Establishment of monoclonal anti-human CD26 antibodies suitable for immunostaining of formalin-fixed tissue

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Abstract

Background

A T cell costimulatory molecule with dipeptidyl peptidase IV (DPPIV) activity in its extracellular region, CD26 is a multifunctional molecule associated with various proteins such as adenosine deaminase, caveolin-1, CXCR4, collagen, and fibronectin, while playing an important role in the regulation of inflammatory responses and tumor biology. We have focused on CD26 as a novel therapeutic target for various tumors and immune disorders, and have developed a humanized anti-CD26 monoclonal antibody (mAb), YS110, which is currently being evaluated in a phase I clinical trial for patients with CD26-expressing tumors, including malignant mesothelioma. Since detection of tumor CD26 expression is required for determining potential eligibility for YS110 therapy, the development of anti-human CD26 mAb that can clearly and reliably detect the denatured CD26 molecule in the formalin-fixed paraffin-embedded tissues is critical.

Methods

To develop novel anti-CD26 mAbs capable of binding to the denatured CD26, we immunized mice with CD26 protein denatured in urea buffer. After the fusion of splenocytes and myeloma cells, the mAbs were screened for specific reactivity with human CD26 by flow cytometry, enzyme-linked immunosorbent assay, and immunohistochemistry. The binding competitiveness of novel anti-CD26 mAbs with the humanized anti-CD26 mAb YS110 was also examined.

Results

We have succeeded in developing novel anti-human CD26 mAbs suitable for immunohistochemical staining of CD26 in formalin-fixed tissue sections with reliable clarity and intensity. Importantly, some of these mAbs exhibit no cross-reactivity with the humanized anti-CD26 mAb.

Conclusions

These novel mAbs are potentially useful as companion diagnostic agents to analyze CD26 expression in the clinical setting while advancing future CD26-related research.

Virtual slides

The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5987140221097729

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Most cited references 28

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The structure and function of CD26 in the T-cell immune response.

Chikao Morimoto, Stuart F. Schlossman (1998)

CD26 is a widely distributed 110 kD cell-surface glycoprotein with known dipeptidyl-peptidase IV (DPP-IV) activity in its extracellular domain. This ecto-enzyme is capable of cleaving amino terminal dipeptides from polypeptides with either L-proline or L-alanine in the penultimate position. On human T cells, CD26 expression appears late in thymic differentiation and is preferentially restricted to the CD4+ helper/memory population, and CD26 can deliver a potent co-stimulatory T-cell activation signal. The cDNA sequence of CD26 predicts a type II membrane protein with only 6 amino acids in its cytoplasmic region, suggesting that, in addition to DPP-IV enzyme activity, other signal-inducing molecules may be associated with CD26. Considerable evidence exists that CD26 interacts, presumably in its extracellular domain, with both CD45, a protein tyrosine phosphatase, and adenosine deaminase (ADA), each of which is capable of functioning in a signal transduction pathway. In addition, CD26 is the receptor for ADA, and ADA on the cell surface is involved in an important immunoregulatory mechanism by which released ADA binds to the cell-surface ADA. This multifunctional molecule may be involved in cell migration and the HIV-1-associated loss of CD4+ cells through the process of programmed cell death. Thus, CD26 appears to play a key role in a number of aspects of lymphocyte function.

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Revisiting an old acquaintance: CD26 and its molecular mechanisms in T cell function.

Kei Ohnuma, Nam Dang, Chikao Morimoto (2008)

The role of CD26 in human T cell biology is puzzling. Despite being extensively characterized, it has been called 'a moonlighting protein' since it has multifunctional effects, but a definitive native ligand has not been identified. We summarize the current knowledge on the molecular mechanisms of CD26-mediated T cell costimulation and immune regulation. Work identifying a ligand for CD26 and elucidating the proximal signaling events associated with CD26-mediated T cell costimulation is also described. Finally, we discuss the involvement of CD26 in various pathophysiologic states as well as its suitability as a potential therapeutic target in selected immune diseases.

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The role of CD26/dipeptidyl peptidase IV in cancer.

Pamela A Havre, Masako Abe, Yasuyo Urasaki … (2008)

CD26/DPPIV is a multifunctional cell surface protein that is widely expressed in most cell types including T lymphocytes, on which it is a marker of activation. It is also present in serum and other body fluids in a truncated form (sCD26/DPPIV). It preferentially cleaves N-terminal dipeptides from polypeptides with proline or alanine in the penultimate position, and in doing so, regulates the activities of a number of cytokines and chemokines. Due in part to this ability to regulate the activity of biopeptides, it can act as a tumor suppressor or activator. It can associate with several proteins, among them fibroblast activating protein-alpha (FAP-alpha), plasminogen, adenosine deaminase (ADA), the tyrosine phosphatase CD45, and the chemokine receptor CXCR4. It can also bind to the extracellular matrix (ECM) and depending on the presence of other ligands, this process can either lead to increased or decreased invasive activity of the cells on which it is expressed. As a result of these characteristics, CD26/DPPIV plays an important role in tumor biology, and is useful as a marker for various cancers, with its levels either on the cell surface or in the serum being increased in some neoplasms and decreased in others. Our group has shown that CD26/DPPIV can be manipulated by such agents as CD26 cDNA-carrying plasmids, siRNA and monoclonal antibodies, resulting in both in vitro and in vivo inhibition of cell growth, enhanced sensitivity to selected chemotherapeutic agents, and enhanced survival of mouse xenograft models. These studies have demonstrated the utility of these tools as potential targeted therapies for specific cancers expressing CD26/DPPIV.

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Author and article information

Contributors

Ryo Hatano

Taketo Yamada

Shuji Matsuoka

Satoshi Iwata

Hiroto Yamazaki

Eriko Komiya

Toshihiro Okamoto

Nam H Dang

Kei Ohnuma

Chikao Morimoto

Journal

Journal ID (nlm-ta): Diagn Pathol

Journal ID (iso-abbrev): Diagn Pathol

Title: Diagnostic Pathology

Publisher: BioMed Central

ISSN (Electronic): 1746-1596

Publication date Collection: 2014

Publication date (Electronic): 6 February 2014

Volume: 9

Page: 30

Affiliations

[1 ]Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan

[2 ]Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan

[3 ]Department of Pathology & Oncology, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan

[4 ]Division of Hematology/Oncology, University of Florida, 1600 SW Archer Road- Box 100278, Room MSB M410A, Gainesville, FL 32610, USA

Article

Publisher ID: 1746-1596-9-30

DOI: 10.1186/1746-1596-9-30

PMC ID: 3944398

PubMed ID: 24502396

SO-VID: 8fc9d967-c86b-4277-b23c-e7175e54660e

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Establishment of monoclonal anti-human CD26 antibodies suitable for immunostaining of formalin-fixed tissue

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Abstract

Background

Methods

Results

Conclusions

Virtual slides

Related collections

Anti-Trafficking Review

Most cited references 28

The structure and function of CD26 in the T-cell immune response.

Revisiting an old acquaintance: CD26 and its molecular mechanisms in T cell function.

The role of CD26/dipeptidyl peptidase IV in cancer.

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