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Tailoring the lifespan of drugs

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1 Tailoring the lifespan of drugs
Jan Terje Andersen

2 Translational research: The importance of academic-industrial partnership in turning basic research into products Basic reserach Preclinical Manufacturing Treatment of diseases

3 Short-lived biological and chemical drugs
1. A major challenge for the therapeutic use of many drugs is their short lifespan. 2. Removed very rapid from the body (minutes, hours, few days). 3. Limits their therapeutic efficacy. 4. Expensive treatment, large doses required, burden for the patient. 5. Many promising drug candidates will never reach the marked due to these obstacles!

4 Why are they eliminated from the body?
The drugs are small. The drugs are removed via the kidneys, excreted in to the urine. The drugs are quickly broken down/ metabolized in the liver that receives up to 60 liters of blood each hour. Liver Kidneys

5 We have developed a technology that can:
Extend the lifespan (half-life) Improve bioavailability Improve therapeutic outcome

6 Albumin as a carrier of drugs
ALBUMIN is an ideal protein that can be utilized as a carrier of drugs! • Why ALBUMIN? - It has a unique half-life of 3 weeks. It is not removed from the blood via the kindeys or the liver. It is a very stable protein, soluble in water.

7 We and others have discovered why albumin is not removed quickly from the body
ALBUMIN is rescued from degradation due to binding to the neonatal Fc receptor (FcRn). WT mice Mice lacking FcRn Long half-life Short half-life Chaudhury et al. J Exp Med ; Andersen et al. EJI 2006

8 The AlbufuseTM technology
Genetic fusion of a drug of interest to albumin Albumin drug Fusion to albumin extends the lifespan of drugs

9 Is it possible to enhance the lifespan of albumin beyond that of nature?

10 Molecular engineering of the ALBUMIN-FcRn interaction
Our secret We know how FcRn binds ALBUMIN -We can design new ALBUMINs with improved binding to FcRn Bioinformatics and biotechnological tools

11 Design of ”super”-ALBUMIN
Albumin gene Albumin drug • ALBUMIN: 585 amino acids. •A single point mutation (1/585) is enough to alter binding to FcRn dramatically!

12 ALBUMIN with a range of FcRn binding strengths
1 2 3 5 4 6 7 9 8 FcRn binding strength AlbufuseTM Flex variants Natural

13 Superior lifespan of AlbufuseTM Flex variants beyond that of natural albumin
Days Level in blood Drug Albufuse-drug Albufuse FLEX variants Albufuse Flex-drug Tailoring the lifespan using Albufuse Flex variants

14 AlbufuseTM FLEX: reduced frequency of dosing and improved bioavailability
Time (days) Drug Level of drug in blood Level of drug in blood Time (days) Albufuse FLEX-Drug

15 Centre for Immune Regulation Department of Molecular Biosciences
OUS-HF Rikshospitalet Department of Immunology Centre for Molecular Biology and Neuroscience (CMBN) Department for Medical Microbiology. Department of Medical Biochemistry Bjørn Dalhus Magnar Bjørås Inger Sandlie Jan Terje Andersen Jørund Sollid Jostein Dalland Muluneh B. Daba Stian Foss Algirdas Grevys

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