Attempts to Extend the Life

Several approaches have been devised in recent years to extend the life span of therapeutic proteins by slowing their clearance from the body. Two main techniques have emerged:

• Increasing the size of the therapeutic protein. This is achieved either by attaching large polymeric chains to the protein (PEGylation) or by attaching other large, non-active proteins that have longer life spans compared to the target therapeutic protein.
  
  
• Altering the physical structure of the therapeutic protein. This is achieved by adding carbohydrate structures to the therapeutic protein (glycosylation) through modifications of the original genetic sequence of the protein. These additional "sugar chains" slow the clearance of the therapeutic protein from the bloodstream.
  
  Limitations of Existing Life Span Extension Solutions
  
  There are several fundamental weaknesses of the existing technologies that attempt to create longer-lasting versions of therapeutic proteins. If the size of the protein is increased by way of attaching large polymeric chains or another protein, the end result is a very large protein. Therapeutic proteins work by binding to specific receptors, and the new "bulkiness" may prevent them from achieving the desired result. The smaller the protein, the bigger this problem becomes. The few successful attempts to increase the size of therapeutic proteins have been with proteins that are already large. Even so, the biological activity of the modified protein is significantly less than that of the unmodified protein, and thus requires a higher injected dose as compared to the unmodified protein's usual dosage.
  
  In the case of glycosylation, the technique requires custom alterations (point mutations) to the protein's genetic structure to increase its life span. The resulting modified protein is entirely new and often generates unexpected adverse reactions, resulting in potentially toxic effects. Creating a protein with a longer life span that is not toxic can be a lengthy trial and error process.
  
  Although the existing modification technologies have been tried on almost all therapeutic proteins, only three proteins have long-acting versions on the market that were developed by such techniques. Two of these were developed by Amgen Inc, and one protein was PEGylated independently by Schering-Plough Corporation and Roche Pharmaceuticals. Each of these marketed longer-lasting therapeutic proteins has captured multi-billion dollar annual sales and is a leader in its respective market based upon annual sales:
  
  
• Utilizing PEGylation, Schering-Plough and Roche independently developed PEGIntron and Pegasys, therapeutic proteins with longer life spans than those of their regular Alpha interferons (used for treating Hepatitis C). These generated sales in 2005 of $2.7 billion.
  
  
• Utilizing additional glycosylation, Amgen developed Aranesp, an anti-anemia therapeutic protein with a longer life span than that of regular EPO, and which generated sales in 2005 of $3.2 billion.
  
  
• Utilizing PEGylation, Amgen developed Neulasta, an anti-neutropenia therapeutic protein with a longer life span than that of regular G-CSF, and which generated sales in 2005 of $2.2 billion.
  
  These products, collectively having revenues of more than $8 billion a year, clearly indicate the potential value of developing improved therapeutic proteins.