An Anti-Gn Glycoprotein Antibody From a Convalescent Patient Potently 2 Inhibits the Infection of Severe Fever with Thrombocytopenia Syndrome Virus

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February 1, 2019

Authors

Ki Hyun Kim^1,2, Jinhee Kim³, Meehyun Ko³, June Young Chun⁴, Hyori Kim^2,7, Seungtaek Kim⁵, Ji-Young Min^3,8, Wan Beom Park⁴, Myoung-don Oh⁴, and Junho Chung^1,2,6

Organizations

Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea
Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
Respiratory Virus Laboratory, Institut Pasteur Korea, Gyeonggi-do, Republic of Korea.
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
Zoonotic Virus Laboratory, Institut Pasteur Korea, Gyeonggi-do, Republic of Korea.
Department of Biomedical Science, Seoul National University College of Medicine, Seoul, Republic of Korea
Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea
GlaxoSmithKline, Rockville, Maryland, United States of America

Abstract

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease localized to China, Japan, and Korea that is characterized by severe hemorrhage and a high fatality rate. Currently, no specific vaccine or treatment has been approved for this disease. To develop a therapeutic agent for SFTS, we isolated antibodies from a phage-displayed antibody library that was constructed from a patient who recovered from SFTS virus (SFTSV) infection. One antibody, designated as Ab10, was reactive to the Gn envelope glycoprotein of SFTSV and protected host cells and A129 mice from infection in both in vitro and in vivo experiments. Notably, Ab10 protected 80% of mice, even when injected 5 days after inoculation with a lethal dose of SFTSV. Using cross-linker assisted mass spectrometry and alanine scanning, we located the non-linear epitope of Ab10 on the Gn glycoprotein domain II and an unstructured stem region, suggesting that Ab10 may inhibit a conformational alteration that is critical for cell membrane fusion between the virus and host cell. Ab10 reacted to recombinant Gn glycoprotein in Gangwon/Korea/2012, HB28, and SD4 strains. Additionally, based on its epitope, we predict that Ab10 binds the Gn glycoprotein in 247 of 272 reported SFTSV isolates previously reported. Together, these data suggest that Ab10 has potential to be developed into a therapeutic agent that could protect against more than 90% of reported SFTSV isolates.

CovalX Technology Used (Click each option to learn more)

HM4

Outcomes

The epitope of Ab10 antibody was found by analyzing the complex of Ab10 antibody and SFTSV Gn-Cκ antigen that were linked with deuterated cross-linkers. The antibody, antigen and antibody/antigen complex were analyzed by MALDI mass spectrometry using a MALDI ToF/ToF tandem mass spectrometer that had been modified with the CovalX HM4 detection system. The use of the CovalX HM4 detection system helped researchers to confirmed that the Ab10 epitope was only within domain II and the stem region of the Gn glycoprotein. From this confirmation, they hypothesized that the Ab10 binds to domain II and the stem region of the Gn glycoprotein simultaneously while also preventing un-shielding of the Gc fusion loop. Therefore, the Ab10 monoclonal antibody has been shown to be effective in treating mouse SFTSV as it is estimated that the Ab10 interacts with most of the SFTSV isolates that are currently known. From these results, researchers believe that the Ab10 monoclonal antibody can possibly be used as a prophylactic and therapeutic to treat a wide variety of SFTS isolates.