Proteasome activator complex PA28 identified as an accessible target in prostate cancer by in vivo selection of human antibodies

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dc.contributor.authorSánchez-Martín, David
dc.contributor.authorMartínez-Torrecuadrada, Jorge
dc.contributor.authorTeesalu, Tambet
dc.contributor.authorSugahara, Kazuki N.
dc.contributor.authorAlvarez-Cienfuegos, Ana
dc.contributor.authorXiménez-Embún, Pilar
dc.contributor.authorFernández-Periáñez, Rodrigo
dc.contributor.authorMartín, M. Teresa
dc.contributor.authorMolina-Privado, Irene
dc.contributor.authorRuppen-Cañás, Isabel
dc.contributor.authorBlanco-Toribio, Ana
dc.contributor.authorCañamero, Marta
dc.contributor.authorCuesta Martínez, Ángel
dc.contributor.authorCompte, Marta
dc.contributor.authorKremer, Leonor
dc.contributor.authorBellas, Carmen
dc.contributor.authorAlonso-Camino, Vanesa
dc.contributor.authorGuijarro-Muñoz, Irene
dc.contributor.authorSanz,Laura
dc.contributor.authorRuoslahti, Erkki
dc.contributor.authorAlvarez-Vallina, Luis
dc.date.accessioned2024-01-18T13:28:35Z
dc.date.available2024-01-18T13:28:35Z
dc.date.issued2013-08-05
dc.description.abstractAntibody cancer therapies rely on systemically accessible targets and suitable antibodies that exert a functional activity or deliver a payload to the tumor site. Here, we present proof-of-principle of in vivo selection of human antibodies in tumor-bearing mice that identified a tumor-specific antibody able to deliver a payload and unveils the target antigen. By using an ex vivo enrichment process against freshly disaggregated tumors to purge the repertoire, in combination with in vivo biopanning at optimized phage circulation time, we have identified a human domain antibody capable of mediating selective localization of phage to human prostate cancer xenografts. Affinity chromatography followed by mass spectrometry analysis showed that the antibody recognizes the proteasome activator complex PA28. The specificity of soluble antibody was confirmed by demonstrating its binding to the active human PA28αβ complex. Whereas systemically administered control phage was confined in the lumen of blood vessels of both normal tissues and tumors, the selected phage spread from tumor vessels into the perivascular tumor parenchyma. In these areas, the selected phage partially colocalized with PA28 complex. Furthermore, we found that the expression of the α subunit of PA28 [proteasome activator complex subunit 1 (PSME1)] is elevated in primary and metastatic human prostate cancer and used anti-PSME1 antibodies to show that PSME1 is an accessible marker in mouse xenograft tumors. These results support the use of PA28 as a tumor marker and a potential target for therapeutic intervention in prostate cancer.
dc.description.departmentDepto. de Bioquímica y Biología Molecular
dc.description.facultyFac. de Farmacia
dc.description.refereedTRUE
dc.description.sponsorshipMinisterio de Economía y Competitividad
dc.description.sponsorshipComunidad de Madrid
dc.description.sponsorshipUS Department of Defense Prostate Cancer Program
dc.description.sponsorshipFundación de Investigación del H. U. Puerta de Hierro travel
dc.description.sponsorshipBoehringer Ingelheim Fonds travel
dc.description.sponsorshipInstituto de Salud Carlos III
dc.description.sponsorshipGobierno Vasco
dc.description.statuspub
dc.identifier.citationSánchez-Martín D, Martínez-Torrecuadrada J, Teesalu T, et al. Proteasome activator complex PA28 identified as an accessible target in prostate cancer by in vivo selection of human antibodies. Proc Natl Acad Sci U S A. 2013;110(34):13791-13796. doi:10.1073/pnas.1300013110
dc.identifier.doi10.1073/pnas.1300013110
dc.identifier.essn1091-6490
dc.identifier.issn0027-8424
dc.identifier.officialurlhttps://doi.org/10.1073/pnas.1300013110
dc.identifier.urihttps://hdl.handle.net/20.500.14352/93863
dc.issue.number34
dc.journal.titleProceedings of the National Academy of Sciences (PNAS)
dc.language.isoeng
dc.page.final13796
dc.page.initial13791
dc.publisherNational Academy of Sciences
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO/BIO2011-22738
dc.relation.projectIDinfo:eu-repo/grantAgreement/S2010/BMD-2312
dc.relation.projectIDinfo:eu-repo/grantAgreement/W81XWH-10-1-0199
dc.relation.projectIDinfo:eu-repo/grantAgreement/FPI-000531
dc.relation.projectIDinfo:eu-repo/grantAgreement/CA10/01231
dc.relation.projectIDinfo:eu-repo/grantAgreement/BFI07.132
dc.rights.accessRightsrestricted access
dc.subject.ucmCiencias Biomédicas
dc.subject.unesco24 Ciencias de la Vida
dc.titleProteasome activator complex PA28 identified as an accessible target in prostate cancer by in vivo selection of human antibodies
dc.typejournal article
dc.volume.number110
dspace.entity.typePublication
relation.isAuthorOfPublication963e050e-5a67-40d7-8e25-3dc7ff5a8619
relation.isAuthorOfPublication.latestForDiscovery963e050e-5a67-40d7-8e25-3dc7ff5a8619
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