Y certain for CDSuping Zhanga,1, Christina C. N. Wua,1, JessieF. Fecteaua, Bing Cuia, Liguang Chena, Ling Zhanga, Rongrong Wua, Laura Rassentia, Fitzgerald Laoa, Stefan Weigandb, and Thomas J. Kippsa,a Department of Medicine, University of California at San Diego Moores Cancer Center, La Jolla, CA 92093; and bDepartment of Discovery Oncology, Pharma Analysis, and Early Development, Roche Diagnostics GmbH, 82377 Penzberg, GermanyEdited by Dennis A. Carson, University of California at San Diego, La Jolla, CA, and approved March 4, 2013 (received for overview December 20, 2012)Chronic lymphocytic leukemia (CLL) cells express high levels of CD44, a cellsurface glycoprotein receptor for hyaluronic acid. We found that a humanized mAb precise for CD44 (RG7356) was directly cytotoxic for leukemia B cells, but had small impact on typical B cells. In addition, RG7356 could induce CLL cells that expressed the zetaassociated protein of 70 kDa (ZAP70) to undergo caspasedependent apoptosis, independent of complement or cytotoxic effector cells. The cytotoxic impact of this mAb was not mitigated when the CLL cells have been cocultured with mesenchymal stromal cells (MSCs) or hyaluronic acid or after they had been stimulated by way of ligation in the Bcell receptor with anti. RG7356 induced speedy internalization of CD44 on CLL cells at 37 , resulting in decreased expression of ZAP70, which we discovered was complexed with CD44. Administration of this mAb at a concentration of 1 mg/kg to immunedeficient mice engrafted with human CLL cells resulted in total clearance of engrafted leukemia cells. These studies indicate that this mAb may possibly have therapeutic activity, particularly in sufferers with CLL that express ZAP70.cell survivalmight occur in vivo, in which case CD44 could be a good target for therapy. In this study, we evaluated the expression degree of surface CD44 on CLL cells and examined the activity of a humanized antiCD44 monoclonal antibody (mAb; RG7356; Roche) (15) on leukemia cells in vitro and in vivo. ResultsExpression of CD44 on CLL Cells. CLL cells from 59 individuals and| preclinical studies | animal model | antibody therapycell chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of mature, antigenstimulated CD5/ CD23 B cells in blood, secondary lymphoid tissues, and marrow (1).Price of 6-Formylnicotinonitrile Many of the circulating CLL cells in patients are arrested inside the G0/G1 phase in the cell cycle and express high levels of antiapoptotic proteins (2).3-Hydroxy-1-methylazetidine web CLL for that reason has been characterized as a approach of defective apoptosis, in lieu of increased proliferation.PMID:23577779 Nonetheless, regardless of their apparent longevity in vivo, CLL cells undergo spontaneous and druginduced apoptosis in vitro, unless rescued by monocytederived Nurselike cells (NLCs), follicular dendritic cells, or mesenchymal stromal cells (MSCs) (three). Therefore, it has been postulated that CLL cells acquire survival signals from these accessory cells, which constitute portion in the CLL Bcell microenvironment in secondary lymphoid tissues and marrow (six). These survival signals can inhibit spontaneous or druginduced apoptosis, especially for CLL cells that express unmutated Ig heavychain variable genes (IGHVs) and/or the zetaassociated protein of 70 kDa (ZAP70), which ordinarily is not expressed by typical B cells (7). Individuals with leukemia cells that possess such qualities usually possess a reasonably quick interval from diagnosis to initial therapy compared with sufferers with CLL cells that express mutated IGHVs or th.