Highly protective antimalarial antibodies via precision library generation and yeast display screening
<jats:p>The monoclonal antibody CIS43 targets the Plasmodium falciparum circumsporozoite protein (PfCSP) and prevents malaria infection in humans for up to 9 mo following a single intravenous administration. To enhance the potency and clinical utility of CIS43, we used iterative site-saturatio...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Rockefeller University Press
2022
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| Online Access: | https://hdl.handle.net/1721.1/145918 |
| _version_ | 1826200456781627392 |
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| author | Banach, Bailey B Tripathi, Prabhanshu Da Silva Pereira, Lais Gorman, Jason Nguyen, Thuy Duong Dillon, Marlon Fahad, Ahmed S Kiyuka, Patience K Madan, Bharat Wolfe, Jacy R Bonilla, Brian Flynn, Barbara Francica, Joseph R Hurlburt, Nicholas K Kisalu, Neville K Liu, Tracy Ou, Li Rawi, Reda Schön, Arne Shen, Chen-Hsiang Teng, I-Ting Zhang, Baoshan Pancera, Marie Idris, Azza H Seder, Robert A Kwong, Peter D DeKosky, Brandon J |
| author2 | Massachusetts Institute of Technology. Department of Chemical Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Chemical Engineering Banach, Bailey B Tripathi, Prabhanshu Da Silva Pereira, Lais Gorman, Jason Nguyen, Thuy Duong Dillon, Marlon Fahad, Ahmed S Kiyuka, Patience K Madan, Bharat Wolfe, Jacy R Bonilla, Brian Flynn, Barbara Francica, Joseph R Hurlburt, Nicholas K Kisalu, Neville K Liu, Tracy Ou, Li Rawi, Reda Schön, Arne Shen, Chen-Hsiang Teng, I-Ting Zhang, Baoshan Pancera, Marie Idris, Azza H Seder, Robert A Kwong, Peter D DeKosky, Brandon J |
| author_sort | Banach, Bailey B |
| collection | MIT |
| description | <jats:p>The monoclonal antibody CIS43 targets the Plasmodium falciparum circumsporozoite protein (PfCSP) and prevents malaria infection in humans for up to 9 mo following a single intravenous administration. To enhance the potency and clinical utility of CIS43, we used iterative site-saturation mutagenesis and DNA shuffling to screen precise gene-variant yeast display libraries for improved PfCSP antigen recognition. We identified several mutations that improved recognition, predominately in framework regions, and combined these to produce a panel of antibody variants. The most improved antibody, CIS43_Var10, had three mutations and showed approximately sixfold enhanced protective potency in vivo compared to CIS43. Co-crystal and cryo-electron microscopy structures of CIS43_Var10 with the peptide epitope or with PfCSP, respectively, revealed functional roles for each of these mutations. The unbiased site-directed mutagenesis and screening pipeline described here represent a powerful approach to enhance protective potency and to enable broader clinical use of antimalarial antibodies.</jats:p> |
| first_indexed | 2024-09-23T11:36:45Z |
| format | Article |
| id | mit-1721.1/145918 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T11:36:45Z |
| publishDate | 2022 |
| publisher | Rockefeller University Press |
| record_format | dspace |
| spelling | mit-1721.1/1459182022-10-22T03:28:45Z Highly protective antimalarial antibodies via precision library generation and yeast display screening Banach, Bailey B Tripathi, Prabhanshu Da Silva Pereira, Lais Gorman, Jason Nguyen, Thuy Duong Dillon, Marlon Fahad, Ahmed S Kiyuka, Patience K Madan, Bharat Wolfe, Jacy R Bonilla, Brian Flynn, Barbara Francica, Joseph R Hurlburt, Nicholas K Kisalu, Neville K Liu, Tracy Ou, Li Rawi, Reda Schön, Arne Shen, Chen-Hsiang Teng, I-Ting Zhang, Baoshan Pancera, Marie Idris, Azza H Seder, Robert A Kwong, Peter D DeKosky, Brandon J Massachusetts Institute of Technology. Department of Chemical Engineering <jats:p>The monoclonal antibody CIS43 targets the Plasmodium falciparum circumsporozoite protein (PfCSP) and prevents malaria infection in humans for up to 9 mo following a single intravenous administration. To enhance the potency and clinical utility of CIS43, we used iterative site-saturation mutagenesis and DNA shuffling to screen precise gene-variant yeast display libraries for improved PfCSP antigen recognition. We identified several mutations that improved recognition, predominately in framework regions, and combined these to produce a panel of antibody variants. The most improved antibody, CIS43_Var10, had three mutations and showed approximately sixfold enhanced protective potency in vivo compared to CIS43. Co-crystal and cryo-electron microscopy structures of CIS43_Var10 with the peptide epitope or with PfCSP, respectively, revealed functional roles for each of these mutations. The unbiased site-directed mutagenesis and screening pipeline described here represent a powerful approach to enhance protective potency and to enable broader clinical use of antimalarial antibodies.</jats:p> 2022-10-21T14:29:40Z 2022-10-21T14:29:40Z 2022 2022-10-21T14:21:07Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/145918 Banach, Bailey B, Tripathi, Prabhanshu, Da Silva Pereira, Lais, Gorman, Jason, Nguyen, Thuy Duong et al. 2022. "Highly protective antimalarial antibodies via precision library generation and yeast display screening." The Journal of Experimental Medicine, 219 (8). en 10.1084/JEM.20220323 The Journal of Experimental Medicine Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Rockefeller University Press Rockefeller University Press |
| spellingShingle | Banach, Bailey B Tripathi, Prabhanshu Da Silva Pereira, Lais Gorman, Jason Nguyen, Thuy Duong Dillon, Marlon Fahad, Ahmed S Kiyuka, Patience K Madan, Bharat Wolfe, Jacy R Bonilla, Brian Flynn, Barbara Francica, Joseph R Hurlburt, Nicholas K Kisalu, Neville K Liu, Tracy Ou, Li Rawi, Reda Schön, Arne Shen, Chen-Hsiang Teng, I-Ting Zhang, Baoshan Pancera, Marie Idris, Azza H Seder, Robert A Kwong, Peter D DeKosky, Brandon J Highly protective antimalarial antibodies via precision library generation and yeast display screening |
| title | Highly protective antimalarial antibodies via precision library generation and yeast display screening |
| title_full | Highly protective antimalarial antibodies via precision library generation and yeast display screening |
| title_fullStr | Highly protective antimalarial antibodies via precision library generation and yeast display screening |
| title_full_unstemmed | Highly protective antimalarial antibodies via precision library generation and yeast display screening |
| title_short | Highly protective antimalarial antibodies via precision library generation and yeast display screening |
| title_sort | highly protective antimalarial antibodies via precision library generation and yeast display screening |
| url | https://hdl.handle.net/1721.1/145918 |
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