Metalloproteinases (MMPs) are enzymes in the body that are critical to tissue regeneration and other normal processes. But when MMPs are overly abundant, cancer can grow and spread. And faulty MMPs have been implicated in a range of other diseases, including asthma, multiple sclerosis and Alzheimer’s.
Now researchers at the University of California at Riverside are developing monoclonal antibodies that can bind to abnormal MMPs without affecting healthy versions of the enzymes. Their inspiration: camelids, a family of animals that includes camels and llamas.
Camelids have naturally occurring antibodies that may help solve one of the fundamental challenges of developing highly specific MMP inhibitors. The binding sites of both MMPs and most human antibodies are buried, making it difficult to get them to stick together, explained Xin Ge, an assistant professor of chemical and environmental engineering at Riverside and a lead researcher on the project in a press release.
Camelid antibodies, on the other hand, have a “convex,” a looped binding site that makes them stickier than human antibodies. Giving camelid antibodies directly to people would likely cause dangerous immune responses, so Ge’s team synthesized human-like antibodies with convex loops. So far, dozens of the experimental antibodies have proven effective at reducing the spread of cancer in rodents, according to the release. The research was published in the journal Proceedings of the National Academy of Sciences.
Oncology researchers have tried a variety of methods for blocking faulty MMPs, but they’ve frequently failed to do so without also affecting normal MMPs and causing side effects. "Clinical trial failures have taught us that selective, rather than broad-based, inhibitors are required for successful MMP therapies,” Ge said in the release.
Gilead is one company that’s having mixed success with an MMP-inhibiting antibody. The experimental drug, GS-5745, failed in ulcerative colitis, prompting the company to abandon a phase 2/3 trial in September. Gilead continues to test the compound in Crohn’s disease, as well as in gastric cancer, where it is in a phase 3 trial in combination with Bristol-Myers Squibb’s checkpoint inhibitor Opdivo (nivolumab).
MMPs are also being investigated for their potential in cancer detection. In 2014, a group of German scientists described nanoparticles they’ve created that can target MMPs in cancer and make them more visible in MRI scans.