1. Protein Modifications -- to increase stability

3. Goal of protein modification Improved bioavailability, including longer circulation time and slower clearance Optimized pharmacokinetics resulting in sustained durationpharmacokinetics Improved safety profile with lower toxicity, immunogenicity, and antigenicity immunogenicityantigenicity Increased efficacy Decreased dosing frequency Improved drug solubility and stability Reduced proteolysis Controlled drug release

4. In an aqueous medium, the long, chain-like PEG molecule is heavily hydrated and in rapid motion. This rapid motion causes the PEG to sweep out a large volume and prevents the approach and interference of other molecules. As a result, when attached to a drug, PEG polymer chains can protect the drug molecules from immune response and other clearance mechanisms, sustaining drug bioavailability

5. http:// www.nektar.com/wt/page/advanced_pegylation http://www.peg-drug.com/index.html

7. Four-Armed Functional PEG

8. Eight-Arm Functional PEG

9. Comb-Shaped Copolymers

14. Chemistry for peptide and protein PEGylation * M.J. Roberts, M.D. Bentley, J.M. Harris Advanced Drug Delivery Reviews 54 (2002) 459–476 PEG-proteins: Reaction engineering and separation issues Chemical Engineering Science 61 (2006) 924 – 939 Conan J. Feea,., James M. Van Alstineb

15. Neoglycosylation Alkoxyamine-mediated neoglycosylation