Newest Cancer Weapon: Genetic Engineered Antibody
For the first time, researchers have been able to use genetic engineering techniques to produce key parts of disease-fighting antibodies in bacterial cells, a Santa Monica-based biotechnology company said in a report published today.
Biologists at International Genetic Engineering Inc. (Ingene) used the technique to produce an antibody fragment that binds specifically to human colon cancer cells. The fragment can potentially be used to deliver radioactive material for detection or cancer drugs for therapy to colon tumors, according to the report in Science magazine.
Several biotechnology companies are on the verge of using whole antibodies produced in specialized animal cells called hybridomas for cancer detection.
‘Easier to Purify’
The antibody fragments produced in bacteria “should be cheaper and easier to purify than whole antibodies and may be less likely to cause an immune reaction,” Ingene Vice President Arup Sen said in a telephone interview. The fragments could thus find wide use in imaging and treating cancer, cardiovascular disease and infectious diseases, he said.
The potential market for such products is huge. The trade journal Genetic Technology News estimates that the market for antibody-based detection of cancers could reach $400 million per year during the next decade, and the therapeutic market could be several times as large.
Antibodies are large proteins produced in white blood cells to help fight off infectious microbes, tumor cells and other foreign materials.
Each antibody recognizes and binds to a specific foreign cell or microbe and signals other components of the blood to join in destroying it. Scientists have adapted this recognition ability for their own purposes.
If an antibody that binds to cancer cells, for example, is tagged with radioisotopes before it is injected into animals, the radioactive material will accumulate at the site of any tumor present. That accumulation can be identified with X-ray film or other detectors and can indicate the presence of a tumor too small to be seen by other means.
NeoRx Corp. of Seattle has completed testing of such labeled antibodies produced in hybridomas for detecting melanoma and is awaiting the Food and Drug Administration’s approval to market it. Other companies are developing similar antibodies but are still testing them.
Cancer drugs can also be attached to the antibodies. Because the drugs would then concentrate at the tumor site rather than being spread throughout the body, the technique would produce fewer side effects than does conventional chemotherapy. Experts predict that it will be two or more years before such therapeutic agents are approved by FDA for cancer treatment.
Most antibodies used for diagnosis and therapy are made from mouse hybridomas because these are easier to work with than human cells. Even so, mouse cells are harder and more expensive to grow than bacterial cells. Moreover, the mouse proteins can also trigger an immune response by the patient’s body, and that response could limit the antibodies’ usefulness.
If the antibodies could be produced in bacteria rather than mouse cells, human genes could be inserted, thereby further reducing chances of an immune response. And because bacteria are relatively easy to grow, the process would be less expensive.
Complex Molecules
But antibodies are complex molecules formed from four separate chains of amino acids that must be folded into the correct three-dimensional conformation and chemically linked together before they are released by the body’s white blood cells.
Many molecular biologists have found that the bacteria used in genetic engineering could not carry out the complex folding and assembly processes necessary for antibody production.
Molecular biologist Marc Better and his colleagues at Ingene got around that problem by using only the section of the antibody, called Fab, that binds to a foreign material. Fab, which contains two amino acid chains, accounts for only about a third of the antibody molecule.
The key step, Better said, was to fuse together the genes that serve as a blueprint for the two amino acid chains in Fab. One of the genes they used was a human gene.
They then inserted the fused genes into the genetic material of the common bacterium Escherichia coli. “Apparently, no one had tried that before,” he said, “but when we did, the E. coli made the protein quite happily.”
(In a separate paper in the same issue of Science, researchers from the Max Planck Institute for Biochemistry in Martinsberg, West Germany, reported that they had used a similar technique to make a different portion of the antibody molecule.)
Ingene has already linked the Fab fragments to radioisotopes and begun testing them in animals, Sen said.
The company hopes to begin human trials of antibodies for colon cancer detection by the end of the year, he added.
