In the year 1989, two students from the Free University of Brussels were assigned to test frozen blood serum from camels, and as they did so they stumbled on an unknown antibody. It was a small version of an antibody found in humans, and it was made up of only two heavy protein chains instead of two heavy chains and two light chains. As they were reported, the antibodies found on the camels was confirmed to be seen in llamas and alpacas as well.
In today's medicine, researchers at the Boston Children's Hospital and MIT show that the mini-antibodies had shrunk further to create nanobodies, as stated in the journal PNAS. This discovery may help solve the ongoing problem in the cancer field, and that is making a CAR T-cell therapy work in solid tumors.
CAR T-cell therapy is highly promising for blood cancers, chimeric antigen receptor can engineer a patient's T-cells genetically to make them better at attacking the cancer cells. The Dana-Farber/Boston Children's Cancer and Blood Disorders Center is using CAR T-cell therapy currently, it is deemed helpful for relapsed acute lymphocytic leukemia and that is just one of the diseases that it can give remedy to.
But CAR T-cells have been reported to not be as effective at eliminating solid tumors. It is difficult to find proteins on solid tumors that are cancer-specific and could serve as safe targets. Solid tumors are protected by a matrix that is extracellular, which means that it has a supportive web of proteins that can act as a barrier and it can weaken the T-cell attack because of the immunosuppressive molecules.
That is where nanobodies come in and do its job. For more than 20 years, they remained in the care of the Belgian team. But that all changed after the patent that they had expired in 2013.
"A lot of people got into the game and began to appreciate nanobodies' unique properties," says Hidde Ploegh, Ph.D., an immunologist in the Program in Cellular and Molecular Medicine at Boston Children's and senior investigator on the PNAS study.
One useful contribution that the nanobodies have is their enhanced targeting abilities. Ploegh and his team at Boston Children's, in collaboration with Noo Jalikhani, Ph.D., and Richard Hynes, Ph.D. at MIT's Koch Institute for Integrative Cancer Research, have retracted nanobodies to carry imaging agents, allowing exact visualization of metastatic cancers.
The Hynes team targeted the nanobodies to the tumors' extracellular matrix or ECM. They aimed the imaging agents of the nanobodies not at the cancer cells directly but at the environment that surrounds it. These markers are very common to a lot of tumors, but they do not appear on normal cells.
"Our lab and the Hynes lab are among the few actively pursuing this approach of targeting the tumor microenvironment," says Ploegh. "Most labs are looking for tumor-specific antigens."
