This document discusses Pegylation, which is the covalent attachment of polyethylene glycol (PEG) polymers to pharmaceutical ingredients. PEGylation increases drug solubility and stability while decreasing immunogenicity and proteolysis. It allows for longer circulation in the body and less frequent dosing. Two main PEGylated drugs on the market are Oncaspar and PEG-Intron. Oncaspar is a PEGylated form of L-asparaginase for cancer, and PEG-Intron is a PEGylated interferon alpha for hepatitis C. Both drugs show improved properties like increased activity, half-life and sustained response due to PEGylation. While PEGylation provides benefits, there are

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2.  What is Pegylation?
 Comparison with other technologies
 Structures of PEG
 Common Pegylation approaches
 Proteins properties
 Why pegylated proteins?
 Products on market
 Oncaspar
 PEG-Intron
• Limitations
• Future perspectives
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3. WHAT IS PEGYLATION?
 Most widely used in delivering anticancer
drugs clinically.
Biopharmaceutical, Dr Frank Leenders JUNE 2006,39-40
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 PEGylation is the covalent coupling of non-toxic,
hydrophilic polyethylene glycol (PEG) to
active pharmaceutical ingredients(API).
 The technology was developed in the 1950s
and 1960s working on the coupling of
polymers to proteins, Later on in 1970s Frank
F. Davis used PEG for protein modifications.
 The first PEG-protein company Enzon,
founded in 1981, and the first PEG-drug
product was PEG-adenosine deaminase,
approved in 1990.
 Nowadays, PEGylated proteins represent a
significant therapeutic and business
importance: worldwide sales of PEGylated
drugs total about $6 billion annually.

4. Comparison with
other Technologies
Pegylation Other delivery systems
In PEGylated products, API is
chemically modified in a
durable fashion, and the drug
is not released from a
formulation but has a
permanent action and is in fact
classed as a new API.
Other formulated products
such as tablets, liquids and
capsules, the formulation
process is reversible, the
drug becomes active after its
release from the
formulation and the API
remains unchanged
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1. Linear shape PEG:
1st generation
2. Branched shape PEG:
2nd generation
3. Hyper branched shape PEG:
3rd generation

6. Common approaches for PEG conjugation with
proteins
 PEG is modified by
functionalization
through the use of
 Cyanuric chloride,
 PEG-succinimidyl succinate,
and
 Imidazolyl formate.
5/20/2015 6nature reviews | drug discovery, (2) (2003 )215

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Properties of PROTEIN DRUGS
High molecular
weight
Great
instability
Relatively short
half lifeEasily
eliminated
Wild tissue
distribution
Potential for
immunogenicity
Frequent dosing
is required
Complicated
dosing regimen

8. WHY PEGYLATED PROTEINS ?
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• Improve stability and solubility
• Reduce immunogenicity and proteolysis
• Improve clinical effects
• Prolong patent protection
• More competitive in market with
an increase commercial opportunity
• Slow clearance from the body
• Less frequent dosing

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10. COMMERCIAL DRUGS
 ONCASPAR*
 PEG-INTRON*
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1.
2.

11. 1.ONCASPAR(l-asparaginase)
 L-asparaginase-an enzyme
 anticancer
 Mechanism of action: described in 4
steps
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12. EE
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Effect of Pegylation on L-Asparaginase
1st generation technology used(linear PEG)

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16. 2.PEG-Intron (Interferon alpha-2)
 An-enzyme
 Anti-HCV
 Mechanism of actions: complex
Binds with receptors
and activate and modulate
the immune system of the
body against HCV.
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17.  Antiviral activity increased from 12- to
135-times
 Anti tumor activity increases 18-times
 Half-life increases (from 3–8 h to 65 h)
 Volume of distribution decreases
(from 31–73 l to 8–12 l)
 Improved sustained response to
chronic hepatitis C
 Decreased systemic clearance (from
6.6–29.2 to 0.06–0.10 l/h)
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Effect of Pegylation on
Interferon α2a:
2nd generation technology
used (branch PEG)

18. Limitation of PEGylation
 PEG has limited conjugation capacity
 possibility of side products due to chemical reactions.
 Loss of activity
 Require specific enzyme for processing
 Each drug require separate Pegylation
 Cost benefit ratio
Biopharmaceutical, Dr Frank Leenders JUNE 2006,39-40.
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19. Future perspectives
 The primary use of Pegylation:
 Large molecules,
however the successful entry for large molecules leads to Pegylation of
 Small molecules.
 Three PEGylated small molecules drugs are in clinical trial
(NKTR-102, EZN-2208 and NKTR-105).
Progress in Polymer Science 38 (2013) 421–444
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