Researchers, using camels as an inspiration, have finally developed antibodies against a group of proteins known as metalloproteinases (MMPs), which are involved in the pathology of diseases that include multiple sclerosis (MS) and cancer.
Results on this work, long a goal of scientists, were published in the journal PNAS, under the title “Active-Site MMP-Selective Antibody Inhibitors Discovered From Convex Paratope Synthetic Libraries.”
MMPs are enzymes that work by cleaving other proteins, and they have an essential role in maintaining proper cell process both inside and outside of the cell. However, when MMPs are too active or present at higher-than-usual levels, they can dysregulate cell function with unwanted consequences. For instance, increased levels of MMPs are known to help cancer cells grow and spread to other organs.
Antibodies that can specifically target faulty MMPs, for this reason, can be a valuable tool for therapeutic strategies against diseases in which these proteins participate, such as MS, cancer, or Alzheimer’s disease. Specific antibodies would also allow researchers to block a certain troublesome MMP without affecting those MMPs whose activity has nothing wrong, increasing a therapy’s potential.
“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,” Xin Ge, the study’s senior leading author and a professor at University of California, Riverside, said in a news release. “As a result, broad-spectrum inhibitors have failed in clinical trials due to their low overall efficacy and side effects.”
Antibodies are preferred to broad-spectrum inhibitors against MMPs, but producing anti-MMPs antibodies has not been easy because these proteins are difficult to bind to (antibodies bind to the targeted proteins, thereby blocking or inhibiting their work).
“Both human antibodies and MMPs have concave — or buried — binding sites, making interactions between them almost impossible,” Ge said. “They simply won’t stick together.”
This led researchers to wonder whether the convex, looped binding sites found in antibodies from camels and llamas would be a better option to bind to the concave MMP sites. They produced billions of variants of human antibodies with the convex loops found in these animals, and tested them. Results showed that several of these antibodies were able to bind and block MMPs with high efficiency. Using laboratory models of cancer, the team then observed that these antibodies reduced the spread of cancer by targeting specific MMPs.
“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,” Ge concluded.