Combinations of Single Chain Variable Fragments From HIV Broadly Neutralizing Antibodies Demonstrate High Potency and Breadth
Broadly neutralizing antibodies (bNAbs) are currently being assessed in clinical trials for their ability to prevent HIV infection. Single chain variable fragments (scFv) of bNAbs have advantages over full antibodies as their smaller size permits improved diffusion into mucosal tissues and facilitat...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.734110/full |
| _version_ | 1818911190180429824 |
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| author | Rebecca T. van Dorsten Rebecca T. van Dorsten Kshitij Wagh Penny L. Moore Penny L. Moore Penny L. Moore Lynn Morris Lynn Morris Lynn Morris |
| author_facet | Rebecca T. van Dorsten Rebecca T. van Dorsten Kshitij Wagh Penny L. Moore Penny L. Moore Penny L. Moore Lynn Morris Lynn Morris Lynn Morris |
| author_sort | Rebecca T. van Dorsten |
| collection | DOAJ |
| description | Broadly neutralizing antibodies (bNAbs) are currently being assessed in clinical trials for their ability to prevent HIV infection. Single chain variable fragments (scFv) of bNAbs have advantages over full antibodies as their smaller size permits improved diffusion into mucosal tissues and facilitates vector-driven gene expression. We have previously shown that scFv of bNAbs individually retain significant breadth and potency. Here we tested combinations of five scFv derived from bNAbs CAP256-VRC26.25 (V2-apex), PGT121 (N332-supersite), 3BNC117 (CD4bs), 8ANC195 (gp120-gp41 interface) and 10E8v4 (MPER). Either two or three scFv were combined in equimolar amounts and tested in the TZM-bl neutralization assay against a multiclade panel of 17 viruses. Experimental IC50 and IC80 data were compared to predicted neutralization titers based on single scFv titers using the Loewe additive and the Bliss-Hill model. Like full-sized antibodies, combinations of scFv showed significantly improved potency and breadth compared to single scFv. Combinations of two or three scFv generally followed an independent action model for breadth and potency with no significant synergy or antagonism observed overall although some exceptions were noted. The Loewe model underestimated potency for some dual and triple combinations while the Bliss-Hill model was better at predicting IC80 titers of triple combinations. Given this, we used the Bliss-Hill model to predict the coverage of scFv against a 45-virus panel at concentrations that correlated with protection in the AMP trials. Using IC80 titers and concentrations of 1μg/mL, there was 93% coverage for one dual scFv combination (3BNC117+10E8v4), and 96% coverage for two of the triple combinations (CAP256.25+3BNC117+10E8v4 and PGT121+3BNC117+10E8v4). Combinations of scFv, therefore, show significantly improved breadth and potency over individual scFv and given their size advantage, have potential for use in passive immunization. |
| first_indexed | 2024-12-19T22:54:45Z |
| format | Article |
| id | doaj.art-4e66858df2204d2d9b96e20214624ad7 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-19T22:54:45Z |
| publishDate | 2021-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-4e66858df2204d2d9b96e20214624ad72022-12-21T20:02:40ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-09-011210.3389/fimmu.2021.734110734110Combinations of Single Chain Variable Fragments From HIV Broadly Neutralizing Antibodies Demonstrate High Potency and BreadthRebecca T. van Dorsten0Rebecca T. van Dorsten1Kshitij Wagh2Penny L. Moore3Penny L. Moore4Penny L. Moore5Lynn Morris6Lynn Morris7Lynn Morris8Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South AfricaMedical Research Council (MRC) Antibody Immunity Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South AfricaTheoretical Division, Los Alamos National Laboratory, Los Alamos, NM, United StatesCenter for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South AfricaMedical Research Council (MRC) Antibody Immunity Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South AfricaCenter for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South AfricaCenter for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South AfricaMedical Research Council (MRC) Antibody Immunity Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South AfricaCenter for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South AfricaBroadly neutralizing antibodies (bNAbs) are currently being assessed in clinical trials for their ability to prevent HIV infection. Single chain variable fragments (scFv) of bNAbs have advantages over full antibodies as their smaller size permits improved diffusion into mucosal tissues and facilitates vector-driven gene expression. We have previously shown that scFv of bNAbs individually retain significant breadth and potency. Here we tested combinations of five scFv derived from bNAbs CAP256-VRC26.25 (V2-apex), PGT121 (N332-supersite), 3BNC117 (CD4bs), 8ANC195 (gp120-gp41 interface) and 10E8v4 (MPER). Either two or three scFv were combined in equimolar amounts and tested in the TZM-bl neutralization assay against a multiclade panel of 17 viruses. Experimental IC50 and IC80 data were compared to predicted neutralization titers based on single scFv titers using the Loewe additive and the Bliss-Hill model. Like full-sized antibodies, combinations of scFv showed significantly improved potency and breadth compared to single scFv. Combinations of two or three scFv generally followed an independent action model for breadth and potency with no significant synergy or antagonism observed overall although some exceptions were noted. The Loewe model underestimated potency for some dual and triple combinations while the Bliss-Hill model was better at predicting IC80 titers of triple combinations. Given this, we used the Bliss-Hill model to predict the coverage of scFv against a 45-virus panel at concentrations that correlated with protection in the AMP trials. Using IC80 titers and concentrations of 1μg/mL, there was 93% coverage for one dual scFv combination (3BNC117+10E8v4), and 96% coverage for two of the triple combinations (CAP256.25+3BNC117+10E8v4 and PGT121+3BNC117+10E8v4). Combinations of scFv, therefore, show significantly improved breadth and potency over individual scFv and given their size advantage, have potential for use in passive immunization.https://www.frontiersin.org/articles/10.3389/fimmu.2021.734110/fullHIVbroadly neutralizing antibodiessingle chain variable fragmentscombinations of scFvHIV prevention |
| spellingShingle | Rebecca T. van Dorsten Rebecca T. van Dorsten Kshitij Wagh Penny L. Moore Penny L. Moore Penny L. Moore Lynn Morris Lynn Morris Lynn Morris Combinations of Single Chain Variable Fragments From HIV Broadly Neutralizing Antibodies Demonstrate High Potency and Breadth Frontiers in Immunology HIV broadly neutralizing antibodies single chain variable fragments combinations of scFv HIV prevention |
| title | Combinations of Single Chain Variable Fragments From HIV Broadly Neutralizing Antibodies Demonstrate High Potency and Breadth |
| title_full | Combinations of Single Chain Variable Fragments From HIV Broadly Neutralizing Antibodies Demonstrate High Potency and Breadth |
| title_fullStr | Combinations of Single Chain Variable Fragments From HIV Broadly Neutralizing Antibodies Demonstrate High Potency and Breadth |
| title_full_unstemmed | Combinations of Single Chain Variable Fragments From HIV Broadly Neutralizing Antibodies Demonstrate High Potency and Breadth |
| title_short | Combinations of Single Chain Variable Fragments From HIV Broadly Neutralizing Antibodies Demonstrate High Potency and Breadth |
| title_sort | combinations of single chain variable fragments from hiv broadly neutralizing antibodies demonstrate high potency and breadth |
| topic | HIV broadly neutralizing antibodies single chain variable fragments combinations of scFv HIV prevention |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.734110/full |
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