Researchers from The University of Texas MD Anderson Cancer Center have developed a first-in-class antibody that targets a protein overexpressed in many cancer types, allowing for the creation of a new radio-theranostic treatment that brings targeted radiation directly to tumor cells.
The development of the antibody was led by Cancer Systems Imaging faculty, including David Piwnica-Worms, M.D., Ph.D. , chair, Seth Gammon, Ph.D. , associate professor, and Margie Sutton, Ph.D. , assistant professor. Their study was published in Theranostics .
"We've been working on this for almost a decade," Piwnica-Worms said. "The ability to effectively target the B7-H3 protein has been an attractive but elusive goal for scientists since the early days of immune checkpoint therapies. This is a very exciting publication because we present an antibody that can precisely target the types of B7-H3 proteins that are found on cancer cells, but avoid the ones found in the blood stream."
Why is targeting B7-H3 so important, and why hasn't it been done before?
B7-H3 is overexpressed in many tumor types, including some of the most aggressive forms of cancer, making it a promising therapeutic target. However, developing therapies that can accurately target this protein has been a challenge for multiple reasons.
For one, its function in the immune response process is complex and not fully understood. Additionally, there are two types, or isoforms, of B7-H3 in humans, and an effective therapy must target only the correct isoform.
The 4lg-B7-H3 isoform is overexpressed on the surface of many tumors and is uncommon in normal tissues. The second isoform – 2lg-B7-H3 – circulates in the bloodstream. Only the 2Ig isoform is common outside of humans, so most preclinical therapies under development have not distinguished between the two. This not only creates the potential for off-target toxicities but also makes impacting the desired target much more difficult.
This study introduces a novel monoclonal antibody that can selectively target just the 4lg isoform.
How is this antibody being used to treat cancer?
The preclinical antibody, described in the study as MIL33B, has multiple potential uses. To test its effectiveness, researchers attached an imaging isotope to the antibody and verified its ability to selectively target 4Ig-B7-H3 in tumors using PET-CT imaging.
A more significant application is its potential use as a radio-theranostic. This class of drugs uses radioisotopes – in this case Lutetium-177 – to more precisely deliver the benefits of molecularly targeted radiation directly to tumor cells, inducing cell death. In preclinical models, this combination was able to shrink tumors and to initiate a lasting immune response.
"When we challenged previously treated tumor models that had responded to initial treatment, we saw that most did not develop new tumors," Piwnica-Worms said. "Initiating a lasting immune response, termed immune memory, from a radio-theranostic would be a significant achievement because it would mean these drugs could have a long-term benefit for patients even after initially attacking the tumor itself."
Two major radio-theranostics have been approved by the Food and Drug Administration, but they have relatively narrow uses. The most notable example is Lutetium-177 vipivotide tetraxetan (Pluvicto), which treats one specific subset of prostate cancers.
To further develop the radio-theranostic, UT MD Anderson and Radiopharm Theranostics created Radiopharm Ventures, LLC. Using the humanized version of the antibody-radioisotope theranostic, now known as BetaBart, Radiopharm Ventures recently dosed the first patient in a Phase I/II trial (NCT07189871), with initial data expected later this year.
