New Antibody Therapy Targets and Reprograms Resistant Tumors in Preclinical Study

A team of scientists at UCLA, in collaboration with international partners, has developed a promising new strategy to treat some of the most aggressive and treatment-resistant cancers, including osteosarcoma and glioblastoma. Their findings, recently published in Signal Transduction and Targeted Therapy, detail a dual-function antibody that can both image and destroy tumors while reprogramming their immune-resistant environments.

At the core of the approach is a monoclonal antibody called DUNP19, specifically engineered to target LRRC15, a protein that appears on the surface of aggressive cancer cells and the surrounding stromal cells that support tumor growth. LRRC15 is rarely found in healthy tissues, making it an ideal candidate for selective treatment.

When linked with radioactive particles, DUNP19 becomes a “radiotheranostic” tool—capable of visualizing tumors for precise imaging and delivering potent, targeted radiation therapy directly to the tumor site. In preclinical mouse models, this therapy slowed tumor progression, extended survival, and reprogrammed the tumor microenvironment to make it more receptive to immune responses.

Osteosarcoma, the most common bone cancer, and glioblastoma, the deadliest brain tumor, are both notoriously unresponsive to conventional therapies. These tumors are reinforced by dense stromal environments and mechanisms that block immune cell infiltration—both linked to LRRC15 expression. By targeting LRRC15, DUNP19 attacks not only the cancer cells but also the protective stroma that fuels tumor survival and suppresses immune responses.

The antibody’s action is enhanced when paired with Lutetium-177, a radioactive isotope that delivers therapeutic radiation directly into LRRC15-expressing cells. Once internalized by tumors, DUNP19 acts like a guided missile, destroying the cancer from within.

In mouse models of osteosarcoma, glioblastoma, triple-negative breast cancer, and aggressive colorectal cancer, DUNP19 linked to radioactive particles either cured the disease, halted tumor growth, or significantly extended survival. In osteosarcoma models, nearly all mice with tumors in bone tissue showed no signs of disease following treatment, while untreated mice succumbed to the cancer. In glioblastoma models, tumor progression was halted, enabling researchers to study the biological changes triggered by therapy.

Beyond tumor destruction, the treatment profoundly altered the tumor environment. Post-treatment analysis revealed a reduction in LRRC15-expressing stromal cells, breaking down the physical and molecular barriers that previously shielded tumors from immune attack. This allowed immune cells—such as CD8+ T cells and natural killer cells—to infiltrate tumors that were once inaccessible. Genetic analysis showed a decline in immune-suppressive signaling and an increase in gene activity associated with immune activation.

These environmental shifts were key to another striking finding: even a single low dose of the LRRC15-targeted therapy significantly improved the effectiveness of immunotherapy in mouse models. By eliminating cells that block immune access, DUNP19 opened the door for immune therapies to work more effectively.

With its ability to simultaneously detect, kill, and reprogram tumors, DUNP19 represents a significant advance in the field of radiotheranostics. A first-in-human clinical trial led by Dr. Noah Federman at UCLA is expected to launch later this year to test the approach in patients with metastatic osteosarcoma.

If successful in humans, this strategy could offer new hope for patients with cancers that have, until now, defied conventional treatments.