Interferon alfacon-1 (DB00069) Approved Drug Chemical Formula: C860H1353N227O255S9 Molecular Weight:19343 Interferon alfacon-1 is a recombinant non-naturally occurring type-I interferon. The 166-amino acid sequence of Interferon alfacon-1 was derived by scanning the sequences of several natural interferon alpha subtypes and assigning the most frequently observed amino acid in each corresponding position. Four additional amino acid changes were made to facilitate the molecular construction, and a corresponding synthetic DNA sequence was constructed using chemical synthesis methodology. Interferon alfacon-1 differs from interferon alfa-2b at 20/166 amino acids (88% homology), and comparison with interferon-beta shows identity at over 30% of the amino acid positions. Interferon alfacon-1 is produced in Escherichia coli (E. coli) cells that have been genetically altered by insertion of a synthetically constructed sequence that codes for Interferon alfacon-1. Prior to final purification, Interferon alfacon-1 is allowed to oxidize to its native state, and its final purity is achieved by sequential passage over a series of chromatography columns. This protein has a molecular weight of 19,434 daltons. Indication/Usage For the treatment of hairy cell leukemia, malignant melanoma, and AIDS-related Kaposi's sarcoma

Pharmacodynamics Mechanism Of Action Toxicity Absorption Half life Upregulates the expression of MHC I proteins, allowing for increased presentation of peptides derived from viral antigens. This enhances the activation of CD8+ T cells that are the precursors for cytotoxic T lymphocytes (CTLs) and makes the macrophage a better target for CTL-mediated killing. Interferon alpha also induce the synthesis of several key antiviral mediators, including 2'-5' oligoadenylate synthetase (2'-5' A synthetase) and protein kinase R. Mechanism Of Action Interferon alpha binds to type I interferon receptors (IFNAR1 and IFNAR2c) which, upon dimerization, activate two Jak (Janus kinase) tyrosine kinases (Jak1 and Tyk2). These transphosphorylate themselves and phosphorylate the receptors. The phosphorylated INFAR receptors then bind to Stat1 and Stat2 (signal transducers and activators of transcription) which dimerize and activate multiple (~100) immunomodulatory and antiviral proteins. Interferon alpha binds less stably to type I interferon receptors than interferon beta. Toxicity Reproductive toxicity studies in pregnant rhesus monkeys and golden Syrian hamsters demonstrated an increase in fetal loss in hamsters treated with Interferon alfacon-1 at doses of > 150 mcg/kg/day, and in rhesus monkeys at doses of 3 and 10 mcg/kg/day. The Interferon alfacon-1 toxicity profile described is consistent with the known toxicity profile of other alpha interferon Absorption Subcutaneous bioavailability averages 99% in golden Syrian hamsters and 83% to 104% in rhesus monkeys. Half life The terminal half-life following subcutaneous dosing was 1.3 hours in golden Syrian hamsters and 3.4 hours in rhesus monkeys. Route of Elimination Clearance, averaging 1.99 mL/minute/kg in golden Syrian hamsters and 0.71 to 0.92 mL/minute/kg in rhesus monkeys, was due predominantly to catabolism and excretion by the kidneys.

Experimental Properties Category Antiviral Agents and Immunosuppressive Agents Affected Organisms Human and other Mammals Sequence MCDLPQTHSLGNRRALILLAQMRRISPFSCLKDRHDFGFPQEEFDGNQFQKAQAISVLHEMIQQTFNLFSTKDSSAAWDESLLEKFYTELYQQLNDLEACVIQEVGVEETPLMNVDSILAVKKYFQRITLYLTEKKYSPCAWEVVRAEIMRSFSLSTNLQERLRRKE Experimental Properties Melting Point: 61 °C Hydrophobiity: 0.336 Isoelectric Point: 5.99 Targets Interferon alpha/beta receptor 1,Interferon alpha/beta receptor 2 Reference Blatt LM, Davis JM, Klein SB, Taylor MW: The biologic activity and molecular characterization of a novel synthetic interferon-alpha species, consensus interferon. J Interferon Cytokine Res. 1996 Jul;16(7):489-99."Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/8836913# http://www.google.com/patents/EP0422697A1?cl=en Brands INFERGEN -Kadmon Pharmaceuticals, LLC.

INFERGEN Formulation Used/Prescribed for Dosage Contraindications Interferon alfacon-1 is a wholly synthetic type-I interferon. The 166-amino acid sequence of interferon alfacon-1 was derived by scanning the sequences of several natural interferon alpha subtypes and assigning the most frequently observed amino acid in each corresponding position resulting in a consensus sequence. INFERGEN is a sterile, clear, colorless, preservative-free liquid for subcutaneous administration. Formulation Single-use vials containing 9 mcg and 15 mcg interferon alfacon-1 at a fill volume of 0.3 mL and 0.5 mL, respectively. INFERGEN vials contain 0.03 mg/mL interferon alfacon-1, sodium chloride (5.9 mg/mL), and sodium phosphate (3.8 mg/mL) in Water for Injection, USP. Used/Prescribed for INFERGEN (interferon alfacon-1) is indicated for treatment of chronic hepatitis C in patients 18 years of age or older with compensated liver disease. Dosage The recommended dose of INFERGEN monotherapy for the initial treatment of chronic HCV infection is 9 mcg administered three times a week as a single subcutaneous injection for 24 weeks Contraindications contraindicated in patients with hepatic decompensation; autoimmune hepatitis; known hypersensitivity reactions such as urticaria, angioedema, bronchoconstriction, anaphylaxis to interferon alphas or to any component of the product Side-effects INFERGEN alone or in combination with ribavirin causes a broad range of serious adverse reactions

References http://www.rxlist.com/infergen-drug.htm http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=29ad47ed-cb94-470b-b3ab-9281abf414d5