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The moral to the story is that the human body is immensely more complex than any computer that we've been able to dream up.
Recently BioPharm International was fortunate to catch up with editorial advisory board member K. John Morrow to hear his reflections and observations about current trends in antibody therapy research. Dr. Morrow, director of biological sciences research at Meridian Biosciences, spoke enthusiastically about what biotechnology researchers hope to accomplish in the near future.
K. John Morrow, Jr., Ph.D.
BioPharm: What are some of the key methods used in antibody research?
John Morrow: One area that's encouraging is the study of libraries or genetic databases (for genomes) looking for unique gene sequences to develop better diagnostic tools for infectious disease. A current approach is to use either genomics or proteomics, going after markers using antibodies or PCR technology to identify the sequences.
For example, say you're dealing with maybe ten or twenty different bacterial strains that are co-existing in the gut and one of these is a pathogen, and it's the one you want to get a diagnostic test for, but they're all quite similar. They all have fairly similar properties; maybe they're members of the same genus. So you look for unique gene sequences and you make peptides from these gene sequences that are specific to your target organism. Then you can make antibodies to those peptides and screen the antibodies to see if they uniquely identify your organism.
Biopharm: Isn't this technique used in cancer research?
JM: All cancer genes are present in all the cells of the body, but they may be over-expressed in a cancer cell. You can look for them by screening the genomes and looking for unique sequences. You look for those, and then once again you make a peptide from one of the gene sequences — not the whole gene — so you don't have to produce the whole protein, but you just get a particular peptide that respresents a good target. In many cancer cells, [certain] receptors that are over-expressed. So what you do is identify the ligand for that receptor, then make a peptide from part of that ligand that will fit into the receptor and target the cancer cell.
BioPharm: What other areas of study are getting more attention these days?
JM: Another approach that I've been following over the years, is cancer therapy with antibodies. Initially, all the antibodies that received FDA approval were "naked antibodies." The investigators didn't couple the antibody to a toxin because they tried that and it didn't work very well. Another approach, the use of antibody fragments, rather than whole antibody molecules, never worked very well because they're cleared out of the body so fast. But scientists are looking at ways of stabilizing these antibody fragments and hooking the fragments to toxin molecules and other agents that could target the cancer cell so you don't have to simply rely upon the host resources.
At this time, numerous companies have FDA approval on antibodies, so they're doing lots of antibody therapies. But to my knowledge, you don't get cures with these antibodies, you get some remission of the cancer and patients can live longer. But you're not getting complete, permanent remission.
I think the idea of using various kinds of toxins is coming back now, and it has a bit more credibility than it did originally. Also, the companies that have all these antibodies produced maybe a hundred different antibodies before they picked the one that they use in their therapy. So they've got a whole stable full of antibodies that didn't work therapeutically, as naked antibodies that they can now conjugate to various kinds of toxins, stabilize the sequences, to make them more robust and get them to really perform well. In the next few years, that area that will really take off.
I'm encouraged that they're looking at these alternate strategies, so hopefully, the naked antibodies that produce maybe a six-month extension of life will be a juncture, a chapter on the road to more successful treatments.
BioPharm: Are scientists using this technology to develop cancer vaccines?
JM: The idea behind cancer vaccinations goes back into the 1970s. This was the focus of the Nixon administration's war on cancer. Nixon's scientific advisors thought we could take on this terrible disease, so what they did was focus on cancer vaccines because at that time many cancer researchers thought cancer was caused by a virus, as there was a lot of evidence that supported this theory. These cancers, however, were in experimental animals, mammals, and birds. They did not have any evidence at the time that there was a single cancer that was caused by a virus in humans. Since that time, they have identified examples such as Epstein-Barr virus, but we're still a long distance away from a comprehensive understanding of the role of viruses in human cancers.
The picture that emerged in this thirty-year hiatus was that cancers are due to a variety of causes. They could be due to oncogenes — normal genes in the cellular repertoire that get out of hand. They could be oncogenes brought in by viruses. They can be normal genes, over-expressed in cells. So what happened was that a simple model of just working on a vaccine wasn't valid. Now we have arrived at a much better understanding of the basis of cancer. Investigators are looking at proteins on cancer cells that might be proteins that you don't see in normal cells. What they're finding is that there are some strong candidates for possible therapeutics.
