title: A mechanistic rationale for combining alemtuzumab and rituximab in the treatment of ALL.
abstract: B-lineage acute lymphoblastic leukemia (ALL) may express CD52 and CD20. Alemtuzumab (ALM) and rituximab (RTX) are therapeutic antibodies directed against CD52 and CD20, respectively, but showed limited activity against ALL in clinical trials. The mechanisms for the impaired responses remained unclear. We studied expression of CD52 and CD20 on ALL cells and found that most cases coexpressed CD52 and CD20. However, distinct CD52-negative (CD52(-)) subpopulations were detected in most cases as the result of defective glycophosphatidyl-inositol anchoring. Although ALM efficiently eradicated CD52-positive (CD52(+)) cells in NOD/scid mice engrafted with primary human ALL, CD52(-) subclones escaped therapy. In the same model, RTX showed limited activity resulting from occurrence of CD20 down-modulation. However, CD52(-) cells concurrently lacked the glycophosphatidyl-inositol-anchored complement regulators CD55 and CD59 and showed increased susceptibility to RTX-mediated complement-dependent cytotoxicity in vitro. At the same time, ALM was shown to inhibit down-modulation of CD20 in response to RTX by depleting the trogocytic capacity of phagocytic cells. Probably because of these complementary mechanisms, combined administration of ALM and RTX induced complete responses in vivo. Based on these data, we propose a mechanistic rationale for combined application of RTX and ALM in ALL.
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands. nijmeijerbart@gmail.com
authors.forename: Bart A
authors.initials: BA
authors.lastname: Nijmeijer
authors.forename: Marianke L J
authors.initials: ML
authors.lastname: van Schie
authors.forename: Constantijn J M
authors.initials: CJ
authors.lastname: Halkes
authors.forename: Marieke
authors.initials: M
authors.lastname: Griffioen
authors.forename: Roelof
authors.initials: R
authors.lastname: Willemze
authors.forename: J H Frederik
authors.initials: JH
authors.lastname: Falkenburg
mesh_terms: D000074323:Alemtuzumab; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D000912:Antibodies, Neoplasm / Q000008:administration & dosage; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D018951:Antigens, CD20 / Q000276:immunology / Q000378:metabolism*; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015153:Blotting, Western; D000074301:CD52 Antigen; D018957:CD59 Antigens / Q000276:immunology / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005434:Flow Cytometry; D006023:Glycoproteins / Q000276:immunology / Q000378:metabolism; D017261:Glycosylphosphatidylinositols / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000069283:Rituximab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000912:Antibodies, Neoplasm; D015703:Antigens, CD; D018951:Antigens, CD20; D000951:Antigens, Neoplasm; D000074301:CD52 Antigen; C000613862:CD52 protein, human; D018957:CD59 Antigens; D015815:Cell Adhesion Molecules; D006023:Glycoproteins; D017261:Glycosylphosphatidylinositols; C483616:ICAM3 protein, human; D012333:RNA, Messenger; D000074323:Alemtuzumab; D000069283:Rituximab