title: Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas.
abstract: Despite the rapid and widespread integration of chimeric CD20 monoclonal antibody (mAb), rituximab, into the management of non-Hodgkin lymphoma, its efficacy remains variable and often modest when used as a single agent. To develop more potent reagents, human immunoglobulin transgenic mice were used to generate a panel of immunoglobulin G1kappa (IgG1kappa) CD20 mAbs. All reagents bound strongly to CD20(+) cells and recruited mononuclear cells for the lysis of malignant B cells. However, 2 mAbs, 2F2 and 7D8, were exceptionally active in complement-dependent cytotoxicity (CDC), being able to lyse a range of rituximab-resistant targets, such as CD20-low chronic lymphocytic leukemia (CLL), in the presence of human plasma or unfractionated blood. Further analysis showed that 2F2 and 7D8, like rituximab, redistributed CD20 into Triton X-100-insoluble regions of the plasma membrane, but that they had markedly slower off-rates. To determine whether off-rate influenced CDC, a non-complement activating F(ab')(2) antihuman kappa reagent was used. This reagent markedly slowed the off-rate of rituximab and increased its CDC activity to that of 2F2 and 7D8. Thus, with increasing evidence that mAb therapeutic activity in vivo depends on complement activation, these new CD20 reagents with their slow off-rates and increased potency in CDC hold considerable promise for improved clinical activity.
authors.affiliation: Genmab, Yalelaan 60, 3584 CM Utrecht, The Netherlands.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Teeling
authors.forename: Ruth R
authors.initials: RR
authors.lastname: French
authors.forename: Mark S
authors.initials: MS
authors.lastname: Cragg
authors.forename: Jeroen
authors.initials: J
authors.lastname: van den Brakel
authors.forename: Marielle
authors.initials: M
authors.lastname: Pluyter
authors.forename: Haichun
authors.initials: H
authors.lastname: Huang
authors.forename: Claude
authors.initials: C
authors.lastname: Chan
authors.forename: Paul W H I
authors.initials: PW
authors.lastname: Parren
authors.forename: C Erik
authors.initials: CE
authors.lastname: Hack
authors.forename: Michael
authors.initials: M
authors.lastname: Dechant
authors.forename: Thomas
authors.initials: T
authors.lastname: Valerius
authors.forename: Jan G J
authors.initials: JG
authors.lastname: van de Winkel
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Glennie
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D018951:Antigens, CD20 / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D001666:Binding Sites, Antibody / Q000276:immunology; D045744:Cell Line, Tumor; D003168:Complement Fixation Tests; D003165:Complement System Proteins / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007700:Kinetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D003165:Complement System Proteins