Tiny antibody makes tumors glow on PET scans by targeting the EphA2 cancer protein

Scientists have engineered a small antibody that seeks out EphA2, a protein overexpressed in many common cancers, and makes tumors visibly light up during PET scans. In mouse studies, tumors carrying EphA2 produced a clear, distinct signal when the antibody was administered, while surrounding healthy tissue did not. If the approach works in humans with similar specificity, it would give oncologists and surgeons a direct visual map of tumor locations that current PET imaging methods often fail to provide with this level of precision.

What EphA2 is and why it makes a useful target

EphA2 is a receptor tyrosine kinase, a type of protein that sits on cell surfaces and receives signals that regulate cell growth and movement. In healthy adult tissue, EphA2 expression is relatively low. In a wide range of tumor types, including breast, lung, prostate, ovarian, and pancreatic cancers, it is overexpressed, often by a factor of 10 or more compared to the surrounding normal cells. That differential makes it an attractive target for imaging agents because an antibody that binds to EphA2 will preferentially accumulate in tumors rather than in the rest of the body.

The antibody developed in this research is a nanobody, a single-domain antibody fragment approximately one-tenth the size of a conventional full antibody. Nanobodies are derived from a class of antibodies found naturally in camelids, including llamas and camels, and have been studied as imaging and therapeutic agents for roughly two decades. Their small size means they clear from the bloodstream faster than full antibodies, which reduces the background signal in imaging and produces a cleaner, higher-contrast picture of where the target protein is located.

How the PET imaging process works with the nanobody

The nanobody is attached to a radioactive tracer, in this case a short-lived radioisotope that emits positrons detectable by a PET scanner. Once injected, the nanobody circulates through the body and binds to cells where EphA2 is present in high concentrations. Because tumors overexpressing EphA2 accumulate more of the nanobody than healthy tissue, they appear as bright spots on the resulting PET scan image. The radioactive tracer then decays over hours, limiting the patient's radiation exposure.

Standard PET scans used in oncology most commonly use fluorodeoxyglucose, a radioactive glucose analog that highlights metabolically active tissue. The problem is that FDG is not specific to cancer. Inflammation, infection, and normal high-metabolism tissues like the brain and heart also take up FDG and can create false positives or obscure tumors in those regions. An EphA2-targeted nanobody addresses that limitation by binding to a molecular marker that is specifically elevated in cancer cells rather than tracking general metabolic activity.

What the mouse study results showed

In the preclinical experiments, mice with implanted tumors expressing EphA2 showed clear tumor-specific signal on PET scans within one to two hours of nanobody injection, according to the study published in the Journal of Nuclear Medicine. Tumors that did not express EphA2 did not produce a signal, confirming that the nanobody's accumulation was driven by protein binding rather than passive tumor accumulation from leaky blood vessels, which is a common confounding factor in tumor imaging research.

The signal-to-background ratio in the EphA2-positive tumors was high enough that small tumors, some as small as 5 millimeters in diameter, were identifiable on PET images. Small tumor detection is where current imaging methods most frequently fall short. A 2022 meta-analysis in Radiology found that FDG-PET sensitivity for detecting primary tumors under 10 millimeters in diameter averaged approximately 58 percent across cancer types. An antibody-targeted approach with higher tumor specificity could meaningfully increase that detection rate for early-stage disease.

Potential applications in surgery and treatment planning

Beyond early detection, the research team identified surgical guidance as a high-value application. Incomplete surgical resection, leaving microscopic tumor margins behind at the surgical site, is one of the leading causes of cancer recurrence after apparently successful operations. A pre-surgical PET scan using the EphA2 nanobody could map the spatial extent of a tumor more accurately than conventional imaging, helping surgeons plan the margins of resection before making the first incision.

The research group, based at the University of California San Diego in collaboration with the Salk Institute, is now preparing an Investigational New Drug application to the FDA to begin Phase I human safety trials. The application is expected to be submitted in the third quarter of 2026. If Phase I safety data is acceptable, imaging efficacy trials in patients with EphA2-expressing cancers, including triple-negative breast cancer and non-small cell lung cancer, are planned to begin in 2027.