Nanobody-based EGFR-targeting immunotoxins for colorectal cancer treatment

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dc.contributor.authorNarbona Corral, Javier
dc.contributor.authorHernández Baraza, Luisa
dc.contributor.authorGarcía Gordo, Rubén
dc.contributor.authorSanz, Laura
dc.contributor.authorLacadena García-Gallo, Francisco Javier
dc.date.accessioned2024-04-19T17:49:35Z
dc.date.available2024-04-19T17:49:35Z
dc.date.issued2023-06-26
dc.description2023 Descuento MDPI
dc.description.abstractImmunotoxins (ITXs) are chimeric molecules that combine the specificity of a targeting domain, usually derived from an antibody, and the cytotoxic potency of a toxin, leading to the selective death of tumor cells. However, several issues must be addressed and optimized in order to use ITXs as therapeutic tools, such as the selection of a suitable tumor-associated antigen (TAA), high tumor penetration and retention, low kidney elimination, or low immunogenicity of foreign proteins. To this end, we produced and characterized several ITX designs, using a nanobody against EGFR (VHH 7D12) as the targeting domain. First, we generated a nanoITX, combining VHH 7D12 and the fungal ribotoxin α-sarcin (αS) as the toxic moiety (VHHEGFRαS). Then, we incorporated a trimerization domain (TIEXVIII) into the construct, obtaining a trimeric nanoITX (TriVHHEGFRαS). Finally, we designed and characterized a bispecific ITX, combining the VHH 7D12 and the scFv against GPA33 as targeting domains, and a deimmunized (DI) variant of α-sarcin (BsITXαSDI). The results confirm the therapeutic potential of α-sarcin-based nanoITXs. The incorporation of nanobodies as target domains improves their therapeutic use due to their lower molecular size and binding features. The enhanced avidity and toxic load in the trimeric nanoITX and the combination of two different target domains in the bispecific nanoITX allow for increased antitumor effectiveness.
dc.description.departmentDepto. de Bioquímica y Biología Molecular
dc.description.facultyFac. de Ciencias Biológicas
dc.description.facultyFac. de Ciencias Químicas
dc.description.fundingtypeDescuento UCM
dc.description.refereedTRUE
dc.description.sponsorshipMinisterio de Ciencia e Innovación (España)
dc.description.sponsorshipComunidad de Madrid
dc.description.sponsorshipUniversidad Complutense de Madrid
dc.description.statuspub
dc.identifier.doi10.3390/biom13071042
dc.identifier.issn2218-273X
dc.identifier.officialurlhttps://doi.org/10.3390/biom13071042
dc.identifier.urihttps://hdl.handle.net/20.500.14352/103282
dc.issue.number7
dc.journal.titleBiomolecules
dc.language.isoeng
dc.page.final17
dc.page.initial1
dc.publisherMDPI
dc.relation.projectIDPID2020-116692RB-I00
dc.relation.projectIDFPU15/04121
dc.relation.projectIDREACT-EU
dc.relation.projectIDPR75/18-21563 , PR87/19-22627
dc.rightsAttribution 4.0 Internationalen
dc.rights.accessRightsopen access
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subject.cdu577.2
dc.subject.cdu616.34-006
dc.subject.cdu615.37
dc.subject.keywordImmunotoxin
dc.subject.keywordNanobody
dc.subject.keywordAntibody engineering
dc.subject.keywordColorectal cancer
dc.subject.keywordAntitumor efficacy
dc.subject.keywordα-sarcin
dc.subject.ucmBiología molecular (Química)
dc.subject.ucmOncología
dc.subject.unesco2302.21 Biología Molecular
dc.subject.unesco3207.13 Oncología
dc.titleNanobody-based EGFR-targeting immunotoxins for colorectal cancer treatment
dc.typejournal article
dc.type.hasVersionVoR
dc.volume.number13
dspace.entity.typePublication
relation.isAuthorOfPublication0d19def2-ee22-456a-a318-74c23d7903c2
relation.isAuthorOfPublication7cd9dda0-1601-4e4b-a15b-49bb5f5621a2
relation.isAuthorOfPublication.latestForDiscovery0d19def2-ee22-456a-a318-74c23d7903c2
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