With their expressive faces and unusually shaped bodies, mammals within the camelid family—including camels, llamas, alpacas, vicuñas, and guanacos—are not the first groups of animals that typically come to mind when people think about cancer research. However now, investigators at the University of California, Riverside (UCR) have these even-toed ungulates to thank for their development of a new cancer treatment that is highly selective in blocking the action of faulty matrix metalloproteinases (MMPs).
MMPs are a group of 26 closely related enzymes that are essential in tissue regeneration and other normal cellular processes. Yet these molecules have been implicated in the proliferations and spread of various tumors, as certain MMPs are overproduced, allowing cancer cells to metastasize. The UCR group is hopeful that the results from their new study—published recently in PNAS in an article entitled “Active-Site MMP-Selective Antibody Inhibitors Discovered from Convex Paratope Synthetic Libraries”—could lead to new treatments, not only for a variety of cancers, but also other diseases that arise from faulty proteinases, such as Alzheimer's, asthma, multiple sclerosis, and arthritis.
In the new study, the investigators described the development of therapeutic monoclonal antibodies that are highly selective to MMPs, meaning they can bind to a specific MMP and block its activity without affecting other MMP family members. The creation of these human antibodies was inspired by antibodies found naturally in the camelid family of animals.
For over 20 years, researchers have developed drugs that block faulty MMPs in order to stop cancers from growing and spreading. However, clinical trials on a variety of promising small molecules have failed—largely because they lack the specificity needed to target faulty MMPs while still allowing “good” MMPs to perform their regular cellular duties.
“Clinical trial failures have taught us that selective, rather than broad-based, inhibitors are required for successful MMP therapies, but achieving this selectivity with small-molecule inhibitors is exceedingly difficult because of the incredible conservation among MMP family members,” explained senior study investigator Xin Ge, Ph.D., assistant professor of chemical and environmental engineering in the Bourns College of Engineering at UCR. “As a result, broad-spectrum inhibitors have failed in clinical trials due to their low overall efficacy and side effects.”
Monoclonal antibodies, with their large and inherently more specific binding sites, have been touted as an alternative to small molecules. Though, until now, scientists have struggled to develop MMP-blocking antibodies due to the incompatibility between their binding sites.
“Both human antibodies and MMPs have concave—or buried—binding sites, making interactions between them almost impossible. Dr. Ge remarked. “They simply won't stick together.”
Taking what has been known about camelid antibodies, Dr. Ge and his colleagues decided to turn toward the convex, looped binding sites found naturally in those animal’s antibodies, which are ideal for interactions with the concave MMP sites. The researchers chemically synthesized billions of variants of human antibodies with the convex loops found in camelids. In testing them, they identified dozens that were highly effective at blocking MMPs and reducing the spread of cancer in laboratory models.
“While we can't use camel or llama antibodies directly in humans because they would cause an immune reaction, we essentially used them as our inspiration in the creation of human antibodies that are now promising candidates against tumor-promoting MMPs,” Dr. Ge concluded.