disease" are used interchangeably to refer to any disease or condition characterized by pathological cell growth or proliferation, including all fibroproliferative or fibrotic conditions, angiogenesis-mediated diseases, neoplastic disorders, and chronic inflammatory disorders mediated by dysregulated or unrestrained cellular proliferation.

[0059] The term "angiogenesis-mediated disease," "angiogenesis-mediated disorder," "angiogenic disease," and "angiogenic disorder" are used interchangeably to refer to any disease characterized by pathological neovascularization, including all solid tumors, rheumatoid arthritis, psoriasis, atherosclerosis, diabetic and other retinopathies, retrolental fibroplasia, age-related macular degeneration, neovascular glaucoma, hemangiomas, thyroid hyperplasias (including Grave's disease), an inflammatory bowel disease such as, for example, Crohn's disease or ulcerative colitis, and corneal transplantation.

[0060] A "fibrotic condition," "fibroproliferative condition," "fibrotic disease," "fibroproliferative disease," "fibrotic disorder," and "fibroproliferative disorder" are used interchangeably to refer to a condition, disease or disorder that is characterized by dysregulated proliferation or activity of fibroblasts and/or pathologic or excessive accumulation of collagenous tissue. Typically, any such disease, disorder or condition is amenable to treatment by administration of a compound having anti-fibrotic activity. Fibrotic disorders include, but are not limited to, pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and pulmonary fibrosis from a known etiology, liver fibrosis, and renal fibrosis. Other exemplary fibrotic conditions include musculoskeletal fibrosis, cardiac fibrosis, post-surgical adhesions, scleroderma, glaucoma, and skin lesions such as keloids.

[0061] The terms "cancer," "neoplasm," and "tumor" are used interchangeably herein to refer to cells which exhibit relatively autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation. Cancerous cells can be benign or malignant.

[0062] As used herein, the term "hepatic fibrosis," used interchangeably herein with "liver fibrosis," refers to the growth of scar tissue in the liver that can occur in the context of a chronic hepatitis infection. [0063] As used herein, the term "liver function" refers to a normal function ofthe liver, including, but not limited to, a synthetic function, including, but not limited to, synthesis of proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'-nucleosidase, γ- glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics; and the like.

[0064] The term "dosing event" as used herein refers to administration of a therapeutic agent to a patient in need thereof, which event may encompass one or more releases of a therapeutic agent from a drug dispensing device. Thus, the term "dosing event," as used herein, includes, but is not limited to, installation of a continuous delivery device (e.g., a pump or other controlled release injectible system); and a single subcutaneous injection followed by installation of a continuous delivery system.

[0065] "Continuous delivery" as used herein (e.g. , in the context of "continuous delivery of a substance to a tissue") is meant to refer to movement of drug to a delivery site, e.g., into a tissue in a fashion that provides for delivery of a desired amount of substance into the tissue over a selected period of time, where about the same quantity of drug is received by the patient each minute during the selected period of time.

[0066] "Controlled release" as used herein (e.g. , in the context of "controlled drug release") is meant to encompass release of substance (e.g., a Type I or Type III interferon receptor agonist, e.g., IFN-α) at a selected or otherwise controllable rate, interval, and/or amount, which is not substantially influenced by the environment of use. "Controlled release" thus encompasses, but is not necessarily limited to, substantially continuous delivery, and patterned delivery (e.g., intermittent delivery over a period of time that is interrupted by regular or irregular time intervals).

[0067] "Immunomodulatory" agent, compound or molecule as used herein refers to any agent, compound or molecule that can stimulate or enhance immune cell-mediated clearance of virally infected tissues.

[0068] "Patterned" or "temporal" as used in the context of drug delivery is meant delivery of drug in a pattern, generally a substantially regular pattern, over a pre-selected period of time (e.g., other than a period associated with, for example a bolus injection). "Patterned" or "temporal" drug delivery is meant to encompass delivery of drug at an increasing, decreasing, substantially constant, or pulsatile, rate or range of rates (e.g., amount of drug per unit time, or volume of drug formulation for a unit time), and further encompasses delivery that is continuous or substantially continuous, or chronic.

[0069] The term "controlled drug delivery device" is meant to encompass any device wherein the release (e.g., rate, timing of release) of a drug or other desired substance contained therein is controlled by or determined by the device itself and not substantially influenced by the environment of use, or releasing at a rate that is reproducible within the environment of use.

[0070] By "substantially continuous" as used in, for example, the context of "substantially continuous infusion" or "substantially continuous delivery" is meant to refer to delivery of drug in a manner that is substantially uninterrupted for a pre-selected period of drug delivery, where the quantity of drug received by the patient during any 8 hour interval in the pre-selected period never falls to zero. Furthermore, "substantially continuous" drug delivery can also encompass delivery of drug at a substantially constant, pre-selected rate or range of rates (e.g., amount of drug per unit time, or volume of drug formulation for a unit time) that is substantially uninterrupted for a pre-selected period of drug delivery.

[0071] By "substantially steady state" as used in the context of a biological parameter that may vary as a function of time, it is meant that the biological parameter exhibits a substantially constant value over a time course, such that the area under the curve defined by the value of the biological parameter as a function of time for any 8 hour period during the time course (AUC8hr) is no more than about 20% above or about 20% below, and preferably no more than about 15% above or about 15% below, and more preferably no more than about 10% above or about 10% below, the average area under the curve ofthe biological parameter over an 8 hour period during the time course (AUC8hr average)- The AUC8hr average s defined as the quotient (q) ofthe area under the curve ofthe biological parameter over the entirety ofthe time course (AUCtotai) divided by the number of 8 hour intervals in the time course (tt0taiι/3days), i-e., q = (AUCtotai)/ (ttotaiι/3days)- For example, in the context of a serum concentration of a drug, the serum concentration ofthe drug is maintained at a substantially steady state during a time course when the area under the curve of serum concentration ofthe drug over time for any 8 hour period during the time course (AUC8i,r) is no more than about 20% above or about 20% below the average area under the curve of serum concentration ofthe drug over an 8 hour period in the time course (AUC8hr average), i-e., the AUC8hr is no more than 20% above or 20% below the AUC8ιιr average for the serum concentration ofthe drug over the time course.

[0072] As used herein, any compound or agent described as "effective for the avoidance or amelioration of side effects induced by PEGylated IFN-α," or as "effective for reducing or eliminating the severity or occurrence of side effects induced by PEGylated IFN-α," or any compound or agent described by language with a meaning similar or equivalent to that of either ofthe foregoing quoted passages, is/are defined as a compound(s) or agent(s) that when co-administered to a patient in an effective amount along with a given dosing regimen of PEGylated IFN-α monotherapy or combination therapy, abates or eliminates the severity or occurrence of side effects experienced by a patient in response to the given dosing regimen of the PEGylated IFN-α monotherapy or combination therapy, as compared to the severity or occurrence of side effects that would have been experienced by the patient in response to the same dosing regimen ofthe PEGylated IFN-α monotherapy or combination therapy without co-administration ofthe agent.

[0073] In many embodiments, the effective amounts of a PEGylated IFN-α and a second therapeutic agent are synergistic amounts. As used herein, a "synergistic combination" or a "synergistic amount" of a PEGylated IFN-α and a second therapeutic agent is a combination or amount that is more effective in the therapeutic or prophylactic treatment of a disease than the incremental improvement in treatment outcome that could be predicted or expected from a merely additive combination of (i) the therapeutic or prophylactic benefit ofthe PEGylated IFN-α when administered at that same dosage as a monotherapy and (ii) the therapeutic or prophylactic benefit ofthe second therapeutic agent when administered at the same dosage as a monotherapy.

[0074] Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope ofthe present invention will be limited only by the appended claims.

[0075] Where a range of values is provided, it is understood that each intervening value, to the tenth ofthe unit ofthe lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both ofthe limits, ranges excluding either or both of those included limits are also included in the invention.

[0076] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing ofthe present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

[0077] It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a therapeutic agent" includes a plurality of such therapeutic agents and reference to "the dosing regimen" includes reference to one or more dosing regimens and equivalents thereof known to those skilled in the art, and so forth.

[0078] The publications discussed herein are provided solely for their disclosure prior to the filing date ofthe present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

DETAILED DESCRIPTION OF THE INVENTION

[0079] The present invention provides methods of treating a viral infection (e.g., methods of treating an HCV infection, methods of treating an HBV infection); and methods of treating a proliferative disorder. The methods generally involve administering a polyethylene glycol- modified IFN-α at a frequency of less than once per week, where the polyethylene glycol- modified IFN-α is a consensus IFN-α molecule conjugated to a single, linear, 30 kD poly(ethylene glycol) molecule. TREATMENT METHODS

[0080] The present invention provides methods of treating a viral infection, e.g., a hepatitis C virus (HCV) infection, a hepatitis B virus (HBV) infection, etc. The present invention further provides methods of treating a proliferative disorder, e.g., cancer, a fibrotic disorder, an angiogenic disorder. The methods generally involve administering to an individual in need thereof an effective amount of a polyethylene glycol-modified interferon-alpha (PEGylated IFN-α), where the PEGylated IFN-α is administered at a frequency of less than once per week, e.g., once every 8 days or less frequently, and where the PEGylated IFN-α is a consensus IFN- α molecule conjugated to a single, linear, 30 kD poly(ethylene glycol) molecule. In some embodiments, the PEGylated IFN-α is administered as monotherapy. In other embodiments, the PEGylated IFN-α is administered in combination therapy with at least one other therapeutic agent. The additional therapeutic agent will depend, in part, upon the nature ofthe disorder being treated. In many embodiments, the PEGylated interferon-α is a consensus interferon, such as INFERGEN® interferon alfacon-1, that is PEGylated with a single, linear, 30 kD poly (ethylene glycol) moiety, i.e., the PEGylated interferon-α is a monoPEG (30 kD, linear)-ylated consensus IFN-α. Viral diseases

[0081] The present invention provides methods for treating viral infection (e.g., HCV infection, HBV infection, etc.). The methods generally involve administering PEGylated IFN- α, e.g., monoPEG (30 kD, linear)-ylated consensus IFN-α, to an individual in an amount that is effective to ameliorate the clinical course ofthe disease, where the PEGylated IFN-α is administered at a frequency of less than once per week. The PEGylated IFN-α is administered at a dosing interval of once every 8 days or more, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In some embodiments, the method for treating a viral infection (e.g., HCV infection, HBV infection, etc.) in an individual involves administering PEGylated IFN-α in monotherapy. In other embodiments, the method provides any ofthe foregoing PEGylated IFN-α regimens for the treatment of a viral infection (e.g., HCV infection, HBV infection, etc.) in an individual, and further provides administering to the individual an effective amount or amounts of one or more additional therapeutic agents.

[0082] In some embodiments, the method provides any ofthe foregoing PEGylated IFN-α regimens for the treatment of a viral infection (e.g., HCV infection, HBV infection, etc.) in an individual, and further provides administering to the individual an effective amount of ribavirin.

[0083] In some embodiments, the method provides any ofthe foregoing PEGylated IFN-α regimens for the treatment of a viral infection (e.g., HCV infection, HBV infection, etc.) in an individual, and further provides administering to the individual an effective amount of pirfenidone or a pirfenidone analog.

[0084] In some embodiments, the method provides any ofthe foregoing PEGylated IFN-α regimens for the treatment of a viral infection (e.g., HCV infection, HBV infection, etc.) in an individual, and further provides administering to the individual an effective amount of a TNF antagonist.

[0085] In some embodiments, the method provides any ofthe foregoing PEGylated IFN-α regimens for the treatment of a viral infection (e.g., HCV infection, HBV infection, etc.) in an individual, and further provides administering to the individual an effective amount of thymosin-α.

[0086] In some embodiments, the method provides any ofthe foregoing PEGylated IFN-α regimens for the treatment of a viral infection (e.g., HCV infection, HBV infection, etc.) in an individual, and further provides administering to the individual an effective amount of a 2'- substituted ribonucleoside analog.

[0087] In some embodiments, the method provides any ofthe foregoing PEGylated IFN-α regimens for the treatment of a viral infection (e.g., HCV infection, HBV infection, etc.) in an individual, and further provides administering to the individual an effective amount of an immunomodulatory nucleoside analog.

[0088] In some embodiments, the method provides any of the foregoing PEGylated IFN-α regimens for the treatment of HCV infection in an individual, and further provides administering to the individual an effective amount of an NS3 inhibitor.

[0089] In some embodiments, the method provides any ofthe foregoing PEGylated IFN-α regimens for the treatment of HCV infection in an individual, and further provides administering to the individual an effective amount of an inhibitor of an HCV RNA-dependent RNA polymerase.

[0090] In some embodiments, a subject method of treating a viral infection (e.g., HCV infection, HBV infection, etc.) involves administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more; and administering an effective amount of a Type II interferon receptor agonist. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In some embodiments, the method provides any ofthe foregoing PEGylated IFN-α and Type II interferon receptor agonist combination regimens for the treatment of a viral infection (e.g., HCV infection, HBV infection, etc.) in an individual, and further provides administering to the individual an effective amount or amounts of one or more additional therapeutic agents. In some embodiments, the methods provide any ofthe foregoing PEGylated IFN-α and Type II interferon receptor agonist combination regimens for the treatment of HCV infection in an individual, and further provide administering to the individual an effective amount of one or more additional drugs selected from the group of ribavirin, pirfenidone, pirfenidone analogs, TNF antagonists, thymosin-α, 2 '-substituted ribonucleoside analogs, immunomodulatory nucleoside analogs, NS3 inhibitors, and inhibitors of HCV RNA-directed RNA polymerase. In some embodiments, the Type II interferon receptor agonist can be an IFN-γ.

[0091] In some embodiments, a subject method of treating a viral infection (e.g., HCV infection, HBV infection, etc.) involves administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more; administering an effective amount of a Type II interferon receptor agonist, e.g., IFN-γ; and administering an effective amount of a TNF-α antagonist. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In some embodiments, the methods provide any ofthe foregoing PEGylated IFN-α, Type II interferon receptor agonist, and TNF-α antagonist combination regimens for the treatment of viral infection (e.g., HCV infection, HBV infection, etc.) in an individual, and further provide administering to the individual an effective amount or amount of one or more additional therapeutic agents. In some embodiments, the methods provide any ofthe foregoing PEGylated IFN-α, Type II interferon receptor agonist, and TNF-α antagonist combination regimens for the treatment of HCV infection in an individual, and further provide administering to the individual an effective amount or amount of one or more additional drugs selected from the group of ribavirin, pirfenidone, pirfenidone analogs, thymosin-α, 2 '-substituted ribonucleoside analogs, immunomodulatory nucleoside analogs, NS3 inhibitors, and inhibitors of HCV RNA-directed RNA polymerase. In some embodiments, the Type II interferon receptor agonist can be an IFN-γ.

[0092] In some embodiments, a subject method of treating a viral infection (e.g., HCV infection, HBV infection, etc.) involves administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more; and administering an effective amount of ribavirin or a ribavirin analog. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In some embodiments, the method provides any ofthe foregoing PEGylated IFN-α and ribavirin or ribavirin analog regimens for the treatment of a viral infection in an individual, and the method further provides administering to the individual an effective amount or amount of one or more additional therapeutic agents. In some embodiments, the methods provide any ofthe foregoing PEGylated IFN-α and ribavirin combination regimens for the treatment of HCV infection in an individual, and further provide administering to the individual an effective amount or amounts of one or more additional drugs selected from the group of Type II interferon receptor agonists, TNF antagonists, pirfenidone, pirfenidone analogs, thymosin-α, 2'-substituted ribonucleoside analogs, immunomodulatory nucleoside analogs, NS3 inhibitors, and inhibitors of HCV RNA- directed RNA polymerase.

[0093] In some embodiments, a subject method of treating a viral infection (e.g., HCV infection, HBV infection, etc.) involves administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more; and administering an effective amount of pirfenidone or a pirfenidone analog. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In some embodiments, the method provides any ofthe foregoing PEGylated IFN-α and pirfenidone or pirfenidone analog combination regimens for the treatment of a viral infection (e.g., HCV infection, HBV infection, etc.) in an individual, and further provides administering to the individual an effective amount or amounts of one or more additional therapeutic agents. In some embodiments, the methods provide any ofthe foregoing PEGylated IFN-α and pirfenidone or pirfenidone analog combination regimens for the treatment of HCV infection in an individual, and further provides administering to the individual an effective amount or amounts of one or more additional drugs selected from the group of ribavirin, Type II interferon receptor agonists, TNF antagonists, thymosin-α, 2'-substituted ribonucleoside analogs, immunomodulatory nucleoside analogs, NS3 inhibitors, and inhibitors of HCV RNA- directed RNA polymerase.

[0094] In some embodiments, a subject method of treating a viral infection (e.g., HCV infection, HBV infection, etc.) involves administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more; and administering an effective amount of a TNF-α antagonist. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In some embodiments, the methods provide any ofthe foregoing PEGylated IFN-α and TNF-α antagonist combination regimens for the treatment of viral infection (e.g., HCV infection, HBV infection, etc.) in an individual, and further provide administering to the individual an effective amount or amount of one or more additional therapeutic agents. In some embodiments, the methods provide any ofthe foregoing PEGylated IFN-α and TNF-α antagonist combination regimens for the treatment of HCV infection in an individual, and further provide administering to the individual an effective amount or amount of one or more additional drugs selected from the group of ribavirin, Type II interferon receptor agonists, pirfenidone, pirfenidone analogs, thymosin-α, 2 '-substituted ribonucleoside analogs, immunomodulatory nucleoside analogs, NS3 inhibitors, and inhibitors of HCV RNA-directed RNA polymerase.

[0095] Whether a subject method is effective in treating a viral infection can be determined by a reduction in number or length of hospital stays, a reduction in time to viral clearance, a reduction of morbidity or mortality in clinical outcomes, or other indicator of disease response.

[0096] In general, an effective amount of PEGylated IFN-α is an amount that is effective to (i) reduce the time to viral clearance, (ii) reduce morbidity or mortality in the clinical course of the disease or (iii) reduce viral load in the patient.

[0097] The present invention provides methods for treating a hepatitis C virus (HCV) infection. The methods generally involve administering PEGylated IFN-α to an individual in need thereof in an amount that is effective to decrease viral load in the individual, and to achieve a sustained viral response.

[0098] Whether a subject method is effective in treating an HCV infection can be determined by measuring viral load, or by measuring a parameter associated with HCV infection, including, but not limited to, liver fibrosis, elevations in serum transaminase levels, and necroinflammatory activity in the liver. Indicators of liver fibrosis are discussed in detail below.

[0099] Viral load can be measured by measuring the titer or level of virus in serum. These methods include, but are not limited to, a quantitative polymerase chain reaction (PCR) and a branched DNA (bDNA) test. Quantitative assays for measuring the viral load (titer) of HCV RNA have been developed. Many such assays are available commercially, including a quantitative reverse transcription PCR (RT-PCR) (Amplicor HCV Monitor™, Roche Molecular Systems, New Jersey); and a branched DNA (deoxyribonucleic acid) signal amplification assay (Quantiplex™ HCV RNA Assay (bDNA), Chiron Corp., Emeryville, California). See, e.g., Gretch et al. (1995) Ann. Intern. Med. 123:321-329.

[00100] In general, an effective amount of PEGylated IFN-α is an amount that alone or in combination with other therapy for HCV infection is effective to reduce viral load to undetectable levels, e.g., to less than about 5000, less than about 1000, less than about 500, or less than about 200 genome copies/mL serum. In some embodiments, an effective amount of PEGylated IFN-α is an amount that is effective to reduce viral load to less than 100 genome copies/mL serum. In many embodiments, the methods ofthe invention achieve a sustained viral response, e.g., the viral load is reduced to undetectable levels for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of treatment.

[00101] As noted above, whether a subject method is effective in treating an HCV infection can be determined by measuring a parameter associated with HCV infection, such as liver fibrosis. Methods of determining the extent of liver fibrosis are discussed in detail below. In some embodiments, the level of a serum marker of liver fibrosis indicates the degree of liver fibrosis.

[00102] As one non-limiting example, levels of serum alanine aminotransferase (ALT) are measured, using standard assays. In general, an ALT level of less than about 45 international units is considered normal. In some embodiments, an effective amount of a PEGylated IFN-α is an amount that alone or in combination with other therapy for HCV infection is effective to reduce ALT levels to less than about 45 U/ml serum.

[00103] A therapeutically effective amount of a PEGylated IFN-α is an amount that alone or in combination with other therapy for HCV infection is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level ofthe marker in an untreated individual, or to a placebo-treated individual. Methods of measuring serum markers include immunological-based methods, e.g., enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.

[00104] In some embodiments, PEGylated IFN-α is administered as monotherapy. In other embodiments, PEGylated IFN-α is administered in combination therapy with at least one additional therapeutic agent. Suitable additional therapeutic agents for the treatment of an HCV infection include, but are not limited to, ribavirin; an NS3 inhibitor (e.g., an agent that specifically inhibits NS3 serine protease activity); an inhibitor of HCV RNA-dependent RNA polymerase (NS5); a nucleoside analog; thymosin-α; and the like. Cancer

[00105] The present invention provides methods of treating cancer in an individual. The methods generally involve administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD polyethylene glycol) molecule, at a dosing interval of 8 days or more. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In some embodiments, the method for treating cancer in an individual involves administering PEGylated IFN-α in monotherapy. In other embodiments, the method involves administering PEGylated IFN-α as an adjuvant to a standard cancer therapy, e.g., in combination therapy with one or more anti-cancer agents.

[00106] In some embodiments, a subject method of treating cancer is a combination therapy involving administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more; and administering an effective amount of pirfenidone or a pirfenidone analog. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In other embodiments, the method provides any ofthe foregoing PEGylated IFN-α and pirfenidone or a pirfenidone analog combination regimens for the treatment of cancer in an individual, and further provides administering to the individual one or more additional anti-cancer agents.

[00107] In some embodiments, a subject method of treating cancer is a combination therapy involving administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more; and administering an effective amount of a Type II interferon receptor agonist, e.g., IFN-γ. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In other embodiments, the method provides any ofthe foregoing PEGylated IFN-α and Type II interferon receptor agonist combination regimens for the treatment of cancer in an individual, and further provides administering to the individual one or more additional anti-cancer agents. In some embodiments, the method provides any ofthe foregoing PEGylated IFN-α and Type II interferon receptor agonist combination regimens for the treatment of cancer in an individual, and further provides administering to the individual an effective amount of pirfenidone or a pirfenidone analog. In some embodiments, the Type II interferon receptor agonist can be an IFN-γ.

[00108] The methods are effective to reduce a tumor load or reduce tumor progression by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 75%, at least about 85%, or at least about 90%, up to total eradication of the tumor or inhibition of tumor progression, when compared to a suitable control. Thus, in these embodiments, "effective amounts" of PEGylated IFN-α are amounts that alone or in combination with other therapy for cancer are sufficient to reduce tumor load or reduce tumor progression by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 75%, at least about 85%, or at least about 90%, up to total eradication ofthe tumor, or total inhibition of tumor progression, when compared to a suitable control. In an experimental animal system, a suitable control may be a genetically identical animal not treated with the subject drug therapy. In non-experimental systems, a suitable control may be the tumor load present before administering the subject drug therapy. Other suitable controls may be a placebo control.

[00109] Whether a tumor load has been decreased can be determined using any known method, including, but not limited to, measuring solid tumor mass; counting the number of tumor cells using cytological assays; fluorescence-activated cell sorting (e.g., using antibody specific for a tumor-associated antigen) to determine the number of cells bearing a given tumor antigen; computed tomography scanning, magnetic resonance imaging, and/or x-ray imaging ofthe tumor to estimate and/or monitor tumor size; measuring the amount of tumor-associated antigen in a biological sample, e.g., blood; and the like.

[00110] The methods are effective to reduce the growth rate of a tumor by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 75%, at least about 85%, or at least about 90%, up to total inhibition of growth ofthe tumor, when compared to a suitable control. Thus, in these embodiments, "effective amounts" of PEGylated IFN-α are amounts of PEGylated IFN-α that alone or in combination with other therapy for cancer are sufficient to reduce tumor growth rate by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 75%, at least about 85%, or at least about 90%, up to total inhibition of tumor growth, when compared to a suitable control. In an experimental animal system, a suitable control may be a genetically identical animal not treated with the subject drug therapy. In non-experimental systems, a suitable control may be the tumor growth rate existing before administering the subject drug therapy. Other suitable controls may be a placebo control. [00111] Whether growth of a tumor is inhibited can be determined using any known method, including, but not limited to, a proliferation assay; a 3H-thymidine uptake assay; and the like.

[00112] The methods are useful for treating a wide variety of cancers, including carcinomas, sarcomas, leukemias, and lymphomas.

[00113] Carcinomas that can be treated using a subject method include, but are not limited to, esophageal carcinoma, hepatocellular carcinoma, basal cell carcinoma (a form of skin cancer), squamous cell carcinoma (various tissues), bladder carcinoma, including transitional cell carcinoma (a malignant neoplasm ofthe bladder), bronchogenic carcinoma, colon carcinoma, colorectal carcinoma, gastric carcinoma, lung carcinoma, including small cell carcinoma and non-small cell carcinoma ofthe lung, adrenocortical carcinoma, thyroid carcinoma, pancreatic carcinoma, breast carcinoma, ovarian carcinoma, prostate carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, renal cell carcinoma, ductal carcinoma in situ or bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical carcinoma, uterine carcinoma, testicular carcinoma, osteogenic carcinoma, epitheheal carcinoma, and nasopharyngeal carcinoma, etc.

[00114] Sarcomas that can be treated using a subject method include, but are not limited to, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, chordoma, osteogenic sarcoma, osteosarcoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, and other soft tissue sarcomas.

[00115] Other solid tumors that can be treated using a subject method include, but are not limited to, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, menangioma, melanoma, neuroblastoma, and retinoblastoma.

[00116] Leukemias that can be treated using a subject method include, but are not limited to, a) chronic myeloproliferative syndromes (neoplastic disorders of multipotential hematopoietic stem cells); b) acute myelogenous leukemias (neoplastic transformation of a multipotential hematopoietic stem cell or a hematopoietic cell of restricted lineage potential; c) chronic lymphocytic leukemias (CLL; clonal proliferation of immunologically immature and functionally incompetent small lymphocytes), including B-cell CLL, T-cell CLL, prolymphocytic leukemia, and hairy cell leukemia; and d) acute lymphoblastic leukemias (characterized by accumulation of lymphoblasts). Lymphomas that can be treated using a subject method include, but are not limited to, B-cell lymphomas (e.g., Burkitt's lymphoma); Hodgkin's lymphoma; and. the like.

[00117] In many embodiments, the effective amounts of PEGylated IFN-α and an additional antineoplastic agent or biological response modifier are synergistic amounts. As used herein, a "synergistic combination" or a "synergistic amount" of PEGylated IFN-α and an additional antineoplastic/biological response modifier is a combined dosage that is more effective in the therapeutic or prophylactic treatment of cancer than the incremental improvement in treatment outcome that could be predicted or expected from a merely additive combination of (i) the therapeutic or prophylactic benefit of PEGylated IFN-α when administered at the same dosage as a monotherapy and (ii) the therapeutic or prophylactic benefit ofthe additional antineoplastic/biological response modifier when administered at that same dosage as a monotherapy.

[00118] In another aspect, the invention features a method of treating cancer by administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is an alkylating agent. In some embodiments, the alkylating agent is a nitrogen mustard. In other embodiments, the alkylating agent is an ethylenimine. In still other embodiments, the alkylating agent is an alkylsulfonate. In additional embodiments, the alkylating agent is a triazene. In further embodiments, the allkylating agent is a nitrosourea.

[00119] In another aspect, the invention features a method of treating cancer by administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is an antimetabolite. In some embodiments, the antimetabolite is a folic acid analog, such as methotrexate. In other embodiments, the antimetabolite is a purine analog, such as mercaptopurine, thioguanine and axathioprine. In still other embodiments, the antimetabolite is a pyrimidine analog, such as 5FU, UFT, capecitabine, gemcitabine and cytarabine. [00120] In another aspect, the invention features a method of treating cancer by administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(efhylene glycol) molecule, at a dosing interval of 8 days or more, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is a vinca alkyloid. In some embodiments, the vinca alkaloid is a taxane, such as paclitaxel. In other embodiments, the vinca alkaloid is a podophyllotoxin, such as etoposide, teniposide, ironotecan, and topotecan.

[00121] In another aspect, the invention features a method of treating cancer by administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is an antineoplastic antibiotic. In some embodiments, the antineoplastic antibiotic is doxorubicin.

[00122] In another aspect, the invention features a method of treating cancer by administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is a platinum complex. In some embodiments, the platinum complex is cisplatin. In other embodiments, the platinum complex is carboplatin.

[00123] In another aspect, the invention features a method of treating cancer by administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is a tyrosine kinase inhibitor. In some embodiments, the tyrosine kinase inhibitor is a receptor tyrosine kinase (RTK) inhibitor, such as type I receptor tyrosine kinase inhibitors (e.g., inhibitors of epidermal growth factor receptors), type II receptor tyrosine kinase inhibitors (e.g., inl ibitors of insulin receptor), type III receptor tyrosine kinase inhibitors (e.g., inhibitors of platelet- derived growth factor receptor), and type IV receptor tyrosine kinase inhibitors (e.g., fibroblast growth factor receptor). In other embodiments, the tyrosine kinase inhibitor is a non-receptor tyrosine kinase inhibitor, such as inhibitors of src kinases or j anus kinases.

[00124] In another aspect, the invention features a method of treating cancer by administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is an inhibitor of a receptor tyrosine kinase involved in growth factor signaling pathway(s). In some embodiments, the inhibitor is genistein. In other embodiments, the inhibitor is an epidermal growth factor receptor (EGFR) tyrosine kinase-specific antagonist, such as IRES S A™ gefitinib, TARCEVA™ erolotinib, or tyrphostin AG1478 (4-(3-chloroanilino)-6,7- dimethoxyquinazoline. In still other embodiments, the inhibitor is any indolinone antagonist of Flk-1/KDR (VEGF-R2) tyrosine kinase activity. In further embodiments, the inhibitor is any ofthe substituted 3-[(4,5,6,7-tetrahydro-lH-indol-2-yl) methylene] -1, 3 -dihydroindol-2-one antagonist of Flk-1/KDR (VEGF-R2), FGF-R1 or PDGF-R tyrosine kinase activity. In additional embodiments, the inhibitor is any substituted 3-[(3- or 4-carboxyethylpyrrol-2-yl) methylidenyl]indolin-2-one antagonist of Flt-1 (NEGF-R1), Flk-1/KDR (NEGF-R2), FGF-R1 or PDGF-R tyrosine kinase activity.

