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Cobra venom is among the more noxious toxins in the animal kingdom—potent enough to fell an elephant. But researchers have found that tacking a snippet of protein from cobra venom onto human immune molecules is a novel and effective way of suppressing inflammatory chemicals involved in several difficult-to-treat ailments, such as rheumatoid arthritis, heart attacks and strokes.
The new technique takes aim at the body's complement system, a group of proteins in the blood that take a scattershot approach to killing invading microbes. Unlike antibodies, which target specific invaders, complement provides general immunity against microbes and act like an infantry, distracting some of the interlopers and buying time while more specific immune system fighters ramp up. These proteins are powerful: They can literally blow holes in bacterial membranes.
Cobra venom factor (CVF), a key protein in the snakes’ toxin, has long been known to interfere with complement activity in mammals by using up components of the system to the point that it stops working. CVF does this so well that the substance is routinely used in experiments on the role of complement in diseases and to sort out the how the system functions.
Indeed, CVF would be an ideal therapeutic molecule for humans but for the fact that it can provoke a harmful immune response, the researchers say. Another consideration, they note, is that cobras are endangered animals, so even if CVF could be made safe for humans, a synthetic source of the protein would be needed to protect the snakes as well as to provide enough of the substance for necessary treatments.
In the new study, scientists at the University of Hawaii at Manoa in Honolulu found a way to defang CVF while preserving its ability to suppress the complement system.
The researchers first spliced DNA encoding for small pieces of CVF and the human complement protein C3. That protein is a key part of the complement system and people without it are at higher risk for certain bacterial infections. They then cloned the genetic material and eventually used fruit fly cells to produce the protein in bulk. In experiments, these hybrid molecules—which are 96 percent human—dramatically depleted complement activity in serum, both in the test tube and in animals.
"Injection of [hybridized] CVF into animals—or adding it to serum in vitro—causes the exhaustive activation of serum complement. It causes no damage to the animal, but will wipe out complement activity until the components can be resynthesized by the animal," says David Fritzinger, a biochemist at the U.H. Manoa's Cancer Research Center and co-author (with Harvard physiologist Gregory Stahl) of the study, published in the January 2009 issue of Developmental & Comparative Immunology. The combined molecule does the same, he adds, without triggering unwanted inflammation.
Fritzinger and protein biochemist Carl-Wilhelm Vogel, who first hit on the idea for a hybrid cobra–human drug in 1994, have licensed their technology to InCode BioPharmaceutics, Inc., in Thousand Oaks, Calif.. The company is funding several studies to test the safety and effectiveness of the approach, Fritzinger says.
"We have shown the protein is able to deplete complement in primates and shows no toxicity, even when injected directly into the pulmonary artery at a dose at least four times that required to completely deplete serum complement in the animal," Fritzinger says. "We have also shown that the protein is effective in limiting tissue damage in a mouse myocardial infarction model."
John Atkinson, a rheumatologist and complement expert at Washington University School of Medicine in Saint Louis, calls the hybrid approach promising, but says the researchers still have to prove that the molecule is both effective and nontoxic, yet won’t trigger an reaction by the human immune system.
"Neither problem is insurmountable," says Atkinson, who was on the InCode board when the company licensed the hybrid molecule but has since stepped down. "They are well on their way to demonstrating that."