title: Development of a Hyperglycosylated IFN Alfacon-1 (CIFN): Toward Bimonthly or Monthly Dosing for Antiviral Therapies.
abstract: Type 1 interferons (IFNs) have been shown to be efficacious against hepatitis C virus (HCV), hepatitis B virus (HBV), and some cancers with a significant drawback of short drug exposure. We have significantly improved the pharmacokinetic (PK) of consensus interferon (CIFN) by glycoengineering. We generated AL-624 by introducing 4 glycosylation sites. AL-624 was expressed, purified, and fractionated to yield 2-Gly, 3-Gly, and 4-Gly. In a rat PK study, AL-624 4-Gly exhibited a 6-fold increase of area under curve (AUC) and more than an 11-fold increase in time to half life (T1/2) over CIFN, suggesting the potential for weekly dosing (QW). In Yellow fever virus hamster model, QW of 4-Gly achieved similar efficacy to daily dosing (QD) CIFN and QW Peg-IFN-α-2a in overall survival rate and reduction of alanine aminotransferase (ALT) level. Further refinement resulted in development of AL-683 by addition of external glycosylation sites and its mouse homologue. AL-683 maintains undiminished biological potency in HCV replicon. In mouse PK/pharmacodynamic (PD) studies, AL-683 homologue has a ∼37-fold improvement in T1/2 and a ∼33-fold improvement in AUC when compared with the unglycosylated mouse IFN-α-1. Significantly improved PD responses were also observed. The significant improvement of AL-683 PK over AL-624 suggests a bimonthly dosing regimen for AL-683. The possibility for once-a-month dosing could be realized by further optimization of manufacturing conditions.
authors: 1 Alios BioPharma , South San Francisco, California.
authors: Joshua S
authors: JS
authors: Taylor
authors: 1 Alios BioPharma , South San Francisco, California.
authors: Qingling
authors: Q
authors: Zhang
authors: 2 Utah State University , Logan, Utah.
authors: Justin G
authors: JG
authors: Julander
authors: 1 Alios BioPharma , South San Francisco, California.
authors: Antitsa D
authors: AD
authors: Stoycheva
authors: 1 Alios BioPharma , South San Francisco, California.
authors: Hua
authors: H
authors: Tan
authors: 1 Alios BioPharma , South San Francisco, California.
authors: Christabel V
authors: CV
authors: Moy
authors: 1 Alios BioPharma , South San Francisco, California.
authors: Sushmita
authors: S
authors: Chanda
authors: 1 Alios BioPharma , South San Francisco, California.
authors: Julian A
authors: JA
authors: Symons
authors: 1 Alios BioPharma , South San Francisco, California.
authors: Leonid N
authors: LN
authors: Beigelman
authors: 1 Alios BioPharma , South San Francisco, California.
authors: Lawrence M
authors: LM
authors: Blatt
authors: 1 Alios BioPharma , South San Francisco, California.
authors: Jin
authors: J
authors: Hong
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D006224:Cricetinae; D015195:Drug Design; D016903:Drug Monitoring; D006031:Glycosylation; D006801:Humans; D016898:Interferon-alpha / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D011994:Recombinant Proteins; C050739:interferon alfacon-1