Antibodies That Block Metalloproteinase Activity Prevent Crohn’s Disease

A new approach to treating chronic autoimmune diseases such as Crohn’s disease and rheumatoid arthritis is based on monoclonal antibodies that specifically target the catalytic zinc-protein complex that is the functional heart of proteolytic enzymes known as metalloproteinases.

Metalloproteinases 2 and 9 are members of the group of enzymes known as matrix metalloproteinases (MMPs). Collectively they are capable of degrading most kinds of extracellular matrix proteins. They are known to be involved in the cleavage of cell surface receptors, the release of apoptotic ligands (such as the FAS ligand), and chemokine activation or inactivation. MMPs are also thought to play a major role in cellular activities such as proliferation, migration (adhesion/dispersion), differentiation, angiogenesis, apoptosis, and host defense. The MMPs are inhibited by specific endogenous tissue inhibitor of metalloproteinases (TIMPs), which comprise a family of four protease inhibitors: TIMP1, TIMP2, TIMP3, and TIMP4.

Investigators at the Weizmann Institute of Science (Rehovot, Israel) used an innovative immunization strategy that exploited aspects of molecular mimicry to produce inhibitory antibodies that showed TIMP-like binding mechanisms toward the activated forms of matrix metalloproteinases 2 and 9 (gelatinases).

In a paper published in the December 25, 2011, online edition of the journal Nature Medicine the investigators described how they immunized mice with a synthetic molecule that mimicked the conserved structure of the metalloenzyme catalytic zinc-histidine complex residing within the enzyme active site. This immunization procedure yielded selective function-blocking monoclonal antibodies directed against the catalytic zinc-protein complex and enzyme surface conformational epitopes of endogenous gelatinases.

In an in vivo study, treatment of a mice model of Crohn’s disease with the monoclonal antibodies prevented development of the syndrome. The action of the antibodies was more specific than that of synthetic low molecular inhibitors of MMPs and had fewer undesirable side effects.

“We are excited not only by the potential of this method to treat Crohn’s, but by the potential of using this approach to explore novel treatments for many other diseases,” said senior author Dr. Irit Sagi, professor of biological regulation at the Weizmann Institute of Science.

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Weizmann Institute of Science