A schematic showing how a human monoclonal antibody containing a loop structure (CDR-H3) inspired by antibodies found naturally in camels can bind to matrix metalloproteinase 14, which has been shown to play a significant role in several types of cancer.
Researchers at the University of California, Riverside have camels and llamas 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 proteinases (enzymes that break down other proteins) that are essential in tissue regeneration and other normal cellular processes. However, when a tumor grows, certain MMPs are over-produced, allowing cancer cells to spread to other parts of the body.
Assistant professor Xin Ge et al described in his research published in the Proceedings of the National Academy of Sciences the development of therapeutic monoclonal antibodies highly selective to MMPs. The creation of these human antibodies was inspired by antibodies found naturally in the camelid family of animals, which includes camels and llamas.
The results could lead to new treatments—not only for a variety of cancers, but also other diseases that arise from faulty proteinases, eg Alzheimer’s, asthma, MS and arthritis. For more than 20 years, scientists have been developing drugs that block faulty MMPs in order to stop cancers from starting and spreading. But 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.
Monoclonal antibodies, with their specific binding sites, have been touted as an alternative to small molecules. However, 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. They simply won’t stick together,” Ge said.
That’s why the researchers turned to the convex, looped binding sites found in camel and llama antibodies that are ideal for interactions with the concave MMP sites. The team chemically synthesized billions of variants of human antibodies with convex loops found in camelids. In testing them, they identified dozens that are 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,” Ge said. Â https://ucrtoday.ucr.edu/43007/antibody-mmp-interaction
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