[00125] In another aspect, the invention features a method of treating cancer by administering to the individual an effective amount of PEGylated IFΝ-α, where the PEGylated IFΝ-α is a conjugate of a single consensus IFΝ-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is an inhibitor of a non-receptor tyrosine kinase involved in growth factor signaling pafhway(s). In some embodiments, the inhibitor is an antagonist of JAK2 tyrosine kinase activity, such as tyrphostin AG490 (2-cyano-3-(3,4-dihydroxyphenyl)-N-(benzyl)-2-propenamide). In other embodiments, the inhibitor is an antagonist of bcr-abl tyrosine kinase activity, such as GLEENEC™ imatinib mesylate.

[00126] In another aspect, the invention features a method of treating cancer by administering to the individual an effective amount of PEGylated IFΝ-α, where the PEGylated IFΝ-α is a conjugate of a single consensus IFΝ-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is a serine/threonine kinase inhibitor. In some embodiments, the serine/threonine kinase inhibitor is a receptor serine/threonine kinase inhibitor, such as antagonists of TGF-β receptor serine/threonine kinase activity. In other embodiments, the serine/threonine kinase inhibitor is a non-receptor serine/threonine kinase inhibitor, such as antagonists ofthe serine/threonine kinase activity ofthe MAP kinases, protein kinase C (PKC), protein kinase A (PKA), or the cyclin-dependent kinases (CDKs).

[00127] In another aspect, the invention features a method of treating cancer by administering to the individual an effective amount of PEGylated IFΝ-α, where the PEGylated IFΝ-α is a conjugate of a single consensus IFΝ-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is an inhibitor of one or more kinases involved in cell cycle regulation. In some embodiments, the inhibitor is an antagonist of CDK2 activation, such as tryphostin AG490 (2-cyano-3-(3,4- dihydroxyphenyl)-Ν-(benzyl)-2-propenamide). In other embodiments, the inhibitor is an antagonist of CDKl/cyclin B activity, such as alsterpaullone. In still other embodiments, the inhibitor is an antagonist of CDK2 kinase activity, such as indirubin-3'-monoxime.

[00128] In another aspect, the invention features a method of treating cancer in a patient by co- administering to the individual (i) an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; (ii) an effective amount of a taxane; and (iii) an effective amount of a platinum complex. In some embodiments, the taxane is paclitaxel and the platinum complex is cisplatin or carboplatin.

[00129] In another aspect, the invention features a method of treating cancer in a patient by co- administering to the individual (i) an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; (ii) an effective amount of a Type II interferon receptor agonist; (iii) an effective amount of a taxane; and (iv) an effective amount of a platinum complex. In some embodiments, the Type II interferon receptor agonist is an IFN-γ, the taxane is paclitaxel and the platinum complex is cisplatin or carboplatin.

[00130] In another aspect, the invention features a method of treating cancer in a patient by co- administering to the individual (i) an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; and (ii) an effective amount of at least one additional antineoplastic drug that is a tumor-associated antigen antagonist, such as an antibody antagonist. In some embodiments involving the treatment of HER2-expressing tumors, the tumor-associated antigen antagonist is an anti- HER2 monoclonal antibody, such as HERCEPTIN™ trastuzumab. In some embodiments involving the treatment of CD20-expressing tumors, such as B-cell lymphomas, the tumor- associated antigen antagonist is an anti-CD20 monoclonal antibody, such as RITUXAN™ rituximab.

[00131] In another aspect, the invention features a method of treating cancer in a patient by co- administering to the individual (i) an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; and (ii) an effective amount of at least one additional antineoplastic drug that is a tumor growth factor antagonist. In some embodiments, the tumor growth factor antagonist is an antagonist of epidermal growth factor (EGF), such as an anti-EGF monoclonal antibody. In other embodiments, the tumor growth factor antagonist is an antagonist of epidermal growth factor receptor erbBl (EGFR), such as an anti-EGFR monoclonal antibody antagonist of EGFR activation or signal transduction, including ERBITUX™ cetuximab, or a small molecule antagonist of EGFR activation or signal transduction, such as IRESSA™ gefitinib and TARCENA™ erolotinib.

[00132] In another aspect, the invention features a method of treating cancer in a patient by co- administering to the individual an effective amount of PEGylated IFΝ-α, where the PEGylated IFΝ-α is a conjugate of a single consensus IFΝ-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; and an effective amount of at least one additional antineoplastic drug that is an Apo-2 ligand agonist.

[00133] In another aspect, the invention features a method of treating cancer in a patient by co- administering to the individual (i) an effective amount of PEGylated IFΝ-α, where the PEGylated IFΝ-α is a conjugate of a single consensus IFΝ-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; and (ii) an effective amount of at least one additional antineoplastic drug that is an anti-angiogenic agent. In some embodiments, the anti-angiogenic agent is a vascular endothelial cell growth factor (VEGF) antagonist, such as an anti-VEGF monoclonal antibody, e.g. AVASTIΝ™ bevacizumab. In other embodiments, the anti-angiogenic agent is an antagonist of NEGF-R1, such as an anti-NEGF-Rl monoclonal antibody. In other embodiments, the anti-angiogenic agent is an antagonist of VEGF-R2, such as an anti-VEGF-R2 monoclonal antibody. In other embodiments, the anti-angiogenic agent is an antagonist of basic fibroblast growth factor (bFGF), such as an anti-bFGF monoclonal antibody. In other embodiments, the anti- angiogenic agent is an antagonist of bFGF receptor, such as an anti-bFGF receptor monoclonal antibody. In other embodiments, the anti-angiogenic agent is an antagonist of TGF-β, such as an anti-TGF-β monoclonal antibody. In other embodiments, the anti-angiogenic agent is an antagonist of TGF-β receptor, such as an anti-TGF-β receptor monoclonal antibody. In other embodiments, the anti-angiogenic agent is a retinoic acid receptor (RXR) ligand. In still other embodiments, the anti-angiogenic agent is a peroxisome proliferator-activated receptor (PPAR) gamma ligand. [00134] In another aspect, the invention features a method of treating cancer in a patient comprising co-administering to the individual (i) an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; and (ii) effective amounts of a RXR ligand and a PPAR gamma ligand.

[00135] In another aspect, the invention features a method of treating cancer in a patient comprising co-administering to the individual (i) an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; and (ii) an effective amount of lometrexol.

[00136] In another aspect, the invention features a method of treating cancer in a patient by subjecting the patient to radiation therapy and by administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days.

[00137] In another aspect, the invention features a method of treating cancer in a patient by subjecting the patient to surgical excision of part or all of a tumor mass carried by the patient and by administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days.

[00138] In another aspect, the invention features a method of treating cancer in a patient by subjecting the patient to radiation therapy and surgical excision of part or all of a tumor mass carried by the patient and by administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days.

[00139] In another aspect, the invention features any ofthe above-described methods of treating a cancer in a patient in which the patient receives (i) an effective amount of PEGylated IFN-α administered at a dosing interval of 8 days or more, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; and (ii) an effective amount of at least one additional drug that is an antineoplastic drug or biological response modifier, where the subject method further comprises subjecting the patient to radiation therapy.

[00140] In another aspect, the invention features any ofthe above-described methods of treating a cancer in a patient in which the patient receives (i) an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; and (ii) an effective amount of at least one additional drug that is an antineoplastic drug or biological response modifier, where the subject method further comprises subjecting the patient to surgical excision of part or all of a tumor mass carried by the patient.

[00141] In another aspect, the invention features any ofthe above-described methods of treating a cancer in a patient in which the patient receives (i) an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; and (ii) an effective amount of at least one additional drug that is an antineoplastic drug or biological response modifier, where the subject method further comprises subjecting the patient to radiation therapy and surgical excision of part or all of a tumor mass carried by the patient.

[00142] In another aspect, the invention features any ofthe above-described methods of treating a cancer in a patient, where the subject method further comprises administering to the patient an effective amount of a Type II interferon receptor agonist, e.g., an IFN-γ. Fibrotic disorders

[00143] The present invention further provides methods of therapeutically treating a fibrotic disorder such as fibrosis ofthe lung, kidney, liver, heart, and the like in individuals who present with clinical signs of fibrotic disorder to reduce risk of death and to improve clinical functions, the methods generally involving administering to the individual (i) an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a. conjugate. of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, and (ii) an effective amount of a Type II interferon receptor agonist. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In some embodiments, the Type II interferon receptor agonist is IFN-γ. In some embodiments, the method provides any ofthe foregoing PEGylated IFN-α and Type II interferon receptor agonist combination regimens for the treatment of a fibrotic disorder in an individual, and further provides administering to the individual an effective amount or amounts of one or more additional anti-fibrotic agents. In some embodiments, the method provides any ofthe foregoing PEGylated IFN-α and Type II interferon receptor agonist combination regimens for the treatment of a fibrotic disorder in an individual, and further provides administering to the individual an effective amount of pirfenidone or a pirfenidone analog and/or an effective amount of a TNF antagonist. Fibrosis is generally characterized by the pathologic or excessive accumulation of collagenous connective tissue. Fibrotic disorders include, but are not limited to, collagen disease, interstitial lung disease, human fibrotic lung disease (e.g., obliterative broncliiolitis, idiopathic pulmonary fibrosis,. pulmonary fibrosis from a known etiology, tumor sfroma in lung disease, systemic sclerosis affecting the lungs, Hermansky-Pudlak syndrome, coal worker's pneumoconiosis, asbestosis, silicosis, chronic pulmonary hypertension, AIDS-associated pulmonary hypertension, sarcoidosis, and the like), fibrotic vascular disease, arterial sclerosis, atherosclerosis, varicose veins, coronary infarcts, cerebral infarcts, myocardial fibrosis, musculoskeletal fibrosis, post-surgical adhesions, human kidney disease (e.g., nephritic syndrome, Alport's syndrome, HIV-associated nephropathy, polycystic kidney disease, Fabry's disease, diabetic nephropathy, chronic glomerulonephritis, nephritis associated with systemic lupus, and the like), cutis keloid formation, progressive systemic sclerosis (PSS), primary sclerosing cholangitis (PSC), liver fibrosis, liver cirrhosis, renal fibrosis, pulmonary fibrosis, cystic fibrosis, chronic graft versus host disease, scleroderma (local and systemic), Grave's opthalmopathy, diabetic retinopathy, glaucoma, Peyronie's disease, penis fibrosis, urefhrostenosis after the test using a cystoscope, inner accretion after surgery, scarring, myelofibrosis, idiopathic retroperitoneal fibrosis, peritoneal fibrosis from a known etiology, drug-induced ergotism, fibrosis incident to benign or malignant cancer, fibrosis incident to microbial infection (e.g., viral, bacterial, parasitic, fungal, etc.), Alzheimer's disease, fibrosis incident to inflammatory bowel disease (including stricture formation in Crohn's disease and microscopic colitis), fibrosis induced by chemical or environmental insult (e.g., excessive exposure to alcohol, cancer chemotherapy, pesticides, radiation (e.g., cancer radiotherapy), and the like), and the like.

[00145] In some embodiments, effective amounts of a PEGylated IFN-α and a Type II interferon receptor agonist are amounts that, when used exclusively or in combination with other therapy for treatment of a fibrotic disorder, are effective to reduce fibrosis or reduce the rate of progression of fibrosis by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared with the degree of fibrosis in the individual prior to treatment or compared to the rate of progression of fibrosis that would have been experienced by the patient in the absence ofthe subject combination therapy.

[00146] In some embodiments, effective amounts of a PEGylated IFN-α and a Type II interferon receptor agonist are amounts that, when used exclusively or in combination with other therapy for the treatment of a fibrotic disorder, are effective to increase, or to reduce the rate of deterioration of, at least one function ofthe organ affected by fibrosis (e.g., lung, liver, kidney, etc.) by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared to the basal level of organ function in the individual prior to a subject combination therapy or compared to the rate of deterioration in organ function that would have been experienced by the individual in the absence ofthe subject combination therapy.

[00147] Methods of measuring the extent of fibrosis in a given organ, and methods of measuring the function of any given organ, are well known in the art.

[00148] A subject combination therapy is effective in reducing clinical symptoms, reducing morbidity or mortality, or reducing risk of death. These clinical outcomes are readily determined by those skilled in the art. Clinical outcome parameters for fibrotic disorders are readily measured by known assays. Idiopathic Pulmonary Fibrosis

[00149] The present invention provides methods of treating idiopathic pulmonary fibrosis (IPF), the methods generally involving co-administering to the individual (i) an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, and (ii) an effective amount of a Type II interferon receptor agonist. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In some embodiments, the Type II interferon receptor agonist is IFN-γ. In some embodiments, the method provides any ofthe foregoing PEGylated IFN-α and Type II interferon receptor agonist combination regimens for the treatment of IPF in an individual, and further providing administering to the individual an effective amount or amounts of one or more additional anti- fibrotic agents. In some embodiments, the method provides any ofthe foregoing PEGylated IFN-α and Type II interferon receptor agonist combination regimens for the treatment of IPF in an individual, and further providing administering to the individual an effective amount of pirfenidone or a pirfenidone analog and/or an effective amount of a TNF antagonist.

[00150] In some embodiments, a diagnosis of IPF is confirmed by the finding of usual interstitial pneumonia (UIP) on histopathological evaluation of lung tissue obtained by surgical biopsy. The criteria for a diagnosis of IPF are known. Ryu et al. (1998) Mayo Clin. Proc. 73:1085-1101,

[00151] In other embodiments, a diagnosis of IPF is a definite or probable IPF made by high resolution computer tomography (HRCT). In a diagnosis by HRCT, the presence ofthe following characteristics is noted: (1) presence of reticular abnormality and/or traction bronchiectasis with basal and peripheral predominance; (2) presence of honeycombing with basal and peripheral predominance; and (3) absence of atypical features such as micronodules, peribronchovascular nodules, consolidation, isolated (non-honeycomb) cysts, ground glass attenuation (or, if present, is less extensive than reticular opacity), and mediastinal adenopathy (or, if present, is not extensive enough to be visible on chest x-ray). A diagnosis of definite IPF is made if characteristics (1), (2), and (3) are met. A diagnosis of probable IPF is made if characteristics (1) and (3) are met.

[00152] In some embodiments, "effective amounts" of a PEGylated IFN-α and a Type II interferon receptor agonist are any combined dosage that, when used exclusively or in combination with other therapy for the treatment of IPF, is effective to decrease disease progression by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or more, compared with a placebo control or an untreated control.

[00153] Disease progression is the occurrence of one or more ofthe following: (1) a decrease in predicted FVC of 10% or more; (2) an increase in A-a gradient of 5 mm Hg or more; (3) a decrease of 15% or more in single breath DLC0- Whether disease progression has occurred is determined by measuring one or more of these parameters on two consecutive occasions 4 to 14 weeks apart, and comparing the value to baseline.

[00154] Thus, e.g., where an untreated or placebo-treated individual exhibits a 50% decrease in FNC over a period of time, an individual administered with an effective combination of a PEGylated IFΝ-α and a Type II interferon receptor agonist exhibits a decrease in FNC of 45%, about 42%, about 40%, about 37%, about 35%, about 32%, about 30%, or less, over the same time period.

[00155] In some embodiments, "effective amounts" of a PEGylated IFΝ-α and a Type II interferon receptor agonist are any combined dosage that, when used exclusively or in combination with other therapy for the treatment of IPF, is effective to increase progression- free survival time, e.g., the time from baseline (e.g., a time point from 1 day to 28 days before beginning of treatment) to death or disease progression is increased by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2- fold, at least about 3 -fold, at least about 4-fold, at least about 5 -fold, or more, compared a placebo-treated or an untreated control individual. Thus, e.g., in some embodiments effective amounts of a PEGylated IFΝ-α and a Type II interferon receptor agonist are any combined dosage that, when used exclusively or in combination with other therapy for the treatment of IPF, is effective to increase the progression-free survival time by at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, or longer, compared to a placebo-treated or untreated control.

[00156] In some embodiments, effective amounts of a PEGylated IFΝ-α and a Type II interferon receptor agonist are any combined dosage that, when used exclusively or in combination with other therapy for the treatment of IPF, is effective to increase at least one parameter of lung function, e.g., an effective amount of a PEGylated IFΝ-α and a Type II interferon receptor agonist are any combined dosage that increases at least one parameter of lung function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5 -fold, or more, compared to an untreated individual or a placebo-treated control individual. In some of these embodiments, a determination of whether a parameter of lung function is increased is made by comparing the baseline value with the value at any time point after the beginning of treatment, e.g., 48 weeks after the beginning of treatment, or between two time points, e.g., about 4 to about 14 weeks apart, after the beginning of treatment.

[00157] In some embodiments, effective amounts of a PEGylated IFN-α and a Type II interferon receptor agonist are any combined dosage that, when used exclusively or in combination with other therapy for the treatment of IPF, is effective to increase the FNC by at least about 10% at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more compared to baseline on two consecutive occasions 4 to 14 weeks apart.

[00158] In some of these embodiments, effective amounts of a PEGylated IFΝ-α and a Type II interferon receptor agonist are any combined dosage that, when used exclusively or in combination with other therapy for the treatment of IPF, results in a decrease in alveolaπarterial (A-a) gradient of at least about 5 mm Hg, at least about 7 mm Hg, at least about 10 mm Hg, at least about 12 mm Hg, at least about 15 mm Hg, or more, compared to baseline.

[00159] In some of these embodiments, effective amounts of a PEGylated IFΝ-α and a Type II interferon receptor agonist are any combined dosage that, when used exclusively or in combination with other therapy for the treatment of IPF, increases the single breath DLC0 by at least about 15 %, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to baseline. CLC0 is the lung diffusing capacity for carbon monoxide, and is expressed as mL CO/mm Hg/second.

[00160] Parameters of lung function include, but are not limited to, forced vital capacity (FNC); forced expiratory volume (FENi); total lung capacity; partial pressure of arterial oxygen at rest; partial pressure of arterial oxygen at maximal exertion.

[00161] Lung function can be measured using any known method, including, but not limited to spirometry. Liver Fibrosis

[00162] The present invention provides methods of treating liver fibrosis, including reducing clinical liver fibrosis, reducing the likelihood that liver fibrosis will occur, and reducing a parameter associated with liver fibrosis, the methods generally involving co-administering to the individual (i) an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, and (ii) an effective amount of a Type II interferon receptor agonist. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In some embodiments, the Type II interferon receptor agonist is IFN-γ. In some embodiments, the method provides any ofthe foregoing PEGylated IFN-α and Type II interferon receptor agonist combination regimens for the treatment of liver fibrosis in an individual, and further provides administering to the individual an effective amount or amounts of one or more additional anti-fibrotic agents. In some embodiments, the method provides any ofthe foregoing PEGylated IFN-α and Type II interferon receptor agonist combination regimens for the treatment of liver fibrosis in an individual, and further provides administering to the individual an effective amount of pirfenidone or a pirfenidone analog and/or an effective amount of a TNF antagonist.

[00163] Liver fibrosis is a precursor to the complications associated with liver cirrhosis, such as portal hypertension, progressive liver insufficiency, and hepatocellular carcinoma. A reduction in liver fibrosis thus reduces the incidence of such complications. Accordingly, the present invention further provides methods of reducing the likelihood that an individual will develop complications associated with cirrhosis ofthe liver.

[00164] The present methods generally involve administering therapeutically effective amounts of a PEGylated IFN-α and a Type II interferon receptor agonist. As used herein, "effective amounts" of a PEGylated IFN-α and a Type II interferon receptor agonist are any combined dosage that, when used exclusively or in combination with other therapy for the treatment of liver fibrosis, is effective in reducing liver fibrosis or reduce the rate of progression of liver fibrosis; and/or that is effective in reducing the likelihood that an individual will develop liver fibrosis; and/or that is effective in reducing a parameter associated with liver fibrosis; and/or that is effective in reducing a disorder associated with cirrhosis ofthe liver; and/or that is effective in increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease an individual suffering from liver fibrosis.

[00165] Whether treatment with a combination of a PEGylated IFN-α and a Type II interferon receptor agonist is effective in reducing liver fibrosis can be determined by any of a number of well-established techniques for measuring liver fibrosis and liver function. Whether liver fibrosis is reduced is determined by analyzing a liver biopsy sample. An analysis of a liver biopsy comprises assessments of two major components: necroinflammation assessed by "grade" as a measure ofthe severity and ongoing disease activity, and the lesions of fibrosis and parenchymal or vascular remodeling as assessed by "stage" as being reflective of long- term disease progression. See, e.g., Brunt (2000) Hepatol. 31 :241-246; and METANIR (1994) Hepatology 20:15-20. Based on analysis ofthe liver biopsy, a score is assigned. A number of standardized scoring systems exist which provide a quantitative assessment ofthe degree and severity of fibrosis. These include the METANIR, Knodell, Scheuer, Ludwig, and Ishak scoring systems.

[00166] The METANIR scoring system is based on an analysis of various features of a liver biopsy, including fibrosis (portal fibrosis, centrilobular fibrosis, and cirrhosis); necrosis (piecemeal and lobular necrosis, acidophilic retraction, and ballooning degeneration); inflammation (portal tract inflammation, portal lymphoid aggregates, and distribution of portal inflammation); bile duct changes; and the Knodell index (scores of periportal necrosis, lobular necrosis, portal inflammation, fibrosis, and overall disease activity). The definitions of each stage in the METANIR system are as follows: score: 0, no fibrosis; score: 1, stellate enlargement of portal tract but without septa formation; score: 2, enlargement of portal tract with rare septa formation; score: 3, numerous septa without cirrhosis; and score: 4, cirrhosis.

[00167] Knodell's scoring system, also called the Hepatitis Activity Index, classifies specimens based on scores in four categories of histologic features: I. Periportal and/or bridging necrosis; II. Intralobular degeneration and focal necrosis; III. Portal inflammation ; and IN. Fibrosis. In the Knodell staging system, scores are as follows: score: 0, no fibrosis; score: 1, mild fibrosis (fibrous portal expansion); score: 2, moderate fibrosis; score: 3, severe fibrosis (bridging fibrosis); and score: 4, cirrhosis. The higher the score, the more severe the liver tissue damage. Knodell (1981) Hepatol. 1:431.

[00168] In the Scheuer scoring system scores are as follows: score: 0, no fibrosis; score: 1, enlarged, fibrotic portal tracts; score: 2, periportal or portal-portal septa, but intact architecture; score: 3, fibrosis with architectural distortion, but no obvious cirrhosis; score: 4, probable or definite cirrhosis. Scheuer (1991) J Hepatol. 13:372.

[00169] The Ishak scoring system is described in Ishak (1995) J Hepatol. 22:696-699. Stage 0, No fibrosis; Stage 1, Fibrous expansion of some portal areas, with or without short fibrous septa; stage 2, Fibrous expansion of most portal areas, with or without short fibrous septa; stage 3, Fibrous expansion of most portal areas with occasional portal to portal (P-P) bridging; stage 4, Fibrous expansion of portal areas with marked bridging (P-P) as well as portal-central (P-C); stage 5, Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); stage 6, Cirrhosis, probable or definite . ..

[00170] The benefit of anti-fibrotic therapy can also be measured and assessed by using the Child-Pugh scoring system which comprises a multicomponent point system based upon abnormalities in serum bilirubin level, serum albumin level, prothrombin time, the presence and severity of ascites, and the presence and severity of encephalopathy. Based upon the presence and severity of abnormality of these parameters, patients may be placed in one of three categories of increasing severity of clinical disease: A, B, or C.

[00171] In some embodiments, therapeutically effective amounts of a PEGylated IFN-α and a Type II interferon receptor agonist are any combined dosage that, when used exclusively or in combination with other therapy for the treatment of liver fibrosis, effects a change of one unit or more in the fibrosis stage based on pre- and post-therapy liver biopsies. In particular embodiments, therapeutically effective amounts of a PEGylated IFN-α and a Type II interferon receptor agonist reduce liver fibrosis by at least one unit in the METANIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.

[00172] Secondary, or indirect, indices of liver function can also be used to evaluate the efficacy of treatment with a subject combination therapy. Morphometric computerized semi- automated assessment ofthe quantitative degree of liver fibrosis based upon specific staining of collagen and/or serum markers of liver fibrosis can also be measured as an indication ofthe efficacy of a subject treatment method. Secondary indices of liver function include, but are not limited to, serum transaminase levels, prothrombin time, bilirubin, platelet count, portal pressure, albumin level, and assessment ofthe Child-Pugh score.

[00173] In another embodiment, effective amounts of a PEGylated IFΝ-α and a Type II interferon receptor agonist are any combined dosage that, when used exclusively or in combination with other therapy for the treatment of liver fibrosis, is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%), at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.

[00174] Serum markers of liver fibrosis can also be measured as an indication ofthe efficacy of a subject treatment method. Serum markers of liver fibrosis include, but are not limited to, hyaluronate, N-terminal procollagen III peptide, 7S domain of type IN collagen, C-terminal procollagen I peptide, and laminin. Additional biochemical markers of liver fibrosis include α- 2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein A, and gamma glutamyl transpeptidase.

[00175] In another embodiment, therapeutically effective amounts of a PEGylated IFΝ-α and a Type II interferon receptor agonist are any combined dosage that, when used exclusively or in combination with other therapy for the treatmen of liver fibrosis, is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level ofthe marker in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological-based methods, e.g., enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.

[00176] Quantitative tests of functional liver reserve can also be used to assess the efficacy of treatment with any ofthe foregoing PEGylated IFΝ-α and Type II interferon receptor agonist combination regimens. These include: indocyanine green clearance (ICG), galactose elimination capacity (GEC), aminopyrine breath test (ABT), antipyrine clearance, monoethylglycine-xylidide (MEG-X) clearance, and caffeine clearance.

[00177] As used herein, a "complication associated with cirrhosis ofthe liver" refers to a disorder that is a sequelae of decompensated liver disease, i.e., or occurs subsequently to and as a result of development of liver fibrosis, and includes, but is not limited to, development of ascites, variceal bleeding, portal hypertension, jaundice, progressive liver insufficiency, encephalopathy, hepatocellular carcinoma, liver failure requiring liver transplantation, and liver-related mortality.

[00178] In another embodiment, therapeutically effective amounts of a PEGylated IFΝ-α and a Type II interferon receptor agonist are any combined dosage that, when used exclusively or in combination with other therapy for the treatment of liver fibrosis, is effective in reducing the incidence of (e.g., the likelihood that an individual will develop) a disorder associated with cirrhosis ofthe liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or in a placebo-treated individual.

[00179] Whether combination therapy with a PEGylated IFN-α and a Type II interferon receptor agonist is effective in reducing the incidence of a disorder associated with cirrhosis of the liver can readily be determined by those skilled in the art.

[00180] Reduction in liver fibrosis increases liver function. Thus, the invention provides methods for increasing liver function, generally involving administering therapeutically effective amounts of a PEGylated IFN-α and a Type II interferon receptor agonist. Liver functions include, but are not limited to, synthesis of proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'-nucleosidase, γ-glutammyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics; and the like.

[00181] Whether a liver function is increased is readily ascertainable by those skilled in the art, using well-established tests of liver function. Thus, synthesis of markers of liver function such as albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, bilirubin, and the like, can be assessed by measuring the level of these markers in the serum, using standard immunological and enzymatic assays. Splanchnic circulation and portal hemodynamics can be measured by portal wedge pressure and/or resistance using standard methods. Metabolic functions can be measured by measuring the level of ammonia in the serum.

[00182] Whether serum proteins normally secreted by the liver are in the normal range can be determined by measuring the levels of such proteins, using standard immunological and enzymatic assays. Those skilled in the art know the normal ranges for such serum proteins. The following are non-limiting examples. The normal range of alanine transaminase is from about 7 to about 56 units per liter of serum. The normal range of aspartate transaminase is from about 5 to about 40 units per liter of serum. Bilirubin is measured using standard assays. Normal bilirubin levels are usually less than about 1.2 mg/dL. Serum albumin levels are measured using standard assays. Normal levels of serum albumin are in the range of from about 35 to about 55 g/L. Prolongation of prothrombin time is measured using standard assays. Normal prothrombin time is less than about 4 seconds longer than control. [00183] In another embodiment, therapeutically effective amounts of a PEGylated IFN-α and a Type II interferon receptor agonist are any combined dosage that, when used exclusively or in combination with other therapy for the treatment of liver fibrosis, is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%o, or more. For example, therapeutically effective amounts of a PEGylated IFN-α and a Type II interferon receptor agonist include any combined dosage that is effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level ofthe serum marker of liver function to within a normal range. Therapeutically effective amounts of a PEGylated IFN-α and a Type II interferon receptor agonist also include any combined dosage effective to increase a reduced level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level ofthe serum marker of liver function to within a normal range. Renal Fibrosis

[00184] Renal fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM) components. Overproduction of transforming growth factor-beta (TGF-β) is believed to underlie tissue fibrosis caused by excess deposition of ECM, resulting in disease. TGF-β 's fibrogenic action results from simultaneous stimulation of matrix protein synthesis, inhibition of matrix degradation and enhanced integrin expression that facilitates ECM assembly.

[00185] The present invention provides methods of treating renal fibrosis, the methods generally involving administering to the individual (i) an effective amount of PEGylated IFN- α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, .30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, and (ii) an effective amount of a Type II interferon receptor agonist. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In some embodiments, the Type II interferon receptor agonist is IFN-γ. In some embodiments, the method provides any ofthe foregoing PEGylated IFN-α and Type II interferon receptor agonist combination regimens for the treatment of renal fibrosis in an individual, and further provides administering to the individual an effective amount or amounts of one or more additional anti-fibrotic agents. In some embodiments, the method provides any ofthe foregoing PEGylated IFN-α and Type II interferon receptor agonist combination regimens for the treatment of renal fibrosis in an individual, and further provides administering to the individual an effective amount of pirfenidone or a pirfenidone analog and/or an effective amount of a TNF antagonist.

[00186] As used herein, "effective amounts" of a PEGylated IFN-α and a Type II interferon receptor agonist are any combined dosage that, when used exclusively or in combination with other therapy for the treatment of renal fibrosis, is effective in reducing renal fibrosis; and/or that is effective in reducing the likelihood that an individual will develop renal fibrosis; and/or that is effective in reducing a parameter associated with renal fibrosis; and/or that is effective in reducing a disorder associated with fibrosis ofthe kidney.

[00187] In one embodiment, effective amounts of a PEGylated IFN-α and a Type II interferon receptor agonist are any combined dosage that, when used exclusively or in combination with other therapy for the treatment of renal fibrosis, is sufficient to reduce renal fibrosis, or reduce the rate of progression of renal fibrosis, by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the degree of renal fibrosis in the individual prior to treatment, or compared to the rate of progression of renal fibrosis that would have been experienced by the patient in the absence of treatment.

[00188] Whether fibrosis is reduced in the kidney is determined using any known method. For example, histochemical analysis of kidney biopsy samples for the extent of ECM deposition and/or fibrosis is performed. Other methods are known in the art. See, e.g., Masseroli et al. (1998) Lab. Invest. 78:511-522; U.S. Patent No. 6,214,542.

[00189] In some embodiments, effective amounts of a PEGylated IFN-α and a Type II interferon receptor agonist are any combined dosage that, when used exclusively or in combination with other therapy for the treatment of renal fibrosis, is effective to increase kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the basal level of kidney function in the individual prior to treatment.

