Llama nanobodies could be used to deliver targeted drugs to human muscle cells

In “proof-of-concept” experiments with mouse and human cells and tissues, Johns Hopkins Medicine researchers say they have engineered tiny proteins, called nanobodies, derived from llama antibodies, that could potentially be used to deliver drugs targeted to human muscle cells. The researchers say the ability to more precisely target these tissues could advance the search for safer and more effective ways to relieve pain during surgery, treat irregular heart rhythms and control seizures.

The results of the experiments were published on February 21 in the Journal of Biological Chemistry.

Scientists aren’t sure why they only exist in certain species, like camelids and sharks, but since their discovery in the 1980s, researchers have studied them for use as a research tool and drug delivery system. anti-cancer with mixed success.

Aware of these experiments, the Johns Hopkins researchers suspected that the nanobodies could be useful as a tool to attach to a cell’s sodium ion channels, which act as a sort of switch that can conduct chemical signals that turn on or off the muscle cells.

Nine varieties of these switches appear in the human body, each specific to a type of tissue such as muscle or nerve. Since the channel proteins have only small differences between them, most drugs cannot tell them apart, which poses safety risks when trying to use them with drugs such as anesthetics. Existing drugs, researchers say, block pain and sedate a patient by “turning off” sodium ion channels in skeletal nerves and muscles, but can also dangerously lower heart rate and interfere with heart rhythms.

Other studies, according to Johns Hopkins Medicine researchers, have indeed shown that nanobodies can be used to transport cargo, an ability that could advance efforts to deliver drugs to specific sodium ion channels, thereby eliminating these side effects.

This is why clinicians and pharmaceutical companies are interested in finding drugs that can modulate these channels – either to turn on or off – distinctly. »

Sandra Gabelli, Ph.D., Associate Professor of Medicine, Johns Hopkins University School of Medicine

Gabelli recognized that the small size of the nanobodies could allow them to bind to areas inaccessible to larger molecules, such as larger antibodies that are often used for similar applications.

In their proof-of-concept experiments, Gabelli’s research team sifted through a very large library of 10 million nanobodies to develop them as biological proteins that could potentially differentiate sodium ion channels in muscle from those in nerves.

Working with Manu Ben-Johny of Columbia University, the researchers attached a fluorescent “reporter” molecule to the nanobodies that lights up when it interacts with the sodium channel. By monitoring the glow, the researchers found that two nanobodies, Nb17 and Nb82, were attached to specific sodium ion channels in skeletal muscle and cardiac muscle.

The researchers also tested the stability of the nanobodies at different temperatures, a key factor in drug development and delivery to clinics. The research team found that the Nb17 and Nb82 nanobodies were resistant to temperatures up to 168.8 and 150.8 degrees Fahrenheit, respectively, indicating that these nanobodies would remain stable under normal conditions.

Next, the researchers plan to image the channels of the nanobodies and the sodium ions bonded together to learn more about how this interaction works.

Other researchers involved in this study include Lakshmi Srinivasan, Sara Nathan, Jesse B. Yoder, Katharine M. Wright, Justin N. Nwafor, Gordon F. Tomaselli, and Mario Amzel of Johns Hopkins University School of Medicine; Vanina Alzogaray, Sebastián Klinke, María S. Labanda and Fernando A. Goldbaum of Fundación Instituto Leloir, Buenos Aires, Argentina; Dakshnamurthy Selvakumar of ForteBio, Sartorius BioAnalytical Instruments, Inc.; Arne Schön and Ernesto Freire from the Krieger School of Arts and Sciences at Johns Hopkins University; and Manu Ben-Johny of Columbia University.

This work was funded by the National Heart, Lung, and Blood Institute (HL128743), the National Institute of General Medical Sciences (GM109441), and the Vivien Thomas Scholars Initiative at Johns Hopkins University.https://www.hopkinsmedicine.org/”>


Journal reference:

Srinivasan, L. et al. (2022) Development of high-affinity nanobodies specific for NaV1.4 and NaV1.5 voltage-gated sodium channel isoforms. Journal of Biological Chemistry. doi.org/10.1016/j.jbc.2022.101763.

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