Natural pathway for half-life extension

Natural pathway for half-life extension

 

ELOCTA® is an extended half-life rFVIII with Fc fusion technology that replaces missing endogenous FVIII1
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Fc fusion is a well-established technology. Fc fusion-based protein therapeutics have been on the market since 19982

ELOCTA consists of B domain-deleted rFVIII genetically fused to the Fc portion of IgG1 and is produced in HEK293-H cells.3 The Fc fusion process does not affect the structure or conformation of either the B domain-deleted rFVIII or the Fc domain in ELOCTA4

ELOCTA® combines the benefits of rFVIII and Fc fusion technology to extend the half-life of FVIII, allowing for personalisation of treatment and offering the potential for intense protection, without additional burden, in all age groups and different clinical settings1
ELOCTA® uses a natural human recycling pathway,5,6 consists of natural components and does not accumulate in the body1-3,6,7
 

The Fc portion of ELOCTA binds to the neonatal Fc receptor (FcRn). FcRn reduces lysosomal degradation of Fc-containing proteins by recycling them to the cell surface followed by release back into the circulation, which is part of the naturally occurring IgG recycling pathway. In this way, Fc reduced clearance prolongs the half-life of ELOCTA in human plasma3,6,8

FcRn recycles Fc-containing proteins (ELOCTA®) to the cell surface followed by release back into the circulation3,6,8

FC Recycling

1- Endothelial cells take up ELOCTA and other proteins from the blood

2- The Fc domain of ELOCTA binds to the FcRn receptor; proteins without an Fc region do not bind

3- ELOCTA and other proteins are sorted

4- ELOCTA is released back into circulation at neutral pH

5- Proteins not bound to FcRn are degraded via endosomal and lysosomal pathways

Fc fusion technology utilises a natural recycling pathway to extend the half-life of ELOCTA3,6,8

Fc, fragment crystallisable; FcRn, neonatal Fc receptor; FVIII, Factor VIII; HEK, human embryonic kidney; IgG1, immunoglobulin G1; rFVIII, recombinant Factor VIII.

References

1. ELOCTA Summary of Product Characteristics. 2020.

2. Czajkowsky DM, Hu J, Shao Z, Pleass RJ. Fc-fusion proteins: new developments and future perspectives. EMBO Mol Med. 2012 Oct;4(10):1015–28.

3. Shapiro A. Development of long-acting recombinant FVIII and FIX Fc fusion proteins for the management of hemophilia. Expert Opin Biol Ther. 2013;13(9):1287-97.

4. Leksa NC, Chiu PL, Bou-Assaf GM, Quan C, Liu Z, Goodman AB, et al. The structural basis for the functional comparability of factor VIII and the long-acting variant recombinant factor VIII Fc fusion protein. J Thromb Haemost. 2017;15(6):1167-79.

5. Peters RT, Toby G, Lu Q, Liu T, Kulman JD, Low SC, et al. Biochemical and functional characterization of a recombinant monomeric factor VIII-Fc fusion protein. J Thromb Haemost. 2013 Jan;11:132–41.

6. Dumont JA, Liu T, Low SC, Zhang X, Kamphaus G, Sakorafas P, et al. Prolonged activity of a recombinant factor VIII-Fc fusion protein in haemophilia A mice and dogs. Blood. 2012 Mar;119(13):3024–30.

7. Powell JS, Josephson NC, Quon D, Ragni MV, Cheng G, Li E, et al. Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients. Blood. 2012 Mar 29;119(13):3031–7.

8. Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007 Sep;7(9):715-25.