PEGylation: A successful Approach to Drug Delivery

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PEGylation A successful Approach to Drug Delivery
                  

• Presentation By
• Ryan Mulkeen

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Why is PEGylation a Hot Topic

• First described in the 1970s, An important
  development as PEGylation modifies a protein
  extensively with maintenance of activity
• Non-toxic, non-immunogenic, highly soluble in
  water and FDA approved
• Since 1990 many PEGylated drugs have been
  synthesized and approved including drugs for
  cancer, Hepatitis, HIV, and MS
• Low cost of manufacturing
• Part of a multi-billion dollar molecular
  medicines market

Chemical Engineering News 83 (2005) 21-29
PEGylation, successful approach to drug delivery.
Drug Discovery Today. 2005 Nov 10(21) Veronese
M. and Pasut G.
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Current Drug Problems
Diagram transpeg.pbwiki.com
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PEG - Polyethylene Glycol

• Synthesized from the polymerization of ethylene
  oxide
• Using chemical tools to link PEG molecules to
  native proteins can yield conjugates with more
  favorable behavior

Diagram transpeg.pbwiki.com
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Major Advantages to PEGylated Molecules
PEGylation, successful approach to drug delivery.
Drug Discovery Today. 2005 Nov 10(21) Veronese
M. and Pasut G.
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Reducing Kidney Filtration

• PEGylation significantly increases the apparent
  size of the conjugated drug compound

Diagram transpeg.pbwiki.com
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PEG is not ready for conjugation reactions by
itself
1.Needs a capped terminus with unreactive
moiety 2. Other end has reactive moiety that is
covalently with reactive partner (protein,
peptide, other compounds)
Diagram transpeg.pbwiki.com
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Paradigm of in vivo PEG linkage

• Cleavage to proceed without liberating any
  reactive and potentially toxic side products

Diagram transpeg.pbwiki.com
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Derivatives
PEGylation, successful approach to drug delivery.
Drug Discovery Today. 2005 Nov 10(21) Veronese
M. and Pasut G.
10
Derivatives
PEGylation, successful approach to drug delivery.
Drug Discovery Today. 2005 Nov 10(21) Veronese
M. and Pasut G.
11
Derivatives
PEGylation, successful approach to drug delivery.
Drug Discovery Today. 2005 Nov 10(21) Veronese
M. and Pasut G.
12
Derivatives
PEGylation, successful approach to drug delivery.
Drug Discovery Today. 2005 Nov 10(21) Veronese
M. and Pasut G.
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Limitations in PEGylation

• Isomerization of polymer
• Excretion from the body
• Polydispersity

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Limitations Polydispersity
Data of a 5 kDa polymer synthesis

• Peptide and protein PEGylation a review of
  problems and solutions. Biomaterials. 2001 22
  ,Veronese M.

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Interferon-ß-1b

• Drug used for treatment of MS (multiple sclerosis
• Short half-lives
• Human antibodies can further decrease
  bioavailability

Image www.multiplesklerosemailingliste.info
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Goals

• After expressing in E.Coli
• Lower Aggregation/ Prolong Solubility
• Lower Immunogenicity
• Improve Potency
• Approach Conjugate with varying PEG sizes and
  of conjugated sites (mono and multi PEGylation)

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Aggregation Studies

• Aggregation forms as pH rises
• Measured by HPLC

• StructureFunction Engineering of
  Interferon-Beta-1b for Improving Stability,
  Solubility, Potency, Immunogenicity, and
  Pharmacokinetic Properties by Site-Selective
  Mono-Pegylation. Bioconjugate Chem. 2006 17,
  618-630. Basu A. et al.

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Immunogenicity

• Assay detecting antigens in a sample
• IgG high affinity for drug without PEG
• Measurement once per week dosing per week

• StructureFunction Engineering of
  Interferon-Beta-1b for Improving Stability,
  Solubility, Potency, Immunogenicity, and
  Pharmacokinetic Properties by Site-Selective
  Mono-Pegylation. Bioconjugate Chem. 2006 17,
  618-630. Basu A. et al.

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Pharmacokinetic Studies

• StructureFunction Engineering of
  Interferon-Beta-1b for Improving Stability,
  Solubility, Potency, Immunogenicity, and
  Pharmacokinetic Properties by Site-Selective
  Mono-Pegylation. Bioconjugate Chem. 2006 17,
  618-630. Basu A. et al.

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Pharmacokinetic Studies

• StructureFunction Engineering of
  Interferon-Beta-1b for Improving Stability,
  Solubility, Potency, Immunogenicity, and
  Pharmacokinetic Properties by Site-Selective
  Mono-Pegylation. Bioconjugate Chem. 2006 17,
  618-630. Basu A. et al.

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Future questions for PEGylation

• What can we learn from the binding/targeting
  chemistry?
• Drugs currently on the market. Can they be
  improved?

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References

• PEGylation, successful approach to drug delivery.
  Drug Discovery Today. 2005 Nov 10(21) Veronese
  M. and Pasut G.
• Peptide and protein PEGylation a review of
  problems and solutions. Biomaterials. 2001 22
  ,Veronese M.
• StructureFunction Engineering of
  Interferon-Beta-1b for Improving Stability,
  Solubility, Potency, Immunogenicity, and
  Pharmacokinetic Properties by Site-Selective
  Mono-Pegylation. Bioconjugate Chem. 2006 17,
  618-630. Basu A. et al.
• Chemical Engineering News 83 (2005) 21-29
• GlycoPEGylation of recombinant theraputic
  proteins produced in Escherichia coli.
  Glycobiology. 2006 16(9) Defrees et.al.

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Extra Slide A small approved drug list