A therapeutic neutralizing antibody targeting receptor binding domain of SARS-CoV-2 spike protein

Cheolmin Kim; Dong Kyun Ryu; Jihun Lee; Young Il Kim; Ji Min Seo; Yeon Gil Kim; Jae Hee Jeong; Minsoo Kim; Jong In Kim; Pankyeom Kim; Jin Soo Bae; Eun Yeong Shim; Min Seob Lee; Man Su Kim; Hanmi Noh; Geun Soo Park; Jae Sang Park; Dain Son; Yongjin An; Jeong No Lee; Ki Sung Kwon; Joo Yeon Lee; Hansaem Lee; Jeong Sun Yang; Kyung Chang Kim; Sung Soon Kim; Hye Min Woo; Jun Won Kim; Man Seong Park; Kwang Min Yu; Se Mi Kim; Eun Ha Kim; Su Jin Park; Seong Tae Jeong; Chi Ho Yu; Youngjo Song; Se Hun Gu; Hanseul Oh; Bon Sang Koo; Jung Joo Hong; Choong Min Ryu; Wan Beom Park; Myoung don Oh; Young Ki Choi; Soo Young Lee

doi:10.1038/s41467-020-20602-5

A therapeutic neutralizing antibody targeting receptor binding domain of SARS-CoV-2 spike protein

Cheolmin Kim, Dong Kyun Ryu, Jihun Lee, Young Il Kim, Ji Min Seo, Yeon Gil Kim, Jae Hee Jeong, Minsoo Kim, Jong In Kim, Pankyeom Kim, Jin Soo Bae, Eun Yeong Shim, Min Seob Lee, Man Su Kim, Hanmi Noh, Geun Soo Park, Jae Sang Park, Dain Son, Yongjin An, Jeong No LeeKi Sung Kwon, Joo Yeon Lee, Hansaem Lee, Jeong Sun Yang, Kyung Chang Kim, Sung Soon Kim, Hye Min Woo, Jun Won Kim, Man Seong Park, Kwang Min Yu, Se Mi Kim, Eun Ha Kim, Su Jin Park, Seong Tae Jeong, Chi Ho Yu, Youngjo Song, Se Hun Gu, Hanseul Oh, Bon Sang Koo, Jung Joo Hong, Choong Min Ryu, Wan Beom Park, Myoung don Oh, Young Ki Choi, Soo Young Lee

Department of Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

138 Citations (Scopus)

Abstract

Vaccines and therapeutics are urgently needed for the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we screen human monoclonal antibodies (mAb) targeting the receptor binding domain (RBD) of the viral spike protein via antibody library constructed from peripheral blood mononuclear cells of a convalescent patient. The CT-P59 mAb potently neutralizes SARS-CoV-2 isolates including the D614G variant without antibody-dependent enhancement effect. Complex crystal structure of CT-P59 Fab/RBD shows that CT-P59 blocks interaction regions of RBD for angiotensin converting enzyme 2 (ACE2) receptor with an orientation that is notably different from previously reported RBD-targeting mAbs. Furthermore, therapeutic effects of CT-P59 are evaluated in three animal models (ferret, hamster, and rhesus monkey), demonstrating a substantial reduction in viral titer along with alleviation of clinical symptoms. Therefore, CT-P59 may be a promising therapeutic candidate for COVID-19.

Original language	English
Article number	288
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20602-5
Publication status	Published - 2021 Dec 1

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-020-20602-5

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Kim, C., Ryu, D. K., Lee, J., Kim, Y. I., Seo, J. M., Kim, Y. G., Jeong, J. H., Kim, M., Kim, J. I., Kim, P., Bae, J. S., Shim, E. Y., Lee, M. S., Kim, M. S., Noh, H., Park, G. S., Park, J. S., Son, D., An, Y., ... Lee, S. Y. (2021). A therapeutic neutralizing antibody targeting receptor binding domain of SARS-CoV-2 spike protein. Nature communications, 12(1), [288]. https://doi.org/10.1038/s41467-020-20602-5

