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Highly specific blood-brain barrier transmigrating single-domain antibodies selected by an In Vivo phage display screening

2021-10-02Journal article Open access
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dc.contributor.authorAguiar, Sandra Isabel
dc.contributor.authorDias, Joana N. R.
dc.contributor.authorS. André, Ana
dc.contributor.authorSilva, Lisete M.
dc.contributor.authorMartins, Diana
dc.contributor.authorCarrapiço, Belmira
dc.contributor.authorCastanho, Miguel
dc.contributor.authorCarriço, João
dc.contributor.authorCavaco, Marco
dc.contributor.authorAires da Silva, Frederico
dc.contributor.author[et al.]
dc.date.accessioned2022-01-07T15:06:35Z
dc.date.available2022-01-07T15:06:35Z
dc.date.issued2021-10-02
dc.descriptionResearch Areas: Pharmacology & Pharmacypt_PT
dc.description.abstractA major bottleneck in the successful development of central nervous system (CNS) drugs is the discovery and design of molecules that can cross the blood-brain barrier (BBB). Nano-delivery strategies are a promising approach that take advantage of natural portals of entry into the brain such as monoclonal antibodies (mAbs) targeting endogenous BBB receptors. However, the main selected mAbs rely on targeting broadly expressed receptors, such as the transferrin and insulin receptors, and in selection processes that do not fully mimic the native receptor conformation, leading to mistargeting and a low fraction of the administered dose effectively reaching the brain. Thus, there is an urgent need to identify new BBB receptors and explore novel antibody selection approaches that can allow a more selective delivery into the brain. Considering that in vitro models fail to completely mimic brain structure complexity, we explored an in vivo cell immunization approach to construct a rabbit derived single-domain antibody (sdAb) library towards BBB endothelial cell receptors. The sdAb antibody library was used in an in vivo phage display screening as a functional selection of novel BBB targeting antibodies. Following three rounds of selections, next generation sequencing analysis, in vitro brain endothelial barrier (BEB) model screenings and in vivo biodistribution studies, five potential sdAbs were identified, three of which reaching >0.6% ID/g in the brain. To validate the brain drug delivery proof-of-concept, the most promising sdAb, namely RG3, was conjugated at the surface of liposomes encapsulated with a model drug, the pan-histone deacetylase inhibitor panobinostat (PAN). The translocation efficiency and activity of the conjugate liposome was determined in a dual functional in vitro BEB-glioblastoma model. The RG3 conjugated PAN liposomes enabled an efficient BEB translocation and presented a potent antitumoral activity against LN229 glioblastoma cells without influencing BEB integrity. In conclusion, our in vivo screening approach allowed the selection of highly specific nano-antibody scaffolds with promising properties for brain targeting and drug delivery.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationAguiar SI, Dias JNR, André AS, Silva ML, Martins D, Carrapiço B, Castanho M, Carriço J, Cavaco M, Gaspar MM [et al.]. Highly specific blood-brain barrier transmigrating single-domain antibodies selected by an In Vivo phage display screening. 2021. Pharmaceutics 13(10):1598. Doi: 10.3390/ pharmaceutics13101598pt_PT
dc.identifier.doi10.3390/pharmaceutics13101598pt_PT
dc.identifier.eissn1999-4923
dc.identifier.urihttp://hdl.handle.net/10400.5/22940
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherMDPIpt_PT
dc.relationFCT IP: IF/01010/2013pt_PT
dc.relationDevelopment of immunoliposomal therapy for treatment of Pneumococcal meningitis
dc.relationTrans-BBB peptides for targeting brain metastasis
dc.relationNot Available
dc.relationResearch Institute for Medicines
dc.relationResearch Institute for Medicines
dc.relationTargeting the transporters of cationic amino acids for cancer radiotheranostics: experimental and computational chemistry approach
dc.relationCentre for Interdisciplinary Research in Animal Health
dc.relationCNC. IBILI
dc.relationCenter for Innovative Biomedicine and Biotechnology
dc.relation.publisherversionhttps://www.mdpi.com/1999-4923/13/10/1598pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectBrain targeting antibodiespt_PT
dc.subjectBlood-brain barrierpt_PT
dc.subjectIn vivo phage displaypt_PT
dc.subjectSingle-domain antibodiespt_PT
dc.subjectDrug deliverypt_PT
dc.titleHighly specific blood-brain barrier transmigrating single-domain antibodies selected by an In Vivo phage display screeningpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleDevelopment of immunoliposomal therapy for treatment of Pneumococcal meningitis
oaire.awardTitleTrans-BBB peptides for targeting brain metastasis
oaire.awardTitleNot Available
oaire.awardTitleResearch Institute for Medicines
oaire.awardTitleResearch Institute for Medicines
oaire.awardTitleTargeting the transporters of cationic amino acids for cancer radiotheranostics: experimental and computational chemistry approach
oaire.awardTitleCentre for Interdisciplinary Research in Animal Health
oaire.awardTitleCNC. IBILI
oaire.awardTitleCenter for Innovative Biomedicine and Biotechnology
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBBB-BIO%2F0508%2F2014/PT
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oaire.citation.conferencePlaceBasel, Switzerlandpt_PT
oaire.citation.titlePharmaceuticspt_PT
oaire.citation.volume13(10):1598pt_PT
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person.familyNameDias
person.familyNameSantos André
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person.familyNameCarrapiço
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person.givenNameJoana
person.givenNameAna Filipa
person.givenNameLisete M.
person.givenNameBelmira
person.givenNameFrederico
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