[00190] In some embodiments, effective amounts of a PEGylated IFN-α and a Type II interferon receptor agonist are any combined dosage that, when used exclusively or in combination with other therapy for the treatment of renal fibrosis, is effective to slow the decline in kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the decline in kidney function that would occur in the absence of treatment. [00191] Kidney function can be measured using any known assay, including, but not limited to, plasma creatinine level (where normal levels are generally in a range of from about 0.6 to about 1.2 mg/dL); creatinine clearance (where the normal range for creatinine clearance is from about 97 to about 137 mL/minute in men, and from about 88 to about 128 mL/minute in women); the glomerular filtration rate (either calculated or obtained from inulin clearance or other methods), blood urea nitrogen (where the normal range is from about 7 to about 20 mg/dL); and urine protein levels. Treatment of Angiogenesis-Mediated Disorders

[00192] The present invention provides methods for treating angiogenic disorders, the methods generally involving co-administering to the individual (i) an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more, and (ii) an effective amount of a Type II interferon receptor agonist. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In some embodiments, the Type II interferon receptor agonist is IFN-γ. In some embodiments, the method provides any ofthe foregoing PEGylated IFN-α and Type II interferon receptor agonist combination regimens for the treatment of an angiogenic disorder in an individual, and futher provides administering to the individual an effective amount or amounts of one or more additional anti-angiogenic agents. In some embodiments, the method provides any ofthe foregoing PEGylated IFN-α and Type II interferon receptor agonist combination regimens for the treatment of an angiogenic disorder in an individual, and further provides administering to the individual an effective amount or amounts of one or more additional drugs selected from the group of pirfenidone, pirfenidone analogs, NEGF antagonists, NEGF-R1 antagonists, NEGF-R2 antagonists, bFGF antagonists, bFGF receptor antagonists, TGF-β antagonists, TGF-β receptor antagonists, RXR ligands, and PPAR gamma ligands.

[00193] In a subject method of treating an angiogenic disorder, "effective amounts" of a PEGylated IFΝ-α and a Type II interferon receptor agonist are any combined dosage that is angiostatic, e.g., an amount that reduces angiogenesis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, or more, compared with the level of angiogenesis in the absence of treatment with the subject combination therapy. [00194] Many systems are available for assessing angiogenesis. For example, as angiogenesis is required for solid tumor growth, the inhibition of tumor growth in an animal model may be used as an index ofthe inhibition of angiogenesis. Angiogenesis may also be assessed in terms of models of wound-healing, in cutaneous or organ wound repair; and in chronic inflammation, e.g., in diseases such as rheumatoid arthritis, atherosclerosis and idiopathic pulmonary fibrosis (IPF). It may also be assessed by counting vessels in tissue sections, e.g., following staining for marker molecules, e.g., CD3H, Factor VIII or PECAM-1.

[00195] Whether angiogenesis is reduced can be determined using any method known in the art, including, e.g., stimulation of neovascularization into implants impregnated with relaxin; stimulation of blood vessel growth in the cornea or anterior eye chamber; stimulation of endothelial cell proliferation, migration or tube formation in vitro; and the chick chorioallantoic membrane assay; the hamster cheek pouch assay; the polyvinyl alcohol sponge disk assay. Such assays are well known in the art and have been described in numerous publications, including, e.g., Auerbach et al. ((1991) Pharmac. Ther. 51:1-11), and references cited therein.

[00196] A system in widespread use for assessing angiogenesis is the corneal micropocket assay of neovascularization, as may be practiced using rat corneas. This in vivo model is widely accepted as being generally predictive of clinical usefulness. See, e.g., O'Reilly et. al. (1994) Cell 79:315-328, Li et. al. (1991) Invest. Ophthalmol. Vis. Sci. 32(11):2898-905; and Miller et. al. (1994) Am. J. Pathol. 145(3):574-84.

[00197] A subject method is useful for treating angiogenic disorders, e.g., any disease characterized by pathological neovascularization. Such disorders include, but are not limited to, solid tumors, hemangiomas, rheumatoid arthritis, atherosclerosis, fibrotic disorders, including idiopathic pulmonary fibrosis (IPF), liver fibrosis, and renal fibrosis; but also include BPH, vascular restenosis, arteriovenous malformations (AVM), retinopathies, including diabetic retinopathy, meningioma, hemangiomas, thyroid hyperplasias (including Grave's disease), neovascular glaucoma, neovascularization associated with corneal injury, neovascularization associated with corneal transplantation, neovascularization associated with corneal graft, psoriasis, angiofibroma, hemophilic joints, hypertrophic scars, osier- weber syndrome, age-related macular degeneration, pyogenic granuloma retrolental fibroplasia, scleroderma, trachoma, vascular adhesions, synovitis, dermatitis, an inflammatory bowel disease such as, for example, Crohn's disease or ulcerative colitis, and endometriosis. PEGYLATED IFN-α

[00198] PEGylated IFN-α that is suitable for use in the present invention includes a monopegylated IFN-α molecule comprised of a single IFN-α polypeptide and a single polyethylene glycol (PEG) moiety, where the PEG moiety is linear and about 30 kD in molecular weight and is directly or indirectly linked through a stable covalent linkage to either the N-terminal residue in the IFN-α polypeptide or a lysine residue in the IFN-α polypeptide. In embodiments of particular interest, the subject methods use a monopegylated consensus interferon (CIFN) molecule comprising a single CIFN polypeptide and a single, linear, 30 kD PEG moiety, where the PEG moiety is directly or indirectly covalently linked to either a lysine resiude in the CIFN polypeptide or the N-terminal residue in the CIFN polypeptide. IFN-α

[00199] The term "interferon-alpha" as used herein refers to a family of related polypeptides that inhibit viral replication and cellular proliferation and modulate immune response. The term "IFN-α" includes IFN-α polypeptides that are naturally occurring; non-naturally- occurring IFN-α polypeptides; and analogs of naturally occurring or non-naturally occurring IFN-α that retain antiviral activity of a parent naturally-occurring or non-naturally occurring IFN-α.

[00200] Suitable alpha interferons include, but are not limited to, naturally-occurring IFN-α (including, but not limited to, naturally occurring IFN-α2a, IFN-α2b); recombinant interferon alpha-2b such as Intron®A interferon available from Schering Corporation, Kenilworth, N.J.; recombinant interferon alpha-2a such as Roferon® interferon available from Hoffmann-La Roche, Nutley, N. J.; recombinant interferon alpha-2C such as Berofor® alpha 2 interferon available from Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield, Conn.; interferon alpha- nl, a purified blend of natural alpha interferons such as Sumiferon available from Sumitomo, Japan or as Wellferon® interferon alpha-nl (INS) available from the Glaxo- Wellcome Ltd., London, Great Britain; and interferon alpha-n3 a mixture of natural alpha interferons made by Interferon Sciences and available from the Purdue Frederick Co., Norwalk, Conn., under the Alferon® Tradename.

[00201] The term "IFN-α," as used herein, also encompasses consensus IFN-α. As used herein, the term "consensus IFN-α" refers to a non-naturally-occurring polypeptide, which includes those amino acid residues that are common to all naturally-occurring human leukocyte IFN-α subtype sequences and which includes, at one or more of those positions where there is no amino acid common to all subtypes, an amino acid which predominantly occurs at that position, provided that at any such position where there is no amino acid common to all subtypes, the polypeptide excludes any amino acid residue which is not present in at least one naturally-occurring subtype. Amino. acid residues that are common to all naturally-occurring human leukocyte IFN-α subtype sequences ("common amino acid residues"), and amino acid residues that occur predominantly at non-common residues ("consensus amino acid residues") are known in the art. See Figure 7 for the amino acid sequence of IFN-alpha conl. Thus, a consensus interferon is a wholly synthetic Type I interferon developed by scanning several interferon-alpha non-allelic subtypes and assigning the most frequently observed amino acids in each position.

[00202] Consensus IFN-α (also referred to as "CIFN" and "IFN-con" and "IFN-alpha con") encompasses but is not limited to the amino acid sequences designated LFN-coni (sometimes referred to as "CIFN-alpha conl," "IFN-alpha conl," or "IFN-conl," or "alphacon"), IFN-con2 and IFN-con3 which are disclosed in U.S. Pat. Nos. 4,695,623 and 4,897,471; and Infergen® (Amgen, Thousand Oaks, Calif.). Consensus interferons are generally defined by determination of a consensus sequence of naturally occurring interferon alphas. PEG-modified CIFN, especially Infergen®, is of particular interest in some embodiments.

[00203] IFN-α polypeptides can be produced by any known method. DNA sequences encoding IFN-con may be synthesized as described in the above-mentioned patents or other standard methods. In many embodiments, IFN-α polypeptides are the products of expression of manufactured DNA sequences transformed or transfected into bacterial hosts, e.g., E. coli, or in eukaryotic host cells (e.g., yeast; mammalian cells, such as CHO cells; and the like). In these embodiments, the IFN-α is "recombinant IFN-α." Where the host cell is a bacterial host cell, the IFN-α is modified to comprise an N-terminal methionine. IFN-α produced in E. coli is generally purified by procedures known to those skilled in the art and generally described in Klein et al. ((1988) J Chromatog. 454:205-215) for IFN-com.

[00204] Bacterially produced IFN-α may comprise a mixture of isoforms with respect to the N- terminal amino acid residue. For example, purified IFN-con may comprise a mixture of isoforms with respect to the N-terminal methionine status. For example, in some embodiments, an IFN-con comprises a mixture of N-terminal methionyl IFN-con, des- methionyl IFN-con with an unblocked N-terminus, and des-methionyl IFN-con with a blocked N-terminus. As one non-limiting example, purified IFN-coni comprises a mixture of methionyl LFN-coni, des-methionyl IFN-coni and des-methionyl IFN-coni with a blocked N- terminus. Klein et al. ((1990) Arch. Biochemistry & Biophys. 276:531-537). Alternatively, IFN-con may comprise a specific, isolated isoform. Isoforms of IFN-con are separated from each other by techniques such as isoelectric focusing which are known to those skilled in the art.

[00205] It is to be understood that IFN-α as described herein may comprise one or more modified amino acid residues, e.g., glycosylations, chemical modifications, and the like. Site of Linkage

[00206] PEG is coupled either directly (i.e., without a linking group), or via a linker (as described in detail below), to an amino group on the IFN-α polypeptide.

[00207] In some embodiments, the PEGylated IFN-α is PEGylated at or near the amino terminus (N-terminus) ofthe IFN-α polypeptide, e.g., the PEG moiety is conjugated to the IFN-α polypeptide at an amino acid residue from amino acid 1 through amino acid 4, or from amino acid 5 through about 10.

[00208] In other embodiments, the PEGylated IFN-α is PEGylated at an amino acid residues from about 10 to about 28.

[00209] In other embodiments, the PEGylated IFN-α is PEGylated at an amino acid residue from amino acids 100-114.

[00210] In some embodiments in which the IFN-α is CIFN, the PEG molecule can be linked to the NH terminal amino acid residue ofthe CIFN polypeptide. In these embodiments, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[00211] In some embodiments, the PEGylated IFN-α comprises CIFN PEGylated at the epsilon amino group of a lysine residue. See Figure 7 for the amino acid sequence of an exemplary IFN-α, showing the locations ofthe lysine residues.

[00212] Generally, the PEG moiety is linked to a surface-exposed lysine ("lys") residue. Whether a lysine is surface exposed can be determined using any known method. Generally, - analysis of hydrophilicity (e.g., Kyte-Doolittle and Hoppe- Woods analysis) and/or predicted surface-forming regions (e.g., Emini surface-forming probability analysis) is carried out using appropriate computer programs, which are well known to those skilled in the art. Suitable computer programs include PeptideStructure, and the like. Alternatively, NMR investigations can identify the surface accessible residues by virtue ofthe chemical shift ofthe protons of a specific functional group in the spectrum and how they are affected by the inclusion of "shift reagents". In other cases, the inaccessibility or accessibility of residues to solvents or environment can be assessed by fluorescence. In yet other cases, the surface exposure of accessible lysines can be ascertained by the chemical reactivity to water soluble reagents e.g., Trinitrobenzene sulfonate or TNBS, and like measurements. [00213] In some embodiments, the invention employs a PEG-modified CIFN, where the PEG moiety is attached to a lysine residue chosen from lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165. In these embodiments, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[00214] In other embodiments, the invention employs a PEG-modified CIFN, where the PEG moiety is attached to a lysine residue chosen from lys121, lys134, lys135, and lys165. In these embodiments, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD. Populations of IFN-α

[00215] In addition, any ofthe methods ofthe invention can employ a PEGylated IFN-α composition that comprises a population of monopegylated IFNα molecules, where the population consists of one or more species of monopegylated IFNα molecules as described above. The subject composition comprises a population of modified IFN-α polypeptides, each with a single PEG molecule linked to a single amino acid residue ofthe polypeptide.

[00216] In some of these embodiments, the population comprises a mixture of a first IFN-α polypeptide linked to a PEG molecule at a first amino acid residue; and at least a second IFN-α polypeptide linked to a PEG molecule at a second amino acid residue, wherein the first and second IFN-α polypeptides are the same or different, and wherein the location ofthe first amino acid residue in the amino acid sequence ofthe first IFN-α polypeptide is not the same as the location ofthe second amino acid residue in the second IFN-α polypeptide. As one non- limiting example, a subject composition comprises a population of PEG-modified IFN-α polypeptides, the population comprising an IFN-α polypeptide linked at its amino terminus to a linear PEG molecule; and an IFN-α polypeptide linked to a linear PEG molecule at a lysine - residue.

[00217] Generally, a given modified IFN-α species represents from about 0.5% to about 99.5% ofthe total population of monopegylated IFNα polypeptide molecules in a population, e.g, a given modified IFN-α species represents about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or about 99.5% ofthe total population of monopegylated IFN-α polypeptide molecules in a population. In some embodiments, a subject composition comprises a population of monopegylated IFN-α polypeptides, which population comprises at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%, IFN-α polypeptides linked to PEG at the same site, e.g., at the N-terminal amino acid.

[00218] In particular embodiments of interest, a subject composition comprises a population of monopegylated CIFN molecules, the population consisting of one or more species of molecules, where each species of molecules is characterized by a single CIFN polypeptide linked, directly or indirectly in a covalent linkage, to a single linear PEG moiety of about 30 kD in molecular weight, and where the linkage is to either a lysine residue in the CIFN polypeptide, or the N-terminal amino acid residue ofthe CIFN polypeptide.

[00219] The amino acid residue to which the PEG is attached is in many embodiments the N- terminal amino acid residue. In other embodiments, the PEG moiety is attached (directly or via a linker) to a surface-exposed lysine residue. In additional embodiments, the PEG moiety is attached (directly or via a linker) to a lysine residue chosen from lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165 ofthe CIFN polypeptide. In further embodiments, the PEG moiety is attached (directly or via a linker) to a lysine residue chosen from lys121, lys134, lys135, and lys165 ofthe CIFN polypeptide.

[00220] As an example, a subject composition comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN polypeptide, and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue of a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different. A subject composition can further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a lysine residue in the CIFN polypeptide, where the location ofthe linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location ofthe linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[00221] As another example, a subject composition comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN polypeptide, and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first surface-exposed lysine residue of a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different. A subject composition can further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a surface-exposed lysine residue in the CIFN polypeptide, where the location ofthe linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location ofthe linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[00222] As another example, a subject composition comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN polypeptide, and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue selected from one of lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165 in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different. A subject composition can further comprise a third monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a second lysine residue selected from one of lys , lys , lys , lys , lys121, lys122, lys134, lys135, and lys165 in a third CIFN polypeptide, where the third CIFN polypeptide is the same or different from either ofthe first and second CIFN polypeptides, where the second lysine residue is located in a position in the amino acid sequence ofthe third CIFN polypeptide that is not the same as the position ofthe first lysine residue in the amino acid sequence ofthe second CIFN polypeptide. A subject composition may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to one of lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165, where the location ofthe linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location ofthe linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[00223] As another example, a subject composition comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN polypeptide, and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue selected from one of lys , lys134, lys135, and lys165 in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different. A subject composition can further comprise a third monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a second lysine residue selected from one of lys121, lys134, lys135, and lys165 in a third CIFN polypeptide, where the third CIFN polypeptide is the same or different from either ofthe first and second CIFN polypeptides, where the second lysine residue is located in a position in the amino acid sequence ofthe third CIFN polypeptide that is not the same as the position ofthe' first lysine residue in the amino acid sequence ofthe second CIFN polypeptide. A subject composition may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to one of lys121, lys134, lys135, and lys165, where the location ofthe linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location ofthe linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[00224] As another non-limiting example, a subject composition comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second lysine residue in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the first lysine is located in a position in the amino acid sequence ofthe first CIFN polypeptide that is not the same as the position ofthe second lysine residue in the amino acid sequence ofthe second CIFN polypeptide. A subject composition may further comprise at least one additional monopegylated CIFN species of molecules characterized by a PEG moiety linked to a lysine residue in the CIFN polypeptide, where the location ofthe linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location ofthe linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[00225] As another non-limiting example, a subject composition comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a first lysine residue chosen from lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165 in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second lysine residue chosen from lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165 in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the second lysine residue is located in a position in the amino acid sequence of in the second CIFN polypeptide that is not the same as the position ofthe first lysine residue in the first CIFN polypeptide. The composition may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to one of lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165, where the location ofthe linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location ofthe linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[00226] As another non-limiting example, a subject composition comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a first lysine residue chosen from lys121, lys134, lys135, and lys165 in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second lysine residue chosen from lys121, lys134, lys135, and lys165 in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the second lysine residue is located in a position in the amino acid sequence of in the second CIFN polypeptide that is not the same as the position ofthe first lysine residue in the first CIFN polypeptide. The composition may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to one of lys , lys134, lys 35, and lys165, where the location ofthe linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location ofthe linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[00227] As another non-limiting example, a subject composition comprises a monopegylated population of CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first surface-exposed lysine residue in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second surface-exposed lysine residue in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the first surface-exposed lysine is located in a position in the amino acid sequence ofthe first CIFN polypeptide that is not the same as the position ofthe second surface-exposed lysine residue in the amino acid sequence ofthe second CIFN polypeptide. A subject composition may further comprise at least one additional monopegylated CIFN species of molecules characterized by a PEG moiety linked to a surface-exposed lysine residue in the CIFN polypeptide, where the location ofthe linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location ofthe linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD .. Linking groups

[00228] In some embodiments, PEG is attached to IFN-α via a linking group. The linking group is any biocompatible linking group, where "biocompatible" indicates that the compound or group is essentially non-toxic and may be utilized in vivo without causing a significant adverse response in the subject, e.g., injury, sickness, disease, undesirable immune response, or death. PEG can be bonded to the linking group, for example, via an ether bond, an ester bond, a thio ether bond or an amide bond. Suitable biocompatible linking groups include, but are not limited to, an ester group, an amide group, an imide group, a carbamate group, a carboxyl group, a hydroxyl group, a carbohydrate, a succinimide group (including, for example, succinimidyl succinate (SS), succinimidyl propionate (SPA), succinimidyl butanoic acid (SBA), succinimidyl carboxymethylate (SCM), succinimidyl succinamide (SSA) or N-hydroxy succinimide (NHS)), an epoxide group, an oxycarbonylimidazole group (including, for example, carbonyldimidazole (CDI)), a nitro phenyl group (including, for example, nifrophenyl carbonate (NPC) or trichlorophenyl carbonate (TPC)), a trysylate group, an aldehyde group, an isocyanate group, a vinylsulfone group, a tyrosine group, a cysteine group, a histidine group or a primary amine.

[00229] In many embodiments, the PEG is a monomethoxyPEG molecule that reacts with primary amine groups on the IFN-α polypeptide. Methods of modifying polypeptides with monomethoxy PEG via reductive alkylation are known in the art. See, e.g., Chamow et al. (1994) Bioconj. Chem. 5:133-140.

[00230] In one non-limiting example, PEG is linked to IFN-α via an SPA linking group. SPA esters of PEG, and methods for making same, are described in U.S. Patent No. 5,672,662. SPA linkages provide for linkage to free amine groups on the IFN-α polypeptide.

[00231] For example, a PEG molecule is covalently attached via a linkage that comprises an amide bond between a propionyl group ofthe PEG moiety and the epsilon amino group of a surface-exposed lysine residue in the IFN-α polypeptide. Such a bond can be formed, e.g., by condensation of an α-methoxy, omega propanoic acid activated ester of PEG (mPEGspa).

[00232] As one non-limiting example, monopegylated CIFN has a linear PEG moiety of about 30 kD attached via a covalent linkage to the CIFN polypeptide, where the covalent linkage is an amide bond between a propionyl group ofthe PEG moiety and the epsilon amino group of a surface-exposed lysine residue in the CIFN polypeptide, where the surface-exposed lysine residue is chosen from lys121, lys134, lys135, and lys165, and the amide bond is formed by condensation of an α-methoxy, omega propanoic acid activated ester of PEG.

[00233] Methods for attaching a PEG molecule to an IFN-α polypeptide are known in the art, and any known method can be used. See, for example, by Park et al, Anticancer Res., 1 :373- 376 (1981); Zaplipsky and Lee, Polyethylene Glycol Chemistry: Biotechnical and Biomedical Applications, J. M. Harris, ed., Plenum Press, NY, Chapter 21 (1992); and U.S. Patent No. 5,985,265. Polyethylene glycol ■

[00234] Polyethylene glycol is soluble in water at room temperature, and has the general formula R-O-(CH2-CH2O)n-R, where R is hydrogen or a protective group such as an alkyl or an alkanol group, and where n is an integer from 1 to 1000. Where R is a protective group, it generally has from 1 to 8 carbons.

[00235] In many embodiments, PEG has at least one hydroxyl group, e.g., a terminal hydroxyl group, which hydroxyl group is modified to generate a functional group that is reactive with an amino group, e.g., an epsilon amino group of a lysine residue, a free amino group at the N- terminus of a polypeptide, or any other amino group such as an amino group of asparagine, glutamine, arginine, or histidine.

[00236] In other embodiments, PEG is derivatized so that it is reactive with free carboxyl groups in the IFN-α polypeptide, e.g., the free carboxyl group at the carboxyl terminus ofthe IFN-α polypeptide. Suitable derivatives of PEG that are reactive with the free carboxyl group at the carboxyl-terminus of IFN-α include, but are not limited to PEG-amine, and hydrazine derivatives of PEG (e.g., PEG-NH-NH2).

[00237] In other embodiments, PEG is derivatized such that it comprises a terminal thiocarboxylic acid group, -COSH, which selectively reacts with amino groups to generate amide derivatives. Because ofthe reactive nature ofthe thio acid, selectivity of certain amino groups over others is achieved. For example, -SH exhibits sufficient leaving group ability in reaction with N-terminal amino group at appropriate pH conditions such that the ε-amino groups in lysine residues are protonated and remain non-nucleophilic. On the other hand, reactions under suitable pH conditions may make some ofthe accessible lysine residues to react with selectivity.

[00238] In other embodiments, the PEG comprises a reactive ester such as an N-hydroxy succinimidate at the end ofthe PEG chain. Such an N-hydroxysuccinimidate-containing PEG molecule reacts with select amino groups at particular pH conditions such as neutral pH 6.5- 7.5. For example, the N-terminal amino groups may be selectively modified under neutral pH conditions. However, if the reactivity ofthe reagent were extreme, accessible-NH2 groups of lysine may also react.

[00239] In other embodiments, the PEG comprises a sufficiently reactive N-hydroxy succinimidyl ester at the end ofthe PEG chain by virtue of having a suitable spacer e.g., a propionyl group, between the end ofthe PEG chain and the ester such that the ester does not hydrolyze rapidly and reacts more selectively at particular pH conditions ranging from neutral to alkaline i.e., pH 7.0-9.0. For example, the ε- amino group of certain lysines in the polypeptide chain may be selectively modified with a N-hydroxysuccinimdyl propionate ester- activated PEG. The specific process conditions used are selected to yield products of definite compositions and activities.

[00240] The PEG can be conjugated directly to the IFN-α polypeptide, or through a linker. In some embodiments, a linker is added to the IFN-α polypeptide, forming a linker-modified IFN- α polypeptide. Such linkers provide various functionalities, e.g., reactive groups such as sulfhydryl, amino, or carboxyl groups to couple a PEG reagent to the linker-modified IFN-α polypeptide.

[00241] In some embodiments, the PEG conjugated to the IFN-α polypeptide is linear. In other embodiments, the PEG conjugated to the IFN-α polypeptide is branched. Branched PEG derivatives such as those described in U.S. Pat. No. 5,643,575, "star-PEG's" and multi-armed PEG's such as those described in Shearwater Polymers, Inc. catalog "Polyethylene Glycol Derivatives 1997-1998." Star PEGs are described in the art including, e.g., in U.S. Patent No. 6,046,305.

[00242] In embodiments of particular interest, the PEG conjugated to the IFN-α polypeptide is linear.

[00243] The PEG-modified IFN-α polypeptides suitable for use in the methods ofthe invention comprise a single molecule of PEG, having a molecular weight of less than 40 kDa. As used herein, and as is well known in the art, "30 kDa" PEG has an average molecular weight of 30 kDa. PEG having an average molecular weight in a range of from about 2 kDa to about 30 kDa, is generally used. For example, the molecular weight ofthe linear PEG molecule is in the range of from about 20 kD to about 40 kD, from about 22 kD to about 38 kD, from about 24 kD to about 36 kD, from about 26 kD to about 34 Id), or from about 28 kD to about 32 kD. In particular embodiments, the PEG has a molecular weight of about 30 kD and is linear.

[00244] The molecular weight of PEG molecules is ascertained by gel filtration column chromatography with suitable molecular weight markers, or by MALDI-TOF mass spectrometry. PEG-modified IFN-α

[00245] PEG-modified IFN-α suitable for use in the methods of the invention has a molecular weight that is less than that of IFN-α2a linked to a single molecule of branched 40 kDa PEG. An exemplary IFN-α2a conjugated to a single molecule of branched 40kDa PEG is referred to as Pegasys® (Reddy et al. ((2002) Adv. Drug Deliv. Rev. 54:571-586). The molecular weight of a subject PEG-modified IFN-α polypeptide is from about 5 kDa to about 20 kDa, from about 6 kDa to about 15 kDa, from about 8 kDa to about 12 kDa, or from about 7 kDa to about 10 kDa less than the molecular weight of Pegasys®. In many embodiments, a subject PEG- modified IFN-α polypeptide has a molecular weight that is about 8 kDa to about 12 kDa less than that of Pegasys®.

[00246] Whether a subject PEG-modified IFN-α has a molecular weight less than that of Pegasys® can be readily determined using standard methods of determining the molecular weight of a protein. Such methods include, but are not limited to, high performance liquid chromatography (HPLC); reverse phase HPLC; size exclusion chromatography; sodium dodecyl sulfate polyacrylamide gel electrophoresis; HPLC size exclusion chromatography (SEC); HPLC/SEC/laser light scattering; and matrix-assisted laser desorption ionization time- of-flight mass spectroscopy (MALDI-TOF MS). Preferably, to determine whether a subject PEG-modified IFN-α has a lower molecular weight than that of Pegasys®, the subject PEG- modified IFN-α and the Pegasys® are subjected to size exclusion HPLC under the same conditions.

[00247] A PEG-modified IFN-α polypeptide suitable for use in the methods ofthe invention has a molecular weight of less than about 60 kDa, and generally is from about 40 kDa to about 55 kDa, or from about 45 kDa to about 50 kDa. In some embodiments, a subject PEG-modified IFN-α polypeptide has a molecular weight of about 50 kDa, e.g., from about 48 kDa to about 52 kDa. Preparing PEG-IFN-α conjugates

[00248] As discussed above, the PEG moiety can be attached, directly or via a linker, to an amino acid residue at or near the N-terminus, or internally (e.g., at a surface-exposed lysine residue). Conjugation can be carried out in solution or in the solid phase.

[00249] Methods for attaching a PEG moiety to an amino acid residue at or near the N-terminus of an IFN-α polypeptide are known in the art. See, e.g., U.S. Patent No. 5,985,265.

[00250] In some embodiments, known methods for selectively obtaining an N-terminally chemically modified IFN-α are used. For example, a method of protein modification by reductive alkylation which exploits differential reactivity of different types of primary amino groups (lysine versus the N-terminus) available for derivatization in a particular protein can be used. Under the appropriate reaction conditions, substantially selective derivatization ofthe protein at the N-terminus with a carbonyl group containing polymer is achieved. The reaction is performed at pH which allows one to take advantage ofthe pKa differences between the ε- amino groups ofthe lysine residues and that ofthe α-amino group ofthe N-terminal residue of the protein. By such selective derivatization attachment of a PEG moiety to the IFN-α is controlled: the conjugation with the polymer takes place predominantly at the N-terminus of the IFN-α and no significant modification of other reactive groups, such as the lysine side chain amino groups, occurs.

[00251] If desired, PEGylated IFN-α is separated from unPEGylated IFN-α using any known method, including, but not limited to, ion exchange chromatography, size exclusion chromatography, and combinations thereof. For example, where the PEG-IFN-α conjugate is a monoPEGylated IFN-α, the products are first separated by ion exchange chromatography to obtain material having a charge characteristic of monoPEGylated material (other multi- PEGylated material having the same apparent charge may be present), and then the monoPEGylated materials are separated using size exclusion chromatography.

[00252] In some embodiments, a modified IFN-α is prepared by reacting an IFN-α polypeptide with a succinimidyl ester of alpha-methoxy, omega-propionylpoly(ethylene glycol) (mPEGspa). In general, the reaction is carried out with IFN-α and mPEGspa in a molar ratio of from about 1 : 1 to about 1 :5. Typically, the reaction is carried out in a solution having a pH of from about 7 to about 9.

[00253] In particular embodiments, CIFN is reacted with mPEGspa that is linear and has a molecular weight of about 30 kD, where the reaction is carried out with a CIFN:mPEGspa molar ratio of from about 1 :1 to about 1 :5, and where the pH ofthe reaction is from about 7 to about 9. In a particular embodiment, the CIFN:mPEGspa ratio is about 1 :2 and the pH ofthe reaction is about 8.

