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PEGylation: A successful Approach to Drug Delivery Presentation By: Ryan Mulkeen

PEGylation: A successful

Approach to Drug Delivery

Presentation By:

Ryan Mulkeen

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.

Current Drug Problems

Current Drug Problems Diagram: transpeg.pbwiki.com

Diagram: transpeg.pbwiki.com

PEG - Polyethylene Glycol

PEG - Polyethylene Glycol • Synthesized from the polymerization of ethylene oxide • Using chemical tools

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

Major Advantages to PEGylated

Molecules

Major Advantages to PEGylated Molecules PEGylation, successful approach to drug delivery. Drug Discovery Today. 2005 Nov;

PEGylation, successful approach to drug delivery. Drug Discovery Today. 2005 Nov; 10(21) Veronese M. and Pasut G.

Reducing Kidney Filtration

Reducing Kidney Filtration • PEGylation significantly increases the apparent size of the conjugated drug compound Diagram:

PEGylation significantly increases the apparent size of the conjugated drug compound

Diagram: transpeg.pbwiki.com

PEG is not ready for conjugation

reactions by itself

PEG is not ready for conjugation reactions by itself 1.Needs a capped terminus with unreactive moiety

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

Paradigm of in vivo PEG linkage

Paradigm of in vivo PEG linkage • Cleavage to proceed without liberating any reactive and potentially

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

Diagram: transpeg.pbwiki.com

Derivatives

Derivatives PEGylation, successful approach to drug delivery. Drug Discovery Today. 2005 Nov; 10(21) Veronese M. and

PEGylation, successful approach to drug delivery. Drug

Discovery Today. 2005 Nov; 10(21) Veronese M. and Pasut G.

Derivatives

Derivatives PEGylation, successful approach to drug delivery. Drug Discovery Today. 2005 Nov; 10(21) Veronese M. and

PEGylation, successful approach to drug delivery. Drug Discovery Today. 2005 Nov; 10(21) Veronese M. and Pasut G.

Derivatives

Derivatives PEGylation, successful approach to drug delivery. Drug Discovery Today. 2005 Nov; 10(21) Veronese M. and

PEGylation, successful approach to drug delivery. Drug Discovery Today.

2005 Nov; 10(21) Veronese M. and Pasut G.

Derivatives

Derivatives PEGylation, successful approach to drug delivery. Drug Discovery Today. 2005 Nov; 10(21) Veronese M. and

PEGylation, successful approach to drug delivery. Drug Discovery Today. 2005 Nov; 10(21) Veronese M. and

Pasut G.

Limitations in PEGylation

Isomerization of polymer Excretion from the body Polydispersity

Limitations: Polydispersity

Limitations: Polydispersity Data of a 5 kDa polymer synthesis • Peptide and protein PEGylation: a review

Data of a 5 kDa polymer synthesis

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

Interferon-β-1b

Drug used for treatment of MS (multiple sclerosis

Short half-lives

Human antibodies can further decrease bioavailability

Interferon- β -1b • Drug used for treatment of MS (multiple sclerosis • Short half-lives •

Image: www.multiplesklerosemailingliste.info

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)

Aggregation Studies

Aggregation Studies • Aggregation forms as pH rises • Structure — Function Engineering of Interferon-Beta-1b for

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.

Immunogenicity

Immunogenicity • Structure — Function Engineering of Interferon-Beta-1b for Improving Stability, Solubility, Potency, Immunogenicity, and Pharmacokinetic

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.

Assay detecting antigens in a sample

IgG high affinity for drug without PEG

Measurement once per week dosing per week

Pharmacokinetic Studies

Pharmacokinetic Studies • Structure — Function Engineering of Interferon-Beta-1b for Improving Stability, Solubility, Potency, Immunogenicity, and

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.

Pharmacokinetic Studies

Pharmacokinetic Studies • Structure — Function Engineering of Interferon-Beta-1b for Improving Stability, Solubility, Potency, Immunogenicity, and

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.

Future questions for PEGylation

What can we learn from the binding/targeting chemistry?

Drugs currently on the market. Can they be improved?

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.

Extra Slide: A small approved drug

list

Extra Slide: A small approved drug list