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

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 PA28?? 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 ? 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.

SUBMITTER: Sanchez-Martin D

PROVIDER: S-EPMC3752212 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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

Sánchez-Martín David D Martínez-Torrecuadrada Jorge J Teesalu Tambet T Sugahara Kazuki N KN Alvarez-Cienfuegos Ana A Ximénez-Embún Pilar P Fernández-Periáñez Rodrigo R Martín M Teresa MT Molina-Privado Irene I Ruppen-Cañás Isabel I Blanco-Toribio Ana A Cañamero Marta M Cuesta Angel M AM Compte Marta M Kremer Leonor L Bellas Carmen C Alonso-Camino Vanesa V Guijarro-Muñoz Irene I Sanz Laura L Ruoslahti Erkki E Alvarez-Vallina Luis L

Proceedings of the National Academy of Sciences of the United States of America 20130805 34

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 biopannin ...[more]

PMID: 23918357

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Project description:There are two immune responses in vertebrates: humoral immunity is mediated by circulating antibodies, whereas cytotoxic T lymphocytes (CTL) confer cellular immunity. CTL lyse infected cells upon recognition of cell-surface MHC Class I molecules complexed with foreign peptides. The displayed peptides are produced in the cytosol by degradation of host proteins or proteins from intracellular pathogens that might be present. Proteasomes are cylindrical multisubunit proteases that generate many of the peptides eventually transferred to the cell surface for immune surveillance. In mammalian proteasomes, six active sites face a central chamber. As this chamber is sealed off from the enzyme's surface, there must be mechanisms to promote entry of substrates. Two protein complexes have been found to bind the ends of the proteasome and activate it. One of the activators is the 19 S regulatory complex of the 26 S proteasome; the other activator is '11 S REG' [Dubiel, Pratt, Ferrell and Rechsteiner (1992) J. Biol. Chem. 267, 22369-22377] or 'PA28' [Ma, Slaughter and DeMartino (1992) J. Biol. Chem. 267, 10515-10523]. During the past 7 years, our understanding of the structure of REG molecules has increased significantly, but much less is known about their biological functions. There are three REG subunits, namely alpha, beta and gamma. Recombinant REGalpha forms a ring-shaped heptamer of known crystal structure. 11 S REG is a heteroheptamer of alpha and beta subunits. REGgamma is also presumably a heptameric ring, and it is found in the nuclei of the nematode work Caenorhabditis elegans and higher organisms, where it may couple proteasomes to other nuclear components. REGalpha and REGbeta, which are abundant in vertebrate immune tissues, are located mostly in the cytoplasm. Synthesis of REG alpha and beta subunits is induced by interferon-gamma, and this has led to the prevalent hypothesis that REG alpha/beta hetero-oligomers play an important role in Class I antigen presentation. In the present review we focus on the structural properties of REG molecules and on the evidence that REGalpha/beta functions in the Class I immune response.

Dataset Information

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

Publications

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

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