Weizmann Institute Scientists Make Headway in Cure for Crohn’s

In diseases such as Crohn's and rheumatoid arthritis, the immune system mistakenly attacks the body's tissues.

But today, thanks to a group of Weizmann Institute scientists, the immune system is learning that “turnabout is fair play”.

The Weizmann Institute of Science, located in Rehovot, Israel, is one of the world’s leading multidisciplinary research institutions.

The scientists at the Weizman have managed to trick the immune systems of mice into targeting one of the body's players in the autoimmune process, an enzyme known as MMP9.


Prof. Irit Sagi of the Biological Regulation Department, along with her research group, have spent years looking for ways to block members of the matrix metalloproteinase (MMP) enzyme family. But, when these proteins, which expedite wound-healing and offer other benefits, get out of control, they can actually help autoimmune disease and cancer metastasis. Blocking these proteins might lead to effective treatments for a number of diseases.

Originally, Sagi and others had designed synthetic drug molecules to directly target MMPs. But these drugs had extremely severe side effects.

Dr. Netta Sela-Passwell began working on an alternative approach in Sagi's lab, when they decided that, rather than attempting to design a synthetic molecule to directly attack MMPs, they would try to trick the immune system into creating natural antibodies that would target them through immunization. Just as immunization with a killed virus induces the immune system to create antibodies that then attack live viruses, an MMP immunization would trick the body into creating antibodies that block the enzyme at its active site.

Soon, an artificial version of the metal zinc-histidine complex at the heart of the MMP9 active site was created. They then injected these small, synthetic molecules into mice and then checked the mice's blood for signs of immune activity against the MMPs. The antibodies they found, which they dubbed "metallobodies," were similar but not identical to TIMPS, and a detailed analysis of their atomic structure suggested they work in a similar way – reaching into the enzyme's cleft and blocking the active site. The metallobodies were selective for just two members of the MMP family – MMP2 and 9 – and they bound tightly to both the mouse versions of these enzymes and the human ones.

As they hoped, when they had induced an inflammatory condition that mimics Crohn's disease in mice, the symptoms were prevented when mice were treated with metallobodies. "We are excited not only by the potential of this method to treat Crohn's," says Sagi, but by the potential of using this approach to explore novel treatments for many other diseases."

Yeda, the technology transfer arm of the Weizmann Institute has applied for a patent for the synthetic immunization molecules as well as the generated metallobodies.

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