[00254] In some embodiments, the invention employs a modified CIFN that is produced by the process of reacting CIFN and a succinimidyl ester of alpha-methoxy, omega- propionylpoly(ethylene glycol) (mPEGspa) that is linear and has a molecular weight of about 30 kD, where the reaction is carried out with a CIFN:mPEGspa molar ratio of from about 1 : 1 to about 1 :5, and where the pH ofthe reaction is from about 7 to about 9. In a particular embodiment, the invention provides a modified CIFN that is produced by the process of reacting CIFN and a succinimidyl ester of alpha-methoxy, omega-propionylpoly(ethylene glycol) (mPEGspa) that is linear and has a molecular weight of about 30 kD, where the reaction is carried out with a CIFN:mPEGspa ratio of about 1 :3, and at a pH of about 8. Ribavirin [00255] Ribavirin, l-β-D-ribofuranosyl-lH-l,2,4-triazole-3-carboxamide, available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif, is described in the Merck Index, compound No. 8199, Eleventh Edition. Its manufacture and formulation is described in U.S. Pat. No. 4,211,771. The invention also contemplates use of derivatives of ribavirin (see, e.g., U.S. Pat. No. 6,277,830). The ribavirin may be administered orally in capsule or tablet form, or in the same or different administration form and in the same or different route as the PEGylated IFN- α. Of course, other types of administration of both medicaments, as they become available are contemplated, such as by nasal spray, transdermally, by suppository, by sustained release dosage form, etc. Any form of administration will work so long as the proper dosages are delivered without destroying the active ingredient. [00256] Ribavirin is generally administered in an amount ranging from about 400 mg to about 1200 mg, from about 600 mg to about 1000 mg, or from about 700 to about 900 mg per day. In some embodiments, ribavirin is administered throughout the entire course of PEGylated IFN-α therapy. Pirfenidone and Analogs Thereof [00257] Pirfenidone (5-mefhyl-l-phenyl-2-(lH)-pyridone) and pirfenidone analogs are useful in combination with PEGylated IFN-α for the treatment of proliferative conditions and viral infections as disclosed herein. Pirfenidone

Figure imgf000069_0001

Pirfenidone analogs I.

Figure imgf000069_0002
ILA II.B

Figure imgf000070_0001
Descriptions for Substituents Ri, R2, X

[00258] Ri*. carbocyclic (saturated and unsaturated), heterocyclic (saturated or unsaturated), alkyls (saturated and unsaturated). Examples include phenyl, benzyl, pyrimidyl, naphfhyl, indolyl, pyrrolyl, furyl, thienyl, imidazolyl, cyclohexyl, piperidyl, pyrrolidyl, morpholinyl, cyclohexenyl, butadienyl, and the like.

[00259] Ri can further include substitutions on the carbocyclic or heterocyclic moieties with substituents such as halogen, nitro, amino, hydroxyl, alkoxy, carboxyl, cyano, thio, alkyl, aryl, heteroalkyl, heteroaryl and combinations thereof, for example, 4-nitrophenyl, 3-chlorophenyl, 2,5-dinitrophenyl, 4-mefhoxyphenyl, 5-methyl-pyrrolyl, 2, 5-dichlorocyclohexyl, guanidinyl- cyclohexenyl and the like.

[00260] R2: alkyl, carbocylic, aryl, heterocyclic. Examples include: methyl, ethyl, propyl, isopropyl, phenyl, 4-nitrophenyl, thienyl and the like.

[00261] X: may be any number (from 1 to 3) of substituents on the carbocyclic or heterocyclic ring. The substituents can be the same or different. Substituents can include hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, halo, nitro, carboxyl, hydroxyl, cyano, amino, thio, alkylamino, haloaryl and the like.

[00262] The substituents may be optionally further substituted with 1-3 substituents from the group consisting of alkyl, aryl, nitro, alkoxy, hydroxyl and halo groups. Examples include: methyl, 2,3 -dimethyl, phenyl, p-tolyl, 4-chlorophenyl, 4-nitrophenyl, 2,5-dichlorophenyl, furyl, thienyl and the like.

[00263] Specific examples include those shown in Table 1 :

Table 1 IA IIB

Figure imgf000070_0002
Figure imgf000071_0001

[00264] U.S. Pat. Nos. 3,974,281; 3,839,346; 4,042,699; 4,052,509; 5,310,562; 5,518,729; 5,716,632; and 6,090,822 describe methods for the synthesis and formulation of pirfenidone and specific pirfenidone analogs in pharmaceutical compositions suitable for use in the methods ofthe present invention. Type II interferon receptor agonists

[00265] Type II interferon receptor agonists include any naturally occurring or non-naturally- occurring ligand of a human Type II interferon receptor that binds to and causes signal transduction via the receptor. Type II interferon receptor agonists include interferons, including naturally-occurring interferons, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising an interferon and a heterologous protein, shuffled interferons; antibody specific for an interferon receptor; non-peptide chemical agonists; and the like. [00266] A specific example of a Type II interferon receptor agonist is IFN-gamma and variants thereof. While the present invention exemplifies use of an IFN-gamma polypeptide, it will be readily apparent that any Type II interferon receptor agonist can be used in a subject method. Interferon-Gamma

[00267] The nucleic acid sequences encoding IFN-gamma polypeptides may be accessed from public databases, e.g., Genbank, journal publications, and the like. While various mammalian IFN-gamma polypeptides are of interest, for the treatment of human disease, generally the human protein will be used. Human IFN-gamma coding sequence may be found in Genbank, accession numbers XI 3274; V00543; and NM_000619. The corresponding genomic sequence may be found in Genbank, accession numbers J00219; M37265; and V00536. See, for example. Gray et al. (1982) Nature 295:501 (Genbank X13274); and Rinderknecht et al. (1984) JR. C 259:6790.

[00268] IFN-γ lb (Actimmune®; human interferon) is a single-chain polypeptide of 140 amino acids. It is made recombinantly in E.coli and is unglycosylated (Rinderknecht et al. 1984, J Biol Chem. 259:6790-6797). Recombinant IFN-gamma as discussed in U.S. Patent No. 6,497,871 is also suitable for use herein.

[00269] The IFN-gamma to be used in the methods ofthe present invention may be any of natural IFN-gamma, recombinant IFN-gamma and the derivatives thereof so far as they have an IFN-γ activity, particularly human IFN-gamma activity. Human IFN-gamma exhibits the antiviral and anti-proliferative properties characteristic ofthe interferons, as well as a number of other immunomodulatory activities, as is known in the art. Although IFN-gamma is based on the sequences as provided above, the production ofthe protein and proteolytic processing can result in processing variants thereof. The unprocessed sequence provided by Gray et al., supra, consists of 166 amino acids (aa). Although the recombinant IFN-gamma produced in E. coli was originally believed to be 146 amino acids, (commencing at amino acid 20) it was subsequently found that native human IFN-gamma is cleaved after residue 23, to produce a 143 aa protein, or 144 aa if the terminal methionine is present, as required for expression in bacteria. During purification, the mature protein can additionally be cleaved at the C terminus after reside 162 (referring to the Gray et al. sequence), resulting in a protein of 139 amino acids, or 140 amino acids if the initial methionine is present, e.g. if required for bacterial expression. The N-terminal methionine is an artifact encoded by the mRNA translational "start" signal AUG that, in the particular case of E. coli expression is not processed away. In other microbial systems or eukaryotic expression systems, methionine may be removed. [00270] For use in the subject methods, any ofthe native IFN-gamma peptides, modifications and variants thereof, or a combination of one or more peptides may be used. IFN-gamma peptides of interest include fragments, and can be variously truncated at the carboxyl terminus relative to the full sequence. Such fragments continue to exhibit the characteristic properties of human gamma interferon, so long as amino acids 24 to about 149 (numbering from the residues ofthe unprocessed polypeptide) are present. Extraneous sequences can be substituted for the amino acid sequence following amino acid 155 without loss of activity. See, for example, U.S. Patent No. 5,690,925. Native IFN- gamma moieties include molecules variously extending from amino acid residues 24-150; 24-151, 24-152; 24- 153, 24-155; and 24-157. Any of these variants, and other variants known in the art and having IFN-γ activity, may be used in the present methods.

[00271] The sequence ofthe IFN-γ polypeptide may be altered in various ways known in the art to generate targeted changes in sequence. A variant polypeptide will usually be substantially similar to the sequences provided herein, i.e., will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids. The sequence changes may be substitutions, insertions or deletions. Scanning mutations that systematically introduce alanine, or other residues, may be used to determine key amino acids. Specific amino acid substitutions of interest include conservative and non-conservative changes. Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).

[00272] Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e.g., acetylation, or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like. IFN-gamma may be modified with one or more polyethylene glycol moieties (PEGylated). In one embodiment, the invention contemplates the use of IFN-gamma variants with one or more non-naturally occurring glycosylation and/or pegylation sites that are engineered to provide glycosyl- and/or PEG-derivatized polypeptides with reduced serum clearance, such as the IFN-gamma polypeptide variants described in International Patent Publication No. WO 01/36001. Also included are modifications of glycosylation, e.g., those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e.g., by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes. Also embraced are sequences that have phosphorylated amino acid residues, e.g., phosphotyrosine, phosphoserine, or phosphothreonine.

[00273] Included in the subject invention are polypeptides that have been modified using ordinary chemical techniques so as to improve their resistance to proteolytic degradation, to optimize solubility properties, or to render them more suitable as a therapeutic agent. For examples, the backbone ofthe peptide may be cyclized to enhance stability (see, for example, Friedler et al. 2000, J Biol. Chem. 275:23783-23789). Analogs may be used that include residues other than naturally occurring L-amino acids, e.g., D-amino acids or non-naturally occurring synthetic amino acids. The protein may be pegylated to enhance stability.

[00274] The polypeptides may be prepared by in vitro synthesis, using conventional methods as known in the art, by recombinant methods, or may be isolated from cells induced or naturally producing the protein. The particular sequence and the manner of preparation will be determined by convenience, economics, purity required, and the like. If desired, various groups may be introduced into the polypeptide during synthesis or during expression, which allow for linking to other molecules or to a surface. Thus cysteines can be used to make thioethers, histidines for linking to a metal ion complex, carboxyl groups for forming amides or esters, amino groups for forming amides, and the like.

[00275] The polypeptides may also be isolated and purified in accordance with conventional methods of recombinant synthesis. A lysate may be prepared ofthe expression host and the lysate purified using HPLC, exclusion chromatography, gel electrophoresis, affinity chromatography, or other purification technique. For the most part, the compositions which are used will comprise at least 20% by weight ofthe desired product, more usually at least about 75% by weight, preferably at least about 95% by weight, and for therapeutic purposes, usually at least about 99.5% by weight, in relation to contaminants related to the method of preparation ofthe product and its purification. Usually, the percentages will be based upon total protein. Type III interferon receptor agonists

[00276] In another aspect, the invention provides a modification of any ofthe above-described methods in which the patient receives additional treatment with a therapeutic agent that is an agonist of a Type III interferon receptor (e.g., "a Type III interferon agonist"). Type III interferon agonists include an IL-28b polypeptide; and IL-28a polypeptide; and IL-29 polypeptide; antibody specific for a Type III interferon receptor; and any other agonist of Type III interferon receptor, including non-polypeptide agonists. [00277] IL-28A, IL-28B, and IL-29 (referred to herein collectively as "Type III interferons" or "Type III IFNs") are described in Sheppard et al. (2003) Nature 4:63-68. Each polypeptide . binds a heterodimeric receptor consisting of IL-Ϊ0 receptor β chain and an IL-28 receptor α. Sheppard et al. (2003), supra. The amino acid sequences of IL-28 A, IL-28B, and IL-29 are found under GenBank Accession Nos. NP_742150, NP_742151, and NP_742152, respectively.

[00278] The amino acid sequence of a Type III IFN polypeptide may be altered in various ways known in the art to generate targeted changes in sequence. A variant polypeptide will usually be substantially similar to the sequences provided herein, i.e. will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids. The sequence changes may be substitutions, insertions or deletions. Scanning mutations that systematically introduce alanine, or other residues, may be used to determine key amino acids. Specific amino acid substitutions of interest include conservative and non-conservative changes. Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).

[00279] Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e.g., acetylation, or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like. Also included are modifications of glycosylation, e.g. those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e.g. by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes. Also embraced are sequences that have phosphorylated amino acid residues, e.g. phosphotyrosine, phosphoserine, or phosphothreonine.

[00280] Included in the subject invention are polypeptides that have been modified using ordinary chemical techniques so as to improve their resistance to proteolytic degradation, to optimize solubility properties, or to render them more suitable as a therapeutic agent. For examples, the backbone ofthe peptide may be cyclized to enhance stability (see Friedler et al. (2000) J. Biol. Chem. 275:23783-23789). Analogs may be used that include residues other than naturally occurring L-amino acids, e.g. D-amino acids or non-naturally occurring synthetic amino acids. The protein may be pegylated to enhance stability. The polypeptides may be fused to albumin.

[00281] The polypeptides may be prepared by in vitro synthesis, using conventional methods as known in the art, by recombinant methods, or may be isolated from cells induced or naturally producing the protein. The particular sequence and the manner of preparation will be determined by convenience, economics, purity required, and the like. If desired, various groups may be introduced into the polypeptide during synthesis or during expression, which allow for linking to other molecules or to a surface. Thus cysteines can be used to make thioethers, histidines for linking to a metal ion complex, carboxyl groups for forming amides or esters, amino groups for forming amides, and the like. TNF Antagonists

[00282] Suitable TNF-α antagonists for use herein include agents that decrease the level of TNF-α synthesis, agents that block or inhibit the binding of TNF-α to a TNF-α receptor (TNFR), and agents that block or inhibit TNFR-mediated signal transduction. Unless otherwise expressly stated, every reference to a "TNF-α antagonist" or "TNF antagonist" herein will be understood to mean a TNF-α antagonist other than pirfenidone or a pirfenidone analog.

[00283] As used herein, the terms "TNF receptor polypeptide" and "TNFR polypeptide" refer to polypeptides derived from TNFR (from any species) which are capable of binding TNF. Two distinct cell-surface TNFRs have described: Type II TNFR (or p75 TNFR or TNFRII) and Type I TNFR (or p55 TNFR or TNFRI). The mature full-length human p75 TNFR is a glycoprotein having a molecular weight of about 75-80 kilodaltons (kD). The mature full- length human p55 TNFR is a glycoprotein having a molecular weight of about 55-60 Id). Exemplary TNFR polypeptides are derived from TNFR Type I and/or TNFR type II. Soluble TNFR includes p75 TNFR polypeptide; fusions of p75 TNFR with heterologous fusion partners, e.g., the Fc portion of an immunoglobulin.

[00284] TNFR polypeptide may be an intact TNFR or a suitable fragment of TNFR. U. S . Pat. No. 5,605,690 provides examples of TNFR polypeptides, including soluble TNFR polypeptides, appropriate for use in the present invention. In many embodiments, the TNFR polypeptide comprises an extracellular domain of TNFR. In some embodiments, the TNFR polypeptide is a fusion polypeptide comprising an extracellular domain of TNFR linked to a constant domain of an immunoglobulin molecule. In other embodiments, the TNFR polypeptide is a fusion polypeptide comprising an extracellular domain ofthe p75 TNFR linked to a constant domain of an IgGl molecule. In some embodiments, when administration to humans is contemplated, an Ig used for fusion proteins is human, e.g., human IgGl.

[00285] Monovalent and multivalent forms of TNFR polypeptides may be used in the present invention. Multivalent forms of TNFR polypeptides possess more than one TNF binding site. In some embodiments, the TNFR is a bivalent, or dimeric, form of TNFR. For example, as described in U.S. Pat. No. 5,605,690 and in Mohler et al., 1993, J. Immunol, 151:1548-1561, a chimeric antibody polypeptide with TNFR extracellular domains substituted for the variable domains of either or both ofthe immunoglobulin heavy or light chains would provide a TNFR polypeptide for the present invention. Generally, when such a chimeric TNFR:antibody polypeptide is produced by cells, it forms a bivalent molecule through disulfide linkages between the immunoglobulin domains. Such a chimeric TNFR:antibody polypeptide is referred to as TNFR:Fc.

[00286] In one embodiment, a subject method involves administration of an effective amount of the soluble TNFR ENBREL® etanercept. ENBREL® is a dimeric fusion protein consisting of the extracellular ligand-binding portion ofthe human 75 kilodalton (pi 5) TNFR linked to the Fc portion of human IgGl . The Fc component of ENBREL® contains the CH2 domain, the CH3 domain and hinge region, but not the CHI domain of IgGl. ENBREL® is produced in a Chinese hamster ovary (CHO) mammalian cell expression system. It consists of 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons. Smith et al. (1990) Science 248:1019-1023; Mohler et al. (1993) J. Immunol. 151:1548-1561; U.S. Pat. No. 5,395,760; and U.S. Pat. No. 5,605,690.

[00287] Also suitable for use are monoclonal antibodies that bind TNF-α. Monoclonal antibodies include "humanized" mouse monoclonal antibodies; chimeric antibodies; monoclonal antibodies that are at least about 80%, at least about 90%, at least about 95%, or 100% human in amino acid sequence; and the like. See, e.g., WO 90/10077; WO 90/04036; and WO 92/02190. Suitable monoclonal antibodies include antibody fragments, such as Fv, F(ab')2 and Fab; synthetic antibodies; artificial antibodies; phage display antibodies; and the like.

[00288] Examples of suitable monoclonal antibodies include infliximab (REMICADE®, Centocor); and adalimumab (HUMIRA™, Abbott) REMICADE® is a chimeric monoclonal anti-TNF-α antibody that includes about 25% mouse amino acid sequence and about 75% human amino acid sequence. REMICADE®comprises a variable region of a mouse monoclonal anti-TNF-α antibody fused to the constant region of a human IgGl . Elliott et al. (1993) Arthritis Rheum. 36:1681-1690; Elliott et al. (1994) Lancet 344:1105-1110; Baert et al. (1999) Gastroenterology 116:22-28. HUMIRA™ is a human, full-length IgGl monoclonal antibody that was identified using phage display technology. Piascik (2003) J. Am. Pharm. Assoc. 43:327-328.

[00289] Also included in the term "TNF antagonist," and therefore suitable for use in a subject method, are stress-activated protein kinase (SAPK) inhibitors. SAPK inhibitors are known in the art, and include, but are not limited to 2-alkyl imidazoles disclosed in U.S. Patent No. 6,548,520; 1,4,5-substituted imidazole compounds disclosed in U.S. Patent No. 6,489,325; 1,4,5-substituted imidazole compounds disclosed in U.S. Patent No. 6,569,871; heteroaryl aminophenyl ketone compounds disclosed in Published U.S. Patent Application No. 2003/0073832; pyridyl imidazole compounds disclosed in U.S. Patent No. 6,288,089; and heteroaryl aminobenzophenones disclosed in U.S. Patent No. 6,432,962. Also of interest are compounds disclosed in U.S. Patent Application Publication No. 2003/0149041 ; and U.S. Patent No. 6,214,854. A stress-activated protein kinase is a member of a family of mitogen- activated protein kinases which are activated in response to stress stimuli. SAPK include, but are not limited to, p38 (Lee et al. (1994) Nature 372:739) and c-jun N-terminal kinase (JNK).

[00290] Methods to assess TNF antagonist activity are known in the art and exemplified herein. For example, TNF antagonist activity may be assessed with a cell-based competitive binding assay. In such an assay, radiolabeled TNF is mixed with serially diluted TNF antagonist and cells expressing cell membrane bound TNFR. Portions ofthe suspension are centrifuged to separate free and bound TNF and the amount of radioactivity in the free and bound fractions determined. TNF antagonist activity is assessed by inhibition of TNF binding to the cells in the presence ofthe TNF antagonist.

[00291] As another example, TNF antagonists may be analyzed for the ability to neutralize TNF activity in vitro in a bioassay using cells susceptible to the cytotoxic activity of TNF as target cells. In such an assay, target cells, cultured with TNF, are treated with varying amounts of TNF antagonist and subsequently are examined for cytolysis. TNF antagonist activity is assessed by a decrease in TNF-induced target cell cytolysis in the presence ofthe TNF antagonist. Additional antiviral therapeutic agents

[00292] Additional therapeutic agents that can be administered in a subject combination therapy include, but are not limited to, NS3 inhibitors (e.g., inhibitors of serine protease activity of HCV non-structural protein-3); NS5 inhibitors (e.g., inhibitors of RNA-dependent RNA polymerase activity of HCV NS5B protein); immune enhancers such as thymosin-α (Zadaxin®; SciClone Pharmaceuticals); nucleoside analogs that function as immunomodulators; inhibitors of inosine monophosphate dehydrogenase (IMPDH); inhibitors of HCV NS3 helicase; ribozymes that are complementary to viral nucleotide sequences; antisense RNA inhibitors; and the like. NS3 inhibitors [00293] Suitable HCN non-structural protein-3 (ΝS3) inhibitors include, but are not limited to, a tri-peptide as disclosed in U.S. Patent Nos. 6,642,204, 6,534,523, 6,420,380, 6,410,531, 6,329,417, 6,329,379, and 6,323,180 (Boeliringer-Ingelheim); a compound as disclosed in U.S. Patent No. 6,143,715 (Boehringer-Ingelheim); a macrocyclic compound as disclosed in U.S. Patent no. 6,608,027 (Boehringer-Ingelheim); anNS3 inhibitor as disclosed in U.S. Patent Nos. 6,617,309, 6,608,067, and 6,265,380 (Vertex Pharmaceuticals); an azapeptide compound as disclosed in U.S. Patent No. 6,624,290 (Schering); a compound as disclosed in U.S. Patent No. 5,990,276 (Schering); a compound as disclosed in Pause et al. (2003) J Biol. Chem. 278:20374-20380; NS3 inhibitor BILN 2061 (Boehringer-Ingelheim; Lamarre et al. (2002) Hepatology 36:301A; and Lamarre et al. (Oct. 26, 2003) Nature doi:10.1038/nature02099); NS3 inhibitor VX-950 (Vertex Pharmaceuticals; Kwong et al (Oct. 24-28, 2003) 54th Ann. Meeting AASLD); NS3 inhibitor SCH6 (Abib et al (October 24-28, 2003) Abstract 137. th Program and Abstracts ofthe 54 Am ual Meeting ofthe American Association for the Study of Liver Diseases (AASLD). October 24-28, 2003. Boston, MA.); any of the NS3 protease inhibitors disclosed in WO 99/07733, WO 99/07734, WO 00/09558, WO 00/09543, WO 00/59929 or WO 02/060926 (e.g., compounds 2, 3, 5, 6, 8, 10, 11, 18, 19, 29, 30, 31, 32, 33, 37, 38, 55, 59, 71, 91, 103, 104, 105, 112, 113, 114, 115, 116, 120, 122, 123, 124, 125, 126 and 127 disclosed in the table of pages 224-226 in WO 02/060926); an NS3 protease inhibitor as disclosed in any one of U.S. Patent Publication Nos. 2003019067, 20030187018, and 20030186895; and the like.

[00294] Of particular interest in many embodiments are NS3 inhibitors that are specific NS3 inhibitors, e.g., NS3 inhibitors that inhibit NS3 serine protease activity and that do not show significant inhibitory activity against other serine proteases such as human leukocyte elastase, porcine pancreatic elastase, or bovine pancreatic chymotrypsin, or cysteine proteases such as human liver cathepsin B. NS5B inhibitors

[00295] Suitable HCV non-structural protein-5 (NS5; RNA-dependent RNA polymerase) inhibitors include, but are not limited to, a compound as disclosed in U.S. Patent No. 6,479,508 (Boehringer-Ingelheim); a compound as disclosed in U.S. Patent No. 6,440,985 (NiroPharma); a compound as disclosed in WO 01/47883, e.g., JTK-003 (Japan Tobacco); a dinucleotide analog as disclosed in Zhong et al. (2003) Antimicrob. Agents Chemother. 47:2674-2681; a benzothiadiazine compound as disclosed in Dhanak et al. (2002) J. Biol Chem. 277(41):38322- 7; anΝS5B inhibitor as disclosed in WO 02/100846 Al or WO 02/100851 A2 (both Shire); an NS5B inhibitor as disclosed in WO 01/85172 Al or WO 02/098424 Al (both Glaxo SmithKline); anNS5B inhibitor as disclosed in WO 00/06529 or WO 02/06246 Al (both Merck); anNS5B inhibitor as disclosed in WO 03/000254 (Japan Tobacco); anNS5B inhibitor as disclosed in EP 1 256,628 A2 (Agouron); JTK-002 (Japan Tobacco); JTK-109 (Japan Tobacco); and the like.

[00296] Of particular interest in many embodiments are NS5 inhibitors that are specific NS5 inhibitors, e.g., NS5 inhibitors that inhibit NS5 RNA-dependent RNA polymerase and that lack significant inliibitory toward other RNA dependent RNA polymerases and toward DNA dependent RNA polymerases. Nucleoside analogs

[00297] Nucleoside analogs that are suitable for use in a subject combination therapy include, but are not limited to, levovirin, viramidine, isatoribine, any L-ribofuranosyl nucleoside as disclosed in U.S. Patent No. 5,559,101 and encompassed by Formula I of U.S. Patent No. 5,559,101 (e.g., 1-β-L-ribofuranosyluracil, l-β-L-ribofuranosyl-5-fluorouracil, 1-β-L- ribofuranosylcytosine, 9-β-L-ribofuranosyladenine, 9-β-L-ribofuranosylhypoxanthine, 9-β-L- ribofuranosylguanine, 9-β-L-ribofuranosyl-6-thioguanine, 2-amino-α-L- ribofurano [ 1 ' ,2 ' : 4, 5] oxazoline, O2,O2-anliydro- 1 -α-L-ribofuranosyluracil, 1 -α-L- ribofuranosyluracil, 1 -(2,3 ,5-tri-O-benzoyl-α-L-ribofuranosyl)-4-thiouracil, 1 -α-L- ribofuranosylcytosine, l-α-L-ribofuranosyl-4-thiouracil, l-α-L-ribofuranosyl-5-fluorouracil, 2- amino-β-L-arabinofurano[r,2' :4,5]oxazoline, O2,O2-anhydro-β-L-arabinofuranosyluracil, 2'- deoxy-β-L-uridine, 3',5'-Di-O-benzoyl-2'-deoxy-4-thio β-L-uridine, 2'-deoxy-β-L-cytidine, 2'-deoxy-β-L-4-thiouridine, 2'-deoxy-β-L-thymidine, 2'-deoxy-β-L-5-fluorouridine, 2',3'- dideoxy-β-L-uridine, and 2'-deoxy-β-L-inosine); a compound as disclosed in U.S. Patent No. 6,423,695 and encompassed by Formula I of U.S. Patent No. 6,423,695; a compound as disclosed in U.S. Patent Publication No. 2002/0058635, and encompassed by Formula 1 of U.S. Patent Publication No. 2002/0058635; a nucleoside analog as disclosed in WO 01/90121 A2 (Idenix); a nucleoside analog as disclosed in WO 02/069903 A2 (Biocryst Pharmaceuticals Inc.); a nucleoside analog as disclosed in WO 02/057287 A2 or WO 02/057425 A2 (both Merck/Isis); and the like. IMPDH inhibitors

[00298] IMPDH inhibitors that are suitable for use in a subject combination therapy include, but are not limited to, NX-497 ((S)-N-3-[3-(3-methoxy-4-oxazol-5-yl-phenyl)-ureido]-benzyl- carbamic acid tetrahydrofiιran-3-yl-ester); Vertex Pharmaceuticals; see, e.g., Markland et al. (2000) Antimicrob. Agents Chemother. 44:859-866); Levovirin (Ribapharm; see, e.g., Watson (2002) Curr Opin Investig Drugs 3(5):680-3); Niramidine (Ribapharm); and the like. Ribozyme and antisense

[00299] Ribozyme and antisense antiviral agents that are suitable for use in a subject combination therapy include, but are not limited to, ISIS 14803 (ISIS Pharmaceuticals/Elan Corporation; see, e.g., Witherell (2001) Curr Opin Investig Drugs. 2(l l):1523-9); Heptazyme™; and the like. Additional therapeutic agents Anti-inflammatory agents

[00300] Suitable anti-inflammatory agents include, but are not limited to, steroidal anti- inflammatory agents, and non-steroidal anti-inflammatory agents.

[00301] Suitable steroidal anti-inflammatory agents include, but are not limited to, hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamefhasone, dexamethasone- phosphate, beclomethasone dipropionate, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylester, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, conisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, chloroprednisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, triamcinolone, and mixtures of two or more ofthe foregoing.

[00302] Suitable non-steroidal anti-inflammatory agents, include, but are not limited to, 1) the oxicams, such as piroxicam, isoxicam, tenoxicam, and sudoxicam; 2) the salicylates, such as aspirin, disalcid, benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal; 3) the acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepiract, clidanac, oxepinac, and felbinac; 4) the fenamates, such as mefenamic, meclofenamic, flufenamic, niflumic, and tolfenamic acids; 5) the propionic acid derivatives, such as ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofenic; and 6) the pyrazoles, such as phenylbutazone, oxyphenbutazone, feprazone, azapropazone, and trimethazone, mixtures of these non-steroidal anti-inflammatory agents may also be employed, as well as the pharmaceutically-acceptable salts and esters of these agents. Side effect management agents

[00303] In some embodiments, a subject therapy comprises administering a palliative agent (e.g., an agent that reduces patient discomfort caused by a therapeutic agent), or other agent for the avoidance, treatment, or reduction of a side effect of a therapeutic agent. Such agents are also referred to as "side effect management agents."

[00304] Suitable side effect management agents include agents that are effective in pain management; agents that ameliorate gastrointestinal discomfort; analgesics, anti- inflammatories, antipsychotics, antineurotics, anxiolytics, and hematopoietic agents. In addition, the invention contemplates the use of any compound for palliative care of patients suffering from pain or any other side effect in the course of treatment with a subject therapy. Exemplary palliative agents include acetaminophen, ibuprofen, and other NSAIDs, H2 blockers, and antacids.

[00305] Analgesics that can be used to alleviate pain in the methods ofthe invention include non-narcotic analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs) acetaminophen, salicylate, acetyl-salicylic acid (aspirin, diflunisal), ibuprofen, Motrin, Naprosyn, Nalfon, and Trilisate, indomethacin, glucametacine, acemetacin, sulindac, naproxen, piroxicam, diclofenac, benoxaprofen, ketoprofen, oxaprozin, etodolac, ketorolac tromethamine, ketorolac, nabumetone, and the like, and mixtures of two or more ofthe foregoing.

[00306] Other suitable analgesics include fentanyl, buprenorphine, codeine sulfate, morphine hydrochloride, codeine, hydromorphone (Dilaudid), levorphanol (Levo-Dromoran), methadone (Dolophine), morphine, oxycodone (in Percodan), and oxymorphone (Numorphan). Also suitable for use are benzodiazepines including, but not limited to, flurazepam (Dalmane), diazepam (Valium), and Versed, and the like.

