RT Journal Article
T1 Proteasome activator complex PA28 identified as an accessible target in prostate cancer by in vivo selection of human antibodies
A1 Sánchez-Martín, David
A1 Martínez-Torrecuadrada, Jorge
A1 Teesalu, Tambet
A1 Sugahara, Kazuki N.
A1 Alvarez-Cienfuegos, Ana
A1 Ximénez-Embún, Pilar
A1 Fernández-Periáñez, Rodrigo
A1 Martín, M. Teresa
A1 Molina-Privado, Irene
A1 Ruppen-Cañás, Isabel
A1 Blanco-Toribio, Ana
A1 Cañamero, Marta
A1 Cuesta Martínez, Ángel
A1 Compte, Marta
A1 Kremer, Leonor
A1 Bellas, Carmen
A1 Alonso-Camino, Vanesa
A1 Guijarro-Muñoz, Irene
A1 Sanz, Laura
A1 Ruoslahti, Erkki
A1 Alvarez-Vallina, Luis
AB Antibody 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.
PB National Academy of Sciences
SN 0027-8424
YR 2013
FD 2013-08-05
LK https://hdl.handle.net/20.500.14352/93863
UL https://hdl.handle.net/20.500.14352/93863
LA eng
NO Sánchez-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
NO Ministerio de Economía y Competitividad
NO Comunidad de Madrid
NO US Department of Defense Prostate Cancer Program
NO Fundación de Investigación del H. U. Puerta de Hierro travel
NO Boehringer Ingelheim Fonds travel
NO Instituto de Salud Carlos III
NO Gobierno Vasco
DS Docta Complutense
RD 11 abr 2025