By David N. Leff

Editor's note: Tuesday's BioWorld Today reported on human preclinical trials of interleukin-9, a suspect perpetrator of asthma, as presented in The Journal of Allergy and Clinical Immunology for February. By coincidence, separate research implicating a different molecular culprit appeared in The Journal of Immunology, also for February.

That parallel article carries the title: "C-C chemokine receptor 3 antagonism by the b-chemokine macrophage inflammatory protein 4, a property strongly enhanced by an amino-terminal alanine-methionine swap."

Its senior author is immunologist/oncologist Gerard Graham, group head of the Institute for Cancer Research in Glasgow, Scotland. "The significant finding of this paper," Graham told BioWorld Today, "is the fact that the molecule it describes, Met-chemokine-b-7 [Ck^b7], can block a receptor on specialized cells that are involved in the course of asthma, and several other allergic inflammations. So the important aspect of this is that we can, potentially, clinically block the movement of these cells into lung, and thereby alleviate, or even prevent, the symptoms of asthma."

Seven of the 11 journal paper's co-authors are researchers at Human Genome Sciences Inc. (HGS), of Rockville, Md. That company's executive vice president for research and development, Craig Rosen, said, "I believe that working with our colleagues in Scotland, we have made a significant advance in understanding how the body's own defenses naturally control asthma and other allergic reactions, such as hayfever and eczema. I hope that our newly found knowledge will help those who suffer from these serious diseases.

"Scientists around the world," Rosen told BioWorld Today, "have long sought a substance to block a structure on the surface of asthma and allergy-inducing eosinophil white blood cells. That structure, called the CCR3 receptor, is also present on other important cells implicated in allergy, including basophils, mast cells, immunoglobulin E, and T_H2 helper T lymphocytes."

Graham explained, "Ck-b-7 is a member of a family of molecules called chemokines. We're interested in them in the context of trying to improve cancer therapies. And HGS is interested in identifying novel chemokines of potential therapeutic molecules. We've amassed a lot of expertise in looking at these molecules, how they talk to cells. HGS sent some of its novel molecules to us, for testing in our own cellular systems. The information we got from our studies suggested that they interact with a receptor, which you find in eosinophils, and that we know to be important in the development of asthma."

Enter Eosinophils - Hell-Bent For Lungs

Eosinophils are spear-carriers in the war that certain of the body's immune elements wage against the lungs of people exposed by heredity or environmental allergens to the breath-robbing ravages of asthma.

"Eosinophils," Graham explained, "migrate from the blood and the bone marrow into the lungs - where they don't normally reside - and release various substances that interfere with normal lung and airway functions. There they produce airways inflammation, which of course is aberrant, and that's what's associated with asthma."

HGS's Rosen picked up the story: "Once the eosinophils accumulate there, and become activated, they release histamine and other things that result in these allergic responses. What we have discovered," he went on, "is a natural protein that blocks eosinophil migration to the lung. So if that cell never gets there, it can't release those damaging agents that cause these allergic responses."

Into this chain of events, Rosen introduced two other key chemokine players, CCR3 and eotaxin: "When eotaxin binds to the CCR3 receptor," he explained, "it causes the eosinophils to migrate. Blocking this play is a chemokine that the body naturally produces; when it binds to this receptor, instead of stimulating it, it acts as a natural antagonist. By having this key protein occupy that site, there should be no migration.

"That blocks the eotaxin response," he pointed out. "We've just modified the protein a little bit in the lab to enhance its activity. We used a mutagenesis approach, where we took the natural antagonist and through protein engineering, made it even stronger. We knew that for a lot of chemokines, by exchanging certain amino acids, we could make their activity either stronger or weaker. So we made a super-potent antagonist by swapping an alanine for a methionine in the extreme N-terminal of Met-Ck^b7."

Next on HGS's agenda is developing this eosinophil-aborting antagonist protein into a therapeutic drug.

Beating Eosinophil To The Lungs

"Right now," Rosen observed, "dosing it means injection to the bloodstream, or inhalation direct to the lungs, because proteins are not pills. So an asthmatic patient could take this protein at the beginning of a severe allergic response, to dampen the attack. Some people get very severe allergic responses and asthma attacks during certain seasons; that's when you would give the drug."

He allowed, "We've done some small-animal preclinical experiments here, and it's actually being tested in primates by one of our collaborators, but HGS hasn't announced that yet. It's recent enough that we don't have all the results.

"HGS is also experimenting with various formulations to enhance the drug's stability," he continued. "We're not there yet - this is early on in the research - but one might imagine in the future, with new modifications, fusion proteins, and depot formulations, we could develop a longer-acting therapeutic - if needed.

"Whether we do it alone or with a collaborator," Rosen said, "we would take our most potent molecule and ask: How well does it work? How does it stack up to other approaches? And even in competition with other agents, what is the response?

"So it's still in the research stage," he concluded, "but it is something that can move along quickly, because there's a lot known in this asthma field, and it's also very important."