Genetic Engineering Yields New Generation of Drugs

Researchers have genetically engineered a hybrid molecule, which is able to transport a drug through the digestive system and may be the basis for a new generation of orally delivered drugs.

Investigators at the University of Southern California School of Pharmacy (Los Angeles, USA; www.usc.edu) used advanced genetic engineering techniques to create a molecule that combined the plasma protein transferrin (Tf) with granulocyte colony-stimulating factor (G-CSF). Transferrin is a beta globulin in blood serum that combines with and transports iron. G-CSF is a glycoprotein that stimulates the production of granulocytes and macrophages by stem cells and is used as a drug by some immunosuppressed individuals.

The G-CSF-Tf fusion protein was engineered by fusing human cytokine DNAs (cDNAs) encoding G-CSF and Tf. The recombinant protein was harvested from protein-free, conditioned medium of transfected HEK293 cells. Preliminary studies conducted in vitro showed that the G-CSF-Tf fusion protein possessed the activity of both Tf receptor (TfR) binding in Caco-2 cells and G-CSF-dependent stimulation of NFS-60 cell proliferation.

Injection of G-CSF-Tf fusion protein into BDF1 mice demonstrated a pharmacologic effect comparable to commercially available G-CSF on the increase of absolute neutrophil counts (ANC). However, the fusion protein elicited a significant increase in absolute neutrophil count (ANC) upon oral administration to BDF1 mice, whereas G-CSF had no such effect. This study also showed that orally administered G-CSF-Tf elicited a sustained myelopoietic effect of up to three days, whereas the injected G-CSF or G-CSF-Tf lasted only one day.

Senior author Dr. Wei-Chiang Shen, professor of pharmaceutical sciences at the University of Southern California, said, "We have finally produced an orally-administered protein with a desirable therapeutic activity. This technique can be used to create orally administered versions of other currently injectable protein drugs such as insulin, growth hormone, and erythropoietin, a medication to increase red blood cell counts. Since recombinant therapeutics utilize human proteins, they do not induce an unwanted immune response like products created from nonhuman sources often do.”



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