Humanized Anti-CD26 Monoclonal Antibody as a Treatment for Malignant Mesothelioma Tumors

Abstract

Purpose: CD26 is a 110-kDa cell surface antigen with a role in tumor development. In this report, we show that CD26 is highly expressed on the cell surface of malignant mesothelioma and that a newly developed humanized anti-CD26 monoclonal antibody (mAb) has an inhibitory effect on malignant mesothelioma cells in both in vitro and in vivo experiments. Experimental Design: Using immunohistochemistry, 12 patients' surgical specimens consisting of seven malignant mesothelioma, three reactive mesothelial cells, and two adenomatoid tumors were evaluated for expression of CD26. The effects of CD26 on malignant mesothelioma cells were assessed in the presence of transfection of CD26-expressing plasmid, humanized anti-CD26 mAb, or small interfering RNA against CD26. The in vivo growth inhibitory effect of humanized anti-CD26 mAb was assessed in human malignant mesothelioma cell mouse xenograft models. Results: In surgical specimens, CD26 is highly expressed in malignant mesothelioma but not in benign mesothelial tissues. Depletion of CD26 by small interfering RNA results in the loss of adhesive property, suggesting that CD26 is a binding protein to the extracellular matrix. Moreover, our in vitro data indicate that humanized anti-CD26 mAb induces cell lysis of malignant mesothelioma cells via antibody-dependent cell-mediated cytotoxicity in addition to its direct anti-tumor effect via p27 kip1 accumulation. In vivo experiments with mouse xenograft models involving human malignant mesothelioma cells show that humanized anti-CD26 mAb treatment drastically inhibits tumor growth in tumor-bearing mice, resulting in enhanced survival. Conclusions: Our data strongly suggest that humanized anti-CD26 mAb treatment may have potential clinical use as a novel cancer therapeutic agent in CD26-positive malignant mesothelioma.

Overexpression of CD26/DPPIV in mesothelioma tissue and mesothelioma cell lines

“…The possibility of humanized anti-CD26 monoclonal antibody treatment for its inhibitory effect has been reported on malignant mesothelioma cell lines in vitro and in vivo experiments (12). This is the new promising strategy in antibody-based treatment of mesothelioma (12,13).…”

“…(12), one of the a promising new developments for the antibody-based treatment of mesothelioma (12,13). CD26 is a widely distributed 110-kDa transmembrane glycoprotein with known dipeptidyl peptidase IV activity in its extracellular domain (14,15).…”

Cytoplasmic mislocalization of the orphan nuclear receptor Nurr1 is a prognostic factor in bladder cancer

“…18 For migration assay, a modified Boyden Chamber method was used. 19 In brief, 2.5 Â 10 4 cells in 500 lL were seeded into the transwell insert chamber with a filter, and the inserts were placed in the lower chambers filled with 750 lL of RPMI-1640 containing 5% fetal calf serum. Chambers were incubated at 37 C under 5% CO 2 atm for 24 hours.…”

Possible new therapeutic agents for malignant pleural mesothelioma: anti-CD26 monoclonal antibody and naftopidil

“…In vivo experimental xenograft models involving human MPM cells demonstrated that humanized anti-CD26 monoclonal antibody (YS110) treatment drastically inhibited tumor growth in tumor-bearing mice and reduced the formation of metastases, resulting in enhanced survival [13]. The active antimesothelioma agent PEM rapidly induces CD26 expression on the cell surface and inhibits in vivo tumor growth synergistically with YS110 [14].…”

“…The mechanisms of YS110 antitumor action for CD26-positive mesotheliomas are the following: (a) cell lysis of MPM cells via antibody-dependent cell-mediated cytotoxicity in addition to its direct antitumor effect via cyclin-dependent kinase (CDK) inhibitor p27 kip1 upregulation and disruption of binding to ECM [13]; (b) G1/S cell cycle arrest and G2/M cell cycle delay by upregulating CDK inhibitor p27 kip1 and p21 cip/ waf1 via multiple signaling pathways [13][14][15]; and (c) induction of nuclear translocation of cell-surface CD26 molecules by internalization of the CD26-YS110 complexes to inhibit proliferation of MPM cells via suppression of POLR2A gene expression [16]. The reduction of distant metastases by YS110 treatment in experimental models may be explained by CD26's function as a binding protein to distinct ECM proteins [13].…”