Kim, C, Ryu, DK, Lee, J, Kim, YI, Seo, JM, Kim, YG, Jeong, JH, Kim, M, Kim, JI, Kim, P, Bae, JS, Shim, EY, Lee, MS, Kim, MS, Noh, H, Park, GS, Park, JS, Son, D, An, Y, Lee, JN, Kwon, KS, Lee, JY, Lee, H, Yang, JS, Kim, KC, Kim, SS, Woo, HM, Kim, JW, Park, MS, Yu, KM, Kim, SM, Kim, EH, Park, SJ, Jeong, ST, Yu, CH, Song, Y, Gu, SH, Oh, H, Koo, BS, Hong, JJ, Ryu, CM, Park, WB, Oh, MD, Choi, YK & Lee, SY 2021, 'A therapeutic neutralizing antibody targeting receptor binding domain of SARS-CoV-2 spike protein', Nature communications, vol. 12, no. 1, 288. https://doi.org/10.1038/s41467-020-20602-5

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title = "A therapeutic neutralizing antibody targeting receptor binding domain of SARS-CoV-2 spike protein",

abstract = "Vaccines and therapeutics are urgently needed for the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we screen human monoclonal antibodies (mAb) targeting the receptor binding domain (RBD) of the viral spike protein via antibody library constructed from peripheral blood mononuclear cells of a convalescent patient. The CT-P59 mAb potently neutralizes SARS-CoV-2 isolates including the D614G variant without antibody-dependent enhancement effect. Complex crystal structure of CT-P59 Fab/RBD shows that CT-P59 blocks interaction regions of RBD for angiotensin converting enzyme 2 (ACE2) receptor with an orientation that is notably different from previously reported RBD-targeting mAbs. Furthermore, therapeutic effects of CT-P59 are evaluated in three animal models (ferret, hamster, and rhesus monkey), demonstrating a substantial reduction in viral titer along with alleviation of clinical symptoms. Therefore, CT-P59 may be a promising therapeutic candidate for COVID-19.",

author = "Cheolmin Kim and Ryu, {Dong Kyun} and Jihun Lee and Kim, {Young Il} and Seo, {Ji Min} and Kim, {Yeon Gil} and Jeong, {Jae Hee} and Minsoo Kim and Kim, {Jong In} and Pankyeom Kim and Bae, {Jin Soo} and Shim, {Eun Yeong} and Lee, {Min Seob} and Kim, {Man Su} and Hanmi Noh and Park, {Geun Soo} and Park, {Jae Sang} and Dain Son and Yongjin An and Lee, {Jeong No} and Kwon, {Ki Sung} and Lee, {Joo Yeon} and Hansaem Lee and Yang, {Jeong Sun} and Kim, {Kyung Chang} and Kim, {Sung Soon} and Woo, {Hye Min} and Kim, {Jun Won} and Park, {Man Seong} and Yu, {Kwang Min} and Kim, {Se Mi} and Kim, {Eun Ha} and Park, {Su Jin} and Jeong, {Seong Tae} and Yu, {Chi Ho} and Youngjo Song and Gu, {Se Hun} and Hanseul Oh and Koo, {Bon Sang} and Hong, {Jung Joo} and Ryu, {Choong Min} and Park, {Wan Beom} and Oh, {Myoung don} and Choi, {Young Ki} and Lee, {Soo Young}",

note = "Funding Information: This study was supported by a Korea National Institute of Health fund (2020-ER5311-00, 2020-ER5323-00, 2019-NI-077-01, 2019-NG-044-01), grants (011555-012664201) from the Agency for Defense Development, grants (PRM1752011) from the Ministry of Science and ICT, and partially supported by the Korea Research Institute of Bioscience and Biotechnology (KRIBB) Research Initiative Program (KGM9942011 and KGM4572013), Republic of Korea. Funding Information: Patents have been filed for CT-P59. C.K., D.K.R., J.L., J.M.S., M.K., J.I.K., P.K., J.S.B., E.Y.S., M.S.L., M.S.K., H.N., G.S.P., J.S.P., D.S., Y.A., J.N.L., K.S.K., and S.Y.L. are employees of Celltrion, Inc. This work was funded by Celltrion, Inc. and several grants listed in Acknowledgements. The remaining authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

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doi = "10.1038/s41467-020-20602-5",

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T1 - A therapeutic neutralizing antibody targeting receptor binding domain of SARS-CoV-2 spike protein

