The antibody that could revolutionize breast cancer treatment
By COLD SPRING HARBOR LABORATORY
A synthetic antibody called RD-43, developed by graduate
student Zhe Qian in collaboration with CSHL’s Antibody
& Phage Display Shared Resource, may help stop the
spread of breast cancer by degrading the PTPRD enzyme.
[Tonks lab/Cold Spring Harbor Laboratory]
An enzyme that may help some breast cancers spread can be stopped with an antibody created in the lab of Cold Spring Harbor Laboratory Professor Nicholas Tonks.
With further development, the antibody might offer an effective drug treatment for those same breast cancers.
Targeting the PTPRD Enzyme
The new antibody targets an enzyme called PTPRD that is
overabundant in some breast cancers. PTPRD belongs to a family of molecules
known as protein tyrosine phosphatases (PTPs), which help regulate many
cellular processes. They do this by working in concert with enzymes called
kinases to control how other proteins inside cells behave. Kinases add small
chemical regulators called phosphates to proteins. PTPs take them off.
Disruptions in the addition or removal of phosphates can
contribute to inflammation, diabetes, and cancer. Some disruptions can be
corrected with kinase-blocking drugs. Tonks explains:
“People have targeted kinases for 25, 30 years. It’s a
multibillion-dollar industry. But many challenges remain. In cancer, patients
will respond to these sorts of kinase inhibitors and then, after a period of
time, resistance develops.”
Challenges and Solutions in Drug Development
Drugs that control PTP activity could have a major impact
on human health. However, such drugs have been difficult to develop. Tonks has
studied PTPs since he discovered them as a postdoctoral researcher. He calls
the enzymes “an untapped resource for drug development.”
Many enzymes can be switched off with small molecules
designed to latch onto and block the part of the enzyme that carries out its
work. But that won’t work for PTPs like PTPRD. So, alternative strategies are
necessary.
To stop PTPRD activity, graduate student Zhe Qian devised
a new kind of PTP blocker. He targeted the enzyme with a synthetic antibody—a
molecule that recognizes and binds to its target in a particular fashion. PTPRD
molecules sit nestled in the outer membranes of cells, with bits protruding
inside and out. Qian designed his antibody to grab onto two PTPRD molecules
from outside a cell simultaneously.
Promising Results and Future Prospects
Qian and colleagues in the Tonks lab showed that when the
antibody binds to its target, it draws pairs of PTPRD proteins together into an
inactive configuration. This not only prevents PTPRD from working but also
leads to the protein’s destruction. The team has shown that once this happens,
breast cancer cells growing in the lab become less invasive.
Tonks and Qian say the same strategy might be used to
block the possible metastasis-promoting enzyme in
patients with breast cancer. Tonks adds that this might be particularly
effective when combined with a kinase-targeting drug.
Reference: “Manipulating PTPRD function with ectodomain
antibodies” by Zhe Qian, Dongyan Song, Jonathan J. Ipsaro, Carmelita Bautista,
Leemor Joshua-Tor, Johannes T.-H. Yeh and Nicholas K. Tonks, 1 August
2023, Genes & Development.
DOI: 10.1101/gad.350713.123
Funding: National Institutes of Health, Robertson
Research Fund, Don Monti Memorial Research Foundation, Irving A. Hansen
Memorial Foundation, Simons Foundation, CSHL-Northwell Health Affiliation,
Howard Hughes Medical Institute. Nicholas Tonks is the Caryl Boies Professor of
Cancer Research at CSHL