metalloproteinases (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.
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
‘Taking inspiration from the camelid family of animals, a University of California team flipped the active site of human antibodies to target tumor-promoting matrix metalloproteinases.’
In research published this week in the Proceedings of the National Academy of Sciences
Xin Ge, an assistant professor of chemical and environmental
engineering in UCR's Bourns College of Engineering, and his colleagues
describe 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, which includes camels and
The results 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.
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
"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. As a result, broad-spectrum inhibitors have failed in clinical
trials due to their low overall efficacy and side effects," Ge said.
Monoclonal antibodies, with their large and inherently more 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
"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.