Nanobodies - miniature proteins derived from camel antibodies - demonstrated powerful potential to accurately and safely deliver radioisotopes as specialized cancer treatments in a project at ORNL.
The unusual antibodies were first observed in 1989 by Belgian researchers studying the immune system of camelids - animals such as camels, alpacas and llamas. The discovery led to the development of synthetic nanobodies, whose small size and simple, stable structure make them better at reaching tiny and sometimes hidden targets such as cancer cells when compared with regular, larger antibodies.
Their size also allows nanobodies to rapidly penetrate the inner layers of solid tumors and avoid surrounding healthy cells. They are quick to clear the system, making nanobodies with radioisotope payloads less likely to cause side effects in patients.
"These qualities make nanobodies an ideal delivery mechanism for precision doses of radiopharmaceuticals such as the actinium-225 produced at ORNL and are shown to be very effective in treating certain cancers," said Mircea Podar of the lab's Biosciences Division.
Podar relied on previous research conducted during the COVID-19 pandemic, during which ORNL scientists explored the production and use of nanobodies to target the SARS-Cov-2 virus.
Podar and colleagues created synthetic nanobodies for the radiopharmaceutical project by inserting synthetic genes into E. coli bacteria, fine-tuning conditions like temperature and adding sequence hooks on their ends. The nanobodies were purified, assembled, hooked to chemical and radioactive payloads and prepared for testing.
These qualities make nanobodies an ideal delivery mechanism for precision doses of radiopharmaceuticals such as the actinium-225 produced at ORNL and are shown to be very effective in treating certain cancers.
The scientists found that the nanobodies precisely bound to HER2-positive proteins associated with breast cancer, including more complex cell clusters that mimicked solid tumors. Tests with tissue culture models measured how quickly the nanobodies attached to and detached from their targets, confirming that they were specific and effective, even after modifications to help them more easily enter cells.
The team also succeeded in attaching markers to nanobodies that make them easily detectable in lab studies and allow them to carry radioisotope payloads.
As part of the project, the scientists created nanobodies that locate DNA damage in cells - essential for evaluating the effectiveness of cancer treatments. These nanobodies accurately tagged damaged DNA sites inside cells, highlighting their ability to help assess and improve cancer therapies.
"The project demonstrated ORNL's capability for reliable in-house nanobody design, production and analysis, and highlights the potential of the technology to transform medical research and treatment," Podar said.
UT-Battelle manages ORNL for DOE's Office of Science, the single largest supporter of basic research in the physical sciences in the United States. The Office of Science is working to address some of the most pressing challenges of our time. For more information, visit energy.gov/science . - Stephanie Seay