[00307] Suitable anti-inflammatory agents include, but are not limited to, Alclofenac; Alclometasone Dipropionate; Algestone Acetonide; Alpha Amylase; Amcinafal; Amcinafide; Amfenac Sodium; Amiprilose Hydrochloride; Anakinra; Anirolac; Anitrazafen; Apazone; Balsalazide Disodium; Bendazac; Benoxaprofen; Benzydamine Hydrochloride; Bromelains; Broperamole; Budesonide; Carprofen; Cicloprofen; Cintazone; Cliprofen; Clobetasol Propionate; Clobetasone Butyrate; Clopirac; Cloticasone Propionate; Cormefhasone Acetate; Cortodoxone; Deflazacort; Desonide; Desoximetasone; -Dexamethasone Dipropionate; Diclofenac Potassium; Diclofenac Sodium; Diflorasone Diacetate; -Diflumidone Sodium; Diflunisal; Difluprednate; Diftalone; Dimethyl Sulfoxide; Drocinonide; Endrysone; Enlimomab Enolicam Sodium; Epirizole; Etodolac; Etofenamate; Felbinac; Fenamole; Fenbufen; Fenclofenac; Fenclorac; Fendosal; Fenpipalone; Fentiazac; Flazalone; Fluazacort; Flufenamic Acid; Flumizole; Flunisolide Acetate; Flunixin; Flunixin Meglumine; Fluocortin Butyl; Fluorometholone Acetate; Fluquazone; Flurbiprofen; Fluretofen; Fluticasone Propionate; Furaprofen; Furobufen; Halcinonide; Halobetasol Propionate; Halopredone Acetate; Ibufenac; Ibuprofen; Ibuprofen Aluminum; Ibuprofen Piconol; Ilonidap; Indomethacin; Indomethacin Sodium; Indoprofen; Indoxole; Intrazole; Isoflupredone Acetate; Isoxepac; Isoxicam; Ketoprofen; Lofemizole Hydrochloride; Lornoxicam; Loteprednol Etabonate; Meclofenamate Sodium; Meclofenamic Acid; Meclorisone Dibutyrate; Mefenamic Acid; Mesalamine; Meseclazone; Methylprednisolone Suleptanate; Morniflumate; Nabumetone; Naproxen; Naproxen Sodium; Naproxol; Nimazone; Olsalazine Sodium; Orgotein; Orpanoxin; Oxaprozin; Oxyphenbutazone; Paranyline Hydrochloride; Pentosan Polysulfate Sodium; Phenbutazone Sodium Glycerate; Pirfenidone; Piroxicam; Piroxicam Cinnamate; Piroxicam Olamine; Pirprofen; Prednazate; Prifelone; Prodolic Acid; Proquazone; Proxazole; Proxazole Citrate; Rimexolone; Romazarit; Salcolex; Salnacedin; Salsalate; Sanguinarium Chloride; Seclazone; Sermetacin; Sudoxicam; Sulindac; Suprofen; Talmetacin; Talniflumate; Talosalate; Tebufelone; Tenidap; Tenidap Sodium; Tenoxicam; Tesicam; Tesimide; Tetrydamine; Tiopinac; Tixocortol Pivalate; Tolmetin; Tolmetin Sodium; Triclonide; Triflumidate; Zidometacin; Zomepirac Sodium.

[00308] Antipsychotic and antineurotic drugs that can be used to alleviate psychiatric side effects in the methods ofthe invention include any and all selective serotonin receptor inhibitors (SSRIs) and other anti-depressants, anxiolytics (e.g. alprazolam), etc. Anti- depressants include, but are not limited to, serotonin reuptake inhibitors such as Celexa®, Desyrel®, Effexor®, Luvox®, Paxil®, Prozac®, Zoloft®, and Serzone®; tricyclics such as Adapin®, Anafrinil®, Elavil®, Janimmine®, Ludiomil®, Pamelor®, Tofranil®, Vivactil®, Sinequan®, and Surmontil®; monoamine oxidase inhibitors such as Eldepryl®, Marplan®, Nardil®, and Parnate®. Anti-anxiety agents include, but are not limited to, azaspirones such as BuSpar®, benzodiazepines such as Ativan®, Librium®, Tranxene®, Cenfrax®, Klonopin®, Paxipam®, Serax®, Valium®, and Xanax®; and beta-blockers such as Inderal® and Tenormin®.

[00309] Agents that reduce gastrointestinal discomfort such as nausea, diarrhea, gastrointestinal cramping, and the like are suitable palliative agents for use in a subject combination therapy. Suitable agents include, but are not limited to, antiemetics, anti-diarrheal agents, H2 blockers, antacids, and the like. [00310] H2 blockers (histamine type 2 receptor antagonists) that are suitable for use as a palliative agent in a subject therapy include, but are not limited to, Cimetidine (e.g., Tagamet, Peptol, Nu-cimet, apo-cimetidine, non-cimetidine); Ranitidine (e.g., Zantac, Nu-ranit, Novo- randine, and apo-ranitidine); and Famotidine (Pepcid, Apo-Famotidine, and Novo-Famotidine). [00311] Suitable antacids include, but are not limited to, aluminum and magnesium hydroxide (Maalox®, Mylanta®); aluminum carbonate gel (Basajel®); aluminum hydroxide (Amphojel®, AlternaGEL®); calcium carbonate (Turns®, Titralac®); magnesium hydroxide; and sodium bicarbonate. [00312] Antiemetics include, but are not limited to, 5-hydroxytryptophan-3 (5HT3) inhibitors; corticosteroids such as dexamethasone and methylprednisolone; Marinol® (dronabinol); prochlorperazine; benzodiazepines; promethazine; and metoclopramide cisapride; Alosetron Hydrochloride; Batanopride Hydrochloride; Bemesetron; Benzquinamide; Chlorpromazine; Chlorpromazine Hydrochloride; Clebopride; Cyclizine Hydrochloride; Dimenhydrinate; Diphenidol; Diphenidol Hydrochloride; Diphenidol Pamoate; Dolasetron Mesylate; Domperidone; Dronabinol; Fludorex; Flumeridone; Galdansetron Hydrochloride; Granisetron; Granisetron Hydrochloride; Lurosetron Mesylate; Meclizine Hydrochloride; Metoclopramide Hydrochloride; Metopimazine; Ondansetron Hydrochloride; Pancopride; Prochlorperazine; Prochlorperazine Edisylate; Prochlorperazine Maleate; Promethazine Hydrochloride; Thiethylperazine; Thiethylperazine Malate; Thiethylperazine Maleate; Trimethobenzamide Hydrochloride; Zacopride Hydrochloride.. [00313] Anti-diarrheal agents include, but are not limited to, Rolgamidine, Diphenoxylate hydrochloride (Lomotil), Metronidazole (Flagyl), Methylprednisolone (Medrol), Sulfasalazine (Azulfidine), and the like. [00314] Suitable hematopoietic agents that can be used to prevent or restore depressed blood cell populations in the methods ofthe invention include erythropoietins, such as EPOGEN™ epoetin-alfa, granulocyte colony stimulating factors (G-CSFs), such as NEUPOGEN filgrastim, granulocyte-macrophage colony stimulating factors (GM-CSFs), thrombopoietins, etc. DOSAGES, FORMULATIONS, AND ROUTES OF ADMINISTRATION [00315] A therapeutic agent used in a subject method, e.g., a PEGylated IFN-α, a Type II interferon receptor agonist, ribavirin, pirfenidone or a pirfenidone analog, a TNF antagonist, is administered to individuals in a formulation with a pharmaceutically acceptable excipient(s). A wide variety of pharmaceutically acceptable excipients are known in the art and need not be discussed in detail herein. Pharmaceutically acceptable excipients have been amply described in a variety of publications, including, for example, A. Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20th edition, Lippincott, Williams, & Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C. Ansel et al, eds., 7th ed., Lippincott, Williams, & Wilkins; and Handbook of Pharmaceutical Excipients (2000) A.H. Kibbe et al, eds., 3rd ed. Amer. Pharmaceutical Assoc.

[00316] The pharmaceutically acceptable excipients, such as vehicles, adjuvants, carriers or diluents, are readily available to the public. Moreover, pharmaceutically acceptable auxiliary substances, such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.

[00317] In the subject methods, the active agents may be administered to the host using any convenient means capable of resulting in the desired therapeutic effect. Thus, the agents can be incorporated into a variety of formulations for therapeutic administration. More particularly, the agents ofthe present invention can be formulated into pharmaceutical compositions by combination with appropriate, pharmaceutically acceptable carriers or diluents, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols.

[00318] As such, administration ofthe agents can be achieved in various ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, subcutaneous, intramuscular, transdermal, intratracheal, etc., administration. In some embodiments, two different routes of administration are used. For example, in some embodiments, IFN-α and IFN-γ are administered subcutaneously, and a p38 inhibitor is administered orally.

[00319] Subcutaneous administration of a therapeutic agent, e.g., a PEGylated IFN-α, a Type II interferon receptor agonist, or a TNF-α antagonist can be accomplished using standard methods and devices, e.g., needle and syringe, a subcutaneous injection port delivery system, and the like. See, e.g., U.S. Patent Nos. 3,547,119; 4,755,173; 4,531,937; 4,311,137; and 6,017,328. A combination of a subcutaneous injection port and a device for administration of a PEGylated IFN-α to a patient through the port is referred to herein as "a subcutaneous injection port delivery system." In some embodiments, subcutaneous administration is achieved by a combination of devices, e.g., bolus delivery by needle and syringe, followed by delivery using a continuous delivery system. [00320] In some embodiments, a therapeutic agent, e.g., a PEGylated IFN-α, a Type II interferon receptor agonist, or a TNF-α antagonist, is delivered by a continuous delivery system. The term "continuous delivery system" is used interchangeably herein with "controlled delivery system" and encompasses continuous (e.g., controlled) delivery devices (e.g., pumps) in combination with catheters, injection devices, and the like, a wide variety of which are known in the art.

[00321] Mechanical or electromechanical infusion pumps can also be suitable for use with the present invention. Examples of such devices include those described in, for example, U.S. Pat. Nos. 4,692,147; 4,360,019; 4,487,603; 4,360,019; 4,725,852; 5,820,589; 5,643,207; 6,198,966; and the like. In general, the present methods of drug delivery can be accomplished using any of a variety of refillable, pump systems. Pumps provide consistent, controlled release over time. Typically, the agent is in a liquid formulation in a drug-impermeable reservoir, and is delivered in a continuous fashion to the individual.

[00322] In one embodiment, the drug delivery system is an at least partially implantable device. The implantable device can be implanted at any suitable implantation site using methods and devices well known in the art. An implantation site is a site within the body of a subject at which a drug delivery device is introduced and positioned. Implantation sites include, but are not necessarily limited to a subdermal, subcutaneous, intramuscular, or other suitable site within a subject's body. Subcutaneous implantation sites are generally preferred because of convenience in implantation and removal ofthe drug delivery device.

[00323] Drug release devices suitable for use in the invention may be based on any of a variety of modes of operation. For example, the drug release device can be based upon a diffusive system, a convective system, or an erodible system (e.g., an erosion-based system). For example, the drug release device can be an electrochemical pump, osmotic pump, an electroosmotic pump, a vapor pressure pump, or osmotic bursting matrix, e.g., where the drug is incorporated into a polymer and the polymer provides for release of drug formulation concomitant with degradation of a drug-impregnated polymeric material (e.g., a biodegradable, drug-impregnated polymeric material). In other embodiments, the drug release device is based upon an electrodiffusion system, an electrolytic pump, an effervescent pump, a piezoelectric pump, a hydrolytic system, etc.

[00324] Drug release devices based upon a mechanical or electromechanical infusion pump can also be suitable for use with the present invention. Examples of such devices include those described in, for example, U.S. Pat. Nos. 4,692,147; 4,360,019; 4,487,603; 4,360,019; 4,725,852, and the like. In general, the present methods of drug delivery can be accomplished using any of a variety of refillable, non-exchangeable pump systems. Pumps and other convective systems are generally preferred due to their generally more consistent, controlled release over time. Osmotic pumps are particularly preferred due to their combined advantages of more consistent controlled release and relatively small size (see, e.g., PCT published application no. WO 97/27840 and U.S. Pat. Nos. 5,985,305 and 5,728,396)). Exemplary osmotically-driven devices suitable for use in the invention include, but are not necessarily limited to, those described in U.S. Pat. Nos. 3,760,984; 3,845,770; 3,916,899; 3,923,426; 3,987,790; 3,995,631; 3,916,899; 4,016,880; 4,036,228; 4,111,202; 4,111,203; 4,203,440; 4,203,442; 4,210,139; 4,327,725; 4,627,850; 4,865,845; 5,057,318; 5,059,423; 5,112,614; 5,137,727; 5,234,692; 5,234,693; 5,728,396; and the like.

[00325] In some embodiments, the drug delivery device is an implantable device. The drug delivery device can be implanted at any suitable implantation site using methods and devices well lαiown in the art. As noted infra, an implantation site is a site within the body of a subject at which a drug delivery device is introduced and positioned. Implantation sites include, but are not necessarily limited to a subdermal, subcutaneous, intramuscular, or other suitable site within a subject's body.

[00326] In some embodiments, a therapeutic agent is delivered using an implantable drug delivery system, e.g., a system that is programmable to provide for administration of a therapeutic agent. Exemplary programmable, implantable systems include implantable infusion pumps. Exemplary implantable infusion pumps, or devices useful in connection with such pumps, are described in, for example, U.S. Pat. Nos. 4,350,155; 5,443,450; 5,814,019; 5,976,109; 6,017,328; 6,171,276; 6,241,704; 6,464,687; 6,475,180; and 6,512,954. A further exemplary device that can be adapted for the present invention is the Synchromed infusion pump (Medtronic).

[00327] In pharmaceutical dosage forms, the agents may be administered in the form of their pharmaceutically acceptable salts, or they may also be used alone or in appropriate association, as well as in combination, with other pharmaceutically active compounds. The following methods and excipients are merely exemplary and are in no way limiting.

[00328] For oral preparations, the agents can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives and flavoring agents.

[00329] The agents can be formulated into preparations for injection by dissolving, suspending or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.

[00330] Furthermore, the agents can be made into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases. The compounds ofthe present invention can be administered rectally via a suppository. The suppository can include vehicles such as cocoa butter, carbowaxes and polyethylene glycols, which melt at body temperature, yet are solidified at room temperature.

[00331] Unit dosage forms for oral or rectal administration such as syrups, elixirs, and suspensions may be provided wherein each dosage unit, for example, teaspoonful, tablespoonful, tablet or suppository, contains a predetermined amount ofthe composition containing one or more inhibitors. Similarly, unit dosage forms for injection or intravenous administration may comprise the inhibitor(s) in a composition as a solution in sterile water, normal saline or another pharmaceutically acceptable carrier.

[00332] The term "unit dosage form," as used herein, refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of compounds ofthe present invention calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier or vehicle. The specifications for the novel unit dosage forms ofthe present invention depend on the particular compound employed and the effect to be achieved, and the pharmacodynamics associated with each compound in the host.

[00333] In connection with each ofthe methods described herein, the invention provides embodiments in which the therapeutic agent(s) is/are administered to the patient by a controlled drug delivery device. In some embodiments, the therapeutic agent(s) is/are delivered to the patient substantially continuously or continuously by the controlled drug delivery device. Optionally, an implantable infusion pump is used to deliver the therapeutic agent(s) to the patient substantially continuously or continuously by subcutaneous infusion.

[00334] In other embodiments, a therapeutic agent is administered to the patient so as to achieve and maintain a desired average daily serum concentration ofthe therapeutic agent at a substantially steady state for the duration ofthe monotherapy or combination therapy. Optionally, an implantable infusion pump is used to deliver the therapeutic agent to the patient by subcutaneous infusion so as to achieve and maintain a desired average daily serum concentration ofthe therapeutic agent at a substantially steady state for the duration ofthe therapeutic agent in monotherapy or combination therapy.

[00335] The administered dose of PEG-modified IFN-α is in a range of from about 5 μg to about 500 μg, e.g., from about 5 μg to about 50 μg, from about 50 μg to about 70 μg, from about 70μg to about 90 μg, from about 90 μg to about 100 μg, from about 100 μg to about 120 μg, from about 120 μg to about 150 μg, from about 150 μg to about 170 μg, from about 170 μg to about 200 μg, from about 200 μg to about 230 μg, from about 230 μg to about 270 μg, from about 270 μg to about 300 μg, from about 300 μg to about 350 μg, from about 350 μg to about 400 μg, from about 400 μg to about 450 μg, or from about 450 μg to about 500 μg. For example, suitable dosages of monoPEG (30 Id), linear)-ylated consensus IFN-α contain an amount of about 5 μg to about 500 μg, or about or about 45 μg to about 450 μg, or about 60 μg to about 400 μg, or about 75 μg to about 350 μg, or about 90 μg to about 300 μg, about 105 μg to about 270 μg, or about 120 μg to about 240 μg, or about 135 μg to about 210 μg, or about 150 μg to about 180 μg, or about 100 μg, or about 150 μg, or about 200 μg, of drug per dose.

[00336] Amounts of PEG-modified IFN-α to be administered are expressed in micrograms, as described above.

[00337] PEG-modified IFN-α is administered at a frequency of less than once per week, e.g., PEGylated IFN-α is administered once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, for a desired treatment duration, e.g., for a period of from about 8 days to about 2 weeks, from about 2 weeks to about 4 weeks, from about 4 weeks to about 6 weeks, from about 6 weeks to about 8 weeks, from about 8 weeks to about 12 weeks, from about 12 weeks to about 16 weeks, from about 16 weeks to about 24 weeks, or from about 24 weeks to about 48 weeks.

[00338] In particular embodiments, a PEG-modified IFN-α is administered once every 8 days for a period of from about 2 weeks to about 4 weeks, from about 4 weeks to about 6 weeks, from about 6 weeks to about 8 weeks, from about 8 weeks to about 12 weeks, from about 12 weeks to about 16 weeks, from about 16 weeks to about 24 weeks, or from about 24 weeks to about 48 weeks.

[00339] In particular embodiments, a PEG-modified IFN-α is administered once every 9 days for a period of from about 2 weeks to about 4 weeks, from about 4 weeks to about 6 weeks, from about 6 weeks to about 8 weeks, from about 8 weeks to about 12 weeks, from about 12 weeks to about 16 weeks, from about 16 weeks to about 24 weeks, or from about 24 weeks to about 48 weeks.

[00340] In particular embodiments, a PEG-modified IFN-α is administered once every 10 days for a period of from about 2 weeks to about 4 weeks, from about 4 weeks to about 6 weeks, from about 6 weeks to about 8 weeks, from about 8 weeks to about 12 weeks, from about 12 weeks to about 16 weeks, from about 16 weeks to about 24 weeks, or from about 24 weeks to about 48 weeks.

[00341] In particular embodiments, a PEG-modified IFN-α is administered once every 11 days for a period of from about 2 weeks to about 4 weeks, from about 4 weeks to about 6 weeks, from about 6 weeks to about 8 weeks, from about 8 weeks to about 12 weeks, from about 12 weeks to about 16 weeks, from about 16 weeks to about 24 weeks, or from about 24 weeks to about 48 weeks.

[00342] In particular embodiments, a PEG-modified IFN-α is administered once every 12 days for a period of from about 2 weeks to about 4 weeks, from about 4 weeks to about 6 weeks, from about 6 weeks to about 8 weeks, from about 8 weeks to about 12 weeks, from about 12 weeks to about 16 weeks, from about 16 weeks to about 24 weeks, or from about 24 weeks to about 48 weeks.

[00343] In particular embodiments, a PEG-modified IFN-α is administered once every 13 days for a period of from about 2 weeks to about 4 weeks, from about 4 weeks to about 6 weeks, from about 6 weeks to about 8 weeks, from about 8 weeks to about 12 weeks, from about 12 weeks to about 16 weeks, from about 16 weeks to about 24 weeks, or from about 24 weeks to about 48 weeks.

[00344] In particular embodiments, a PEG-modified IFN-α is administered once every 14 days for a period of from about 2 weeks to about 4 weeks, from about 4 weeks to about 6 weeks, from about 6 weeks to about 8 weeks, from about 8 weeks to about 12 weeks, from about 12 weeks to about 16 weeks, from about 16 weeks to about 24 weeks, or from about 24 weeks to about 48 weeks.

[00345] In some embodiments, PEG-modified IFN-α is administered at a dosage of about 45 μg to about 270 μg, or about 180 μg, or about 120 μg once every 8 days subcutaneously for a period of from about 2 weeks to about 4 weeks, from about 4 weeks to about 6 weeks, from about 6 weeks to about 8 weeks, from about 8 weeks to about 12 weeks, from about 12 weeks to about 16 weeks, from about 16 weeks to about 24 weeks, or from about 24 weeks to about 48 weeks. The dosage may be delivered by a single bolus injection. [00346] In some embodiments, the PEG-modified IFN-α is administered in a combination therapy, e.g., another anti-viral agent or other therapeutic agent is administered: (1) substantially simultaneously and in a separate formulation; (2) substantially simultaneously and in the same formulation; or (3) in separate formulations, and at separate times. Combination therapies are discussed in detail below.

[00347] Any subject monotherapy or combination therapy can be modified to include administration of a side effect management agent. Side effects of PEGylated IFN-α and/or Type II interferon receptor agonist treatment include, but are not limited to, fever, malaise, tachycardia, chills, headache, arthralgia, myalgia, myelosuppression, suicide ideation, platelet suppression, neutropenia, lymphocytopenia, erythrocytopenia (anemia), and anorexia. In some embodiments, an effective amount of a palliative agent reduces a side effect induced by treatment with a PEGylated IFN-α and/or Type II interferon receptor agonist by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or more, compared to the rate of occurrence or the degree or extent ofthe side effect when the PEGylated IFN-α and/or Type II interferon receptor agonist is administered without the palliative agent. For example, if a fever is experienced with the PEGylated IFN-α and/or Type II interferon receptor agonist therapy, then the body temperature of an individual treated with the PEGylated IFN-α and/or Type II interferon receptor agonist therapy and palliative agent according to the instant invention is reduced by at least 0.5 degree Fahrenheit, and in some embodiments is within the normal range, e.g., at or near 98.6 °F.

[00348] Side effects of pirfenidone or a pirfenidone analog include gastrointestinal disturbances and discomfort. Gastrointestinal disturbances include nausea, diarrhea, gastrointestinal cramping, and the like. In some embodiments, an effective amount of a palliative agent reduces a side effect induced by treatment with a pirfenidone or a pirfenidone analog by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or more, compared to the rate of occurrence or the degree or extent ofthe side effect when the pirfenidone or pirfenidone analog is administered without the palliative agent.

[00349] Side effects of other, additional therapeutic agents (e.g., anti-angiogenic agents; anti- cancer agents such as anti-proliferative agents, anti-neoplastic agents, and cytotoxic agents; anti-fibrotic agents; TNF-α antagonists; and anti-inflammatory agents) are well known. For example, side effects of anti-neoplastic agents include gastrointestinal discomfort. Other side effects of additional therapeutic agents include fever, malaise, etc. Combination therapies

[00350] In some embodiments, the additional therapeutic agent(s) is administered during the entire course of PEG-modified IFN-α treatment, and the beginning and end ofthe treatment periods coincide. In other embodiments, the additional therapeutic agent(s) is administered for a period of time that is overlapping with that ofthe PEG-modified IFN-α treatment, e.g., treatment with the additional therapeutic agent(s) begins before the PEG-modified IFN-α treatment begins and ends before the PEG-modified IFN-α treatment ends; treatment with the additional therapeutic agent(s) begins after the PEG-modified IFN-α treatment begins and ends after the IFN-α treatment ends; treatment with the additional therapeutic agent(s) begins after the PEG-modified IFN-α treatment begins and ends before the PEG-modified IFN-α treatment ends; or treatment with the additional therapeutic agent(s) begins before the PEG-modified IFN-α treatment begins and ends after the PEG-modified IFN-α treatment ends.

[00351] In some embodiments, a subject combination therapy comprises administering PEGylated IFN-α and ribavirin to treat a viral infection. Ribavirin, 1-β-D-ribofuranosyl-lH- l,2,4-triazole-3-carboxamide, available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif., is described in the Merck Index, compound No. 8199, Eleventh Edition. Its manufacture and formulation is described in U.S. Pat. No. 4,211,771. The invention also contemplates use of derivatives of ribavirin (see, e.g., U.S. Pat. No. 6,277,830).

[00352] In some embodiments, a subject combination therapy comprises administering PEGylated IFN-α and a Type II interferon receptor agonist to treat a viral infection. In some embodiments, the Type II interferon receptor agonist is IFN-γ.

[00353] In some embodiments, a subject combination therapy comprises administering PEGylated IFN-α and pirfenidone or a pirfenidone analog to treat a viral infection. In some of these embodiments, the methods further comprise administering an effective amount of ribavirin.

[00354] In some embodiments, a subject combination therapy comprises administering PEGylated IFN-α , a Type II interferon receptor agonist, and a TNF antagonist to treat a viral infection. In some embodiments, the Type II interferon receptor agonist is IFN-γ. In some embodiments, the TNF antagonist is ENBREL®. In some embodiments, the TNF antagonist is REMICADE®. In some embodiments, the TNF antagonist is HUMIRA®.

[00355] Other antiviral agents can be delivered in a subject method for treating a viral disease, where the method is a combination therapy comprising administering PEGylated IFN-α and a second anti-viral agent. For example, compounds that inhibit inosine monophosphate dehydrogenase (IMPDH) may have the potential to exert direct anti viral activity, and such compounds can be administered in combination with an IFN-α composition, as described herein. Drugs that are effective inhibitors of hepatitis C NS3 protease may be administered in combination with PEGylated IFN-α, as described herein. Hepatitis C NS3 protease inhibitors inhibit viral replication. Other agents such as inhibitors of HCV NS3 helicase are also attractive drugs for combinational therapy, and are contemplated for use in combination therapies described herein. Ribozymes such as Heptazyme™ and phosphorothioate oligonucleotides which are complementary to HCV protein sequences and which inhibit the expression of viral core proteins are also suitable for use in combination therapies described herein. In addition, suitable analogs of ribavirin including enantiomers and immune enhancers such as Zadaxin® are also suitable for use in combination therapies described herein. In addition, inhibitors of HCV RNA-dependent RNA polymerase are suitable for use in a subject combination therapy.

[00356] In some embodiments, a subject method for treating cancer comprises administering PEGylated IFN-α and a second therapeutic agent, where the second therapeutic agent is an anti-cancer agent (e.g., an anti-proliferative agent, an anti-neoplastic agent, a cytotoxic agent, and the like).

[00357] In some embodiments, a subject method for treating cancer comprises administering PEGylated IFN-α, pirfenidone or a pirfenidone analog, and a third therapeutic agent, where the third therapeutic agent is an anti-cancer agent (e.g., an anti-proliferative agent, an antineoplastic agent, a cytotoxic agent, and the like).

[00358] In some embodiments, a subject method for treating a proliferative disorder (e.g., a fibrotic disorder, an angiogenic disorder, a cancer) comprises administering PEGylated IFN-α and a Type II interferon receptor agonist. In some of these embodiments, the Type II interferon receptor agonist is IFN-γ. In some embodiments, the method further comprises administering an additional anti-fibrotic agent to treat a fibrotic disorder. In some embodiments, a subject method comprises administering PEGylated IFN-α , a Type II interferon receptor agonist, and an additional anti-angiogenic agent to treat an angiogenic disorder.

[00359] In some embodiments, a subject method for treating cancer comprises administering PEGylated IFN-α, a Type II interferon receptor agonist, and a TNF antagonist. In some of these embodiments, the Type II interferon receptor agonist is IFN-γ. In some embodiments, the TNF antagonist is ENBREL®. In some embodiments, the TNF antagonist is REMICADE®. In some embodiments, the TNF antagonist is HUMIRA®. PEGylated IFN-α and ribavirin in combination therapy for the treatment of viral infections

[00360] In some embodiments, a subject combination therapy comprises administering PEGylated IFN-α and ribavirin to treat a viral infection, e.g., an HCV infection, an HBV infection, etc. Ribavirin, l-β-D-ribofuranosyl-lH-l,2,4-triazole-3-carboxamide, available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif, is described in the Merck Index, compound No. 8199, Eleventh Edition. Its manufacture and formulation is described in U.S. Pat. No. 4,211,771. The invention also contemplates use of derivatives of ribavirin (see, e.g., U.S. Pat. No. 6,277,830).

[00361] Ribavirin is generally administered in an amount ranging from about 30 mg to about 60 mg, from about 60 mg to about 125 mg, from about 125 mg to about 200 mg, from about 200 mg to about 300 gm, from about 300 mg to about 400 mg, from about 400 mg to about 1200 mg, from about 600 mg to about 1000 mg, or from about 700 to about 900 mg per day, or about 10 mg/kg body weight per day. In some embodiments, ribavirin is administered orally in dosages of about 400 mg, about 800 mg, or about 1200 mg per day.

[00362] In some embodiments, a subject method for treating a viral infection (e.g., an HCV infection, an HBV infection, etc.) comprises administering combined effective amounts of PEGylated IFN-α and ribavirin, wherein PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, wherein the PEGylated IFN-α is administered subcutaneously at a dosing interval of 8 days or more, e.g., the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days, in an amount of from about 45 μg to about 270 μg, e.g., in amounts of 100 μg per dosage, 150 μg per dosage, or 200 μg per dosage; and wherein the ribavirin is administered orally in an amount ranging from about 30 mg to about 60 mg, from about 60 mg to about 125 mg, from about 125 mg to about 200 mg, from about 200 mg to about 300 gm, from about 300 mg to about 400 mg, from about 400 mg to about 1200 mg, from about 600 mg to about 1000 mg, or from about 700 to about 900 mg per day, or about 10 mg/kg body weight per day for the desired treatment duration.

[00363] In some embodiments, a subject method for treating a viral infection (e.g., an HCV infection, an HBV infection, etc.) comprises administering to an individual combined effective amounts of PEGylated IFN-α and ribavirin, wherein monoPEG(30 kD, linear)-ylated consensus IFN-α is administered at a dosage of 100 μg at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days for the desired treatment duration; and ribavirin is administered orally daily in an amount of about 1,000 mg to about 1,200 mg for the desired treatment duration.

[00364] In some embodiments, a subject method for treating a viral infection (e.g., an HCV infection, an HBV infection, etc.) comprises administering to an individual combined effective amounts of PEGylated IFN-α and ribavirin, wherein monoPEG(30 kD, linear)-ylated consensus IFN-α is administered at a dosage of 100 μg at a dosing interval of once every 8 days for the desired treatment duration; and ribavirin is administered orally daily in an amount of about 1,000 mg to about 1,200 mg for the desired treatment duration.

[00365] In some embodiments, a subject method for treating a viral infection (e.g., an HCV infection, an HBV infection, etc.) comprises administering to an individual combined effective amounts of PEGylated IFN-α and ribavirin, wherein monoPEG(30 kD, linear)-ylated consensus IFN-α is administered at a dosage of 100 μg at a dosing interval of once every 10 days for the desired treatment duration; and ribavirin is administered orally daily in an amount of about 1,000 mg to about 1,200 mg for the desired treatment duration.

[00366] In some embodiments, a subject method for treating a viral infection (e.g., an HCV infection, an HBV infection, etc.) comprises administering to an individual combined effective amounts of PEGylated IFN-α and ribavirin, wherein monoPEG(30 kD, linear)-ylated consensus IFN-α is administered at a dosage of 150 μg at a dosing interval of once every 8 days for the desired treatment duration; and ribavirin is administered orally daily in an amount of about 1,000 mg to about 1,200 mg for the desired treatment duration.

