title: Antigenic modulation limits the effector cell mechanisms employed by type I anti-CD20 monoclonal antibodies.
abstract: Following the success of rituximab, 2 other anti-CD20 monoclonal antibodies (mAbs), ofatumumab and obinutuzumab, have entered clinical use. Ofatumumab has enhanced capacity for complement-dependent cytotoxicity, whereas obinutuzumab, a type II mAb, lacks the ability to redistribute into lipid rafts and is glycoengineered for augmented antibody-dependent cellular cytotoxicity (ADCC). We previously showed that type I mAbs such as rituximab have a propensity to undergo enhanced antigenic modulation compared with type II. Here we assessed the key effector mechanisms affected, comparing type I and II antibodies of various isotypes in ADCC and antibody-dependent cellular-phagocytosis (ADCP) assays. Rituximab and ofatumumab depleted both normal and leukemic human CD20-expressing B cells in the mouse less effectively than glycoengineered and wild-type forms of obinutuzumab, particularly when human immunoglobulin G1 (hIgG1) mAbs were compared. In contrast to mouse IgG2a, hIgG1 mAbs were ineffective in ADCC assays with murine natural killer cells as effectors, whereas ADCP was equivalent for mouse IgG2a and hIgG1. However, rituximab's ability to elicit both ADCC and ADCP was reduced by antigenic modulation, whereas type II antibodies remained unaffected. These data demonstrate that ADCP and ADCC are impaired by antigenic modulation and that ADCP is the main effector function employed in vivo.
authors: Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, and.
authors: Thomas R W
authors: TR
authors: Tipton
authors: Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, and.
authors: Ali
authors: A
authors: Roghanian
authors: Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, and.
authors: Robert J
authors: RJ
authors: Oldham
authors: Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, and.
authors: Matthew J
authors: MJ
authors: Carter
authors: Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, and.
authors: Kerry L
authors: KL
authors: Cox
authors: Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, and.
authors: C Ian
authors: CI
authors: Mockridge
authors: Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, and.
authors: Ruth R
authors: RR
authors: French
authors: Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, and.
authors: Lekh N
authors: LN
authors: Dahal
authors: Southampton Experimental Cancer Medicine Centre/Cancer Research UK, Protein Core Facility, General Hospital, Southampton, United Kingdom; and.
authors: Patrick J
authors: PJ
authors: Duriez
authors: Promega UK Ltd., Southampton Science Park, Southampton, United Kingdom.
authors: Philip G
authors: PG
authors: Hargreaves
authors: Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, and.
authors: Mark S
authors: MS
authors: Cragg
authors: Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, and.
authors: Stephen A
authors: SA
authors: Beers
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived / Q000737:chemistry; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D016525:Antigenic Modulation; D000941:Antigens / Q000737:chemistry*; D018951:Antigens, CD20 / Q000737:chemistry*; D001402:B-Lymphocytes / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D007694:Killer Cells, Natural / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010587:Phagocytosis; D017452:Receptors, IgG / Q000378:metabolism; D000069283:Rituximab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000941:Antigens; D018951:Antigens, CD20; D007074:Immunoglobulin G; D017452:Receptors, IgG; D000069283:Rituximab; C527517:ofatumumab