High throughput development of TCR-mimic antibody that targets survivin-2B80-88/HLA-A*A24 and its application in a bispecific T-cell engager

High throughput development of TCR-mimic antibody that targets survivin-2B80-88/HLA-A*A24 and its application in a bispecific T-cell engager

Abstract Intracellular tumor-associated antigens are targeted by antibodies known as T-cell receptor mimic antibodies (TCRm-Abs), which recognize T-cell epitopes with better stabilities and higher affinities than T-cell receptors. However, TCRm-Abs have been proven difficult to produce using convent...

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Autores principales: Nobuyuki Kurosawa, Yuka Wakata, Kenta Ida, Aki Midorikawa, Masaharu Isobe
Formato: article
Lenguaje:EN
Publicado: Nature Portfolio 2019
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Acceso en línea:https://doaj.org/article/c7b6f569eba748bc82727b189112c54a
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spelling oai:doaj.org-article:c7b6f569eba748bc82727b189112c54a2021-12-02T15:08:20ZHigh throughput development of TCR-mimic antibody that targets survivin-2B80-88/HLA-A*A24 and its application in a bispecific T-cell engager10.1038/s41598-019-46198-52045-2322https://doaj.org/article/c7b6f569eba748bc82727b189112c54a2019-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-46198-5https://doaj.org/toc/2045-2322Abstract Intracellular tumor-associated antigens are targeted by antibodies known as T-cell receptor mimic antibodies (TCRm-Abs), which recognize T-cell epitopes with better stabilities and higher affinities than T-cell receptors. However, TCRm-Abs have been proven difficult to produce using conventional techniques. Here, we developed TCRm-Abs that recognize the survivin-2B-derived nonamer peptide, AYACNTSTL (SV2B80-88), presented on HLA-A*24 (SV2B80-88/HLA-A*24) from immunized mice by using a fluorescence-activated cell sorting-based antigen-specific plasma cells isolation method combined with a high-throughput single-cell-based immunoglobulin-gene-cloning technology. This approach yielded a remarkable efficiency in generating candidate antibody clones that recognize SV2B80-88/HLA-A*24. The screening of the antibody clones for their affinity and ability to bind key amino-acid residues within the target peptide revealed that one clone, #21-3, specifically recognized SV2B80-88/HLA-A*24 on T2 cells. The specificity of #21-3 was further established through survivin-2B-positive tumor cell lines that exogenously or endogenously express HLA-A*24. A bispecific T-cell engager comprised of #21-3 and anti-CD3 showed specific cytotoxicity towards cells bearing SV2B80-88/HLA-A*24 by recruiting and activating T-cells in vitro. The efficient development of TCRm-Ab overcomes the limitations that hamper antibody-based immunotherapeutic approaches and enables the targeting of intracellular tumor-associated antigens.Nobuyuki KurosawaYuka WakataKenta IdaAki MidorikawaMasaharu IsobeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-11 (2019)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Nobuyuki Kurosawa
Yuka Wakata
Kenta Ida
Aki Midorikawa
Masaharu Isobe
High throughput development of TCR-mimic antibody that targets survivin-2B80-88/HLA-A*A24 and its application in a bispecific T-cell engager
description Abstract Intracellular tumor-associated antigens are targeted by antibodies known as T-cell receptor mimic antibodies (TCRm-Abs), which recognize T-cell epitopes with better stabilities and higher affinities than T-cell receptors. However, TCRm-Abs have been proven difficult to produce using conventional techniques. Here, we developed TCRm-Abs that recognize the survivin-2B-derived nonamer peptide, AYACNTSTL (SV2B80-88), presented on HLA-A*24 (SV2B80-88/HLA-A*24) from immunized mice by using a fluorescence-activated cell sorting-based antigen-specific plasma cells isolation method combined with a high-throughput single-cell-based immunoglobulin-gene-cloning technology. This approach yielded a remarkable efficiency in generating candidate antibody clones that recognize SV2B80-88/HLA-A*24. The screening of the antibody clones for their affinity and ability to bind key amino-acid residues within the target peptide revealed that one clone, #21-3, specifically recognized SV2B80-88/HLA-A*24 on T2 cells. The specificity of #21-3 was further established through survivin-2B-positive tumor cell lines that exogenously or endogenously express HLA-A*24. A bispecific T-cell engager comprised of #21-3 and anti-CD3 showed specific cytotoxicity towards cells bearing SV2B80-88/HLA-A*24 by recruiting and activating T-cells in vitro. The efficient development of TCRm-Ab overcomes the limitations that hamper antibody-based immunotherapeutic approaches and enables the targeting of intracellular tumor-associated antigens.
format article
author Nobuyuki Kurosawa
Yuka Wakata
Kenta Ida
Aki Midorikawa
Masaharu Isobe
author_facet Nobuyuki Kurosawa
Yuka Wakata
Kenta Ida
Aki Midorikawa
Masaharu Isobe
author_sort Nobuyuki Kurosawa
title High throughput development of TCR-mimic antibody that targets survivin-2B80-88/HLA-A*A24 and its application in a bispecific T-cell engager
title_short High throughput development of TCR-mimic antibody that targets survivin-2B80-88/HLA-A*A24 and its application in a bispecific T-cell engager
title_full High throughput development of TCR-mimic antibody that targets survivin-2B80-88/HLA-A*A24 and its application in a bispecific T-cell engager
title_fullStr High throughput development of TCR-mimic antibody that targets survivin-2B80-88/HLA-A*A24 and its application in a bispecific T-cell engager
title_full_unstemmed High throughput development of TCR-mimic antibody that targets survivin-2B80-88/HLA-A*A24 and its application in a bispecific T-cell engager
title_sort high throughput development of tcr-mimic antibody that targets survivin-2b80-88/hla-a*a24 and its application in a bispecific t-cell engager
publisher Nature Portfolio
publishDate 2019
url https://doaj.org/article/c7b6f569eba748bc82727b189112c54a
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