Rabbit derived VL single-domains as promising scaffolds to generate antibody–drug conjugates

Detalhes bibliográficos
Autor(a) principal: André, Ana
Data de Publicação: 2023
Outros Autores: 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
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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spelling 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
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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
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dc.relation.none.fl_str_mv Sci Rep. 2023 Mar 24;13(1):4837
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