Researchers in the US have developed a way to make large, protein-based drugs suitable for oral rather than injectable delivery by fusing them with a carrier molecule, reports Phil Taylor.
The scientists, from the University of Southern California School of Pharmacy, have found that joining proteins such as granulocyte colony-stimulating factor (G-CSF) to transferrin, a plasma protein, allows the drug to survive the journey through the gastrointestinal (GI) tract and cross over into the bloodstream.
Dr Wei-Chiang Shen, professor and acting chair of the university's department of pharmaceutical sciences, said: "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."
Shen, along with colleagues David Ann and Yun Bai, will report in the 17 May issue of the Proceedings of the National Academy of Sciences the process by which transferrin was fused with G-CSF and initial studies of the resulting molecule in mice.
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 have posed their own problems. For example, Pfizer and Sanofi-Aventis have faced a long regulatory path to approval for an inhaled formulation of insulin because of concerns that long-term treatment with their drug, called Exubera, could adversely affect lung function.
The team's first breakthrough came when they discovered that transferrin can bind to receptors on the intestinal epithelial cells and be transported across the GI tract to the bloodstream.
"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," said Shen.
The next step, he explained, 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 Amgen's Neupogen (filgrastim) and Neulasta (pegfilgrastim) - injectable drugs that are used to keep cancer patients' white blood cell count at normal levels during chemotherapy.
"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," said Shen.
The researchers administered the resulting recombinant fusion protein orally to mice, and found that it increased the white blood cell count for three days, three times the duration of action seen with Neupogen.
Importantly, "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," said Shen.
USC holds the patent to the new recombinant fusion protein technology, and the research was supported by grants from the National Institutes of Health.