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

2023Journal article Open access
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dc.contributor.authorAndré, Ana
dc.contributor.authorDias, Joana N. R.
dc.contributor.authorAguiar, Sandra I
dc.contributor.authorNogueira, Sara
dc.contributor.authorBule, Pedro
dc.contributor.authorCarvalho, Joana
dc.contributor.authorAntónio, João P. M.
dc.contributor.authorCavaco, Marco
dc.contributor.authorNeves, Vera
dc.contributor.authorOliveira, Soraia
dc.contributor.authorVicente, Gonçalo
dc.contributor.authorCarrapiço, Belmira
dc.contributor.authorBraz, Berta São
dc.contributor.authorRütgen, Barbara
dc.contributor.authorGano, Lurdes
dc.contributor.authorCorreia, João D. G.
dc.contributor.authorCastanho, Miguel A. R. B.
dc.contributor.authorGonçalves, João Rafael
dc.contributor.authorGois, Pedro M. P.
dc.contributor.authorGil, Solange
dc.contributor.authorTavares, Luis
dc.contributor.authorSilva, Frederico Aires da
dc.date.accessioned2023-03-28T13:59:41Z
dc.date.available2023-03-28T13:59:41Z
dc.date.issued2023
dc.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/.pt_PT
dc.description.abstractAntibody-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.pt_PT
dc.description.sponsorshipThis 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).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationSci Rep. 2023 Mar 24;13(1):4837pt_PT
dc.identifier.doi10.1038/s41598-023-31568-xpt_PT
dc.identifier.eissn2045-2322
dc.identifier.urihttp://hdl.handle.net/10451/56867
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringer Naturept_PT
dc.relationSAICT/2017/32085pt_PT
dc.relationSmartBox: Engineering the first generation of ROS responsive ADCs
dc.relationDevelopment of novel antibody-drug conjugated molecules for treatment of B-cell malignancies
dc.relationCLINICAL AND IMMUNOLOGICAL CHARACTERIZATION OF NATURALLY OCCURRING CANINE LYMPHOMA: DEVELOPMENT AND APPLICATION OF ENGINEERED RECOMBINANT ANTIBODIES FOR DIAGNOSIS AND TREATMENT
dc.relationCentre for Interdisciplinary Research in Animal Health
dc.relationResearch Institute for Medicines
dc.relationResearch Institute for Medicines
dc.relation.publisherversionhttps://www.nature.com/srep/pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.titleRabbit derived VL single-domains as promising scaffolds to generate antibody–drug conjugatespt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleSmartBox: Engineering the first generation of ROS responsive ADCs
oaire.awardTitleDevelopment of novel antibody-drug conjugated molecules for treatment of B-cell malignancies
oaire.awardTitleCLINICAL AND IMMUNOLOGICAL CHARACTERIZATION OF NATURALLY OCCURRING CANINE LYMPHOMA: DEVELOPMENT AND APPLICATION OF ENGINEERED RECOMBINANT ANTIBODIES FOR DIAGNOSIS AND TREATMENT
oaire.awardTitleCentre for Interdisciplinary Research in Animal Health
oaire.awardTitleResearch Institute for Medicines
oaire.awardTitleResearch Institute for Medicines
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FQUI-OUT%2F3989%2F2021/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBD%2F131468%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBD%2F90514%2F2012/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F00276%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04138%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04138%2F2020/PT
oaire.citation.issue1pt_PT
oaire.citation.titleScientific Reportspt_PT
oaire.citation.volume13pt_PT
oaire.fundingStream3599-PPCDT
oaire.fundingStreamOE
oaire.fundingStreamOE
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
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person.familyNameGois
person.familyNameGil Neves
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person.givenNameMiguel
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person.givenNamePedro
person.givenNameSolange
person.givenNameLuis Manuel
person.givenNameFrederico Nuno Castanheira
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rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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