An IFN-beta-albumin fusion protein that displays improved pharmacokinetic and pharmacodynamic properties in nonhuman primates.
The long half-life and stability of human serum albumin (HSA) make it an attractive candidate for fusion to short-lived therapeutic proteins. Albuferon (Human Genome Sciences [HGS], Inc., Rockville, MD) beta is a novel recombinant protein derived from a gene fusion of interferon-beta (IFN-beta ) and HSA. In vitro, Albuferon beta displays antiviral and antiproliferative activities and triggers the IFN-stimulated response element (ISRE) signal transduction pathway. Array analysis of 5694 independent genes in Daudi-treated cells revealed that Albuferon beta and IFN-beta induce the expression of an identical set of 30 genes, including 9 previously not identified. In rhesus monkeys administered a dose of 50 microg/kg intravenously (i.v.) or subcutaneously (s.c.) or 300 microg/kg s.c., Albuferon beta demonstrated favorable pharmacokinetic properties. Subcutaneous bioavailability was 87%, plasma clearance at 4.7-5.7 ml/h/kg was approximately 140-fold lower than that of IFN-beta, and the terminal half-life was 36-40 h compared with 8 h for IFN-beta. Importantly, Albuferon beta induced sustained increases in serum neopterin levels and 2',5' mRNA expression. At a molar dose equivalent to one-half the dose of IFN-beta, Albuferon beta elicited comparable neopterin responses and significantly higher 2',5'-OAS mRNA levels in rhesus monkeys. The enhanced in vivo pharmacologic properties of IFN-beta when fused to serum albumin suggest a clinical opportunity for improved IFN-beta therapy.
Sung
Cynthia
C
Human Genome Sciences, Inc, Rockville, MD 20850, USA.
Nardelli
Bernardetta
B
LaFleur
David W
DW
Blatter
Erich
E
Corcoran
Marta
M
Olsen
Henrik S
HS
Birse
Charles E
CE
Pickeral
Oxana K
OK
Zhang
Junli
J
Shah
Devanshi
D
Moody
Gordon
G
Gentz
Solange
S
Beebe
Lisa
L
Moore
Paul A
PA
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D066298:In Vitro Techniques; D007370:Interferon Type I / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008253:Macaca mulatta; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000494:pharmacology; D011994:Recombinant Proteins; D012709:Serum Albumin / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D000998:Antiviral Agents; D007370:Interferon Type I; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D012709:Serum Albumin