AU - Kim, Cheolmin

AU - Ryu, Dong Kyun

AU - Lee, Jihun

AU - Kim, Young Il

AU - Seo, Ji Min

AU - Kim, Yeon Gil

AU - Jeong, Jae Hee

AU - Kim, Minsoo

AU - Kim, Jong In

AU - Kim, Pankyeom

AU - Bae, Jin Soo

AU - Shim, Eun Yeong

AU - Lee, Min Seob

AU - Kim, Man Su

AU - Noh, Hanmi

AU - Park, Geun Soo

AU - Park, Jae Sang

AU - Son, Dain

AU - An, Yongjin

AU - Lee, Jeong No

AU - Kwon, Ki Sung

AU - Lee, Joo Yeon

AU - Lee, Hansaem

AU - Yang, Jeong Sun

AU - Kim, Kyung Chang

AU - Kim, Sung Soon

AU - Woo, Hye Min

AU - Kim, Jun Won

AU - Park, Man Seong

AU - Yu, Kwang Min

AU - Kim, Se Mi

AU - Kim, Eun Ha

AU - Park, Su Jin

AU - Jeong, Seong Tae

AU - Yu, Chi Ho

AU - Song, Youngjo

AU - Gu, Se Hun

AU - Oh, Hanseul

AU - Koo, Bon Sang

AU - Hong, Jung Joo

AU - Ryu, Choong Min

AU - Park, Wan Beom

AU - Oh, Myoung don

AU - Choi, Young Ki

AU - Lee, Soo Young

N1 - Funding Information: This study was supported by a Korea National Institute of Health fund (2020-ER5311-00, 2020-ER5323-00, 2019-NI-077-01, 2019-NG-044-01), grants (011555-012664201) from the Agency for Defense Development, grants (PRM1752011) from the Ministry of Science and ICT, and partially supported by the Korea Research Institute of Bioscience and Biotechnology (KRIBB) Research Initiative Program (KGM9942011 and KGM4572013), Republic of Korea. Funding Information: Patents have been filed for CT-P59. C.K., D.K.R., J.L., J.M.S., M.K., J.I.K., P.K., J.S.B., E.Y.S., M.S.L., M.S.K., H.N., G.S.P., J.S.P., D.S., Y.A., J.N.L., K.S.K., and S.Y.L. are employees of Celltrion, Inc. This work was funded by Celltrion, Inc. and several grants listed in Acknowledgements. The remaining authors declare no competing interests. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12/1

Y1 - 2021/12/1

N2 - Vaccines and therapeutics are urgently needed for the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we screen human monoclonal antibodies (mAb) targeting the receptor binding domain (RBD) of the viral spike protein via antibody library constructed from peripheral blood mononuclear cells of a convalescent patient. The CT-P59 mAb potently neutralizes SARS-CoV-2 isolates including the D614G variant without antibody-dependent enhancement effect. Complex crystal structure of CT-P59 Fab/RBD shows that CT-P59 blocks interaction regions of RBD for angiotensin converting enzyme 2 (ACE2) receptor with an orientation that is notably different from previously reported RBD-targeting mAbs. Furthermore, therapeutic effects of CT-P59 are evaluated in three animal models (ferret, hamster, and rhesus monkey), demonstrating a substantial reduction in viral titer along with alleviation of clinical symptoms. Therefore, CT-P59 may be a promising therapeutic candidate for COVID-19.

AB - Vaccines and therapeutics are urgently needed for the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we screen human monoclonal antibodies (mAb) targeting the receptor binding domain (RBD) of the viral spike protein via antibody library constructed from peripheral blood mononuclear cells of a convalescent patient. The CT-P59 mAb potently neutralizes SARS-CoV-2 isolates including the D614G variant without antibody-dependent enhancement effect. Complex crystal structure of CT-P59 Fab/RBD shows that CT-P59 blocks interaction regions of RBD for angiotensin converting enzyme 2 (ACE2) receptor with an orientation that is notably different from previously reported RBD-targeting mAbs. Furthermore, therapeutic effects of CT-P59 are evaluated in three animal models (ferret, hamster, and rhesus monkey), demonstrating a substantial reduction in viral titer along with alleviation of clinical symptoms. Therefore, CT-P59 may be a promising therapeutic candidate for COVID-19.

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A therapeutic neutralizing antibody targeting receptor binding domain of SARS-CoV-2 spike protein

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