BioPharm: What other approaches are researchers using in antibody therapy?
JM: There's another approach, DNA immunization, in which the genes, rather than the protein antigens themselves, are used for immunization. The host is immunized by direct administration of viral genes, composed of DNA that encodes for the antigen that would normally be produced by the cells infected with the virus. Then they secrete this protein into the circulation and the host's body generates antibodies against this protein. This is an area of great interest because it represents an effective short cut. There are good models from animal systems, so this is a strong possibility for the development of new viral vaccines.
BioPharm: Based on the areas of concentration you've discussed, do you think that there is going to be a great influx of new instrumentation and techniques developed?
JM: Yes. I am interested in the history of science, particularly genetics. In the 1950s there were technical advances in chromosome visualization, which opened up a whole field. And it wasn't because in the 1950s people got smarter; it was because they figured out how to stain and visualize chromosomes better. Then researchers started computerizing the chromosome technology, so instead of having to use scissors and glue, to cut chromosomes out from photographs, you could do it all on the computer. All this technology revolutionized the field of human genetics, but it was a technical advance. It wasn't really any great intellectual breakthrough. Much of science proceeds that way. That's why I feel that technical developments and advances in instrumentation are so critical for the progress of science.
Computers are constantly improving and driving all our instrumentation. Take PCR machines. They used to cost $20,000, but now you can get a PCR machine for a couple of thousand dollars, and in a few years, you'll have thermocyclers that will cost a few hundred. What it means is these machines are better; they're faster; they're more economical. You can adapt them for a lot more purposes. There is a huge instrumentation establishment working day and night to come up with new scientific devices. So progress is driven by improvements in the electronics, which keep getting better and better. I think a lot of health issues that we are grappling with will be addressed by implantable instrumentation that will monitor patients. Small computers, inserted inside the patient, will release therapeutic antibodies at a controlled level. So patients will be administered antibodies while maintaining a normal lifestyle.
BioPharm: Are genomics and proteomics just buzzwords, or do they represent significant fields for advancing drug development?
JM: I don't like these terms because to me they're flashy, and I think they tend to cover up a world of complexity. When people were talking about sequencing the human genome, they said as soon as we had completed the genome sequencing project, all of these new drugs were just going to roll off the assembly line. But the biology was daunting, and progress has been much slower than we envisioned. So I tend to be skeptical. With regards to proteomics, we are seeing vast amounts of research leading to new products, and at last, some notable progress. By analogy, back in the 1970s when the biotechnology industry was in its infancy, everybody was saying that these companies were just going to be developing new products like the computer industry. But the early days of biotech were disappointing. There was a lot of hype and they came up with some products, but these companies were out there just desperately trying to survive for years and years. The human body is immensely more complex than any computer that we've been able to dream up.
Designing new computer technology is simple compared to understanding the human body. Imagine how much is out there that we don't have a clue about. We don't even understand the causative basis of Alzheimer's disease. We don't understand what the cause and effect relationship is between the neurofibrillary plaques and the amyloid protein. There are basic questions about devastating diseases such as cancer and HIV that we're still grappling with, and we seem to be years away from understanding them.
BioPharm: Do you think that proteins hold more promise than small molecules?
JM: For what researchers are finding in the field of therapeutics, I think the protein molecules seem to be much more exciting than small molecules. But the problem with the protein molecules is you've got to inject them, they can't be ingested orally. So now the answer may be peptides. Maybe peptides could be designed from big proteins and these peptides could be created in a format stable enough to be put into a capsule. Because anything you have to inject with a syringe into a patient is always going to meet with patient resistance — it's a big block to gain acceptance.
BioPharm: Are researchers taking a more holistic approach today?
JM: I think that we are gradually coming to the recognition that all the diseases we're struggling with today are networks of changes that take place in a normally functioning system, ending in a pathological state. It's not like the past when patients with a bacterial disease would receive penicillin and the drug would kill the organism. What we're finding is that all the present challenges are networks, or spider webs that just infiltrate a healthy organism and bring its normal functioning capability to a halt. So knocking these out won't be possible using a single agent. You're not going to have a magic bullet, but rather you'll have an arsenal of bullets that will simultaneously attack components of these disease networks.
Pam Holland-Moritz is senior editor at BioPharm International, 732.346.3059, fax732.596.0053, firstname.lastname@example.org.