Affordable Access

deepdyve-link
Publisher Website

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

Authors
  • D, Sánchez-Martín
  • J, Martínez-Torrecuadrada
  • Tambet Teesalu
  • Kazuki Sugahara
  • A, Alvarez-Cienfuegos
  • P, Ximénez-Embún
  • R, Fernández-Periáñez
  • Mt, Martín
  • I, Molina-Privado
  • I, Ruppen-Cañás
  • A, Blanco-Toribio
  • M, Cañamero
  • Am, Cuesta
  • M, Compte
  • L, Kremer
  • C, Bellas
  • V, Alonso-Camino
  • I, Guijarro-Muñoz
  • L, Sanz
  • Erkki Ruoslahti
  • And 1 more
Type
Published Article
Journal
Proceedings of the National Academy of Sciences
Publisher
Proceedings of the National Academy of Sciences
Volume
110
Issue
34
Identifiers
DOI: 10.1073/pnas.1300013110
Source
Ruoslahti Lab
License
Unknown

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.

Report this publication

Statistics

Seen <100 times