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In vivo pretargeting based on cysteine-selective antibody modification with IEDDA bioorthogonal handles for click chemistry

2020Journal article Restricted access
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dc.contributor.authorFerreira, Vera F. C.
dc.contributor.authorOliveira, Bruno
dc.contributor.authorD'Onofrio, Alice
dc.contributor.authorFarinha, Carlos
dc.contributor.authorGano, Lurdes
dc.contributor.authorPaulo, António
dc.contributor.authorBernardes, Gonçalo J. L.
dc.contributor.authorMendes, Filipa
dc.date.accessioned2021-04-01T15:59:01Z
dc.date.available2021-04-01T15:59:01Z
dc.date.issued2020
dc.descriptionCopyright © 2020 American Chemical Society.pt_PT
dc.description.abstractPretargeted imaging has emerged as an effective multistep strategy aiming to improve imaging contrast and reduce patient radiation exposure through decoupling of the radioactivity from the targeting vector. The inverse electron-demand Diels-Alder (IEDDA) reaction between a trans-cyclooctene (TCO)-conjugated antibody and a labeled tetrazine holds great promise for pretargeted imaging applications due to its bioorthogonality, rapid kinetics under mild conditions, and formation of stable products. Herein, we describe the use of functionalized carbonylacrylic reagents for site-specific incorporation of TCO onto a human epidermal growth factor receptor 2 (HER2) antibody (THIOMAB) containing an engineered unpaired cysteine residue, generating homogeneous conjugates. Precise labeling of THIOMAB-TCO with a fluorescent or radiolabeled tetrazine revealed the potential of the TCO-functionalized antibody for imaging the HER2 after pretargeting in a cellular context in a HER2 positive breast cancer cell line. Control studies with MDA-MD-231 cells, which do not express HER2, further confirmed the target specificity of the modified antibody. THIOMAB-TCO was also evaluated in vivo after pretargeting and subsequent administration of an 111In-labeled tetrazine. Biodistribution studies in breast cancer tumor-bearing mice showed a significant activity accumulation on HER2+ tumors, which was 2.6-fold higher than in HER2- tumors. Additionally, biodistribution studies with THIOMAB without the TCO handle also resulted in a decreased uptake of 111In-DOTA-Tz on HER2+ tumors. Altogether, these results clearly indicate the occurrence of the click reaction at the tumor site, i.e., pretargeting of SK-BR-3 HER2-expressing cells with THIOMAB-TCO and reaction through the TCO moiety present in the antibody. The combined advantages of site-selectivity and stability of TCO tagged-antibodies could allow application of biorthogonal chemistry strategies for pretargeting imaging with minimal side-reactions and background.pt_PT
dc.description.sponsorshipThis work is funded by Fundação para a Ciência eTecnologia−FCT (PTDC/BTM-TEC/29256/2017 (co-funded by Lisboa2020−EU FEDER to F.M.) and UID/Multi/04349/2019). V.F.C.F. also acknowledges FCT for the PhD fellowship (SFRH/BD/108623/2015) and the Federation of European Biochemical Societies for a Summer Fellowship. Funding is also acknowledged to the Royal Society (URF to G.J.L.B., URF/R/180019) and FCT Portugal (iFCTto G.J.L.B., IF/00624/2015 and FCT Stimulus to B.L.O., CEECIND/02335/2017). This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreements 807281,702428, and 852985pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationBioconjug Chem. 2021 Jan 20;32(1):121-132pt_PT
dc.identifier.doi10.1021/acs.bioconjchem.0c00551pt_PT
dc.identifier.eissn1520-4812
dc.identifier.issn1043-1802
dc.identifier.urihttp://hdl.handle.net/10451/47211
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherACS Publicationspt_PT
dc.relationURF/R/180019pt_PT
dc.relationIF/00624/2015pt_PT
dc.relationCentre for Nuclear Sciences and Technologies
dc.relationNew Molecular Imaging tools for Cystic Fibrosis
dc.relationNanoparticle-Based Therapeutic Applications and Detection of Carbon Monoxide Releasing Molecules
dc.relationBMX-targeted ligand-drug conjugates for prostate cancer therapy
dc.relationSite-selective protein-modification chemistries for antibody-drug conjugates (ADCs)
dc.relation.publisherversionhttps://pubs.acs.org/journal/bcchespt_PT
dc.titleIn vivo pretargeting based on cysteine-selective antibody modification with IEDDA bioorthogonal handles for click chemistrypt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleCentre for Nuclear Sciences and Technologies
oaire.awardTitleNew Molecular Imaging tools for Cystic Fibrosis
oaire.awardTitleNanoparticle-Based Therapeutic Applications and Detection of Carbon Monoxide Releasing Molecules
oaire.awardTitleBMX-targeted ligand-drug conjugates for prostate cancer therapy
oaire.awardTitleSite-selective protein-modification chemistries for antibody-drug conjugates (ADCs)
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/9471 - RIDTI/PTDC%2FBTM-TEC%2F29256%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FMulti%2F04349%2F2019/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBD%2F108623%2F2015/PT
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/807281/EU
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/702428/EU
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/852985/EU
oaire.citation.endPage132pt_PT
oaire.citation.issue1pt_PT
oaire.citation.startPage121pt_PT
oaire.citation.titleBioconjugate Chemistrypt_PT
oaire.citation.volume32pt_PT
oaire.fundingStream9471 - RIDTI
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStreamOE
oaire.fundingStreamH2020
oaire.fundingStreamH2020
oaire.fundingStreamH2020
person.familyNameOliveira
person.familyNameD'Onofrio
person.familyNameFarinha
person.familyNameBernardes
person.familyNameFernandes Mendes
person.givenNameBruno
person.givenNameAlice
person.givenNameCarlos
person.givenNameGonçalo
person.givenNameFilipa
person.identifier1114568
person.identifierB-2057-2010
person.identifier.ciencia-idA016-1DDF-E7CB
person.identifier.ciencia-id5F17-E751-DBE9
person.identifier.ciencia-id1711-EA6A-041A
person.identifier.orcid0000-0002-7687-4746
person.identifier.orcid0000-0001-6740-8607
person.identifier.orcid0000-0002-5467-1710
person.identifier.orcid0000-0001-6594-8917
person.identifier.orcid0000-0003-0646-1687
person.identifier.ridT-5374-2018
person.identifier.ridA-7110-2010
person.identifier.scopus-author-id24577505300
person.identifier.scopus-author-id6603173042
person.identifier.scopus-author-id14046757500
person.identifier.scopus-author-id36465350400
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.identifierhttp://doi.org/10.13039/501100008530
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.nameEuropean Commission
project.funder.nameEuropean Commission
project.funder.nameEuropean Commission
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
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