[Frontiers In Bioscience, Landmark, 23, 1754-1779, June 1, 2018]

A novel role for CD26/dipeptidyl peptidase IV as a therapeutic target

Kei Ohnuma1, Ryo Hatano1, Eriko Komiya1, Haruna Otsuka1, Takumi Itoh1, Noriaki Iwao2, Yutaro Kaneko3, Taketo Yamada4,5, Nam H. Dang6, Chikao Morimoto1

1Department 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, 2Department of Hematology, Juntendo University Shizuoka Hospital, Nagaoka 1129, Izunokuni-city, Shizuoka 410-2295, Japan, 3Y’s AC Co., Ltd., 5-3-14, Toranomon, Minato-ku, Tokyo 105-0001, Japan, 4Department of Pathology, Keio University school of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan, 5Department of Pathology, Saitama Medical University, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama 350-0459, Japan, 6Division of Hematology/Oncology, University of Florida, 1600 SW Archer Road-Box 100278, Room MSB M410A, Gainesville, FL 32610, U.S.A.


1. Abstract
2. Introduction
3. Immune mediated disorders
3.1. Chronic graft-versus-host disease
3.2. Middle East respiratory syndrome coronavirus
3.3. Psoriatic pruritus
4. Cancers
4.1. Novel mechanism of CD26/DPPIV in cancer immunology
4.2. Malignant pleural mesothelioma
4.3. Other cancers
5. Summary and perspectives
6. Acknowledgement
7. References


CD26 is a 110 kDa surface glycoprotein with intrinsic dipeptidyl peptidase IV activity that is expressed on numerous cell types and has a multitude of biological functions. The role of CD26 in immune regulation has been extensively characterized, with recent findings elucidating its linkage with signaling pathways and structures involved in T-lymphocyte activation as well as antigen presenting cell-T-cell interaction. In this paper, we will review emerging data on CD26-mediated immune regulation suggesting that CD26 may be an appropriate therapeutic target for the treatment of selected immune disorders as well as Middle East respiratory syndrome coronavirus. Moreover, we have had a long-standing interest in the role of CD26 in cancer biology and its suitability as a novel therapeutic target in selected neoplasms. We reported robust in vivo data on the anti-tumor activity of anti-CD26 monoclonal antibody in mouse xenograft models. We herein review significant novel findings and the early clinical development of a CD26-targeted therapy in selected immune disorders and cancers, advances that can lead to a more hopeful future for patients with these intractable diseases.


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Abbreviation: AA, amino acid; ADA, adenosine deaminase; ADCC, antibody-dependent cellular cytotoxicity; aGVHD, acute graft-versus-host disease; alloHSCT, allogeneic hematopoietic stem cell transplantation; AP-1, activator protein-1; APCs, antigen presenting cells; A20-luc, luciferase-transfected A20 cell; B6 WT, parental C57BL/6 mice; Cav-Ig, soluble Fc fusion proteins containing the N-terminal domain of caveolin-1; CB, cord blood; CD26KO, CD26 knockout; cGVHD, chronic graft-versus-host disease; CRC, colorectal cancer; CTL, cytotoxic T lymphocyte; CTLA-4, cytotoxic T-lymphocyte–associated antigen 4; ΔCNS-77 Tg mice, mice carrying human IFNG transgene with deleting IL26 transcription; DPPIV, dipeptidyl peptidase IV; ECM, extracellular matrix; EGR2, early growth response 2; ELISA, enzyme-linked immunosorbent assay; EMT, epithelial to mesenchymal transition; ERK, extracellular signal-regulated kinase; FIH, first-in-human; GIST, gastrointestinal stromal tumors; GVHD, graft-versus-host disease; GVL, graft-versus-leukemia; HuCB, human umbilical cord blood; IBD, inflammatory bowel diseases; i.d., intradermal injection; IFN, interferon; IL, interleukin; IMQ, imiquimod; JKT-hCD26WT, Jurkat cells transfected with full-length human CD26/DPPIV; LAG3, lymphocyte activation gene-3; LBL/ALL, lymphoblastic lymphoma/acute lymphoblastic leukemia: mAb, monoclonal antibody; MAPK, mitogen-activated protein kinase; MERS-CoV, Middle East respiratory syndrome coronavirus; MERS-CoV S1-Fc, S1 domain of MERS-CoV fused to the Fc region of human IgG; MPM, malignant pleural mesothelioma; NFAT, nuclear factor of activated T cells; NOG, NOD/Shi-scidIL2rγnull; OB, obliterative bronchiolitis; PBL, peripheral blood lymphocyte; PD-1, programmed cell death 1; PSO, psoriasis; RA, rheumatoid arthritis; RBD, receptor binding domain; RCC, renal cell carcinoma; RECIST, response evaluation criteria in solid tumors; sCD26, soluble CD26; sDPPIV, soluble dipeptidyl peptidase IV; siRNA, small interfering RNA; SP, substance P; SSTR4, somatostatin receptor 4; Tg, transgenic; T-LGL, T-large granular lymphocyte; TME, tumor microenvironment; TNF, tumor necrosis factor; Tr1, Type 1 regulatory T cells; WHO, World Health Organization; 190-IFNG Tg mice, mice carrying human IFNG and IL26 transgene

Key Words CD26, DPPIV, Caveolin-1, Humanized anti-CD26 monoclonal antibody, Graft-versus-host disease, Malignant pleural mesothelioma, Review

Send correspondence to: Kei Ohnuma, 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, Tel: 81-3-3868-2310, Fax: 81-3-3868-2310, E-mail: kohnuma@juntendo.ac.jp