A humanized anti-CD26 monoclonal antibody inhibits cell growth of malignant mesothelioma via retarded G2/M cell cycle transition

Abstract

BackgroundMalignant Mesothelioma (MM) is a highly aggressive tumor with poor prognosis. Multimodal treatments and novel molecular targeted therapies against MM are in high demand in order treat this disease effectively. We have developed a humanized monoclonal antibody YS110 against CD26 expressed in 85 % of MM cases. CD26 is thought to be involved in tumor growth and invasion by interacting with collagen and fibronectin, or affecting signal transduction processes.MethodsWe evaluated the direct anti-tumor effect of YS110 against MM cell lines, NCI-H2452 and JMN, and investigated its effects on cell cycle and on the cell cycle regulator molecules. In addition, we investigated synergistic effects of YS110 and anti-tumor agent pemetrexed (PMX) against MM cell line both in vitro and in vivo.ResultsYS110 suppressed the proliferation of NCI-H2452 cells by approximately 20 % in 48 h. Based on cell cycle analysis, percentage of cells in G2/M phase increased 8.0 % on the average after YS110 treatment; in addition, cell cycle regulator p21 cip/waf1 was increased and cyclin B1 was decreased after YS110 treatment. Inhibitory phosphorylation of both cdc2 (Tyr15) and cdc25C (Ser216) were elevated. Furthermore, activating phosphorylation of p38 MAPK (Thr180/Tyr182) and ERK1/2 (Thr202/Tyr204) were augmented at 24 h after YS110 treatment. PMX rapidly induced CD26 expression on cell surface and the treatment with both YS110 and PMX inhibited in vivo tumor growth accompanied by a synergistic reduction in the MIB-1 index.ConclusionThis is a first report of a novel anti-proliferative mechanism of the humanized anti-CD26 monoclonal antibody YS110, which resulted in G2/M cell cycle delay through regulation of quantity and activity of various cell cycle regulating molecules.

Phase I study of YS110, a recombinant humanized monoclonal antibody to CD26, in Japanese patients with advanced malignant pleural mesothelioma

“…We will investigate the relationship between CD26 expression or other biomarkers and clinical outcome of YS110. YS110 has been found to induce MPM cell lysis via antibody-dependent cytotoxicity [12,15,23]. It has also been shown to induce cell cycle arrest in CD26 + malignant mesothelioma cells and to control the growth of MPM cells via up-regulation of the cyclin-dependent kinase inhibitors p21 or p27.…”

“…Extensive in vitro and in vivo studies have shown that YS110 possesses antitumor activity for malignant mesothelioma cell lines. [11,15] Single or repeated intravenous administration of YS110 has also been found to be safe in nonhuman primates. [16] The first phase I study of YS110 in humans was conducted in France and found that its administration at doses up to 6 mg/kg weekly was generally well tolerated and showed promising efficacy in 33 patients with advanced or refractory CD26expressing tumors including malignant mesothelioma, renal cell carcinoma, and urothelial carcinoma [16].…”

Current and Emerging Therapy for Malignant Pleural Mesothelioma: Focus on CD26/Dipeptidyl Peptidase IV as a Therapeutic Target

“…Cellular localization analysis revealed that YS110 caused an increase in transport via caveolin-dependent endocytosis and accumulation of CD26 to the nucleus of MPM resulting in suppression of POLR2 gene expression and subsequent growth suppression of MPM cells, while highlighting a secondary anti-tumor mechanism of anti-CD26 mABs [ 96 , 97 ]. Meanwhile, a recently published paper demonstrated that YS110 caused retarded G2/M cell cycle progression through inhibition of phosphorylation of cdc2 and cdc25C and activation of ERK1/2 [ 98 ]. Importantly, a synergistic effect between YS110 and the first line anti-MPM chemotherapeutic agent pemetrexed was observed, as the combination of YS110 and pemetrexed showed superior anti-tumor activity associated with combinatorial G1/S and G2/M cell cycle transition inhibition than either agent alone in a mouse xenograft model of MPM [ 98 ].…”

“…Meanwhile, a recently published paper demonstrated that YS110 caused retarded G2/M cell cycle progression through inhibition of phosphorylation of cdc2 and cdc25C and activation of ERK1/2 [ 98 ]. Importantly, a synergistic effect between YS110 and the first line anti-MPM chemotherapeutic agent pemetrexed was observed, as the combination of YS110 and pemetrexed showed superior anti-tumor activity associated with combinatorial G1/S and G2/M cell cycle transition inhibition than either agent alone in a mouse xenograft model of MPM [ 98 ].…”

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

“…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].…”