EXPLORING fusion technology
Fc fusion technology:
Seeking prolonged protection by extending half-life
Our proprietary Fc fusion technology:- Has been shown to increase the systemic half-life of biopharmaceuticals*
- May provide reduced dosing frequency via longer systemic half-life*
Structure of Fc fusion molecules:
- Well-known and validated traditional Fc-fusion drugs, such as Enbrel™ for the treatment of rheumatoid arthritis, consist of two copies of a biopharmaceutical linked to the Fc region of an antibody to improve pharmacokinetics, solubility, and production efficiency
- Biogen Idec's hemophilia therapeutic area has developed proprietary Fc-fusion technology that links a single copy of the drug to the Fc region on an antibody to optimize the pharmacokinetic and pharmacodynamic properties of the biopharmaceutical as compared to the drug alone or the traditional Fc-fusion form
Half-life extension with recycling*:
- Fc fusion technology links the therapeutic agent to the Fc portion of an antibody to optimize the pharmacokinetic and pharmacodynamic properties*
- Fc binds to the neonatal Fc receptor (FcRn) in endothelial cells that line the blood vessels*
- The fusion molecule, upon binding, is protected from degradation and re-released into circulation, keeping the molecule in circulation longer*
- Fc fusion molecules have increased systemic half-lives resulting from the binding of Fc to FcRn*
- Fc binding to the FcRn is thought to be the mechanism by which endogenous IgG retains its long plasma half-life*
Protection of the Fc fusion molecule and endothelial recycling through binding to FcRn*
- Proteins in the bloodstream are continuously taken out of circulation through non-specific pinocytosis (uptake) by endothelial cells lining the vasculature. That is, vesicles are formed at the cell surface that normally take proteins like FIX or FVIII out of the bloodstream
- The Fc portion of the molecule protects clotting factors from degradation in the endothelial cells lining the blood vessels
- These vesicles fuse with early endosomes and are normally targeted for degradation in the lysosomal pathway; this is the mechanism for intracellular protein destruction
- The Fc region of an IgG (or of rFIXFc or rFVIIIFc) binds to the neonatal Fc receptor (FcRn) inside these early endosomes
- This binding diverts these vesicles away from the lysosomal degradation pathway, directing them back to the endothelial cell surface, where they are secreted into the circulation.
- The vesicles fuse to the cell surface and release the Fc-containing proteins back into circulation. This mechanism has been shown to be responsible for the long plasma half-life of endogenous IgG antibodies
- Fusing therapeutic proteins (FIX and FVIII) to the Fc region of an antibody enables protein to bind to FcRn and utilize this same naturally occurring pathway to protect them from degradation
- Fc fusion proteins are maintained in the circulation longer than the therapeutic protein alone, thereby conferring a longer plasma half life upon the fusion
References
* Dumont JA, Low SC, Peters RT, Bitonti AJ. Monomeric Fc fusions: impact on pharmacokinetic and biological activity of protein therapeutics. Biodrugs. 2006; 20(3):151-160.
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Structure of Fc fusion Molecules
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