LOS ANGELES, May 6 - Transferrin, a plasma protein found in blood, can be fused with large, protein-based drugs such as granulocyte colony-stimulating factor (G-CSF) to create a new oral compound that is capable of surviving the journey through the gastrointestinal (GI) tract and then able to cross over into the bloodstream to be used by the body, according to research from the University of Southern California School of Pharmacy.
This technology may allow for oral administration of drugs that previously could only be given by injection, notes Wei-Chiang Shen, Ph.D., professor and acting chair of the Department of Pharmaceutical Sciences. Shen, along with colleagues David Ann, Ph.D., professor of molecular pharmacology and toxicology, and Yun Bai, doctoral student in the Department of Pharmaceutical Sciences, wrote a paper on this research that will appear in the May 17 issue of the Proceedings of the National Academy of Sciences (PNAS), which is currently available online.
"Many of today's oral medications are made from small molecules, like amino acids or lipids, and their permeability allows them to be absorbed from the intestine into the body," says Shen. "On the other hand, protein-based drugs are large and bulky, which can prevent them from crossing the intestine and gaining access to the sites where they are needed. They are also very sensitive to digestive enzymes and may be destroyed by stomach acid before they can be absorbed." To sidestep the difficulty of getting these large protein drugs through the GI tract intact, pharmaceutical scientists have looked at other ways to deliver protein-based drugs-such as via needle-free injections or through inhalation. But, these delivery methods pose their own significant challenges. Ultimately, Shen and colleagues began to reconsider the possibilities of oral drug administration.
Their first breakthrough came when they began to recognize the potential uses of transferrin. "We discovered that transferrin can bind to receptors on the intestinal epithelial cells and be transported across the GI tract to the blood stream," Shen says. "Humans naturally produce transferrin to move iron through the blood to the liver, spleen and bone marrow. It has been used to carry some protein-based drugs in a piggy-back fashion to their necessary site of action."
The next step, Shen explains, was isolating the genetic code for G-CSF, a protein factor that stimulates white blood cell production in the body. G-CSF is used to make Neupogen(r) and Neulasta(r) - injectable drugs that work to keep an individual's white blood cell count at normal levels during chemotherapy.
After that, the researchers needed to bring transferrin and G-CSF together, a process that is detailed in the PNAS paper. "Through recombinant DNA technology, we combined the genetic codes for both human transferrin and G-CSF to create a new recombinant DNA, which, when expressed in a cell, will produce a protein with half transferrin and half G-CSF," says Shen. "We refer to this method as recombinant fusion protein technology."
Recombinant DNA technology utilizes a series of procedures to join (recombine) segments of two or more different DNA molecules. When put into cell culture, a recombinant DNA molecule multiplies itself to form a colony of daughter cells that secretes the desired protein. These cells become "factories" for the production of the protein coded for by the inserted DNA.
As it turned out, this was the case as well for the transferrin/G-CSF combination.
"Our recombinant fusion protein was administered orally, and when tested in mice, increased the white blood cell count for three days, whereas the injectable agents only maintain effectiveness for one day," Shen says. "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."
Recombinant DNA technology has and will enable the pharmaceutical industry to produce safer, more pure and more effective versions of therapeutic proteins, Shen adds.
"Since recombinant therapeutics utilize human proteins, they do not induce an unwanted immune response like products created from non-human sources often do."
On behalf of Shen and his collaborators, USC holds the patent to the new recombinant fusion protein technology. The research was supported by grants from the National Institutes of Health.
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