By David N. Leff

Science Editor

The hallmark of asthma is wheezing. This sonic vibration signifies the gasping for breath that marks the attempt of asthmatic sufferers to inhale enough oxygen to stay alive.

Not all of them succeed. During the decade of the 1980s - from 1982 to 1993 - deaths from asthma among 5- to 24-year-olds nearly doubled. Today, official NIH estimates put at 17 million the number of Americans with asthma, 4.8 million of them under the age of 18.

How does this disorder kill its victims?

"Lack of oxygen is the short answer," explained molecular geneticist Nicholas Nicolaides, research director at Magainin Pharmaceuticals Inc., of Plymouth Meeting, Pa. "The problem with this increased mortality rate," he explained, "is that patients come into the clinic, and normally get a bronchodilator, which opens up their constricted airways, allowing them to breathe. Over time, an increased group of patients no longer respond to these bronchodilators. So they're unable to get oxygen, and suffocate.

"Asthma is an inflammatory disease of the lung," Nicolaides pointed out. "As more and more inflammatory cells enter the airways, the effects of mediators produced by these inflammatory cells become so great that it's virtually impossible to block their effects on the smooth muscle by a pharmaceutical agent."

Nicolaides is co-author of a paper in the February 2000 issue of The Journal of Allergy and Clinical Immunology, published today, Feb. 1, titled "IL-9 [interleukin-9] and its receptor in allergic and nonallergic lung disease increased expression in asthma." Its senior author is immunologist Qutayba Hamid, at McGill University in Montreal.

Summing up the article's findings, Hamid observed: "Biopsy specimens demonstrated a highly significant increased expression of interleukin-9 in the airways of asthmatics, compared to normal individuals or those with other lung diseases." He added, "We also demonstrated a differential increase of IL-9 in asthma that correlates with clinical features. Based on these results, the previous genetic mapping studies, and the biology of IL-9, it is our view that an antibody to IL-9 has significant promise as a therapy for asthma."

Just such a human anti-IL-9 antibody is under development by Magainin, in partnership with Genentech Inc., of South San Francisco. (See BioWorld Today, Jan. 1, 1999, p. 1.)

The Mouse That Wheezed

Initially, the Magainin researchers isolated IL-9 from the genomes of asthmatic humans, where it is located on the long arm of human chromosome 5. They then extrapolated this finding to the syntenic (species-similar) genomes of asthmatic-like wheezy mice.

"Our collaboration with Genentech," Nicolaides recounted, "began with an antibody that blocked murine IL-9, and the animals' wheezy response. That was the basis of our partnership. Now Magainin and Genentech are exploring working together to generate a human antibody that can block the human IL-9 protein. That effort is still preclinical, with animal experiments ongoing, and we are now starting to move toward the development of the human antibody.

"Once we find an antibody that has good neutralizing activity against the human protein," he continued, "it can then be further evaluated for toxicity and in vivo efficacy - probably in monkey studies. After that, an IND would be filed and Phase I clinical trials begun."

The preclinical human study reported today, Nicolaides related, "looked at a spectrum of different patients, snipping a section of bronchial tissue out of either allergic asthmatics, healthy allergics, normal nonallergics, those with chronic bronchitis and sarcoidosis, a nonallergic inflammatory disease, not associated with the asthmatic response. There was a very significant correlation of the IL-9 level in the airways of the asthmatics, compared to all those other cohorts." He pointed out, "This is the human segment of the entire study that's been evolving for the last three to four years, where IL-9's tight association with asthma has now been proven in the clinical case. And that's the take-home message."

Nicolaides observed, "The goal of the pharmaceutical industry is to generate a pill. That's really their gold standard. Antibodies being proteins," he went on, "must be delivered via the bloodstream, or administered directly into the lung. But Magainin hasn't given up on seeking a small-molecule, orally available IL-9 blocker.

Big Pharma's Grail: Trading Needle For Pill

"What we've done," he said, "is create a proprietary Asthma Gene Database containing genes that are tightly tied to the IL-9 pathway, and the asthmatic response. And we've now begun to generate prototype inhibitors of these different targets to show that we could use a small-molecular-weight chemical to short-circuit the IL-9 pathway. This should lead to a small chemical that could be a pill."

Nicolaides also observed that he and his co-authors are now engaged in researching, "How IL-9 relates to other cytokines, because there are various reports out there that say this or that other interleukin is the dominant player in asthma. So what we continue to try to understand is how IL-9 is the asthma gene."

By coincidence, a different publication, also out today, puts a different spin on a candidate cytokine entitled to the title of key asthma perpetrator. The February issue of The Journal of Immunology reports: "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."

The paper's transatlantic consortium of eleven co-authors represent Human Genome Sciences Inc. in Rockville, Md.; the Beatson Institute for Cancer Research in Glasgow, Scotland; and Serono Pharmaceutical Research Institute in Geneva, Switzerland.

Instead of an antibody clobbering the IL-9 cytokine, this group reports an antagonist to the CCR3 receptor, which runs decisive interference against the rogue immune-system eosinophil cell - player of a central role in asthma and allergic reactions.

Editor's note: A full account of the CCR3 receptor research will appear in Wednesday's issue of BioWorld Today.