[00367] In some embodiments, a subject method for treating a viral infection (e.g., an HCV infection, an HBV infection, etc.) comprises administering to an individual combined effective amounts of PEGylated IFN-α and ribavirin, wherein monoPEG(30 kD, linear)-ylated consensus IFN-α is administered at a dosage of 150 μg at a dosing interval of once every 10 days for the desired treatment duration; and ribavirin is administered orally daily in an amount of about 1,000 mg to about 1,200 mg for the desired treatment duration.

[00368] In some embodiments, a subject method for treating a viral infection (e.g., an HCV infection, an HBV infection, etc.) comprises administering to an individual combined effective amounts of PEGylated IFN-α and ribavirin, wherein monoPEG(30 kD, linear)-ylated consensus IFN-α is administered at a dosage of 200 μg at a dosing interval of once every 8 days for the desired treatment duration; and ribavirin is administered orally daily in an amount of about 1,000 mg to about 1,200 mg for the desired treatment duration. [00369] In some embodiments, a subject method for treating a viral infection comprises administering to an individual combined effective amounts of PEGylated IFN-α and ribavirin, wherein monoPEG(30 kD, linear)-ylated consensus IFN-α is administered at a dosage of 200 μg at a dosing interval of once every 10 days for the desired treatment duration; and ribavirin is administered orally daily in an amount of about 1,000 mg to about 1,200 mg for the desired treatment duration.

[00370] In any ofthe above embodiments, a subject combination therapy may further comprise administering an effective amount of pirfenidone or a pirfenidone analog. Pirfenidone is typically administered orally. Pirfenidone can be administered orally daily in a single dose or in two or more divided doses.

[00371] Effective dosages of pirfenidone or a specific pirfenidone analog include a weight- based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally. Other doses and formulations of pirfenidone and specific pirfenidone analogs suitable for use in the treatment of fibrotic diseases are described in U.S. Pat. Nos., 5,310,562; 5,518,729; 5,716,632; and 6,090,822.

[00372] Any ofthe above-described combination therapies for the treatment of HCV infection can further comprise administering an additional anti-hepatitis C viral agent, e.g., an NS3 inhibitor, an inhibitor of an HCV RNA-dependent RNA polymerase, and the like.

[00373] Any ofthe above-described therapies can further comprise administering a side effect management agent, e.g., a non-steroidal anti-inflammatory drug, a histamine type 2 receptor antagonist, an antacid, a hematopoietic agent, and the like. PEGylated IFN-α and IFN-γ in combination therapy

[00374] The present invention provides combination therapies using monoPEG(30 kD, linear)- ylated consensus IFN-α and a Type II interferon receptor agonist in combined effective amounts for the treatment of viral infections. In addition, the present invention provides combination therapies using monoPEG(30 kD, linear)-ylated consensus IFN-α and a Type II interferon receptor agonist in combined effective amounts for the treatment of proliferative disorders, including fibrotic disorders, angiogenic disorders, and cancer.

[00375] Effective dosages of PEGylated IFN-α are described above.

[00376] In some embodiments, the Type II interferon receptor agonist is an IFN-γ. Effective dosages of IFN-γ can range from about 0.5 μg/m2 to about 500 μg/m2, usually from about 1.5 μg/m2 to 200 μg/m2, depending on the size ofthe patient. This activity is based on 106 international units (U) per 50 μg of protein. IFN-γ can be administered daily, every other day, three times a week, or substantially continuously or continuously.

[00377] In some embodiments, a subject method for treating a viral infection (e.g., an HCV infection, an HBV infection, etc.) or proliferative disorder (e.g., a cancer, a fibrotic disorder, an angiogenic disorder, etc.) in an individual comprises administering combined effective amounts of PEGylated IFN-α and IFN-γ, wherein PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, wherein the PEGylated IFN-α is administered subcutaneously to the individual at a dosing interval of 8 days or more, e.g., the PEGylated IFN-α is administered subcutaneously to the individual at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days, in an amount of from about 45 μg to about 270 μg per dose, e.g., in amounts of 100 μg per dose, 150 μg per dose, or 200 μg per dose; and wherein IFN-γ is administered subcutaneously to the individual daily (qd), every other day (qod), three times per week (tiw), two times per week (biw), once weekly (qw), substantially continuously, or continuously, in an amount of from about 25 μg to about 500 μg, from about 50 μg to about 400 μg, or from about 100 μg to about 300 μg, or about 200 μg of drug per dose when delivered as a bolus or per day when delivered as a continuous or substantially continuous infusion. In many embodiments of interest, IFN-γ lb is administered.

[00378] Where the dosage is 200 μg IFN-γ per dose, the amount of IFN-γ per body weight (assuming a range of body weights of from about 45 kg to about 135 kg) is in the range of from about 4.4 μg IFN-γ per kg body weight to about 1.48 μg IFN-γ per kg body weight.

[00379] The body surface area of subject individuals generally ranges from about 1.33 m to 9 9 about 2.50 m . Thus, in many embodiments, an IFN-γ dosage ranges from about 150 μg/m to about 20 μg/m2. For example, an IFN-γ dosage ranges from about 20 μg/m2 to about 30 μg/m2, from about 30 μg/m2 to about 40 μg/m2, from about 40 μg/m2 to about 50 μg/m2, from about 50 μg/m2 to about 60 μg/m2, from about 60 μg/m2 to about 70 μg/m2, from about 70 μg/m2 to about 80 μg/m2, from about 80 μg/m2 to about 90 μg/m2, from about 90 μg/m2 to about 100 ι O 9 9 μg/m , from about 100 μg/m to about 110 μg/m , from about 110 μg/m to about 120 μg/m , from about 120 μg/m2 to about 130 μg/m2, from about 130 μg/m2 to about 140 μg/m2, or from about 140 μg/m2 to about 150 μg/m2. In some embodiments, the dosage groups range from about 25 μg/m2 to about 100 μg/m2. In other embodiments, the dosage groups range from about 25 μg/m2 to about 50 μg/m2. [00380] IFN-γ is typically administered subcutaneously. For example, IFN-γ can be administered subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for a period of from about 2 weeks to about 52 weeks, from about 52 weeks to about 2 years, or longer. Viral infections

[00381] The present invention provides methods of treating a viral infection (e.g., an HCV infection, an HBV infection, etc.) in an individual. The methods generally involve administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more; and administering an effective amount of a Type II interferon receptor agonist, e.g., IFN-γ. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In some embodiments, the method for treating a viral infection in an individual involves administering PEGylated IFN-α, and a Type II interferon receptor agonist, in combination therapy with one or more additional therapeutic agents. In some embodiments, the methods involve administering PEGylated IFN- α, a Type II interferon receptor agonist, and ribavirin. In some embodiments, the methods involve administering PEGylated IFN-α, a Type II interferon receptor agonist, and pirfenidone or a pirfenidone analog.

[00382] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 Id), linear)-ylated consensus IFN-α and IFN-γ in the treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.) in a patient comprising co- administering to the patient a dosage of monoPEG(30 Id), linear)-ylated consensus IFN-α containing an amount of about 100 μg of drug per dose, subcutaneously at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; and a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for the desired treatment duration.

[00383] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ in the treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.) in a patient comprising co- administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 150 μg of drug per dose, subcutaneously at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; and a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for the desired treatment duration.

[00384] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ in the treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.) in a patient comprising co- administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 200 μg of drug per dose, subcutaneously at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; and a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for the desired treatment duration.

[00385] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ in the treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.) in a patient comprising co- administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 100 μg of drug per dose, subcutaneously at a dosing interval of once every 8 days; and a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for the desired treatment duration.

[00386] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ in the treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.) in a patient comprising co- administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 150 μg of drug per dose, subcutaneously at a dosing interval of once every 8 days; and a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for the desired treatment duration.

[00387] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 Id), linear)-ylated consensus IFN-α and IFN-γ in the treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.) in a patient comprising co- administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 200 μg of drug per dose, subcutaneously at a dosing interval of once every 8 days; and a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for the desired treatment duration.

[00388] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ in the treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.) in a patient comprising co- administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 100 μg of drug per dose, subcutaneously at a dosing interval of once every 10 days; and a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for the desired treatment duration.

[00389] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ in the treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.) in a patient comprising co- administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 150 μg of drug per dose, subcutaneously at a dosing interval of once every 10 days; and a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for the desired treatment duration.

[00390] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ in the treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.) in a patient comprising co- administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 200 μg of drug per dose, subcutaneously at a dosing interval of once every 10 days; and a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for the desired treatment duration.

[00391] In any ofthe above-described embodiments featuring monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ combination therapy for the treatment of a viral infection, the IFN- γ can be administered to the patient at a dosage of 50 μg, 100 μg, or 200 μg of drug per dose of IFN-γ, by subcutaneous injection three times per week (tiw). [00392] In any ofthe above-described embodiments featuring a combination therapy comprising administering monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ to treat a viral infection, the combination therapy may further include administering a dosage of ribavirin or a derivative thereof, in an amount of about 400 mg, 800 mg, 1000 mg, or 1200 mg orally daily for the desired treatment duration.

[00393] In one embodiment, the present invention provides for treatment of a viral infection . (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 100 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

00394] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 100 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 8 days; 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

00395] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 100 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

00396] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 100 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 8 days; 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more. [00397] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 100 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; and 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00398] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 100 μg monoPEG(30 Id), linear)-ylated consensus IFN-α administered subcutaneously every 8 days; and 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00399] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 100 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; and 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00400] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 100 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 8 days; and 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00401] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 150 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

[00402] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 150 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 8 days; 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more. [00403] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 150 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

[00404] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, and HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 150 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 8 days; 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

[00405] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 150,μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; and 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00406] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 150 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 8 days; and 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00407] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 150 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; and 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00408] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 150 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 8 days; and 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy. [00409] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 200 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

[00410] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 200 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 8 days; 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

[00411] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having an viral infection a regimen of 200 μg monoPEG(30 kD, linear)-ylated consensus IFN- α administered subcutaneously every 10 days; 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

[00412] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having an viral infection a regimen of 200 μg monoPEG(30 kD, linear)-ylated consensus IFN- α administered subcutaneously every 8 days; 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

[00413] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 200 μg monoPEG(30 Id), linear)-ylated consensus IFN-α administered subcutaneously every 10 days; and 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy. [00414] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 200 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 8 days; and 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00415] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 200 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; and 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00416] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 200 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 8 days; and 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00417] In any ofthe above-described embodiments featuring a combination therapy comprising administering monoPEG(30 Id), linear)-ylated consensus IFN-α and IFN-γ to treat a viral infection, the combination therapy may further include administering a dosage of pirfenidone or a pirfenidone analog, such as a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration.

[00418] In any ofthe above-described embodiments featuring a combination therapy comprising administering monoPEG(30 Id), linear)-ylated consensus IFN-α and IFN-γ to treat an HCV infection, the combination therapy may further include administering a dosage of an additional anti-hepatitis C viral agent, e.g., anNS3 inhibitor, an inhibitor of an HCV RNA- dependent RNA polymerase, and the like. Proliferative disorders

[00419] The present invention provides methods of treating a proliferative disorder (e.g., cancer, a fibrotic disorder, an angiogenic disorder) in an individual. The methods generally involve administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more; and administering an effective amount of a Type II interferon receptor agonist, e.g., IFN-γ. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In some embodiments, the method for treating a proliferative disorder in an individual involves administering PEGylated IFN-α, and a Type II interferon receptor agonist, in combination therapy with one or more additional therapeutic agents. In some embodiments, the methods involve administering PEGylated IFN-α, a Type II interferon receptor agonist, and pirfenidone or a pirfenidone analog.

[00420] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising co-administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 100 μg of drug per dose, subcutaneously at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; and a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for the desired treatment duration.

[00421] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising co-administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 150 μg of drug per dose, subcutaneously at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; and a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for the desired treatment duration.

[00422] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising co-administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 200 μg of drug per dose, subcutaneously at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days; and a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for the desired treatment duration.

[00423] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising co-administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 100 μg of drug per dose, subcutaneously at a dosing interval of once every 8 days; and a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for the desired treatment duration.

[00424] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising co-administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 150 μg of drug per dose, subcutaneously at a dosing interval of once every 8 days; and a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for the desired treatment duration.

[00425] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 Id), linear)-ylated consensus IFN-α and IFN-γ in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising co-administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 200 μg of drug per dose, subcutaneously at a dosing interval of once every 8 days; and a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for the desired treatment duration.

[00426] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 Id), linear)-ylated consensus IFN-α and IFN-γ in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising co-administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 100 μg of drug per dose, subcutaneously at a dosing interval of once every 10 days; and a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for the desired treatment duration.

[00427] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 Id), linear)-ylated consensus IFN-α and IFN-γ in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising co-administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 150 μg of drug per dose, subcutaneously at a dosing interval of once every 10 days; and a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for the desired treatment duration.

[00428] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising co-administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 200 μg of drug per dose, subcutaneously at a dosing interval of once every 10 days; and a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for the desired treatment duration.

[00429] In any ofthe above-described embodiments featuring monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ combination therapy for the treatment of a proliferative disorder, the IFN-γ can be administered to the patient at a dosage of 50 μg, 100 μg or 200 μg of drug by subcutaneous injection three times per week (tiw) for the desired treatment duration.

[00430] In any ofthe above-described embodiments featuring a combination therapy comprising administering monoPEG(30 Id), linear)-ylated consensus IFN-α and IFN-γ to treat a fibrotic disorder, the combination therapy may further include administering a dosage of an additional agent, e.g., an anti-fibrotic agent. Suitable anti-fibrotic agents include a steroidal anti-inflammatory agent; and a TNF antagonist.

[00431] In any ofthe above-described embodiments featuring a combination therapy comprising administering monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ to treat an angiogenic disorder, the combination therapy may further include administering a dosage of an additional agent, e.g., an anti-angiogenic agent.

[00432] Any ofthe above-described embodiments featuring a combination therapy comprising administering monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ for the treatment of cancer can be used as an adjuvant to a standard cancer therapy. Standard cancer therapies include surgery (e.g., surgical removal of cancerous tissue),, radiation therapy, bone marrow transplantation, chemotherapeutic treatment, biological response modifier treatment, and certain combinations ofthe foregoing.

[00433] Radiation therapy includes, but is not limited to, x-rays or gamma rays that are delivered from either an externally applied source such as a beam, or by implantation of small radioactive sources.

[00434] Chemotherapeutic agents are non-peptidic (i.e., non-proteinaceous) compounds that reduce proliferation of cancer cells, and encompass cytotoxic agents and cytostatic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, plant (vinca) alkaloids, and steroid hormones.

[00435] Agents that act to reduce cellular proliferation are known in the art and widely used. Such agents include alkylating agents, such as nitrogen mustards, nitrosoureas, ethylenimine derivatives, alkyl sulfonates, and triazenes, including, but not limited to, mechlorethamine, cyclophosphamide (Cytoxan™), melphalan (L-sarcolysin), carmustine (BCNU), lomustine (CCNU), semustine (methyl-CCNU), streptozocin, chlorozotocin, uracil mustard, chlormethine, ifosfamide, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, dacarbazine, and temozolomide.

[00436] Antimetabolite agents include folic acid analogs, pyrimidine analogs, purine analogs, and adenosine deaminase inliibitors, including, but not limited to, cytarabine (CYTOSAR-U), cytosine arabinoside, fluorouracil (5-FU), floxuridine (FudR), 6-thioguanine, 6-mercaptopurine (6-MP), pentostatin, 5 -fluorouracil (5-FU), methotrexate, 10-propargyl-5,8-dideazafolate (PDDF, CB3717), 5,8-dideazatetrahydrofolic acid (DDATHF), leucovorin, fludarabine phosphate, pentostatine, and gemcitabine.

[00437] Suitable natural products and their derivatives, (e.g., vinca alkaloids, antitumor antibiotics, enzymes, lymphokines, and epipodophyllotoxins), include, but are not limited to, Ara-C, paclitaxel (Taxol®), docetaxel (Taxotere®), deoxycoformycin, mitomycin-C, L- asparaginase, azathioprine; brequinar; alkaloids, e.g. vincristine, vinblastine, vinorelbine, vindesine, etc.; podophyllotoxins, e.g. etoposide, teniposide, etc.; antibiotics, e.g. anthracycline, daunorubicin hydrochloride (daunomycin, rubidomycin, cerubidine), idarubicin, doxorubicin, epirubicin and morpholino derivatives, etc.; phenoxizone biscyclopeptides, e.g. dactinomycin; basic glycopeptides, e.g. bleomycin; anthraquinone glycosides, e.g. plicamycin (mithramycin); anthracenediones, e.g. mitoxantrone; azirinopyrrolo indolediones, e.g. mitomycin; macrocyclic immunosuppressants, e.g. cyclosporine, FK-506 (tacrolimus, prograf), rapamycin, etc. ; and the like.

[00438] Other anti-proliferative cytotoxic agents are navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafme, cyclophosphamide, ifosamide, and droloxafine.

[00439] Microtubule affecting agents that have antiproliferative activity are also suitable for use and include, but are not limited to, allocolchicine (NSC 406042), Halichondrin B (NSC 609395), colchicine (NSC 757), colchicine derivatives (e.g., NSC 33410), dolstatin 10 (NSC 376128), maytansine (NSC 153858), rhizoxin (NSC 332598), paclitaxel (Taxol®), Taxol® derivatives, docetaxel (Taxotere®), thiocolchicine (NSC 361792), frityl cysterin, vinblastine sulfate, vincristine sulfate, natural and synthetic epothilones including but not limited to, eopthilone A, epothilone B, discodermolide; estramustine, nocodazole, and the like.

[00440] Hormone modulators and steroids (including synthetic analogs) that are suitable for use include, but are not limited to, adrenocorticosteroids, e.g. prednisone, dexamethasone, etc.; estrogens and pregestins, e.g. hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, estradiol, clomiphene, tamoxifen; etc.; and adrenocortical suppressants, e.g. aminoglutethimide; 17α-ethinylestradiol; diethylstilbestrol, testosterone, fluoxymesterone, dromostanolone propionate, testolactone, methylprednisolone, methyl-testosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, Flutamide (Drogenil), Toremifene (Fareston), and Zoladex®. Estrogens stimulate proliferation and differentiation, therefore compounds that bind to the estrogen receptor are used to block this activity. Corticosteroids may inhibit T cell proliferation.

[00441] Other chemotherapeutic agents include metal complexes, e.g. cisplatin (cis-DDP), carboplatin, etc.; ureas, e.g. hydroxyurea; and hydrazines, e.g. N-methylhydrazine; epidophyllotoxin; a topoisomerase inhibitor; procarbazine; mitoxantrone; leucovorin; tegafur; etc.. Other anti-proliferative agents of interest include immunosuppressants, e.g. mycophenolic acid, thalidomide, desoxyspergualin, azasporine, leflunomide, mizoribine, azaspirane (SKF 105685); Iressa® (ZD 1839, 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6- (3 -(4-morpholinyl)propoxy)quinazoline); etc.

[00442] "Taxanes" include paclitaxel, as well as any active taxane derivative or pro-drug. "Paclitaxel" (which should be understood herein to include analogues, formulations, and derivatives such as, for example, docetaxel, TAXOL™, TAXOTERE™ (a formulation of docetaxel), 10-desacetyl analogs of paclitaxel and 3'N-desbenzoyl-3'N-t-butoxycarbonyl analogs of paclitaxel) may be readily prepared utilizing techniques known to those skilled in the art (see also WO 94/07882, WO 94/07881, WO 94/07880, WO 94/07876, WO 93/23555, WO 93/10076; U.S. Pat. Nos. 5,294,637; 5,283,253; 5,279,949; 5,274,137; 5,202,448; 5,200,534; 5,229,529; and EP 590,267), or obtained from a variety of commercial sources, including for example, Sigma Chemical Co., St. Louis, Mo. (T7402 from Taxus brevifolia; or T-1912 from Taxus yannanensis).

[00443] Paclitaxel should be understood to refer to not only the common chemically available form of paclitaxel, but analogs and derivatives (e.g., Taxotere™ docetaxel, as noted above) and paclitaxel conjugates (e.g., paclitaxel-PEG, paclitaxel-dextran, or paclitaxel-xylose).

[00444] Also included within the term "taxane" are a variety of known derivatives, including both hydrophilic derivatives, and hydrophobic derivatives. Taxane derivatives include, but not limited to, galactose and mannose derivatives described in International Patent Application No. WO 99/18113; piperazino and other derivatives described in WO 99/14209; taxane derivatives described in WO 99/09021, WO 98/22451, and U.S. Patent No. 5,869,680; 6-thio derivatives described in WO 98/28288; sulfenamide derivatives described in U.S. Patent No. 5,821,263; and taxol derivative described in U.S. Patent No. 5,415,869. It further includes prodrugs of paclitaxel including, but not limited to, those described in WO 98/58927; WO 98/13059; and U.S. Patent No. 5,824,701.

[00445] Biological response modifiers suitable for use in connection with the methods ofthe invention include, but are not limited to, (1) inhibitors of tyrosine kinase (RTK) activity; (2) inhibitors of serine/threonine kinase activity; (3) tumor-associated antigen antagonists, such as antibodies that bind specifically to a tumor antigen; (4) apoptosis receptor agonists; (5) interleuldn-2; (6) IFN-α; (7) IFN-γ (8) colony-stimulating factors; and (9) inliibitors of angiogenesis.

[00446] In one aspect, the invention features a method of treating cancer by co-administering monoPEG(30 Id), linear)-ylated consensus IFN-α and IFN-γ as an adjuvant to any therapy in which the cancer patient receives treatment with at least one additional antineoplastic drug, where the additional drug is an alkylating agent. In some embodiments, the alkylating agent is a nitrogen mustard. In other embodiments, the alkylating agent is an ethylenimine. In still other embodiments, the alkylating agent is an alkylsulfonate. In additional embodiments, the alkylating agent is a triazene. In further embodiments, the allkylating agent is a nitrosourea.

[00447] In another aspect, the invention features a method of treating cancer by co- administering monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ as an adjuvant to any therapy in which the cancer patient receives treatment with at least one additional antineoplastic drug, where the additional drug is an an antimetabolite. In some embodiments, the antimetabolite is a folic acid analog, such as methotrexate. In other embodiments, the antimetabolite is a purine analog, such as mercaptopurine, thioguanine and axathioprine. In still other embodiments, the antimetabolite is a pyrimidine analog, such as 5FU, UFT, capecitabine, gemcitabine and cytarabine.

[00448] In another aspect, the invention features a method of treating cancer by co- administering monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ as an adjuvant to any therapy in which the cancer patient receives treatment with at least one additional antineoplastic drug, where the additional drug is a vinca alkyloid. In some embodiments, the vinca alkaloid is a taxane, such as paclitaxel In other embodiments, the vinca alkaloid is a podophyllotoxin, such as etoposide, teniposide, ironotecan, and topotecan.

[00449] In another aspect, the invention features a method of treating cancer by co- administering monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ as an adjuvant to any therapy in which the cancer patient receives treatment with at least one additional antineoplastic drug, where the additional drug is an antineoplastic antibiotic. In some embodiments, the antineoplastic antibiotic is doxorubicin.

[00450] In another aspect, the invention features a method of treating cancer by co- administering monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ as an adjuvant to any therapy in which the cancer patient receives treatment with at least one additional antineoplastic drug, where the additional drug is a taxane. In some embodiments, the taxane is paclitaxel or docetaxel.

[00451] In another aspect, the invention features a method of treating cancer by co- administering monoPEG(30 Id), linear)-ylated consensus IFN-α and IFN-γ as an adjuvant to any therapy in which the cancer patient receives treatment with at least one additional antineoplastic drug, where the additional drug is a platinum complex. In some embodiments, the platinum complex is cisplatin. In other embodiments, the platinum complex is carboplatin.

[00452] In another aspect, the invention features a method of treating cancer by co- administering monoPEG(30 Id), linear)-ylated consensus IFN-α and IFN-γ as an adjuvant to any therapy in which the cancer patient receives treatment with a taxane and a platinum complex. In some embodiments, the taxane is paclitaxel and the platinum complex is carboplatin.

[00453] In one aspect, the invention contemplates a combination therapy comprising co- administering monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is a tyrosine kinase inhibitor. In some embodiments, the tyrosine kinase inhibitor is a receptor tyrosine kinase (RTK) inhibitor, such as type I receptor tyrosine kinase inhibitors (e.g., inhibitors of epidermal growth factor receptors), type II receptor tyrosine kinase inhibitors (e.g., inhibitors of insulin receptor), type III receptor tyrosine kinase inhibitors (e.g., inhibitors of platelet-derived growth factor receptor), and type IV receptor tyrosine kinase inhibitors (e.g., fibroblast growth factor receptor). In other embodiments, the tyrosine kinase inhibitor is a non-receptor tyrosine kinase inhibitor, such as inhibitors of src kinases or janus kinases.

[00454] In another aspect, the invention contemplates a combination therapy comprising co- administering monoPEG(30 Id), linear)-ylated consensus IFN-α and IFN-γ as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is an inhibitor of a receptor tyrosine kinase involved in growth factor signaling pathway(s). In some embodiments, the inhibitor is genistein. In other embodiments, the inhibitor is an EGFR tyrosine kinase-specific antagonist, such as IRESSA™ gefitinib (ZD18398; Novartis), TARCEVA™ erolotinib (OSI-774; Roche; Genentech; OSI Pharmaceuticals), or tyrphostin AG1478 (4-(3-chloroanilino)-6,7- dimethoxyquinazoline. In still other embodiments, the inhibitor is any indolinone antagonist of Flk-1/KDR (VEGF-R2) tyrosine kinase activity described in U.S. Patent Application Publication No. 2002/0183364 Al, such as the indolinone antagonists of Flk-1/KDR (VEGF- R2) tyrosine kinase activity disclosed in Table 1 on pages 4-5 thereof. In further embodiments, the inhibitor is any ofthe substituted 3-[(4,5,6,7-tetrahydro-lH-indol-2-yi) methylene]-l,3- dihydroindol-2-one antagonists of Flk-1/KDR (VEGF-R2), FGF-R1 or PDGF-R tyrosine kinase activity disclosed in Sun, L., et al, J. Med. Chem.. 43(14): 2655-2663 (2000). In additional embodiments, the inhibitor is any substituted 3-[(3- or 4-carboxyethylpyrrol-2-yl) methylidenyl]indolin-2-one antagonist of Flt-1 (VEGF-R1), Flk-1/KDR (VEGF-R2), FGF-R1 or PDGF-R tyrosine kinase activity disclosed in Sun, L., et al, J. Med. Chem.. 42(25): 5120- 5130 (1999).

[00455] In another aspect, the invention contemplates a combination therapy comprising co- administering monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is an inhibitor of a non-receptor tyrosine kinase involved in growth factor signaling pathway(s). In some embodiments, the inhibitor is an antagonist of JAK2 tyrosine kinase activity, such as tyrphostin AG490 (2-cyano-3-(3,4- dihydroxyphenyl)-N-(benzyl)-2-propenamide). In other embodiments, the inhibitor is an antagonist of bcr-abl tyrosine kinase activity, such as GLEEVEC™ imatinib mesylate (STI- 571; Novartis).

[00456] In another aspect, the invention contemplates a combination therapy comprising co- administering monoPEG(30 Id), linear)-ylated consensus IFN-α and IFN-γ as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is a serine/threonine kinase inhibitor. In some embodiments, the serine/threonine kinase inhibitor is a receptor serine/threonine kinase inhibitor, such as antagonists of TGF-β receptor serine/threonine kinase activity. In other embodiments, the serine/threonine kinase inhibitor is a non-receptor serine/threonine kinase inhibitor, such as antagonists ofthe serine/threonine kinase activity ofthe MAP kinases, protein kinase C (PKC), protein kinase A (PKA), or the cyclin-dependent kinases (CDKs).

[00457] In another aspect, the invention contemplates a combination therapy comprising co- administering monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is an inhibitor of one or more kinases involved in cell cycle regulation. In some embodiments, the inhibitor is an antagonist of CDK2 activation, such as tryphostin AG490 (2-cyano-3-(3,4-dihydroxyphenyl)-N-(benzyl)-2- propenamide). In other embodiments, the inliibitor is an antagonist of CDKl/cyclin B activity, such as alsterpaullone. In still other embodiments, the inhibitor is an antagonist of CDK2 kinase activity, such as indirubin-3'-monoxime. In additional embodiments, the inliibitor is an ATP pool antagonist, such as lometrexol (described in U.S. Patent Application Publication No. 2002/0156023 Al).

[00458] In another aspect, the invention contemplates a combination therapy comprising co- administering monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is an a tumor-associated antigen antagonist, such as an antibody antagonist. In some embodiments involving the treatment of HER2-expressing tumors, the tumor-associated antigen antagonist is an anti-HER2 monoclonal antibody, such as HERCEPTIN™ trastuzumab. In some embodiments involving the treatment of CD20- expressing tumors, such as B-cell lymphomas, the tumor-associated antigen antagonist is an anti-CD20 monoclonal antibody, such as RITUXAN™ rituximab.

[00459] In another aspect, the invention contemplates a combination therapy comprising co- administering monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is a tumor growth factor antagonist. In some embodiments, the tumor growth factor antagonist is an antagonist of epidermal growth factor (EGF), such as an anti-EGF monoclonal antibody. In other embodiments, the tumor growth factor antagonist is an antagonist of epidermal growth factor receptor erbBl (EGFR), such as an anti-EGFR monoclonal antibody inhibitor of EGFR activation or signal transduction, including ERBITUX™ cetuximab, or a small molecule antagonist of EGFR activation or signal transduction, such as IRESSA™ gefitinib and TARCEVA™ erolotinib.

[00460] In another aspect, the invention contemplates a combination therapy comprising co- administering monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is an Apo-2 ligand agonist. In some embodiments, the Apo-2 ligand agonist is any ofthe Apo-2 ligand polypeptides described in WO 97/25428.

[00461] In another aspect, the invention contemplates a combination therapy comprising co- administering monoPEG(30 kD, linear)-ylated consensus IFN-α and IFN-γ as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is an anti-angiogenic agent. In some embodiments, the anti-angiogenic agent is a vascular endothelial cell growth factor (VEGF) antagonist, such as an anti-VEGF monoclonal antibody, e.g. AVASTIN™ bevacizumab (Genentech). In other embodiments, the anti-angiogenic agent is an antagonist of VEGF-R1, such as an anti-VEGF-Rl monoclonal antibody. In other embodiments, the anti-angiogenic agent is an antagonist of VEGF-R2, such as an anti-VEGF-R2 monoclonal antibody. In other embodiments, the anti-angiogenic agent is an antagonist of basic fibroblast growth factor (bFGF), such as an anti-bFGF monoclonal antibody. In other embodiments, the anti- angiogenic agent is an antagonist of bFGF receptor, such as an anti-bFGF receptor monoclonal antibody. In other embodiments, the anti-angiogenic agent is an antagonist of TGF-β, such as an anti-TGF-β monoclonal antibody. In other embodiments, the anti-angiogenic agent is an antagonist of TGF-β receptor, such as an anti-TGF-β receptor monoclonal antibody. In other embodiments, the anti-angiogenic agent is a retinoic acid receptor (RXR) ligand, such as any RXR ligand described in U.S. Patent Application Publication No. 2001/0036955 Al or in any of U.S. Pat. Nos. 5,824,685; 5,780,676; 5,399,586; 5,466,861; 4,810,804; 5,770,378; 5,770,383; or 5,770,382. In still other embodiments, the anti-angiogenic agent is a peroxisome proliferator-activated receptor (PPAR) gamma ligand, such as any PPAR gamma ligand described in U.S. Patent Application Publication No. 2001/0036955 Al. PEGylated IFN-α and pirfenidone or a pirfenidone analog in combination therapy

[00462] The invention provides combination therapy methods using monoPEG(30 kD, linear)- ylated consensus IFN-α and pirfenidone or a pirfenidone analog in combined effective amounts for the treatment of viral infections (e.g., HCV infections, HBV infections, etc.). In addition, the invention provides combination therapy methods using monoPEG(30 kD, linear)-ylated consensus IFN-α and pirfenidone or a pirfenidone analog in combined effective amounts for the treatment of cancer.

