Malignant mesothelioma (MM) is an aggressive cancer arising from the mesothelial cells lining the pleura. MM is usually associated with history of chronic asbestos exposure (1). Because of the long latency period between asbestos exposure and tumor development, the annual incidence of 2500 new cases in US is expected to increase by more than 50% in the coming decade (2). Moreover incidence world wide is projected to rise substantially in the next decades (3). The prognosis is very poor with a mediam survival of 4-12 months despite the therapies currently used, including surgery, radiotherapy and chemotherapy (4). Because of the inefficacy of the conventional treatments, development of novel therapeutic strategies is urgently needed.
CD26 is 110 kDa surface glycoprotein with dipeptidyl peptidase IV (DPPIV) activity, able to cleave selected biological factors to alter their functions (5). CD26/DPPIV is involved in T-lymphocyte costimulation and signal transduction processes (6, 7), and regulates topoisomerase II alpha levels in hematologic malignancies, affecting sensitivity to doxorubicin and etoposide (8). Expressed in various tissues (4, 9), CD26 is involved in the development of certain human cancers (9-12). CD26 is also known to serve as a binding motif for ECM in human and rodents (13, 14). Previously, we reported that CD26 is a collagen binding protein utilizing a CD26-positive JMN cell line derived from malignant mesothelioma (15). Moreover, our previous works have shown that anti-CD26 monoclonal antibody (mAb) inhibits growth of CD26-positive T-cell malignancies (16, 17) and renal cell carcinoma (18).
CD26 structure consists of three regions—an extracellular region, a 22 residue hydrophobic transmembrane domain, and a 6 amino acid cytoplasmic region, with its extracellular region containing a membrane-proximal glycosylated domain, a cysteine-rich domain, and a 260 amino acid C-terminal domain containing DPP IV enzyme activity. Our previous report shows that the murine anti-CD26 mAb 14D10, which recognizes the cell membrane-proximal glycosylated region starting with the 20 amino acid flexible stalk region of human CD26, has a direct anti-tumor effect by inducing G VS arrest while concomitantly blocking the adhesion of cancer cells to the ECM. However, another murine anti-CD26 mAb termed 5F8, which detects the cysteine-rich domain of CD26, lacks this biological activity (18).
Since human malignant mesothelioma (MM) is a highly malignant tumor resistant to apparent conventional treatment, the detection of novel target and development of new treatment strategies for MM is urgently needed (4,19).
USPTO Backgrounds
USPTO Backgrounds