In an interview with PharmaShots, Fred David Mast, Senior Research Scientist at Seattle Children’s Research Institute shared his views on the study demonstrating that Nanobodies could be an exceptional resource for superior COVID-19 protective and therapeutic interventions. The results of this study were published in E-life

Shots:

• Seattle Children’s Research Institute’s scientists collaborated with researchers from Rockefeller University to investigate the powerful tools for diagnosing & treating a COVID-19
• In a recent study published in E-life, scientists from Seattle Children’s Aitchison, Sather, Myler & Debley labs in collaboration with Rockefeller University’s Chait, Rout & Bieniasz labs showed that the nanobodies can become an exceptional resource for superior COVID-19 protection & therapeutic interventions to provide the effective treatment of diseases, commonly found in low-resource countries
• ExeVir’s XVR011 is being evaluated in the P-I trials for COVID-19 while multiple other groups are in the preclinical stage

Tuba: What are nanobodies? How do nanobodies kill the SARS-CoV-2 virus?

Fred David Mast: Nanobodies are small, single-domain molecules. They are derived from a specialized type of antibody that is found in camels, llamas, alpacas, and oddly enough, sharks. Our COVID-19 nanobodies come from two llamas, Rocky and Marley (https://www.rockefeller.edu/news/28238-llama-nanobodies-covid-19-research/). When you compare nanobodies to monoclonal antibodies they are about 1/10th the size, but they remain just as capable as monoclonal antibodies in binding tightly to their target. In the case of SARS-CoV-2, nanobodies that recognize the viral surface protein spike are quite effective at incapacitating the virus.

The mechanism(s) by which nanobodies “kill” the virus depends on where the nanobody binds to the spike protein. For example, nanobodies can block the interaction between the virus and its host human cells, prevent the spike from triggering fusion with the host cell, or mimic the host receptor ACE2 and prematurely trigger the spike protein such that it is no longer functional.

Tuba: Discuss the advantages of nanobodies over other antibodies & vaccines?

Fred David Mast: Because of their small size, it is easier and a lot cheaper to manufacture nanobodies as compared to monoclonal antibodies. Similar to small molecule drugs, nanobodies are capable of binding regions not accessible to the larger monoclonal antibodies. Nanobodies are also extremely stable and don’t require expensive refrigeration for storage and shipping. In fact, they can be freeze-dried for easy storage and shipping. We demonstrated this in our recent study, where we selected a few of our nanobodies for freeze-drying. After reconstituting them, the nanobodies retained their potent binding ability and activity. This stability also enables the delivery of nanobodies by nebulization, a process that aerosolizes the nanobodies for inhalation into an individual’s airway passage and even deep into the lungs. And their small size makes nanobodies readily amenable to modifications that can further tune and enhance their potency, the length of time they stay in the body, etc. 

Tuba: What are the other possible applications of nanobodies therapy? Is there any approved formulation of nanobodies available in the market or in the late-stage pipeline?

Fred David Mast: There are no approved nanobody-based therapies currently available for treating COVID-19. Yet nanobodies remain one of the most exciting prospects in this space and there are a few lead compounds that are in development. For example, ExeVir has a lead nanobody compound, XVR011, that is phase 1 clinical trials, and several other groups are in the preclinical stage.

The potential application of nanobodies that I find most exciting is in formulating combinations of nanobodies that each individually targets distinct regions on the viral spike protein. Our research has demonstrated remarkable synergy between nanobodies that target distinct regions of the spike, making them more efficacious than if they were provided individually. This approach also makes it substantially more difficult for SARS-CoV-2 variants to escape neutralization, a troubling and recurring theme with existing therapeutic monoclonal antibodies.

Tuba: Can you please list out the name and efforts of your collaborative teams/labs involved in this research?

Fred David Mast: Our research team is composed of four research labs that together comprise the National Center for Dynamic Interactome Research (www.ncdir.org). Our COVID-19 nanobody project is primarily being led by Brian Chait and Michael Rout at the Rockefeller University in New York, and by John Aitchison at the Center for Global Infectious Disease Research at Seattle Children’s Research Institute in Seattle.

Tuba: Would you like to reveal the various funds that you have received for this project?

Fred David Mast: Our funding has been disclosed in our eLife paper.

Tuba: When do you plan to initiate a clinical study of these nanobodies?

Fred David Mast: We are currently engaged in preclinical work validating cocktails of our nanobodies in animal studies. We plan on moving forward with optimized and well-chosen formulations of variant-resistant and synergistic nanobody cocktails to become used as prophylactics and therapeutics.

Source: Freepik

About Author:

Fred David Mast is the Senior Research Scientist at Seattle Children’s Research Institute. He holds a Doctorate of Philosophy (Ph.D.) in Cell Biology from the University of Alberta, Bachelor of Science with Distinction, in Cell Biology from the University of Alberta, Bachelor of Science transfer program, Science; Music; Cell Biology from the MacEwan University

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