Peginterferon alfa-2b

Peginterferon alfa-2b

Systematic (IUPAC) name
PEGylated human interferon alpha 2b
Clinical data
AHFS/Drugs.com	Consumer Drug Information
MedlinePlus	a605030
Pregnancy cat.	contraindicated[1]
Legal status	?
Pharmacokinetic data
Half-life	22-60 hrs
Identifiers
CAS number	99210-65-8 Y
ATC code	L03AB10
DrugBank	BTD00048
UNII	G8RGG88B68 N
KEGG	D02745 Y
ChEMBL	CHEMBL1201561 N
Chemical data
Formula	C860H1353N229O255S9
Mol. mass	19269.1 g/mol
N(what is this?)  alfa-2b (verify)

Pegylated interferon alfa-2b is a treatment for hepatitis C developed by Schering-Plough, brand name is PegIntron.

It was approved in January 2001.

It has also been approved as treatment for melanoma with nodal involvement after surgical resection, under the brand name Sylatron by Merck in April 2011.

PEG-interferon alpha is a pegylated interferon composed of 165 amino acids. The PEG (polyethylene glycol) protects the molecule from proteolytic breakdown and increases the biological half-life of the interferon protein. It is also used in patients with neurofibromatosis to shrink neurofibromas.

Mechanism of Action

One of the major mechanisms of PEG-interferon alpha-2b utilizes the JAK-STAT signaling pathway. The basic mechanism works such that PEG-interferon alpha-2b will bind to its receptor, interferon-alpha receptor 1 and 2 (IFNAR1/2). Upon ligand binding the Tyk2 protein associated with IFNAR1 is phosphorylated which in turn phosphorylates Jak1 associated with IFNAR2. This kinase continues its signal transduction by phosphorylation of signal transducer and activator of transcription (STAT) 1 and 2 via Jak 1 and Tyk2 respectively. The phosphorylated STATs then dissociate from the receptor heterodimer and form an interferon transcription factor with p48 and IRF9 to form the interferon stimulate transcription factor-3 (ISGF3). This transcription factor then translocates to the nucleus where it will transcribe several genes involved in cell cycle control, cell differentiation, apoptosis, and immune response.^[2][3]

PEG-interferon alpha-2b acts as a multifunctional immunoregulatory cytokine by transcribing several genes, including interleukin 4 (IL4). This cytokine is responsible for inducing T helper cells to become type 2 helper T cells. This ultimately results in the stimulation of B cells to proliferate and increase their antibody production. This ultimately allows for an immune response, as the B cells will help to signal the immune system that a foreign antigen is present.^[4]

Another major mechanism of type I interferon alpha (IFNα) is to stimulate apoptosis in malignant cell lines. Previous studies have shown that IFNα can cause cell cycle arrest in U266, Daudi, and Rhek-1 cell lines.^[5]

A follow-up study researched to determine if the caspases were involved in the apoptosis seen in the previous study as well as to determine the role of mitochondrial cytochrome c release. The study confirmed that there was cleavage of caspase-3, -8, and -9. All three of these cysteine proteases play an important role in the initiation and activation of the apoptotic cascade. Furthermore, it was shown that IFNα induced a loss in the mitochondrial membrane potential which resulted in the release of cytochrome c from the mitochondria. Follow-up research is currently being conducted to determine the upstream activators of the apoptotic pathway that are induced by IFNα.^[6]

Host genetic factors influencing treatment response

For genotype 1 hepatitis C treated with Pegylated_interferon-alpha-2a or Pegylated_interferon-alpha-2b (brand names Pegasys or PEG-Intron) combined with ribavirin, it has been shown that genetic polymorphisms near the human IL28B gene, encoding interferon lambda 3, are associated with significant differences in response to the treatment. This finding, originally reported in Nature^[7], showed that genotype 1 hepatitis C patients carrying certain genetic variant alleles near the IL28B gene are more likely to achieve sustained virological response after the treatment than others. A later report from Nature^[8] demonstrated that the same genetic variants are also associated with the natural clearance of the genotype 1 hepatitis C virus.

References

1. ^ http://www.fda.gov/downloads/Drugs/DrugSafety/UCM133677.pdf See line 27
2. ^ Ward A. et al. "The Jak-Stat pathway in normal and perturbed hematopoiesis". BLOOD. January 2000; VOL 95, Number 1, 19-26
3. ^ PATHWAYS :: IFN alpha
4. ^ Thomas H. et al. "Mechanisms of Action of Interferon and Nucleoside Analogues". Journal of hepatology.2004 Feb; 40(2):364.
5. ^ Sangfel O, Erickson S, et al. (1997). Cell Growth Differ.,8;343-352
6. ^ Thyrell et al. “Mechanisms of Interferon-alpha induced apoptosis in malignant cells”. Oncogene: Nature Publishing Group. 2002. 21; 1251-1262
7. ^ Ge D, Fellay J, Thompson AJ, et al. (2009). "Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance". Nature 461 (7262): 399–401. doi:10.1038/nature08309. PMID 19684573. 
8. ^ Thomas DL, Thio CL, Martin MP, et al. (2009). "Genetic variation in IL28B and spontaneous clearance of hepatitis C virus". Nature 461 (7265): 798–801. doi:10.1038/nature08463. PMID 19759533. 

External links

• "FDA Approval Information"
• "Peg Intron Website"
• "Medicines patent loophole 'found'" at bbc.co.uk
• [1] "Related Deaths from this Drug"*