Achievement Unlocked : New ‘Trojan horse’ antibody strategy shows promise against all Ebola viruses

Do you remember the story of Troy ? Where the Greek soldiers hid in a wooden horse and were led into the city of Troy by the citizens of Troy themselves ? A similar strategy has been developed by a team which  included scientists from Albert Einstein College of Medicine, U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), Integrated Biotherapeutics, Vanderbilt University Medical Center, and The Scripps Research Institute.

The team of scientists describe a new therapeutic strategy to target a hidden Achilles’ heel (To infect and multiply in human cells) shared by all known types of Ebola virus. Two antibodies developed with this strategy blocked the invasion of human cells by all five ebolaviruses.

Microscopic image of an Ebola virus

To think of such a strategy, they had to have an entirely different approach on developing the antibody. Ebola and many other viruses enter host cell compartments called lysosomes. Once safely inside the lysosomes, the viruses transform and expose key portions of their exterior that the research team successfully targeted using monoclonal antibodies.(antibody produced from a single clone of cells)

The Ebola viruses then use resources of the host body like NPC1, a protein which transports cholesterol, to get out of the lysosomes and then multiply in the body.

The research team realized that monoclonal antibodies could potentially thwart all infections caused by Ebola virus by neutralizing the viral protein that binds to NPC1, or by neutralizing NPC1 itself. But both the targets, the viral protein that binds to NPC1 and NPC1, reside only in lysosomes deep within cells–making them invisible to the immune system and shielded from attack by conventional antibodies.

Dr. Chandran, Dr. Dye and co-senior author Jonathan R. Lai, Ph.D., associate professor of biochemistry at Einstein and an expert in engineering antibodies, devised the clever “Trojan Horse” strategy for overcoming the virus’s invisibility cloak:they tricked the viruses into carrying the means of their own destruction along with them into host cells.

To do so, the research team synthesized two types of “bispecific” antibodies, each consisting two antibodies combined into one molecule.One bispecific antibody was devised to neutralize the viral protein that binds to NPC1, the other to target NPC1.

Both had one antibody in common: antibody FVM09, which binds to the surface of all ebolaviruses while the virus is outside cells, allowing the bispecific antibodies to hitch a ride with the virus into the lysosome. FVM09 was developed by co-senior author M. Javad Aman, Ph.D. at Integrated Biotherapeutics.

Once in the lysosome, the bispecific antibodies are released from the viral surface allowing the bispecific antibodies to swing into action. Both the antibodies have the potential for preventing Ebola virus from interacting with NPC1 and escaping from the lysosome into the cytoplasm.

Both bispecific antibodies successfully neutralized all five viruses. Work in the high-containment facilities at USAMRIID confirmed that these antibodies also blocked infection by the actual Zaire, Sudan, and Bundibugyo ebolaviruses.

To summarize everything, the team of scientists developed a Trojan horse strategy consisting a system of bispecific antibodies to prevent the Ebola virus from interacting with the host body.

As a next step in this research, both bispecific antibodies will need to be tested in nonhuman primates first.

The antibodies developed by the research team represent an important advance against one of the world’s most dangerous pathogens.

If you can’t quite imagine about what exactly happens in this technique, here’s a video from Albert Einstein College of Medicine explaining the same.

 

The above research has been published in Biology News

Edited by – Siddhi Rao.

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