Proteasome activator complex PA28 identified as an accessible target in prostate cancer by in vivo selection of human antibodies
Year: 2013
Type: article
Abstract: 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.
Authors: David Sánchez-Martín, Jorge Martínez-Torrecuadrada, Tambet Teesalu, Kazuki N. Sugahara, Ana Alvarez-Cienfuegos, Pilar Ximénez-Embún, Rodrigo Fernández-Periáñez, M. Teresa Martín, Irene Molina-Privado, Isabel Ruppen-Cañás, Ana Blanco-Toribio, Marta Cañamero, Ángel M. Cuesta, Marta Compte, Leonor Kremer, Carmen Bellas, Vanesa Alonso-Camino, Irene Guijarro-Muñoz, Laura Sanz, Erkki Ruoslahti, Luis Alvarez-Vallina
Institutions: Hospital Universitario Puerta de Hierro Majadahonda, Spanish National Cancer Research Centre, University of California, Santa Barbara, Sanford Burnham Prebys Medical Discovery Institute, University of Tartu, Consejo Superior de Investigaciones Científicas, Centro Nacional de Biotecnología
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: G1955573659, G4119534169, G515665421
OpenAlex ID: W2168017406