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

2023-03-24Journal article Open access
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dc.contributor.authorAndre, Ana S
dc.contributor.authorDias, Joana N. R.
dc.contributor.authorAguiar, Sandra I
dc.contributor.authorNogueira, Sara
dc.contributor.authorBule, Pedro
dc.contributor.authorCarvalho, Joana Ines
dc.contributor.authorAntónio, J.P.M.
dc.contributor.authorCarrapiço, Belmira
dc.contributor.authorFerreira São Braz, Berta
dc.contributor.authorSolange, Gil
dc.date.accessioned2024-06-29T22:47:39Z
dc.date.available2024-06-29T22:47:39Z
dc.date.issued2023-03-24
dc.descriptionResearch Areas: Science & Technologypt_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 cancerpt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationAndré AS, Dias JNR, Aguiar S, Nogueira S, Bule P, Carvalho JI, António JPM, Cavaco M, Neves V, Oliveira S, et al. 2023. Rabbit derived VL single-domains as promising scaffolds to generate antibody–drug conjugates. Scientific Reports, 13(1):4837. doi:10.1038/s41598-023-31568-xpt_PT
dc.identifier.doi10.1038/s41598-023-31568-xpt_PT
dc.identifier.issn2045-2322
dc.identifier.urihttp://hdl.handle.net/10400.5/31200
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherNATURE Portfoliopt_PT
dc.relationSAICT/2017/32085pt_PT
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/articles/s41598-023-31568-xpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectTherapeuticpt_PT
dc.subjectActivitypt_PT
dc.subjectNext-Generationpt_PT
dc.subjectStrategiespt_PT
dc.subjectSelectionpt_PT
dc.subjectPeptidept_PT
dc.titleRabbit derived VL single-domains as promising scaffolds to generate antibody–drug conjugatespt_PT
dc.typejournal article
dspace.entity.typePublication
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//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/Concurso de Projetos IC&DT em Todos os Domínios Científicos/PTDC%2FQUI-OUT%2F3989%2F2021/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.conferencePlaceNature Portfoliopt_PT
oaire.citation.titleScientifc Reportspt_PT
oaire.citation.volume13(1)pt_PT
oaire.fundingStreamOE
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStreamConcurso de Projetos IC&DT em Todos os Domínios Científicos
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
person.familyNameAguiar
person.familyNameBule
person.familyNameCarrapiço
person.familyNameFernandes Ferreira São Braz
person.givenNameSandra
person.givenNamePedro
person.givenNameBelmira
person.givenNameBerta Maria
person.identifierA-3500-2009
person.identifierD-2518-2010
person.identifier.ciencia-id8E10-C536-8517
person.identifier.ciencia-id171E-F0CF-89F7
person.identifier.ciencia-idB11B-C3C7-3ADF
person.identifier.orcid0000-0002-3041-383X
person.identifier.orcid0000-0003-2531-9926
person.identifier.orcid0000-0002-1936-5697
person.identifier.orcid0000-0003-2688-0459
person.identifier.scopus-author-id56008623000
project.funder.identifierhttp://doi.org/10.13039/501100001871
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project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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