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Background:
• First developed by Davis, Abuchowski and colleagues in the
1970s
• In early 1990s PEG attached to alpha-2a, but it lacked the
required profile of improving pharmacokinetics
• Pegylation of interferon alpha-2b was achieved with the
addition of a linear PEG, designed to degrade to allow the full
potency of the interferon, while achieving a longer half-life.
Structure:
•PEG moieties are inert, longchain amphiphilic
molecules that are produced by linking repeating
units of ethylene oxide.
•Can be linear or branched in their structure
•Increasing the size with PEG, the absorption and
½ life are prolongued and the clearance of the IFN
is decreased.
•Goal of pegylation is to decrease clearence,
retention of biological activity, get a stable linkage
and enhance water solubility CH3—(OCH2CH2)n--OH
• Pegylation is achieved by O
the covalent attachment of mPEG—O—O2C—C—NH
PEG derivatives that utilize
amino groups of lysines and
the N-terminus of mPEG—O—O2C—NH—(CH2)4
polypeptide molecules as the
modification site
Interferon Beta-2a (Avonex)
• FDA approval on May 17 1996 for Relapsing
Remitting MS
• Clinical trials showed that it slowed MS
progression and had an extra benefit of slowing or
preventing the development of MS-related brain
atropy.
•The exact mechanism of IFN beta activity in
treating MS is unknown, but studies have shown
that interlukin 10 levels in the cerebrospinal fluid
were increased in patients
• Structurally IFNb-2a is a 166 amino acid
glycoprotein.
• Produced by recombinant DNA technology using • Some side effects include:
genetically engineered mammalian cells which the
human beta gene has been introduced into •Flu-like symptoms
• Amino acid sequence is the same as human beta
interferon. They are both glycosylated at the
•Muscle aches
asparagines residue at position 80
•Chills
Combination Therapy with
Ribavirin
• Many times interferons and peginterferons
are used in combination with Ribavirin
• It is a purine nucleoside analogue with a
modified base and a D-ribose sugar moiety
• 1st made in 1970 by Drs. Joseph
Witkowski and Roland Robins
• It inhibits the replication of a variety of
RNA and DNA viruses and is serves as an
immunomodulator to enhance type 1
cytokine production. This increases the
end of treatment response and reduces
post-treatment relapse.
• Mechanism is not well known, but there
are 4 proposed mechanisms
Conclusion
• Interferons have overlapping but different
biological activities
• Their mechanisms of action are not fully
understood, therefore there is a lot of room for
future growth within this field
• Interferon based strategies can possibly be further
tailored to each individual patient according to
early response dynamics
• Other immunomodulatiors that are being tested
include: Zadaxin and Ceplene
References