Man's best friend has an enemy, the canine hookworm, which seemsslated to befriend humankind too. This intestinal parasite(Ancylostoma caninum) infests an estimated one-half of all dogs inthe U.S. at one time or another.But cell biologist Matthew Moyle points out that "these hookwormsare not generally lethal. They just cause the animal majordiscomfort." He adds reassuringly, "The hookworm cannot completeits life cycle in humans."Moyle, a cell biology group leader at Corvas International Inc. ofSan Diego, has a paper in today's issue of the Journal of BiologicalChemistry (JBC) titled "A Hookworm Glycoprotein That InhibitsNeutrophil Function Is a Ligand of the Integrin CD11b/CD 18."That hookworm's 41-kilodalton glycoprotein is the parasite's secretweapon for disarming its canine victim. Moyle, who co-discoveredthat molecule two years ago, has named it NIF, for "neutrophilinhibitory factor." Neutrophils are white blood cells (WBCs) thatmount the body's front-line immune defenses against invadingpathogens or tissue damage. They do this by making blood vesselsleaky so they can exfiltrate at the scene of the invasion or injury, andproduce countermeasures, which cause inflammation.Medical students learn the four Latin hallmarks of inflammation:dolor (pain), rubor (redness), calor (heat) and tumor (swelling).By deploying its NIF, a canine hookworm can block its target'sWBC defenses, leaving it free to colonize the animal's gut by thetens of thousands. One adult A. caninum measures a centimeter orso in length by a millimeter thick.Moyle and his co-workers at Corvas reasoned that NIF's potentsuppression of WBC function might be turned to advantage to curbinflammatory diseases in humans, such as acute asthma, trauma-induced shock, inflammatory bowel disease, and ARDS (adultrespiratory distress syndrome). "At present," Moyle told BioWorld,"there are no commercially available therapies that specificallyaddress inappropriate white blood cell activation in those seriousinflammatory disorders."The first step in his team's research, as reported in JBC, was topurify 100 micrograms of NIF protein from 10,000 homogenizedcanine hookworms (approximately one ounce). They then cloned themolecule's cDNA, which encoded a NIF polypeptide 274 aminoacids in length. "NIF has no significant sequence homologies to anypreviously reported protein," their JBC paper states.The researchers then determined their recombinant NIF's bioactivityin blocking human neutrophils from adhering to human umbilicalvein endothelial cells. NIF also prevented those WBCs fromreleasing hydrogen peroxide, a toxic substance that activatedneutrophils emit and which damages inflamed tissue."Now we're working with various animal models of inflammation,primarily rabbits and rats, to see how NIF performs as a potentialtherapeutic agent," said Moyle. "We're moving rapidly forward, andhope to be in the clinic for human safety trials by the end of the firstquarter of 1995."He noted that "this whole program is on fast-forward." It will be justthree years since he and his Corvas colleague, George Vlasuk,discovered NIF in January 1992."We're a small public company with about 100 employees," Moylesaid. "We hope to take NIF into the clinic and beyond by our ownefforts." But, he allowed, "All biotech companies in our position,with a drug like this, would be looking for a partner."Having developed a very high-level expression vector in a stable ofmammalian cells that are making NIF in fairly large quantities,Corvas will have enough of the recombinant protein for a full rangeof clinical trials, at least through Phase I, Moyle said.The company's vice president of business development, Pieter Bax,added that Corvas will have the money as well as the molecules."Corvas has adequate cash in the bank for another 21 months or so,based on our current burn rate of about $1 million a month," Baxtold BioWorld.NIF does its anti-inflammatory job by binding specifically to areceptor on the surface of neutrophils. This receptor, known asCD11b/CD18, belongs to a class of proteins called integrins. Theseare transmembrane adhesion molecules that integrate, or tether, thecytoskeletons inside of cells to their extracellular matrices."There are no known naturally occurring inhibitors to this particularintegrin,"Moyle said. "NIF will be the first of its type."Corvas has filed for patents to protect the apparently uniquesequence and properties of its anti-inflammatory hookworm spinoff.Molecular Cell biologist Robert Pytela of the University ofCalifornia, San Francisco, School of Medicine is a pioneer integrinresearcher; he cloned the first integrin cDNA CD111b/CD18 from amouse receptor in 1988. This is the NIF receptor that Moyle is nowusing."NIF is definitely unique," Pytela told BioWorld. "It's the first timethat type of natural inhibitor was discovered." He added that "it'sunlikely this is an unrelated case, developed by this one hookwormspecies." Other pathogenic organisms will be found that deploy thesame molecular strategy, he predicted.
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.