title: Targeting chronic lymphocytic leukemia cells with a humanized monoclonal antibody specific for CD44.
abstract: Chronic lymphocytic leukemia (CLL) cells express high levels of CD44, a cell-surface glycoprotein receptor for hyaluronic acid. We found that a humanized mAb specific for CD44 (RG7356) was directly cytotoxic for leukemia B cells, but had little effect on normal B cells. Moreover, RG7356 could induce CLL cells that expressed the zeta-associated protein of 70 kDa (ZAP-70) to undergo caspase-dependent apoptosis, independent of complement or cytotoxic effector cells. The cytotoxic effect of this mAb was not mitigated when the CLL cells were cocultured with mesenchymal stromal cells (MSCs) or hyaluronic acid or when they were stimulated via ligation of the B-cell receptor with anti-µ. RG7356 induced rapid internalization of CD44 on CLL cells at 37 °C, resulting in reduced expression of ZAP-70, which we found was complexed with CD44. Administration of this mAb at a concentration of 1 mg/kg to immune-deficient mice engrafted with human CLL cells resulted in complete clearance of engrafted leukemia cells. These studies indicate that this mAb might have therapeutic activity, particularly in patients with CLL that express ZAP-70.
authors.affiliation: Department of Medicine, University of California at San Diego Moores Cancer Center, La Jolla, CA 92093, USA.
authors.forename: Suping
authors.initials: S
authors.lastname: Zhang
authors.forename: Christina C N
authors.initials: CC
authors.lastname: Wu
authors.forename: Jessie-F
authors.initials: JF
authors.lastname: Fecteau
authors.forename: Bing
authors.initials: B
authors.lastname: Cui
authors.forename: Liguang
authors.initials: L
authors.lastname: Chen
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Rongrong
authors.initials: R
authors.lastname: Wu
authors.forename: Laura
authors.initials: L
authors.lastname: Rassenti
authors.forename: Fitzgerald
authors.initials: F
authors.lastname: Lao
authors.forename: Stefan
authors.initials: S
authors.lastname: Weigand
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology*; D017209:Apoptosis; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D007963:Leukocytes, Mononuclear / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D010587:Phagocytosis; D013696:Temperature; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018960:Hyaluronan Receptors; C576196:RG7356; D051746:ZAP-70 Protein-Tyrosine Kinase