Selective Cytotoxicity of A6 Peptide Against ZAP-70 Expressing CLL B-Cells

摘要

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western world. It is characterized by the clonal expansion of CD5+/CD23+ B cells in blood, bone marrow, and secondary lymphoid tissues. Survival of CLL cells is enabled by cells of the tissue microenvironment and by signals from the extracellular matrix, which are mediated in part through interactions with CD44, a surface glycoprotein highly expressed on CLL B cells and putative cancer stem cells. CD44 is a hyaluronic acid (HA) receptor and interacts with other surface and cytosolic proteins expressed by CLL cells, including CD38, CD49d, MMP9, and, most recently, the zeta-associated protein of 70 kDa (ZAP-70). Complexes comprised of CD44, CD38, MMP-9, CD49d, and ZAP70 results in enhanced B cell signaling and growth or survival of CLL cells and may partially account for why expressions of ZAP-70 and/or CD38 are associated with more a aggressive disease. We discovered that a monoclonal antibody (mAb) specific for CD44 is directly cytotoxic for leukemia B cells, but has little effect on normal B cells. This mAb can induce ZAP-70 positive CLL cells to undergo caspase-dependent apoptosis independent of complement or cytotoxic effector cells (Proc Natl Acad Sci, USA 2013, PMID: 23530247). The cytotoxic effect of the mAb was neither mitigated when the CLL cells were co-cultured with mesenchymal stromal cells (MSCs) nor with hyaluronic acid. It was also not reduced when stimulated via ligation of the B-cell receptor with anti-mu, suggesting that targeting CD44 may provide an effective approach for anti-cancer therapy.