Rabbit derived VL single-domains as promising scaffolds to generate antibody–drug conjugates
Autor(a) principal: | |
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Data de Publicação: | 2023 |
Outros Autores: | , , , , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10451/56867 |
Resumo: | © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
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Rabbit derived VL single-domains as promising scaffolds to generate antibody–drug conjugates© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Antibody-drug conjugates (ADCs) are among the fastest-growing classes of therapeutics in oncology. Although ADCs are in the spotlight, they still present significant engineering challenges. Therefore, there is an urgent need to develop more stable and effective ADCs. Most rabbit light chains have an extra disulfide bridge, that links the variable and constant domains, between Cys80 and Cys171, which is not found in the human or mouse. Thus, to develop a new generation of ADCs, we explored the potential of rabbit-derived VL-single-domain antibody scaffolds (sdAbs) to selectively conjugate a payload to Cys80. Hence, a rabbit sdAb library directed towards canine non-Hodgkin lymphoma (cNHL) was subjected to in vitro and in vivo phage display. This allowed the identification of several highly specific VL-sdAbs, including C5, which specifically target cNHL cells in vitro and present promising in vivo tumor uptake. C5 was selected for SN-38 site-selective payload conjugation through its exposed free Cys80 to generate a stable and homogenous C5-DAB-SN-38. C5-DAB-SN-38 exhibited potent cytotoxicity activity against cNHL cells while inhibiting DNA-TopoI activity. Overall, our strategy validates a platform to develop a novel class of ADCs that combines the benefits of rabbit VL-sdAb scaffolds and the canine lymphoma model as a powerful framework for clinically translation of novel therapeutics for cancer.This work was supported by the Portuguese Funding Agency, Fundação para a Ciência e Tecnologia, FCT IP (SAICT/2017/32085, PTDC/QUI-OUT/3989/2021 and Ph.D. fellowship SFRH/BD/131468/2017 to ASA and SFRH/BD/90514/2012 to JD). CIISA has provided support through Project UIDB/00276/2020, funded by FCT and LA/P/0059/2020-AL4AnimalS. Research Institute for Medicines (iMed.ULisboa) acknowledges the financial support of Fundação para a Ciência e Tecnologia (Projects: PTDC/QUI-OUT/3989/2021; UIDB/04138/2020 and UIDP/04138/2020). The NMR spectrometers are part of the National NMR Network (PTNMR) and are partially supported by Infrastructure Project Nº 022161 (co-financed by FEDER through COMPETE 2020, POCI and PORL and FCT through PIDDAC).Springer NatureRepositório da Universidade de LisboaAndré, AnaDias, Joana N. R.Aguiar, Sandra INogueira, SaraBule, PedroCarvalho, JoanaAntónio, João P. M.Cavaco, MarcoNeves, VeraOliveira, SoraiaVicente, GonçaloCarrapiço, BelmiraBraz, Berta SãoRütgen, BarbaraGano, LurdesCorreia, João D. G.Castanho, Miguel A. R. B.Gonçalves, João RafaelGois, Pedro M. P.Gil, SolangeTavares, LuisSilva, Frederico Aires da2023-03-28T13:59:41Z20232023-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/56867engSci Rep. 2023 Mar 24;13(1):483710.1038/s41598-023-31568-x2045-2322info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T17:04:50Zoai:repositorio.ul.pt:10451/56867Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:07:23.482591Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Rabbit derived VL single-domains as promising scaffolds to generate antibody–drug conjugates |
title |
Rabbit derived VL single-domains as promising scaffolds to generate antibody–drug conjugates |
spellingShingle |
Rabbit derived VL single-domains as promising scaffolds to generate antibody–drug conjugates André, Ana |
title_short |
Rabbit derived VL single-domains as promising scaffolds to generate antibody–drug conjugates |
title_full |
Rabbit derived VL single-domains as promising scaffolds to generate antibody–drug conjugates |
title_fullStr |
Rabbit derived VL single-domains as promising scaffolds to generate antibody–drug conjugates |
title_full_unstemmed |
Rabbit derived VL single-domains as promising scaffolds to generate antibody–drug conjugates |
title_sort |
Rabbit derived VL single-domains as promising scaffolds to generate antibody–drug conjugates |
author |
André, Ana |
author_facet |
André, Ana Dias, Joana N. R. Aguiar, Sandra I Nogueira, Sara Bule, Pedro Carvalho, Joana António, João P. M. Cavaco, Marco Neves, Vera Oliveira, Soraia Vicente, Gonçalo Carrapiço, Belmira Braz, Berta São Rütgen, Barbara Gano, Lurdes Correia, João D. G. Castanho, Miguel A. R. B. Gonçalves, João Rafael Gois, Pedro M. P. Gil, Solange Tavares, Luis Silva, Frederico Aires da |
author_role |
author |
author2 |
Dias, Joana N. R. Aguiar, Sandra I Nogueira, Sara Bule, Pedro Carvalho, Joana António, João P. M. Cavaco, Marco Neves, Vera Oliveira, Soraia Vicente, Gonçalo Carrapiço, Belmira Braz, Berta São Rütgen, Barbara Gano, Lurdes Correia, João D. G. Castanho, Miguel A. R. B. Gonçalves, João Rafael Gois, Pedro M. P. Gil, Solange Tavares, Luis Silva, Frederico Aires da |
author2_role |
author author author author author author author author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório da Universidade de Lisboa |
dc.contributor.author.fl_str_mv |
André, Ana Dias, Joana N. R. Aguiar, Sandra I Nogueira, Sara Bule, Pedro Carvalho, Joana António, João P. M. Cavaco, Marco Neves, Vera Oliveira, Soraia Vicente, Gonçalo Carrapiço, Belmira Braz, Berta São Rütgen, Barbara Gano, Lurdes Correia, João D. G. Castanho, Miguel A. R. B. Gonçalves, João Rafael Gois, Pedro M. P. Gil, Solange Tavares, Luis Silva, Frederico Aires da |
description |
© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
publishDate |
2023 |
dc.date.none.fl_str_mv |
2023-03-28T13:59:41Z 2023 2023-01-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10451/56867 |
url |
http://hdl.handle.net/10451/56867 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Sci Rep. 2023 Mar 24;13(1):4837 10.1038/s41598-023-31568-x 2045-2322 |
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openAccess |
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Springer Nature |
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Springer Nature |
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