By David N. Leff
Upwards of 2 million Americans - most of them women beyond their childbearing years - suffer from the painful, swollen, eroding joints of rheumatoid arthritis (RA). Now 200 of these sufferers are in a multi-center, double-blind, placebo-controlled clinical trial of a humanized monoclonal antibody aimed squarely at a primary perpetrator of RA - complement 5 by name.
C5 gets that moniker because it is the fifth protein in the human complement cascade's complex of nine molecules. C5 is the head hit-man in the joint-destroying complex of C5, C6, C7, C8 and C9.
"It's been shown," observed immunologist Louis Matis, "that deposition on chondrocytes [joint cartilage cells] of terminal complement complex C5 through C9 can lead to chondrocyte activation and destruction." In other words, autoimmune polyarthritis.
Matis is chief scientific officer and senior vice president of research at Alexion Pharmaceuticals Inc., in New Haven, Conn. He and his associates there engineered the humanized anti-C5 monoclonal antibody now undergoing its first Phase II clinical trial.
"We're over halfway along enrolling those 200 patients in that Phase II safety and efficacy study," Alexion's senior director of clinical development, rheumatologist Christopher Mojcik, told BioWorld Today. "It will soon extend to 30 academic and free-standing rheumatology clinics across the U.S. The protocol calls for three active-dose-ranging treatment groups and one placebo cohort. Participants will receive injections of the antibody for three months, followed by another three months of follow-up observation, to measure joint tenderness, swelling and disability. At the end of the trial, all participants will be offered a year's worth of the proven drug."
Matis introduced the preclinical, murine version of his anti-C5 antibody five years ago. He reported at the time that "it prevented incipient rheumatoid arthritis in a classical mouse model of RA and mitigated the effects of the full-blown autoimmune disease." (See BioWorld Today, Sept. 13, 1995, p. 1.)
Oldest Lab Mouse Strain Takes On RA
Those RA-prone mice came to Alexion from the Jackson Laboratory, in Bar Harbor, Maine - among the largest purveyors in the world of experimental animals. The DBA mice that modeled RA in particular are described in the Jackson Lab catalog as "the oldest inbred strains. Immunization with type II collagen [specific to bones and joints] induces an autoimmune arthritis in susceptible mice."
Jointly with pathologists at Yale University, the Alexion scientists conducted extensive genetic breeding experiments with those mice to identify the specific role of terminal complement in the immune system on the generation of joint inflammation. In these experiments, over 90 percent of wild-type animals challenged with self-antigens contracted RA, but none of the mice bred to be C5-deficient did so.
"This collagen arthritis," Matis observed, "is a frequently used preclinical model for RA." Now Alexion has gone from preclinical to clinical by humanizing the original all-mouse monoclonal. Matis is senior author of a paper in the April 15, 2000, issue of the twice-monthly Journal of Immunology. Its title: "A role for complement in antibody-mediated inflammation: C5-deficient DBA/1 mice are resistant to collagen-induced arthritis."
"This was a genetic study," he told BioWorld Today, "in which we developed a newly inbred strain of DBA/1 mouse - a very arthritis-susceptible strain - that was lacking in C5. It contrasts with our 1995 study, which we did in animals with functional C5, which we blocked with a C5-inhibiting antibody. We now show that - in the genetic absence of C5 - there was a critical requirement of C5 for the induction of arthritis.
"We know that the way the antibody works," Matis went on, "is by preventing the cleavage of C5. It binds to a site on that molecule, which Alexion determined by proprietary observation. It's a critical site, which prevents the convertase enzyme - the protease - from cleaving C5 into its active proinflammatory components."
Matis and his co-authors mounted this new preclinical study to confirm their conviction that C5 is indeed the mortal enemy No. 1 of rheumatoid arthritic joints. "The reason that we did this investigation," he recalled, "was because previous studies elsewhere have produced some conflicting results with respect to the role of complement in autoimmune arthritis in preclinical models. Some have said it was primarily a T-cell-mediated process."
Matis suggests that his current journal article may have laid this hypothesis to rest. "I believe we have clearly established," he observed, "that a highly susceptible strain of C5-minus mouse does not develop arthritis, whereas its wild-type C5-positive littermates do. And when we boosted the anti-C5 mice with autologous collagen, they were still RA-resistant."
More Autoimmune Diseases Go To Trial
But complement is no respecter of diseases. When its C5-through-C9 complex defects from backing the body's immune defenses and becomes a street gang, wielding autoantibodies, it doesn't limit its mayhem to RA.
On this score, Matis noted that "Alexion's fully humanized monoclonal antibody is now in clinical development for a number of indications, where we believe that there is a humoral [autoantibody] component to the inflammation, some of which in turn is mediated by complement." He and Mojcik ticked off the five other disease entities in which clinical trials are ongoing or imminent:
¿Membranous nephritis - Phase II, since October 1999, with 160 patients at 27 centers. An orphan kidney disease in which sufferers lose albumin in their urine. Fewer than 200,000 cases in the population.
¿ Psoriasis - a 12-patient pilot study at three centers. This autoimmune disease affects 2 percent of the population.
¿ Lupus nephritis - Inflammatory renal disease occurring in some people with systemic lupus erythematosus. - A 40-patient trial, starting imminently at the University of Colorado, which has received NIH funding for this study.
¿ Dermatomyositis - 12-patient trial starts soon at up to four centers. An autoimmune disease involving muscles and skin, in which antibodies against various components of those tissues are thought to activate complement. It produces inflammation leading to severe skin rash, as well as muscle inflammation, weakness and damage.
¿ Bullous pemphigoid - 12-patient trial starts soon at two centers. A blistering skin disease in which preclinical studies demonstrate that certain antibodies against components in the skin activate complement, and lead to the cutaneous pathology and blistering.