MD Anderson researchers have engineered a first-in-class antibody that homes in on a cancer-linked protein while sparing healthy tissue, enabling a new targeted radiation drug now in early clinical testing. The approach could open radio-theranostics to many more tumor types.
A team at The University of Texas MD Anderson Cancer Center has engineered a first-in-class antibody that zeroes in on a protein found on many tumors but largely absent from healthy tissue, paving the way for a new targeted radiation treatment now being tested in patients.
The work, published in the journal Theranostics, centers on B7-H3, a protein that is overexpressed in a wide range of cancers, including some of the most aggressive forms. Because of that pattern, B7-H3 has long been viewed as a promising bullseye for new therapies. But turning that idea into a safe, precise drug has proved difficult.
The team has been pursuing the problem for years, according to David Piwnica-Worms, chair of Cancer Systems Imaging at MD Anderson, who co-led the research with associate professor Seth Gammon and assistant professor Margie Sutton.
“We’ve been working on this for almost a decade,” Piwnica-Worms said in a news release. “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.”
The new antibody is designed to distinguish between two versions, or isoforms, of B7-H3 that exist in humans.
One isoform, called 4Ig-B7-H3, is found at high levels on the surface of many tumor cells but is uncommon in normal tissues. The other, 2Ig-B7-H3, circulates in the bloodstream and is the dominant form seen in most nonhuman species used in preclinical research.
That difference has tripped up earlier efforts. Many experimental therapies have not clearly distinguished between the two isoforms, raising the risk of off-target side effects and making it harder to deliver a strong hit to tumor cells without also binding to proteins in the blood.
The MD Anderson team’s monoclonal antibody, known in the study as MIL33B, was built to selectively recognize only the 4Ig isoform on tumor cells. In preclinical tests, the researchers attached an imaging isotope to the antibody and used PET-CT scans to confirm that it homed in on 4Ig-B7-H3 in tumors while sparing other tissues.
That targeting ability opened the door to a more powerful use: turning MIL33B into a radio-theranostic.
Radio-theranostics are a growing class of drugs that combine a targeting molecule, such as an antibody, with a radioactive isotope. The targeting component guides the radioisotope directly to cancer cells, where it delivers a focused dose of radiation from the inside out. The same molecule can often be used with different isotopes for both imaging and treatment, allowing doctors to see where the drug goes and then attack the tumor.
In this case, the team linked MIL33B to Lutetium-177, a beta-emitting radioisotope already used in other cancer therapies. In animal models, this combination shrank tumors and did more than just kill cancer cells. It also appeared to spark a durable 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 added.
That kind of long-term protection is known as immune memory, when the immune system “remembers” a threat and can respond more quickly if it returns. For cancer patients, that could translate into longer-lasting benefits beyond the initial tumor shrinkage.
“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,” added Piwnica-Worms.
So far, only two major radio-theranostic drugs have been approved by the Food and Drug Administration, and each is limited to relatively narrow indications. One of the best-known examples, Lutetium-177 vipivotide tetraxetan (Pluvicto), is used for a specific subset of prostate cancers that express a particular surface marker.
By contrast, B7-H3 is overexpressed across many tumor types, suggesting that a safe, isoform-specific therapy could eventually reach a much broader group of patients, including those whose cancers currently lack targeted treatment options.
To move the new approach toward the clinic, MD Anderson partnered with Radiopharm Theranostics to form Radiopharm Ventures, LLC. Using a humanized version of the antibody-radioisotope construct, now called BetaBart, the company has launched a Phase I/II clinical trial.
The first patient in that trial has already been dosed, and initial data are expected later this year, according to the institution. Early-phase trials typically focus on safety, dosing and how the drug behaves in the body, while also looking for preliminary signs of effectiveness.
The study that underpins this work was funded by the National Cancer Institute of the National Institutes of Health. The authors note that MD Anderson has an institutional financial interest in Radiopharm Ventures, and that Piwnica-Worms has a personal financial relationship with the company. Those relationships are being managed under the cancer center’s institutional conflict-of-interest policies.
Beyond the specifics of this antibody, the research highlights a broader shift in oncology: the push to design smarter, more selective therapies that not only attack tumors but also enlist the immune system for lasting control.
If BetaBart and similar agents prove safe and effective in humans, they could help extend the benefits of radio-theranostics beyond today’s niche indications, offering new hope to patients whose cancers have been difficult to treat with existing tools.
For now, the work represents a key proof of concept: that it is possible to build an antibody that threads the needle between two nearly identical protein isoforms, and then harness that precision to deliver radiation exactly where it is needed most.