Keratinocyte growth factor

The expression of recombinant proteins in cells in which they do not naturally occur is termed heterologous protein production (Chapter 3). The first biopharmaceutical produced by genetic engineering to gain marketing approval (in 1982) was recombinant human insulin (tradename Humulin ), produced in E. coli. An example of a more recently approved biopharmaceutical that is produced in E. coli is that of Kepivance, a recombinant keratinocyte growth factor used to treat oral mucositis (Chapter 10). Many additional examples are provided in subsequent chapters. 

Keratinocyte growth factor is a 140 amino acid, 16.3 kDa member of the FGF family. It differs from native keratinocyte growth factor in that the first 23 N-terminal amino acids have been deleted, which improves its stability. After cell growth the product is recovered and purified by a multistep chromatographic protocol. It is presented in lyophilized format in single-use vials and containing mannitol, sucrose, polysorbate 20 and histidine as excipients. It is administered by daily i.v. injection, usually for several days. 

Chen, B.L., T. Arakawa, C.F. Morris, W.C. Kenney, C.M. Wells, and C.G. Pitt. 1994. Aggregation pathway of recombinant human keratinocyte growth factor and its stabilization. Pharm Res 11 1581-1587. 

Danilenko DM. Preclinical and early clinical development of keratinocyte growth factor, an epithelial-specific tissue growth factor. Toxicol Pathol 1999 27(1) 64-71. 

Palifermin (Kepivance) [Growth Factor/Keratinocyte Growth Factor] Uses Oral mucositis w/ BMT Action Synthetic k -atinocyte GF Dose Phase 1 60 mcg/kg IV daily x 3, 3rd dose 24-48 h before chemo Phase 2 60 mcg/kg IV daily x 3, immediately after stem cell inf Caution [C, /-] Contra N/A Disp Inj SE Unusual mouth sensations, tongue thickening, rash EMS May cause rash and taste alt ations OD May cause severe HA symptomatic and supportive... 

Mecfianism of Action An antineoplasticadjunct that binds to the keratinocyte growth factor receptor, present on epithelial cells of the buccal mucosa and tongue, resulting in the proliferation, differentiation, and migration of epithelial cells. Therapeutic Effect Reduces incidence and duration of severe oral mucositis. 

Recombinant human keratinocyte growth factor Heparin (0.5% w/v) Solution -50 fold increased stability at 37°C [21]... 

Chen, B.L.,T. Arakawa, E. Hsu, L.O. Narhi, T.J. Tressel, and S.L. Chien, Strategies to suppress aggregation of recombinant keratinocyte growth factor during liquid formulation development. J Pharm Sci, 1994. 83(12) 1657-61. 

Zhang MZ, et al. A new strategy for enhancing the stability of lyophilized protein the effect of the reconstitution medium on keratinocyte growth factor. Pharm Res 1995 12(10) 1447-1452. 

Pagratis, N., Bell, C., Chang, Y., Jennings, S., Fitzwater, T., Jellinek, D. etal. (1997) Potent 2 -amino-, and 2 -fluoro-2 -deoxyribonucleotide RNA inhibitors of keratinocyte growth factor. Nature Biotech., 15, 68-73. 

Jeschke, M.G., et al. 2002. Non-viral liposomal keratinocyte growth factor (KGF) cDNA gene transfer improves dermal and epidermal regeneration through stimulation of epithelial and mesenchymal factors. Gene Ther 9 1065. 

Palifermin Kepavance rh Keratinocyte growth factor Growth factor 12/15/2004... 

Human recombinant keratinocytes growth factor KGF receptor... 

C23. Culig, Z., Hobisch, A., Cronauer, M. V., Radmayr, C., Trapman, J., et al, Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-1, keratinocyte growth factor and epidermal growth factor. Cancer Res. 54,5474—5478 (1995). 

Chen, B. L., and Arakawa, T. (1996), Stabilization of recombinant human keratinocyte growth factor by osmolytes and salts, /. Pharm. Sci., 85,419 422. 

Keratinocyte growth factors (KGFs) Wound healing FGRike receptor ... 

Methionine Oxidation of Human Keratinocyte Growth Factor... 

---