title: Alemtuzumab induction of intracellular signaling and apoptosis in malignant B lymphocytes.
abstract: The molecular changes induced by alemtuzumab following binding of CD52 on B tumor cells were investigated. Alemtuzumab alone had no detectable impact on cell signaling but cross-linking of alemtuzumab on the surface of B tumor lines with anti-human Fc antibodies induced a transient Ca(2+) flux followed by phosphorylation of several kinases involved in stress and survival pathways, and expression of associated proteins including TNF-α. Cross-linking of alemtuzumab also induced capping and caspase-dependent apoptosis of the tumor lines. When using primary cells from B-CLL patients, alemtuzumab alone was capable of inducing protein phosphorylation and apoptosis through the cross-linking of alemtuzumab by FcγRIIb receptors on B-CLL cells. Apoptosis was prevented by blocking of FcγRIIb receptors with anti-CD32 antibody. Overall, our results indicate that cross-linking of alemtuzumab on B tumor cells can occur naturally through Fc receptor interaction and leads to the activation of specific cellular pathways and induction of apoptosis.
authors.affiliation: Genzyme Corporation, Framingham, MA 01701-9322, USA. trihung.nguyen@genzyme.com
authors.forename: Tri-Hung
authors.initials: TH
authors.lastname: Nguyen
authors.forename: Evis
authors.initials: E
authors.lastname: Havari
authors.forename: Rajashree
authors.initials: R
authors.lastname: McLaren
authors.forename: Mindy
authors.initials: M
authors.lastname: Zhang
authors.forename: Yide
authors.initials: Y
authors.lastname: Jiang
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Madden
authors.forename: Bruce
authors.initials: B
authors.lastname: Roberts
authors.forename: Johanne
authors.initials: J
authors.lastname: Kaplan
authors.forename: Srinivas
authors.initials: S
authors.lastname: Shankara
mesh_terms: D000074323:Alemtuzumab; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D017452:Receptors, IgG / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000906:Antibodies; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha; D000074323:Alemtuzumab; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium