title: Monoclonal antibodies directed to CD20 and HLA-DR can elicit homotypic adhesion followed by lysosome-mediated cell death in human lymphoma and leukemia cells.
abstract: mAbs are becoming increasingly utilized in the treatment of lymphoid disorders. Although Fc-FcgammaR interactions are thought to account for much of their therapeutic effect, this does not explain why certain mAb specificities are more potent than others. An additional effector mechanism underlying the action of some mAbs is the direct induction of cell death. Previously, we demonstrated that certain CD20-specific mAbs (which we termed type II mAbs) evoke a nonapoptotic mode of cell death that appears to be linked with the induction of homotypic adhesion. Here, we reveal that peripheral relocalization of actin is critical for the adhesion and cell death induced by both the type II CD20-specific mAb tositumomab and an HLA-DR-specific mAb in both human lymphoma cell lines and primary chronic lymphocytic leukemia cells. The cell death elicited was rapid, nonapoptotic, nonautophagic, and dependent on the integrity of plasma membrane cholesterol and activation of the V-type ATPase. This cytoplasmic cell death involved lysosomes, which swelled and then dispersed their contents, including cathepsin B, into the cytoplasm and surrounding environment. The resulting loss of plasma membrane integrity occurred independently of caspases and was not controlled by Bcl-2. These experiments provide what we believe to be new insights into the mechanisms by which 2 clinically relevant mAbs elicit cell death and show that this homotypic adhesion-related cell death occurs through a lysosome-dependent pathway.
authors.affiliation: CRUK Paterson Institute for Cancer Research, School of Cancer and Imaging Sciences, School of Medicine, University of Manchester, Manchester, United Kingdom.
authors.forename: Andrei
authors.initials: A
authors.lastname: Ivanov
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Beers
authors.forename: Claire A
authors.initials: CA
authors.lastname: Walshe
authors.forename: Jamie
authors.initials: J
authors.lastname: Honeychurch
authors.forename: Waleed
authors.initials: W
authors.lastname: Alduaij
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Cox
authors.forename: Kathleen N
authors.initials: KN
authors.lastname: Potter
authors.forename: Stephen
authors.initials: S
authors.lastname: Murray
authors.forename: Claude H T
authors.initials: CH
authors.lastname: Chan
authors.forename: Tetyana
authors.initials: T
authors.lastname: Klymenko
authors.forename: Jekaterina
authors.initials: J
authors.lastname: Erenpreisa
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Glennie
authors.forename: Tim M
authors.initials: TM
authors.lastname: Illidge
authors.forename: Mark S
authors.initials: MS
authors.lastname: Cragg
mesh_terms: D000199:Actins / Q000502:physiology; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D018951:Antigens, CD20 / Q000276:immunology / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication; D002460:Cell Line; D006684:HLA-DR Antigens / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D008247:Lysosomes / Q000187:drug effects / Q000502:physiology*; D021962:Membrane Microdomains / Q000502:physiology; D008871:Microvilli / Q000502:physiology
chemical_list: D000199:Actins; D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D006684:HLA-DR Antigens