[00463] Effective dosages of PEGylated IFN-α are described above.

[00464] Effective dosages of pirfenidone or a pirfenidone analog generally include orally administered weight-based dosages in the range from about 5 mg/kg/day to about 125 mg/kg/day, and orally administered fixed dosages in the range of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day. Viral infections

[00465] The present invention features methods of treating a viral infection (e.g., HCV infections, HBV infections, etc.) in an individual. The methods generally involve administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more; and administering an effective amount of pirfenidone or a pirfenidone analog. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In some embodiments, the method for treating a viral infection in an individual involves administering PEGylated IFN-α, and pirfenidone or a pirfenidone analog, in combination therapy with one or more additional therapeutic agents. In some embodiments, the methods involve administering PEGylated IFN-α, a pirfenidone or a pirfenidone analog, and ribavirin.

[00466] In some embodiments, a subject method for treating a viral infection (e.g., HCV infections, HBV infections, etc.) comprises administering to an individual combined effective amounts of PEGylated IFN-α and pirfenidone or a pirfenidone analog, wherein monoPEG(30 Id), linear)-ylated consensus IFN-α is administered at a dosage of 100 μg of drug per dose, subcutaneously at a dosing interval of once every 8 days for the desired treatment duration; in combination with a dosage of pirfenidone or a specific pirfenidone analog containing an amount of about 400 mg to about 3,600 mg of drug per dose orally qd, optionally in two or more divided doses per day, for. the desired treatment duration.

[00467] In some embodiments, a subject method for treating a viral infection (e.g., HCV infections, HBV infections, etc.) comprises administering to an individual combined effective amounts of PEGylated IFN-α and pirfenidone or a pirfenidone analog, wherein monoPEG(30 kD, linear)-ylated consensus IFN-α is administered at a dosage of 150 μg of drug per dose, subcutaneously at a dosing interval of once every 8 days for the desired treatment duration; in combination with a dosage of pirfenidone or a specific pirfenidone analog containing an amount of about 400 mg to about 3,600 mg of drug per dose orally qd, optionally in two or more divided doses per day, for the desired treatment duration.

[00468] In some embodiments, a subject method for treating a viral infection (e.g., HCV infections, HBV infections, etc.) comprises administering to an individual combined effective amounts of PEGylated IFN-α and pirfenidone or a pirfenidone analog, wherein monoPEG(30 kD, linear)-ylated consensus IFN-α is administered at a dosage of 200 μg of drug per dose, subcutaneously at a dosing interval of once every 8 days for the desired treatment duration; in combination with a dosage of pirfenidone or a specific pirfenidone analog containing an amount of about 400 mg to about 3,600 mg of drug per dose orally qd, optionally in two or more divided doses per day, for the desired treatment duration.

[00469] In some embodiments, a subject method for treating a viral infection (e.g., HCV infections, HBV infections, etc.) comprises administering to an individual combined effective amounts of PEGylated IFN-α and pirfenidone or a pirfenidone analog, wherein monoPEG(30 Id), linear)-ylated consensus IFN-α is administered at a dosage of 100 μg of drug per dose, subcutaneously at a dosing interval of once every 10 days for the desired treatment duration; in combination with a dosage of pirfenidone or a specific pirfenidone analog containing an amount of about 400 mg to about 3,600 mg of drug per dose orally qd, optionally in two or more divided doses per day, for the desired treatment duration.

[00470] In some embodiments, a subject method for treating a viral infection (e.g., HCV infections, HBV infections, etc.) comprises administering to an individual combined effective amounts of PEGylated IFN-α and pirfenidone or a pirfenidone analog, wherein monoPEG(30 Id), linear)-ylated consensus IFN-α is administered at a dosage of 150 μg of drug per dose, subcutaneously at a dosing interval of once every 10 days for the desired treatment duration; in combination with a dosage of pirfenidone or a specific pirfenidone analog containing an amount of about 400 mg to about 3,600 mg of drug per dose orally qd, optionally in two or more divided doses per day, for the desired treatment duration. [00471] In some embodiments, a subject method for treating a viral infection (e.g., HCV infections, HBV infections, etc.) comprises administering to an individual combined effective amounts of PEGylated IFN-α and pirfenidone or a pirfenidone analog, wherein monoPEG(30 Id), linear)-ylated consensus IFN-α is administered at a dosage of 200 μg of drug per dose, subcutaneously at a dosing interval of once every 10 days for the desired treatment duration; in combination with a dosage of pirfenidone or a specific pirfenidone analog containing an amount of about 400 mg to about 3,600 mg of drug per dose orally qd, optionally in two or more divided doses per day, for the desired treatment duration.

[00472] In any ofthe above-described methods featuring a combination therapy comprising administering monoPEG(30 Id), linear)-ylated consensus IFN-α and pirfenidone or a pirfenidone analog to treat a viral infection, the pirfenidone or specific pirfenidone analog can be administered to the patient at a dosage of about 400 mg to about 1200 mg, or about 1200 mg to about 2400 mg, of drug per dose orally per day (qd), optionally in two or more divided doses per day, for the desired treatment duration.

[00473] In any ofthe above-described methods featuring a combination therapy comprising administering monoPEG(30 Id), linear)-ylated consensus IFN-α and pirfenidone or a pirfenidone analog to treat a viral infection, the combination therapy can further comprise administering ribavirin, or a derivative thereof, in an amount of about 400 mg, 800 mg, 1,000 mg or 1,200 mg orally daily for the desired treatment duration.

[00474] In any ofthe above-described methods featuring a combination therapy comprising administering monoPEG(30 kD, linear)-ylated consensus IFN-α and pirfenidone or a pirfenidone analog to treat an HCV infection, the combination therapy can be modified to further comprise administering an NS3 inhibitor, an HCV RNA-dependent RNA polymerase, and the like. Cancer

[00475] The present invention features methods of treating cancer in an individual. The methods generally involve administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 Id) poly(ethylene glycol) molecule, at a dosing interval of 8 days or more; and administering an effective amount of pirfenidone or a pirfenidone analog. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In other embodiments, the method involves administering PEGylated IFN-α and pirfenidone or a pirfenidone analog as an adjuvant to a standard cancer therapy, e.g., in combination therapy with one or more anti-proliferative agents.

[00476] In some embodiments, a subject method for treating cancer comprises administering to an individual combined effective amounts of PEGylated IFN-α and pirfenidone or a pirfenidone analog, wherein monoPEG(30 kD, linear)-ylated consensus IFN-α is administered at a dosage of 100 μg of drug per dose, subcutaneously at a dosing interval of once every 8 days for the desired treatment duration; in combination with a dosage of pirfenidone or a specific pirfenidone analog containing an amount of about 400 mg to about 3,600 mg of drug per dose orally qd, optionally in two or more divided doses per day, for the desired treatment duration.

[00477] In some embodiments, a subject method for treating cancer comprises administering to an individual combined effective amounts of PEGylated IFN-α and pirfenidone or a pirfenidone analog, wherein monoPEG(30 kD, linear)-ylated consensus IFN-α is administered at a dosage of 150 μg of drug per dose, subcutaneously at a dosing interval of once every 8 days for the desired treatment duration; in combination with a dosage of pirfenidone or a specific pirfenidone analog containing an amount of about 400 mg to about 3,600 mg of drug per dose orally qd, optionally in two or more divided doses per day, for the desired treatment duration.

[00478] In some embodiments, a subject method for treating cancer comprises administering to an individual combined effective amounts of PEGylated IFN-α and pirfenidone or a pirfenidone analog, wherein monoPEG(30 kD, linear)-ylated consensus IFN-α is administered at a dosage of 200 μg of drag per dose, subcutaneously at a dosing interval of once every 8 days for the desired treatment duration; in combination with a dosage of pirfenidone or a specific pirfenidone analog containing an amount of about 400 mg to about 3,600 mg of drag per dose orally qd, optionally in two or more divided doses per day, for the desired treatment duration.

[00479] In some embodiments, a subject method for treating cancer comprises administering to an individual combined effective amounts of PEGylated IFN-α and pirfenidone or a pirfenidone analog, wherein monoPEG(30 kD, linear)-ylated consensus IFN-α is administered at a dosage of 100 μg of drug per dose, subcutaneously at a dosing interval of once every 10 days for the desired treatment duration; in combination with a dosage of pirfenidone or a specific pirfenidone analog containing an amount of about 400 mg to about 3,600 mg of drug per dose orally qd, optionally in two or more divided doses per day, for the desired treatment duration. [00480] In some embodiments, a subject method for treating cancer comprises administering to an individual combined effective amounts of PEGylated IFN-α and pirfenidone or a pirfenidone analog, wherein monoPEG(30 kD, linear)-ylated consensus IFN-α is administered at a dosage of 150 μg of drag per dose, subcutaneously at a dosing interval of once every 10 days for the desired treatment duration; in combination with a dosage of pirfenidone or a specific pirfenidone analog containing an amount of about 400 mg to about 3,600 mg of drug per dose orally qd, optionally in two or more divided doses per day, for the desired treatment duration. ,

[00481] In some embodiments, a subject method for treating cancer comprises administering to an individual combined effective amounts of PEGylated IFN-α and pirfenidone or a pirfenidone analog, wherein monoPEG(30 kD, linear)-ylated consensus IFN-α is administered at a dosage of 200 μg of drug per dose, subcutaneously at a dosing interval of once every 10 days for the desired treatment duration; in combination with a dosage of pirfenidone or a specific pirfenidone analog containing an amount of about 400 mg to about 3,600 mg of drug per dose orally qd, optionally in two or more divided doses per day, for the desired treatment duration.

[00482] In any ofthe above-described methods featuring a combination therapy comprising administering monoPEG(30 kD, linear)-ylated consensus IFN-α and pirfenidone or a specific pirfenidone analog to treat cancer, the pirfenidone or specific pirfenidone analog can be administered at a dosage of about 400 mg to about 1200 mg, or about 1200 mg to about 2400 mg, of drug per dose orally qd, optionally in two or more divided doses per day, for the desired treatment duration.

[00483] Any ofthe above-described embodiments featuring a combination therapy comprising administering monoPEG(30 kD, linear)-ylated consensus IFN-α and pirfenidone or a pirfenidone analog can be used as an adjuvant to a standard cancer therapy. Standard cancer therapies include surgery (e.g., surgical removal of cancerous tissue), radiation therapy, bone marrow transplantation, chemotherapeutic treatment, biological response modifier treatment, and certain combinations ofthe foregoing, as described above.

[00484] In one aspect, the invention features a method of treating cancer by co-administering monoPEG(30 Id), linear) -ylated consensus IFN-α and pirfenidone or pirfenidone analog as an adjuvant to any therapy in which the cancer patient receives treatment with at least one additional antineoplastic drug, where the additional drug is an alkylating agent. In some embodiments, the alkylating agent is a nitrogen mustard. In other embodiments, the alkylating agent is an ethylenimine. In still other embodiments, the alkylating agent is an alkylsulfonate. In additional embodiments, the alkylating agent is a triazene. In further embodiments, the allkylating agent is a nitrosourea.

[00485] In another aspect, the invention features a method of treating cancer by co- administering monoPEG(30 kD, linear)-ylated consensus IFN-α and pirfenidone or pirfenidone analog as an adjuvant to any therapy in which the cancer patient receives treatment with at least one additional antineoplastic drug, where the additional drug is an an antimetabolite. In some embodiments, the antimetabolite is a folic acid analog, such as methotrexate. In other embodiments, the antimetabolite is a purine analog, such as mercaptopurine, thioguanine and axathioprine. In still other embodiments, the antimetabolite is a pyrimidine analog, such as 5FU, UFT, capecitabine, gemcitabine and cytarabine.

[00486] In another aspect, the invention features a method of treating cancer by co- administering monoPEG(30 kD, linear)-ylated consensus IFN-α and pirfenidone or pirfenidone analog as an adjuvant to any therapy in which the cancer patient receives treatment with at least one additional antineoplastic drug, where the additional drag is a vinca alkyloid. In some embodiments, the vinca alkaloid is a taxane, such as paclitaxel. In other embodiments, the vinca alkaloid is a podophyllotoxin, such as etoposide, teniposide, ironotecan, and topotecan.

[00487] In another aspect, the invention features a method of treating cancer by co- administering monoPEG(30 kD, linear)-ylated consensus IFN-α and pirfenidone or pirfenidone analog as an adjuvant to any therapy in which the cancer patient receives treatment with at least one additional antineoplastic drug, where the additional drag is an antineoplastic antibiotic. In some embodiments, the antineoplastic antibiotic is doxorubicin.

[00488] In another aspect, the invention features a method of treating cancer by co- administering monoPEG(30 Id), linear)-ylated consensus IFN-α and pirfenidone or pirfenidone analog as an adjuvant to any therapy in which the cancer patient receives treatment with at least one additional antineoplastic drug, where the additional drag is a platinum complex. In some embodiments, the platinum complex is cisplatin. In other embodiments, the platinum complex is carboplatin.

[00489] In another aspect, the invention features a method of treating cancer by co- administering monoPEG(30 kD, linear)-ylated consensus IFN-α and pirfenidone or pirfenidone analog as an adjuvant to any therapy in which the cancer patient receives treatment with a taxane and a platinum complex. In some embodiments, the taxane is paclitaxel and the platinum complex is carboplatin.

[00490] In one aspect, the invention contemplates a combination therapy comprising administering monoPEG(30 Id), linear)-ylated consensus IFN-α and pirfenidone or a pirfenidone analog as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drag is a tyrosine kinase inhibitor. In some embodiments, the tyrosine kinase inhibitor is a receptor tyrosine kinase (RTK) inliibitor, such as type I receptor tyrosine kinase inhibitors (e.g., inhibitors of epidermal growth factor receptors), type II receptor tyrosine kinase inhibitors (e.g., inhibitors of insulin receptor), type III receptor tyrosine kinase inhibitors (e.g., inhibitors of platelet-derived growth factor receptor), and type IV receptor tyrosine kinase inhibitors (e.g., fibroblast growth factor receptor). In other embodiments, the tyrosine kinase inhibitor is a non-receptor tyrosine kinase inliibitor, such as inhibitors of src kinases or j anus kinases.

[00491] In another aspect, the invention contemplates a combination therapy comprising administering monoPEG(30 Id), linear)-ylated consensus IFN-α and pirfenidone or a pirfenidone analog as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drag is an inhibitor of a receptor tyrosine kinase involved in growth factor signaling pathway(s). In some embodiments, the inhibitor is genistein. In other embodiments, the inhibitor is an EGFR tyrosine kinase-specific antagonist, such as IRESSA™ gefitinib (ZD18398; Novartis), TARCEVA™ erolotinib (OSI-774; Roche; Genentech; OSI Pharmaceuticals), or tyrphostin AG1478 (4-(3-chloroanilino)-6,7-dimethoxyquinazoline. In still other embodiments, the inhibitor is any indolinone antagonist of Flk-1/KDR (VEGF-R2) tyrosine kinase activity described in U.S. Patent Application Publication No. 2002/0183364 Al, such as the indolinone antagonists of Flk-1/KDR (VEGF-R2) tyrosine kinase activity disclosed in Table 1 on pages 4- 5 thereof. In further embodiments, the inhibitor is any ofthe substituted 3-[(4,5,6,7-tetrahydro- lH-indol-2-yl) methylene] -1, 3 -dihydroindol-2-one antagonists of Flk-1/KDR (VEGF-R2), FGF-R1 or PDGF-R tyrosine kinase activity disclosed in Sun, L., et al, J. Med. Chem., 43(14): 2655-2663 (2000). In additional embodiments, the inliibitor is any substituted 3-[(3- or 4- carboxyethylpyrrol-2-yl) methylidenyl]indolin-2-one antagonist of Flt-1 (VEGF-R1), Flk- 1/KDR (NEGF-R2), FGF-R1 or PDGF-R tyrosine kinase activity disclosed in Sun, L., et al, L Med. Chem.. 42(25): 5120-5130 (1999).

[00492] In another aspect, the invention contemplates a combination therapy comprising administering monoPEG(30 kD, linear)-ylated consensus IFΝ-α and pirfenidone or a pirfenidone analog as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drag is an inhibitor of a non- receptor tyrosine kinase involved in growth factor signaling pathway(s). In some embodiments, the inhibitor is an antagonist of JAK2 tyrosine kinase activity, such as tyrphostin AG490 (2-cyano-3-(3,4-dihydroxyphenyl)-N-(benzyl)-2-propenamide). In other embodiments, the inhibitor is an antagonist of bcr-abl tyrosine kinase activity, such as GLEENEC™ imatinib mesylate (STI-571; Νovartis).

[00493] In another aspect, the invention contemplates a combination therapy comprising administering monoPEG(30 kD, linear)-ylated consensus IFΝ-α and pirfenidone or a pirfenidone analog as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drag is a serine/threonine kinase inhibitor. In some embodiments, the serine/threonine kinase inhibitor is a receptor serine/threonine kinase inhibitor, such as antagonists of TGF-β receptor serine/threonine kinase activity. In other embodiments, the serine/threonine kinase inhibitor is a non-receptor serine/threonine kinase inhibitor, such as antagonists ofthe serine/threonine kinase activity of the MAP kinases, protein kinase C (PKC), protein kinase A (PKA), or the cyclin-dependent kinases (CDKs).

[00494] In another aspect, the invention contemplates a combination therapy comprising administering monoPEG(30 kD, linear)-ylated consensus IFΝ-α and pirfenidone or a pirfenidone analog as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drag is an inhibitor of one or more kinases involved in cell cycle regulation. In some embodiments, the inhibitor is an antagonist of CDK2 activation, such as tryphostin AG490 (2-cyano-3-(3,4-dihydroxyphenyl)- Ν-(benzyl)-2-propenamide). In other embodiments, the inhibitor is an antagonist of CDKl/cyclin B activity, such as alsterpaullone. In still other embodiments, the inhibitor is an antagonist of CDK2 kinase activity, such as indirubin-3'-monoxime. In additional embodiments, the inhibitor is an ATP pool antagonist, such as lometrexol (described in U.S. Patent Application Publication No. 2002/0156023 Al).

[00495] In another aspect, the invention contemplates a combination therapy comprising administering monoPEG(30 Id), linear)-ylated consensus IFN-α and pirfenidone or a pirfenidone analog as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drag is an a tumor- associated antigen antagonist, such as an antibody antagonist. In some embodiments involving the treatment of HER2-expressing tumors, the tumor-associated antigen antagonist is an anti- HER2 monoclonal antibody, such as HERCEPTTN™ trastuzumab. In some embodiments involving the treatment of CD20-expressing tumors, such as B-cell lymphomas, the tumor- associated antigen antagonist is an anti-CD20 monoclonal antibody, such as RITUXAN™ rituximab. [00496] In another aspect, the invention contemplates a combination therapy comprising administering monoPEG(30 Id), linear)-ylated consensus IFN-α and pirfenidone or a pirfenidone analog as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is a tumor growth factor antagonist. In some embodiments, the tumor growth factor antagonist is an antagonist of epidermal growth factor (EGF), such as an anti-EGF monoclonal antibody. In other embodiments, the tumor growth factor antagonist is an antagonist of epidermal growth factor receptor erbBl (EGFR), such as an anti-EGFR monoclonal antibody inhibitor of EGFR activation or signal transduction, including ERBITUX™ cetuximab, or a small molecule antagonist of EGFR activation or signal transduction, such as IRES S A™ gefitinib and TARCEVA™ erolotinib.

[00497] In another aspect, the invention contemplates a combination therapy comprising administering monoPEG(30 kD, linear)-ylated consensus IFN-α and pirfenidone or a pirfenidone analog as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is an Apo-2 ligand agonist. In some embodiments, the Apo-2 ligand agonist is any ofthe Apo-2 ligand polypeptides described in WO 97/25428.

[00498] In another aspect, the invention contemplates a combination therapy comprising administering monoPEG(30 kD, linear)-ylated consensus IFN-α and pirfenidone or a pirfenidone analog as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drag is an anti-angiogenic agent. In some embodiments, the anti-angiogenic agent is a vascular endothelial cell growth factor (VEGF) antagonist, such as an anti-VEGF monoclonal antibody, e.g. AVASTIN™ bevacizumab (Genentech). In other embodiments, the anti-angiogenic agent is an antagonist of VEGF-R1, such as an anti-VEGF-Rl monoclonal antibody. In other embodiments, the anti- angiogenic agent is an antagonist of VEGF-R2, such as an anti-VEGF-R2 monoclonal antibody. In other embodiments, the anti-angiogenic agent is an antagonist of basic fibroblast growth factor (bFGF), such as an anti-bFGF monoclonal antibody. In other embodiments, the anti-angiogenic agent is an antagonist of bFGF receptor, such as an anti-bFGF receptor monoclonal antibody. In other embodiments, the anti-angiogenic agent is an antagonist of TGF-β, such as an anti-TGF-β monoclonal antibody. In other embodiments, the anti- angiogenic agent is an antagonist of TGF-β receptor, such as an anti-TGF-β receptor monoclonal antibody. In other embodiments, the anti-angiogenic agent is a retinoic acid receptor (RXR) ligand, such as any RXR ligand described in U.S. Patent Application Publication No. 2001/0036955 Al or in any of U.S. Pat. Nos. 5,824,685; 5,780,676; 5,399,586; 5,466,861; 4,810,804; 5,770,378; 5,770,383; or 5,770,382. In still other embodiments, the anti-angiogenic agent is a peroxisome proliferator-activated receptor (PPAR) gamma ligand, such as any PPAR gamma ligand described in U.S. Patent Application Publication No. 2001/0036955 Al. PEGylated IFN-α, IFN-γ, and TNF antagonist in combination therapy

[00499] The present invention provides combination therapies using monoPEG(30 kD, linear)- ylated consensus IFN-α, a Type II interferon receptor agonist, and a TNF antagonist, in combined effective amounts to treat a viral infection (e.g., an HCV infection, an HBV infection, etc.) in an individual In addition, the present invention provides combination therapies using monoPEG(30 kD, linear)-ylated consensus IFN-α, a Type II interferon receptor agonist, and a TNF antagonist, in combined effective amounts to treat a fibrotic disorder in an individual. In many embodiments, the Type II interferon receptor agonist is IFN-γ.

[00500] Effective dosages of PEGylated IFN-α are described above.

[00501] Effective dosages of IFN-γ are described above.

[00502] Effective dosages of a TNF-α antagonist range from 0.1 μg to 40 mg per dose, e.g., from about 0.1 μg to about 0.5 μg per dose, from about 0.5 μg to about 1.0 μg per dose, from about 1.0 μg per dose to about 5.0 μg per dose, from about 5.0 μg to about 10 μg per dose, from about 10 μg to about 20 μg per dose, from about 20 μg per dose to about 30 μg per dose, from about 30 μg per dose to about 40 μg per dose, from about 40 μg per dose to about 50 μg per dose, from about 50 μg per dose to about 60 μg per dose, from about 60 μg per dose to about 70 μg per dose, from about 70 μg to about 80 μg per dose, from about 80 μg per dose to about 100 μg per dose, from about 100 μg to about 150 μg per dose, from about 150 μg to about 200 μg per dose, from about 200 μg per dose to about 250 μg per dose, from about 250 μg to about 300 μg per dose, from about 300 μg to about 400 μg per dose, from about 400 μg to about 500 μg per dose, from about 500 μg to about 600 μg per dose, from about 600 μg to about 700 μg per dose, from about 700 μg to about 800 μg per dose, from about 800 μg to about 900 μg per dose, from about 900 μg to about 1000 μg per dose, from about 1 mg to about 10 mg per dose, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.

[00503] In some embodiments, the TNF-α antagonist is ENBREL® etanercept. Effective dosages of etanercept range from about 0.1 μg to about 40 mg per dose, from about 0.1 μg to about 1 μg per dose, from about 1 μg to about 10 μg per dose, from about 10 μg to about 100 μg per dose, from about 100 μg to about 1 mg per dose, from about 1 mg to about 5 mg per dose, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.

[00504] In some embodiments, effective dosages of a TNF-α antagonist are expressed as mg/kg body weight. In these embodiments, effective dosages of a TNF-α antagonist are from about 0.1 mg/kg body weight to about 10 mg/kg body weight, e.g., from about 0.1 mg/kg body weight to about 0.5 mg/kg body weight, from about 0.5 mg/kg body weight to about 1.0 mg/kg body weight, from about 1.0 mg/kg body weight to about 2.5 mg/kg body weight, from about 2.5 mg/kg body weight to about 5.0 mg/kg body weight, from about 5.0 mg/kg body weight to about 7.5 mg/kg body weight, or from about 7.5 mg/kg body weight to about 10 mg/kg body weight.

[00505] In some embodiments, the TNF-α antagonist is REMICADE® infliximab. Effective dosages of REMICADE® range from about 0.1 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.0 mg/kg, from about 1.0 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to about 2.0 mg/kg, from about 2.0 mg/kg to about 2.5 mg/kg, from about 2.5 mg/kg to about 3.0 mg/kg, from about 3.0 mg/kg to about 3.5 mg/kg, from about 3.5 mg/kg to about 4.0 mg/kg, from about 4.0 mg/kg to about 4.5 mg/kg, from about 4.5 mg/kg to about 5.0 mg/kg, from about 5.0 mg/kg to about 7.5 mg/kg, or from about 7.5 mg/kg to about 10 mg/kg per dose.

[00506] In some embodiments the TNF-α antagonist is HUMIRA™ adalimumab. Effective dosages of HUMIRA™ range from about 0.1 μg to about 35 mg, from about 0.1 μg to about 1 μg, from about 1 μg to about 10 μg, from about 10 μg to about 100 μg, from about 100 μg to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, or from about 35 mg to about 40 mg per dose.

[00507] In many embodiments, a TNF-α antagonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. The TNF-α antagonist can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously.

[00508] In many embodiments, multiple doses of a TNF-α antagonist are administered. For example, a TNF-α antagonist is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[00509] Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compounds, the severity ofthe symptoms and the susceptibility ofthe subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound. Viral infections

[00510] The present invention features methods of treating a viral infection (e.g., an HCV infection, an HBV infection, etc.) in an individual. The methods generally involve administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 Id) poly(ethylene glycol) molecule, at a dosing interval of 8 days or more; administering an effective amount of a Type II interferon receptor agonist, e.g., IFN-γ; and administering an effective amount of a TNF antagonist. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In some embodiments, the method for treating a viral infection in an individual involves administering PEGylated IFN-α, a Type II interferon receptor agonist, and a TNF antagonist, in combination therapy with one or more additional therapeutic agents, e.g., ribavirin.

[00511] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 Id), linear)-ylated consensus IFN-α, IFN-γ and TNF-α antagonist in the treatment of viral infection (e.g., an HCV infection, an HBV infection, etc.) in a patient, comprising administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 100 μg of drug per dose, subcutaneously once every 8 days, a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, and a dosage of a TNF-α antagonist selected from the group consisting of (i) ENBREL® in an amount of about 25 mg of drag subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks and (iii) HUMIRA™ in an amount of about 40 mg of drag subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[00512] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 kD, linear)-ylated consensus IFN-α, IFN-γ and TNF-α antagonist in the treatment of viral infection (e.g., an HCV infection, an HBV infection, etc.) in a patient, comprising administering to the patient a dosage of monoPEG(30 Id), linear)-ylated consensus IFN-α containing an amount of about 150 μg of drug per dose, subcutaneously once every 8 days, a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, and a dosage of a TNF-α antagonist selected from the group consisting of (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks and (iii) HUMIRA™ in an amount of about 40 mg of drag subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

00513] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 Id), linear)-ylated consensus IFN-α, IFN-γ and TNF-α antagonist in the treatment of viral infection (e.g., an HCV infection, an HBV infection, etc.) in a patient, comprising administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 200 μg of drug per dose, subcutaneously once every 8 days, a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, and a dosage of a TNF-α antagonist selected from the group consisting of (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks and (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[00514] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 kD, linear)-ylated consensus IFN-α, IFN-γ and TNF-α antagonist in the treatment of viral infection (e.g., an HCV infection, an HBV infection, etc.) in a patient, comprising administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 100 μg of drug per dose, subcutaneously once every 10 days, a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, and a dosage of a TNF-α antagonist selected from the group consisting of (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks and (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[00515] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 kD, linear)-ylated consensus IFN-α, IFN-γ and TNF-α antagonist in the treatment of viral infection (e.g., an HCV infection, an HBV infection, etc.) in a patient, comprising administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 150 μg of drug per dose, subcutaneously once every 10 days, a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, and a dosage of a TNF-α antagonist selected from the group consisting of (i) ENBREL® in an amount of about 25 mg of drag subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks and (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration. [00516] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 kD, linear)-ylated consensus IFN-α, IFN-γ and TNF-α antagonist in the treatment of viral infection (e.g., an HCV infection, an HBV infection, etc.) in a patient, comprising administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 200 μg of drug per dose, subcutaneously once every 10 days, a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drag per dose of IFN-γ subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, and a dosage of a TNF-α antagonist selected from the group consisting of (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks and (iii) HUMIRA™ in an amount of about 40 mg of drag subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[00517] In any ofthe above-described methods featuring combination therapy comprising administering monoPEG(30 kD, linear)-ylated consensus IFN-α, IFN-γ and TNF antagonist to treat viral infection, the IFN-γ can be administered to the patient at a dosage of 50 μg, 100 μg, or 200 μg of drag per dose of IFN-γ, by subcutaneous injection three times per week (tiw) for the desired treatment duration.

[00518] In any ofthe above-described methods featuring combination therapy comprising administering monoPEG(30 kD, linear)-ylated consensus IFN-α, Type II interferon receptor agonist, and TNF antagonist to treat a viral infection (e.g., an HCV infection, an HBV infection, etc.), the combination therapy can further comprise administering a dosage of ribavirin or a derivative thereof, in an amount of about 400 mg, 800 mg, 1000 mg, or 1200 mg orally daily for the desired treatment duration.

[00519] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 100 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

[00520] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 100 μg monoPEG(30 Id), linear)-ylated consensus IFN-α administered subcutaneously every 8 days; 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

[00521] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 100 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

[00522] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 100 μg monoPEG(30 Id), linear)-ylated consensus IFN-α administered subcutaneously every 8 days; 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

[00523] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 100 μg monoPEG(30 Id), linear)-ylated consensus IFN-α administered subcutaneously every 10 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00524] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 100 μg monoPEG(30 kD, lmear)-ylated consensus IFN-α administered subcutaneously every 8 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00525] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 100 μg monoPEG(30 Id), linear)-ylated consensus IFN-α administered subcutaneously every 10 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00526] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 100 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 8 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™. subcutaneously qw or qow; and 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00527] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 150 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

[00528] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 150 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 8 days; 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

[00529] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 150 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

[00530] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 150 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 8 days; 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

[00531] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 150 μg monoPEG(30 Id), linear)-ylated consensus IFN-α administered subcutaneously every 10 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00532] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 150 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 8 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00533] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 150 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00534] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 150 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 8 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00535] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 200 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

[00536] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 200 μg monoPEG(30 Id), linear)-ylated consensus IFN-α administered subcutaneously every 8 days; 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

[00537] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having an viral infection a regimen of 200 μg monoPEG(30 kD, linear)-ylated consensus IFN- α administered subcutaneously every 10 days; 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

[00538] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having an viral infection a regimen of 200 μg monoPEG(30 kD, linear)-ylated consensus IFN- α administered subcutaneously every 8 days; 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

[00539] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 200 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00540] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 200 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 8 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00541] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 200 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00542] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 200 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 8 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00543] In any ofthe above-described methods featuring combination therapy comprising administering monoPEG(30 kD, linear)-ylated consensus IFN-α, Type II interferon receptor agonist, and TNF antagonist to treat a viral infection (e.g., an HCV infection, and HBV infection, etc.), the combination therapy can further comprise administering a weight-based dosage of pirfenidone or a pirfenidone analog in the range of about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3,600 mg per day, or about 800 mg to about 2,400 mg per day, or about 1,000 mg to about 1,800 mg per day, or about 1,200 mg to about 1,600 mg per day, orally for the desired treatment duration.

[00544] In any ofthe above-described methods for featuring combination therapy comprising administering monoPEG(30 kD, linear)-ylated consensus IFN-α, IFN-γ and a TNF-α antagonist to treat an HCV infection, the combination therapy can further comprise administering an additional anti-hepatitis C viral agent, e.g., anNS3 inhibitor, an HCV RNA- dependent RNA polymerase, and the like. Fibrotic disorders

[00545] The present invention features methods of treating a fibrotic disorder in an individual. The methods generally involve administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more; administering an effective amount of a Type II interferon receptor agonist, e.g., IFN-γ; and administering an effective amount of a TNF antagonist. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In some embodiments, the method for treating a fibrotic disorder in an individual involves administering PEGylated IFN-α, a Type II interferon receptor agonist, and a TNF antagonist, in combination therapy with one or more additional therapeutic agents. In some embodiments, the methods involve administering PEGylated IFN-α, a Type II interferon receptor agonist, a TNF antagonist, and pirfenidone or a pirfenidone analog.

[00546] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 Id), linear)-ylated consensus IFN-α, IFN-γ and TNF-α antagonist in the treatment of a fibrotic disorder in a patient, comprising administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 100 μg of drug per dose, subcutaneously once every 8 days, a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drag per dose of IFN-γ subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, and a dosage of a TNF-α antagonist selected from the group consisting of (i) ENBREL® in an amount of about 25 mg of drag subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks and (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[00547] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 kD, linear)-ylated consensus IFN-α, IFN-γ and TNF-α antagonist in the treatment of a fibrotic disorder in a patient, comprising administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 150 μg of drug per dose, subcutaneously once every 8 days, a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, and a dosage of a TNF-α antagonist selected from the group consisting of (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks and (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[00548] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 Id), linear)-ylated consensus IFN-α, IFN-γ and TNF-α antagonist in the treatment of a fibrotic disorder in a patient, comprising administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 200 μg of drug per dose, subcutaneously once every 8 days, a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, and a dosage of a TNF-α antagonist selected from the group consisting of (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drag intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks and (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[00549] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 Id), linear)-ylated consensus IFN-α, IFN-γ and TNF-α antagonist in the treatment of a fibrotic disorder in a patient, comprising administering to the patient a dosage of monoPEG(30 Id), linear)-ylated consensus IFN-α containing an amount of about 100 μg of drag per dose, subcutaneously once every 10 days, a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, and a dosage of a TNF-α antagonist selected from the group consisting of (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks and (iii) HUMIRA™ in an amount of about 40 mg of drag subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[00550] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 kD, linear)-ylated consensus IFN-α, IFN-γ and TNF-α antagonist in the treatment of a fibrotic disorder in a patient, comprising administering to the patient a dosage of monoPEG(30 Id), linear)-ylated consensus IFN-α containing an amount of about 150 μg of drug per dose, subcutaneously once every 10 days, a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drag per dose of IFN-γ subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, and a dosage of a TNF-α antagonist selected from the group consisting of (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks and (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[00551] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 kD, linear)-ylated consensus IFN-α, IFN-γ and TNF-α antagonist in the treatment of a fibrotic disorder in a patient, comprising administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 200 μg of drug per dose, subcutaneously once every 10 days, a dosage of IFN-γ containing an amount of about 10 μg to about 300 μg of drug per dose of IFN-γ subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, and a dosage of a TNF-α antagonist selected from the group consisting of (i) ENBREL® in an amount of about 25 mg of drag subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks and (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration. [00552] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 100 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00553] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 100 μg monoPEG(30 Id), linear)-ylated consensus IFN-α administered subcutaneously every 8 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00554] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 100 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00555] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 100 μg monoPEG(30 Id), linear)-ylated consensus IFN-α administered subcutaneously every 8 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00556] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 150 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00557] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 150 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 8 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00558] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 150 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00559] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 150 μg monoPEG(30 Id), linear)-ylated consensus IFN-α administered subcutaneously every 8 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00560] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 200 μg monoPEG(30 Id), linear)-ylated consensus IFN-α administered subcutaneously every 10 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00561] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 200 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 8 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and 50 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00562] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 200 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00563] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 200 μg monoPEG(30 Id), linear)-ylated consensus IFN-α administered subcutaneously every 8 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and 100 μg Actimmune® human IFN-γlb administered subcutaneously tiw; for the desired duration of therapy.

[00564] The anti-fibrotic effect or other therapeutic benefit of any ofthe above-described regimens featuring monoPEG(30 kD, linear)-ylated consensus IFN-α, Type II interferon receptor agonist and a TNF-α antagonist combination therapy can be enhanced by co- administering to the patient a weight-based dosage of pirfenidone or a pirfenidone analog in the range of about 5 mg/kg of body weight to about 125 mg/kg of body weight, or a fixed dosage of pirfenidone or a pirfenidone analog in the range of about 400 mg to about 3600 mg, or about 800 mg to about 2400 mg, or about 1000 mg to about 1800 mg, or about 1200 mg to about 1600 mg, orally qd for the desired duration of monoPEG(30 kD, linear)-ylated consensus IFN-α, Type II interferon receptor agonist and TNF-α antagonist therapy.

[00565] Any ofthe above-described methods for treating a fibrotic disorder using a combination therapy with monoPEG(30 kD, linear)-ylated consensus IFN-α, a Type II interferon receptor agonist, and a TNF-α antagonist can be modified to further comprise administering an additional anti-fibrotic agent. PEGylated IFN-α and TNF antagonist in combination therapy

[00566] The present invention provides combination therapies using monoPEG(30 kD, linear)- ylated consensus IFN-α and a TNF antagonist, in combined effective amounts to treat a viral infection (e.g., an HCV infection, an HBV infection, etc.) in an individual. In many embodiments, the TNF antagonist is etanercept, infliximab or adalimumab.

[00567] Effective dosages of PEGylated IFN-α are described above.

[00568] Effective dosages of TNF antagonist are described above.

[00569] The present invention features methods of treating a viral infection (e.g., an HCV infection, an HBV infection, etc.) in an individual. The methods generally involve administering to the individual an effective amount of PEGylated IFN-α, where the PEGylated IFN-α is a conjugate of a single consensus IFN-α molecule and a single, linear, 30 kD poly(ethylene glycol) molecule, at a dosing interval of 8 days or more; and administering an effective amount of a TNF antagonist. In some embodiments, the PEGylated IFN-α is administered at a dosing interval of once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. In some embodiments, the method for treating a viral infection in an individual involves administering PEGylated IFN-α and a TNF antagonist, in combination therapy with one or more additional therapeutic agents, e.g., ribavirin.

[00570] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 kD, linear)-ylated consensus IFN-α and TNF-α antagonist in the treatment of viral infection (e.g., an HCV infection, an HBV infection, etc.) in a patient, comprising administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 100 μg of drug per dose, subcutaneously once every 8 days, and a dosage of a TNF-α antagonist selected from the group consisting of (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks and (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[00571] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 kD, linear)-ylated consensus IFN-α and TNF-α antagonist in the treatment of viral infection (e.g., an HCV infection, an HBV infection, etc.) in a patient, comprising administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 150 μg of drug per dose, subcutaneously once every 8 days, and a dosage of a TNF-α antagonist selected from the group consisting of (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drag intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks and (iii) HUMIRA™ in an amount of about 40 mg of drag subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[00572] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 kD, linear)-ylated consensus IFN-α and TNF-α antagonist in the treatment of viral infection (e.g., an HCV infection, an HBV infection, etc.) in a patient, comprising administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 200 μg of drug per dose, subcutaneously once every 8 days, and a dosage of a TNF-α antagonist selected from the group consisting of (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks and (iii) HUMIRA™ in an amount of about 40 mg of drag subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[00573] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 Id), linear)-ylated consensus IFN-α and TNF-α antagonist in the treatment of viral infection (e.g., an HCV infection, an HBV infection, etc.) in a patient, comprising administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 100 μg of drug per dose, subcutaneously once every 10 days, and a dosage of a TNF-α antagonist selected from the group consisting of (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drag intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks and (iii) HUMIRA™ in an amount of about 40 mg of drag subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[00574] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 kD, linear)-ylated consensus IFN-α and TNF-α antagonist in the treatment of viral infection (e.g., an HCV infection, an HBV infection, etc.) in a patient, comprising administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 150 μg of drag per dose, subcutaneously once every 10 days, and a dosage of a TNF-α antagonist selected from the group consisting of (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks and (iii) HUMIRA™ in an amount of about 40 mg of drag subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[00575] In one embodiment, the invention provides a method using an effective amount of monoPEG(30 kD, linear)-ylated consensus IFN-α and TNF-α antagonist in the treatment of viral infection (e.g., an HCV infection, an HBV infection, etc.) in a patient, comprising administering to the patient a dosage of monoPEG(30 kD, linear)-ylated consensus IFN-α containing an amount of about 200 μg of drug per dose, subcutaneously once every 10 days, and a dosage of a TNF-α antagonist selected from the group consisting of (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks and (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[00576] In any ofthe above-described methods featuring combination therapy comprising administering monoPEG(30 Id), linear)-ylated consensus IFN-α and TNF antagonist to treat viral infection (e.g., an HCV infection, an HBV infection, etc.), the combination therapy can further comprise administering IFN-γ at a dosage of 50 μg, 100 μg, or 200 μg by subcutaneous injection three times per week (tiw) for the desired treatment duration.

[00577] In any ofthe above-described methods featuring combination therapy comprising administering monoPEG(30 Id), linear)-ylated consensus IFN-α and TNF antagonist to treat a viral infection (e.g., an HCV infection, an HBV infection, etc.), the combination therapy can further comprise administering a dosage of ribavirin or a derivative thereof, in an amount of about 400 mg, 800 mg, 1000 mg, or 1200 mg orally daily for the desired treatment duration. [00578] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 100 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

[00579] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 100 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 8 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

[00580] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 100 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; and a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; for the desired duration of therapy.

[00581] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 100 μg monoPEG(30 Id), linear)-ylated consensus IFN-α administered subcutaneously every 8 days; and a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; for the desired duration of therapy.

[00582] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 150 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

[00583] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 150 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 8 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

[00584] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 150 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; and a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; for the desired duration of therapy.

[00585] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 150 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 8 days; and a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; for the desired duration of therapy.

[00586] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 200 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

[00587] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 200 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 8 days; a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks tiiereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; and ribavirin administered orally qd; for the desired duration of therapy. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

[00588] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 200 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 10 days; and a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; for the desired duration of therapy.

[00589] In one embodiment, the present invention provides for treatment of a viral infection (e.g., an HCV infection, an HBV infection, etc.), comprising administering to an individual having a viral infection a regimen of 200 μg monoPEG(30 kD, linear)-ylated consensus IFN-α administered subcutaneously every 8 days; and a dosage of TNF-α antagonist selected from the group consisting of (i) 25 mg ENBREL® administered subcutaneously biw (ii) 3 mg REMICADE®/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter and (iii) 40 mg HUMIRA™ subcutaneously qw or qow; for the desired duration of therapy.

[00590] In any ofthe above-described methods featuring combination therapy comprising administering monoPEG(30 kD, linear)-ylated consensus IFN-α and TNF antagonist to treat a viral infection (e.g., an HCV infection, and HBV infection, etc.), the combination therapy can further comprise administering a weight-based dosage of pirfenidone or a pirfenidone analog in the range of about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3,600 mg per day, or about 800 mg to about 2,400 mg per day, or about 1,000 mg to about 1,800 mg per day, or about 1,200 mg to about 1,600 mg per day, orally for the desired treatment duration.

[00591] In any ofthe above-described methods for featuring combination therapy comprising administering monoPEG(30 Id), linear)-ylated consensus IFN-α and a TNF-α antagonist to treat an HCV infection, the combination therapy can further comprise administering an additional anti-hepatitis C viral agent, e.g., an NS3 inhibitor, an HCV RNA-dependent RNA polymerase, and the like. SUBJECT SUITABLE FOR TREATMENT

[00592] Individuals who are suitable for treatment according to a subject method for treating a fibrotic disorder include individuals who have been clinically diagnosed with fibrosis, as well as individuals who have not yet developed clinical fibrosis but who are considered at risk of developing fibrosis.

[00593] Individuals who are suitable for treatment with a subject method for treating cancer include individuals having any type of cancer, including individuals who have been diagnosed with a cancer and who have not yet been treated for the cancer; individuals who have been diagnosed with a cancer, and who have been treated for the cancer with a treatment regimen other than a subject treatment regimen, including individuals who have failed previous treatment regimens for the cancer; and individuals who have been diagnosed with a cancer, and who have been treated with the cancer such that the cancer is in remission, but who are at risk for re-growth ofthe cancer.

[00594] Individuals who are suitable for treatment with a subject method for treating an angiogenic disorder include individuals having any type of angiogenic disorder, including individuals who have been diagnosed with an angiogenic disorder and who have not yet been treated for the angiogenic disorder; individuals who have been diagnosed with an angiogenic disorder, and who have been treated for the angiogenic disorder with a treatment regimen other than a subject treatment regimen, including individuals who have failed previous treatment regimens for the angiogenic disorder.

[00595] Individuals who are suitable for treatment according to a subject method for treating a viral infection include individuals who have been clinically diagnosed with a viral infection; individuals who have been exposed to an invidual having a viral infection; individuals who are at risk of contracting a viral infection; and the like.

[00596] Of particular interest in some embodiments are individuals who have been clinically diagnosed as infected with a hepatitis virus (e.g., HAV, HBN, HCN, delta, etc.), particularly HCN. Such individuals are suitable for treatment with a method ofthe instant invention. Individuals who are infected with HCV are identified as having HCV RΝA in their blood, and/or having anti-HCV antibody in their serum. Such individuals include naϊve individuals (e.g., individuals not previously treated for HCV, particularly those who have not previously received IFΝ-α-based or ribavirin-based therapy) and individuals who have failed prior treatment for HCV ("treatment failure" patients). Treatment failure patients include non- responders (i.e., individuals in whom the HCV titer was not significantly or sufficiently reduced by a previous treatment for HCV, e.g., a previous IFΝ-α monotherapy, a previous IFΝ-α and ribavirin combination therapy, or a previous pegylated IFΝ-α and ribavirin combination therapy); and relapsers (i.e., individuals who were previously treated for HCV, e.g., a previous IFΝ-α monotherapy, a previous IFΝ-α and ribavirin combination therapy, or a previous pegylated IFΝ-α and ribavirin combination therapy, whose HCV titer decreased significantly in response to the previous treatment, and subsequently increased). In particular embodiments of interest, individuals have an HCV titer of at least about 105, at least about 5 x 105, or at least about 106, genome copies of HCV per milliliter of serum. The patient may be infected with any HCV genotype (genotype 1, including la and lb, 2, 3, 4, 6, etc. and subtypes (e.g., 2a, 2b, 3a, etc.)), particularly a difficult to treat genotype such as HCV genotype 1 and particular HCV subtypes and quasispecies.

[00597] Any of the above-described regimens for the treatment of HCV infection, including PEGylated IFΝ-α monotherapy regimens; PEGylated IFΝ-α and ribavirin combination regimens; PEGylated IFΝ-α and pirfenidone or pirfenidone analog combination regimens; PEGylated IFΝ-α and Type II interferon receptor agonist combination regimens; PEGylated IFΝ-α, pirfenidone or pirfenidone analog, and ribavirin combination regimens; PEGylated IFN-α, Type II interferon receptor agonist and ribavirin combination regimens; PEGylated IFN-α, Type II interferon receptor agonist, and pirfenidone or pirfenidone analog combination regimens; PEGylated IFN-α, Type II interferon receptor agonist, pirfenidone or pirfenidone analog, and ribavirin combination regimens; PEGylated IFN-α and TNF antagonist combination regimens; PEGylated IFN-α, TNF antagonist and ribavirin combination regimens; PEGylated IFN-α, TNF antagonist and pirfenidone or pirfenidone analog combination regimens; PEGylated IFN-α, TNF antagonist, pirfenidone or pirfenidone analog, and ribavirin combination regimens; PEGylated IFN-α, Type II interferon receptor agonist, and TNF antagonist combination regimens; PEGylated IFN-α, Type II interferon receptor agonist, TNF antagonist and ribavirin combination regimens; PEGylated IFN-α, Type II interferon receptor agonist, TNF antagonist, and pirfenidone or pirfenidone analog combination regimens; and PEGylated IFN-α, Type II interferon receptor agonist, TNF antagonist, pirfenidone or pirfenidone analog, and ribavirin combination regimens; can be administered to individuals who have failed previous treatment (e.g. who failed previous threatment with IFN-α and/or ribavirin) for HCV infection ("treatment failure patients," including non-responders and relapsers).

[00598] Thus, in some embodiments, the present invention provides any ofthe above-described regimens for the treatment of HCV infection in which the subject regimen is modified to treat a treatment failure patient for a duration of 48 weeks.

[00599] In other embodiments, the invention provides any ofthe above-described regimens for HCV in which the subject regimen is modified to treat a non-responder patient, where the patient receives a 48 week course of therapy.

[00600] In other embodiments, the invention provides any ofthe above-described regimens for the treatment of HCV infection in which the subject regimen is modified to treat a relapser patient, where the patient receives a 48 week course of therapy.

[00601] In other embodiments, the invention provides any ofthe above-described regimens for the treatment of HCV infection in which the subject regimen is modified to treat a naϊve patient infected with HCV genotype 1, where the patient receives a 48 week course of therapy.

[00602] In other embodiments, the invention provides any ofthe above-described regimens for the treatment of HCV infection in which the subject regimen is modified to treat a naϊve patient infected with HCV genotype 4, where the patient receives a 48 week course of therapy.

[00603] In other embodiments, the invention provides any ofthe above-described regimens for the treatment of HCV infection in which the subject regimen is modified to treat a naϊve patient infected with HCV genotype 1, where the patient has a high viral load (HVL), where "HVL" refers to an HCN viral load of greater than 2 x 106 HCN genome copies per mL serum, and where the patient receives a 48 week, course of therapy.

EXAMPLES [00604] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric. Standard abbreviations may be used, e.g., bp, base pair(s); kb, kilobase(s); pi, picoliter(s); s, second(s); min, minute(s); hr, hour(s); and the like.

Example 1 : Pharmacokinetic and pharmacodynamics analysis of PEG-alfacon [00605] The following is a summary ofthe results of pharmacokinetic and pharmacodynamic data analysis that uses results from a single dose study of PEG-alfacon. Individual and mean PK profiles were examined and mean PD profiles of serum 2'5'-oligoadenylate synthetase (OAS) activity were examined. Additionally, PK profiles were used to simulate serum drug profiles predicted for multiple PEG-Alfacon doses given at 10 day intervals. [00606] The pharmacokinetic data were taken from the single dose, range finding clinical study of PEG-alfacon. Groups of 6 healthy male and female volunteers were given a single subcutaneous injection of PEG-alfacon in doses ranging from 15 to 210 μg in an escalating dose design. Samples from volunteers who received doses from 60 μg and higher were selected for this analysis. The final treatment group received a 210 μg dose that was identified in the escalation phase as the maximum tolerated dose. Baseline serum PEG-alfacon values from samples obtained 5 min before dosing were measurable in two cases (subjects 531 and 532, 120 μg dose group). Baseline values were subtracted from subsequent samples to obtain baseline corrected values for these two cases and data are shown with and without baseline correction. [00607] Individual data were subjected to noncompartmental and compartmental pharmacokinectic analysis. Mean data were analyzed in three steps with the aid of commercially available Kinetica™ software: noncompartmental pharmacokinetic analysis, compartmental pharmacokinetic analysis and compartmental pharmacokinetic/pharmacodynamic analysis.

[00608] Results from noncompartmental pharmacokinetic analysis of serum drug concentrations are summarized in Table 2. Peak concentrations were achieved within 36 to 72 h after sc dosing and increased with dose from a mean of 665 pg/mL after a 60 μg dose to approximately 3600 pg/mL after 210 μg. Mean profiles are shown in Figure 1. Table 2 shows mean PK parameters calculated from individual profiles and PK parameters calculated from mean serum profiles. In general there was reasonable agreement between the methods although there was considerable variation between subjects within each group that could not be readily explained by sex, BMI or thigh vs abdominal injection site variables. As an example, subject 424 had one quantifiable value following a 90 μg dose and other samples were below assay detection, while samples from subject 425 were all above 6000 pg/mL for PEG-alfacon following the same dose.

[00609] Table 2 compares the mean pharmacokinetic parameters for each dose group calculated using noncompartmental methods with corresponding parameters calculated using compartmental analysis of mean serum concentrations for each dose group. Data were insufficient to calculate parameters with noncompartmental methods for subjects 318, 423, 425, 529 and 747.Both methods resulted in calculated parameters that were in general agreement with values for AUC parameters (reflecting total drug exposure over time), and elimination half-life (tι/2) showing similar values with each method. Peak serum concentrations tended to be slightly lower for mean data compared to means of individual maximum concentrations. There was considerable variability within groups with %CN ranging from approximately 30 to 70% across all parameters.

[00610] Mean serum profiles for each dose group were fitted to a 1 -compartment body model using commercially available software. Individual serum profiles were also fitted to a 1- compartment body model. In 6 ofthe 36 individual datasets drag profiles, data were insufficient to permit calculation of a 1 -compartment body model (Subjects 315, 318, 321, 425, 529, 747). Table 2 Mean noncompartmental pharmacokinetic parameters* 60 U2 90 uε 120 uεa 150 uε 180 uε 210 με n/dose 5 4 6 6 6 5 Cmax [pg/mL] 665±274 1454±467 2979±1829 2608±1492 2298±1065 3610±1179 [580] [1090] [2203] [2441] [2150] [2938] tmax [h] 72±0 70±43 49±36 37±23 54±28 62±27 [72] [72] [48] [48] [48] [72] AUC o-last 57.9±34.2 156.2±52.9 2420.5±156.0 296.8±203.2 250.3±H7.2 537.6±253.7 [ng/mL*h] (59.1) [136.1] [214.6] [320.0] [277.5] [474.3] tm [h] 119±133 44±9 23±8 40±17 51±29 75±28 [39.8] [38.5] [30] [62] [65] [87] Mean Compartmental pharmacokinetic parameters Cmax [pg/mL] 877±257 1364± 654 2752±1425 2656±1529 2306±971 3819±1333 [619] [1288] [2572] [2557] [2116] [3027] *max [h] 48±19 72±59 34±16 35±22 47±118 50±18 [65] [44] [44] [44] [43] [44] AUC 0. 95.2±29.8 149.6±102.4 278.8±189.3 329.6±222.2 290.0±133.4 620.7±269.6 [ng/mL*h] [53.2] [153.9] [341.3] [333.0] [293.5] [526.2] m [h]] 38±17 38±29 30±22 38±20 39±14 68±40 [27] [29] [51] [47] [57] [85]

""calculated from individual serum profiles±sd [calculated from mean serum profiles] Calculated using baseline corrected values for subjects 531 and 532 [00611] Dose corrected Cmax and AUC values are expected to be constant for drags that follow linear kinetics. As shown in Table 3, there was considerable variation in both dose-corrected parameters. There was no consistent trend among doses, suggesting that variation within groups may explain deviations from dose proportional increase. [00612] Table 3. Dose Corrected Cmax and AUC parameters calculated from individual means and from mean profiles (mean) for values determined using noncompartmental methods. Table 3 Dose Cmax AUC o-Iast [μg] [pg/mL] [pg/mL*h] 60 11 964 90 16 1735 120* 25 2017 150 17 1979 180 13 1390 210 17 2560 mean60 10 986 mean90 12 1512 meanl20* 18 1789 meanl50 16 2133 mean 180 12 1542 mean210 14 2258 * calculated using baseline corrected values for subjects 531 and 32 [00613] Dose corrected AUCo-ιast and Cmax values were plotted versus body mass index (BMI) to examine potential effects of body weight on drug absorption from the subcutaneous injection. Results as shown in Figure 2a-b, indicate no consistent trends in drug absorption with change in BMI. [00614] Fits of mean serum concentration data with the 1 -compartment model resulted in reasonable curves for single subcutaneous doses ranging from 60 through 210 μg as shown in Figure 3 for mean profiles.

[00615] Simulations used pharmacokinetic parameters calculated from the fitted curves to model serumdrug profiles following multiple dosing regimens. Figure 4a simulates the serum profiles expected with a dosing regimen of 60 μg administered every 10 days using mean parameters calculated from each dose group. Baseline corrected values were used for subjects 531 and 532 to calculate mean parameters in the 120 μg dose group for all simulations. In general, there is good agreement among each simulation. Steady state is reached during the first dose interval and trough levels fall below the 300 pg/mL level that is the limit of assay quantification. Simulations based on mean data from the 60 μg dose group had peak concentrations that were approximately 50% of peak concentrations in simulations calculated from mean data from subjects given a 150 μg dose of PEG-alfacon. The difference is can be attributed to variability among treatment groups, as there is no apparent treatment group (dose) related change in simulation profiles. Additional simulations are shown in Figure 4b-g for 100, 150 and 200 μg doses administered every 10 and every 7 days. Profiles show the expected pattern of change with increasing dose. There is little effect from shortening the dosing interval to 7 days.

[00616] Mean serum OAS response profiles are shown in Figure 5 where PD response is shown as % change from baseline. Standard deviations were comparable to mean values in many cases that reflects considerable variability within each treatment group.

[0061 ] Figure 6 shows the results of PK-PD modeling. Calculated EC50 values, which reflect the concentration of drug resulting in 50% of maximum effect, varied greatly among doses. Similarly, the calculated Emax value had large differences with dose as shown in Table 4. Table 4 Emax Dose (% OAS EC50 (meg) Change) (pε/mL) 60 313 127 90 7932 27701 120 791 1046 150 470 202 180 717 591 210 441 212 While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope ofthe invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope ofthe present invention. All such modifications are intended to be within the scope ofthe claims appended hereto.

Claims

CLAIMS What is claimed is:
1. A method of treating a virus infection in an individual, comprising administering to an individual in need thereof an effective amount of monoPEG (30 Id), linear)-ylated consensus interferon-α at a dosing interval of every 8 days to every 14 days.
2. The method of claim 1, wherein the viral infection is a hepatitis C virus infection.
3. The method of claim 1 or 2, further comprising administering an effective amount of ribavirin.
4. The method of any of claims 1-3, further comprising administering an effective amount of IFN-γ.
5. The method of any of claims 1 -A, further comprising administering an effective amount of pirfenidone or a pirfenidone analog.
6. The method of claims 1-5, further comprising administering an effective amount of a TNF antagonist.
7. The method of claim 6, wherein the TNF antagonist is selected from the group consisting of ENBREL® etanercept, REMICADE® infliximab, and HUMIRA™ adalimumab.
8. The method of any of claims 1-7, wherein the dosing interval is every 8 days.
9. The method of any of claims 1 -7, wherein the dosing interval is every 10 days.
10. The method of claim 2, wherein a sustained viral response is achieved.
11. A method of treating cancer in an individual, the method comprising administering to an individual in need thereof an effective amount of monoPEG (30 kD, linear)-ylated consensus interferon-α at a dosing interval of every 8 days to every 14 days.
12. The method of claim 11, further comprising administering an effective amount of pirfenidone or a pirfenidone analog.
13. The method of claim 11 or 12, wherein the cancer is a solid tumor.
14. The method of any of claims 11-13, further comprising administering an additional anti-neoplastic agent or biological response modifier.
15. The method of claim 14, wherein the additional antineoplastic agent or biological response modifier is selected from an alkylating agent, a nitrosourea, an antimetabolite, an anti-tumor antibody, a steroid hormone, a vinca alkyloid, and a taxane.
16. The method of any of claims 11-15, further comprising administering effective amounts of a taxane, and a platinum complex.
17. The method of claim 16, wherein the taxane is selected from the group consisting of paclitaxel, docetaxel, topotecan and ironotecan and the platinum complex is cisplatin or carboplatin.
18. The method of any of claims 11-17, further comprising administering an effective amount of IFN-γ.
19. A method of treating a fibrotic disease in an individual, the method comprising administering to an individual suffering from a fibrotic disease a combination of monoPEG (30 Id), linear)-ylated consensus interferon-α at a dosing interval of every 8 days to every 14 days, and IFN-γ in amounts that are effective in the treatment or prophylaxis of the fibrotic disease in the individual.
20. The method of claim 19, further comprising administering an effective amount of a TNF antagonist. ..
21. The method of claim 20, wherein the TNF antagonist is selected from the group consisting of ENBREL® etanercept, REMICADE® infliximab, and HUMIRA™ adalimumab.
22. The method of anyof claims 19-21 , wherein the fibrotic disease is pulmonary fibrosis.
23. The method of claim 22, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.
24. The method of any of claims 19-21 , wherein the fibrotic disease is liver fibrosis.
25. The method of any of claims 19-21 , wherein the fibrotic disease is renal fibrosis.
26. The method of any of claims 1-25, wherein the individual is a human.
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