Quick, without looking, how many pieces are there in astandard set of dominos? The answer: 28.

Line up these small tiles one behind the other, a half-inchor so apart, then nudge tile one. It will tip over tile two,and create a ripple effect that runs down the whole rowuntil it topples tile 28. That's the well-known dominoeffect, or cascade.

It would take at least a score of those dominos to modelthe human complement cascade. But instead of a singleline-up, the row of C proteins would have to fork,because complement can act in one of two discretepathways, the classical and the alternative. But at the endof each cascade, the effect is the same: hemolysis _ thedeath of red blood cells, and eventually of the tissues theynourish. (See BioWorld Today, May 10, 1995, p. 1.)

Complement (C) is the immune system's executionsquad, mainly to dispose of invading infective pathogens.It's in the news lately as the body's blind agent ofhyperacute rejection, killing alien organ grafts on sight.(See BioWorld Today, Aug. 30, 1995, p. 1.)

Just as the C cascade inflames and destroys foreigntissues, so it is suspected of attacking some of the body'sown home-grown cells and tissues, misapprehended byautoimmune antibodies as illegal immigrants.

Once a clique of informer antibodies hooks up with thecomplement system, the last five proteins in the cascade_ C5, C6, C7, C8 and C9 _ swing into action. C5 is theringleader of this quintet, known aptly as the "C terminalcomplex." It's job is indeed to terminate target cells _with extreme prejudice.

First, this gruesome goon squad strikes its target withinflammation. Second, it turns loose a gang of cytokines,such as tumor necrosis factor (TNF), interleukin-1 (IL)and IL-6, and other murderous molecules, to finish off thecells fingered for termination.

Very recently, Centocor Inc., of Malvern, Pa. andCelltech Ltd., of Slough, U.K., reported initial preclinicalsuccess in treating mice with rheumatoid arthritis bycutting off expression of the TNF cytokine. (SeeBioWorld Today, Aug. 8, 1995, p. 1.)

Enter Alexion, Upstaging Downstream Cytokine

Now, Alexion Pharmaceuticals Inc., of New Haven,Conn., aims to upstage those killer mediators ofinflammation, by blocking their upstream progenitorprotein, C5, prime perpetrator of the complementterminal complex.

"We know," the company's vice president ofimmunology research, Louis Matis, told BioWorldToday, "that complement's activities, besides mediatingits own pro-inflammatory effects, include inducing therelease of all the secondary inflammation mediators, suchas the cytokines."

Mice are the mammals of preclinical choice in modelingrheumatoid arthritis. A shot of bovine collagen at the baseof their tails mimics the progressive symptoms of humanrheumatoid arthritis _ from swollen joints (i.e. paws), todeterioration of synovial fluid and cartilage.

"Because of similarities in the pathology, in terms ofsynovitis, pannus formation, erosion of cartilage andbone," Matis explained, "the mouse model in many waysrecapitulates the articular inflammation of humanrheumatoid arthritis."

Alexion raised a monoclonal antibody specific for murineC5, and tested it in a controlled trial to prevent incipientrheumatoid arthritis, and mitigate the effects of the full-blown autoimmune disease, by disarming the C terminalcomplex.

A paper titled "Anti-C5 monoclonal antibody therapyprevents collagen-induced arthritis, and amelioratesestablished disease" succinctly sums up their results. Itappeared in the Sept. 12, 1995 Proceedings of theNational Academy of Sciences (PNAS).

The article's senior author is Alexion's Louis Matis. Hewrote: "Until now, the role of activated terminalcomplement components in inflammation has not beenexamined using inhibitors that specifically target thecomplement cascade at the C5 molecule."

Matis told BioWorld Today that this PNAS data "for thefirst time demonstrate that complement plays a significantrole not just in initiating inflammation but in itsprogression."

Humanized C5 Monoclonal Equals Murine Version

Since submitting it early this year for publication, headded, "we have developed a fully humanized antibody toC5, which represents a potentially very effectivetherapeutic in patients with rheumatoid arthritis. In exvivo and in vitro testing," he continued, "we'vedemonstrated that this humanized C5 antibody hasaffinity and potency equivalent to our original murinemonoclonal."

Although Alexion's intent is "to go forward in suchtreatment of rheumatoid arthritis," Matis "can't say wehave Phase I clinical trials planned at this time."

What the company does plan, its senior vice president andchief operating officer, David Kaiser, told BioWorldToday, is to join forces "with a biotech or majorpharmaceutical partner." He is discussing such a workingalliance with "more than one" prospective candidatecompany, "obviously looking for a partner with strengthsin that [rheumatoid arthritis] market, good contacts withthose types of physician's groups, and a degree ofexpertise in terms of clinical development.

"Basically," Kaiser summed up, "we're looking forsomeone who's a pro in that particular segment oftherapeutics, and who is interested in helping us drive thisthrough the approval process and into the marketplace." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.