NDLI: KIR/HLA interactions negatively affect rituximab- but not GA101 (obinutuzumab)-induced antibody-dependent cellular cytotoxicity.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Terszowski, Grzegorz Klein, Christian Stern, Martin
Description	Author Affiliation: Terszowski G ( Department of Biomedicine, University Hospital Basel, CH-4031 Basel, Switzerland); Klein C ( Pharma Research and Early Development, Roche Glycart AG, CH-8952 Schlieren, Switzerland.); Stern M ( Department of Biomedicine, University Hospital Basel, CH-4031 Basel, Switzerland)
Abstract	Ab-dependent cellular cytotoxicity (ADCC) mediated by NK cells is regulated by inhibitory killer cell Ig-like receptors (KIRs), which interact with target cell HLA class I. We analyzed how KIR/HLA interactions influence ADCC induced by rituximab and by GA101, a novel type II CD20 Ab glycoengineered for increased FcgRIII binding and ADCC capacity. We found that KIR/HLA interactions strongly and selectively inhibit rituximab-induced in vitro ADCC toward target cells expressing cognate HLA KIR ligands. NK cells of donors carrying all three ligands to inhibitory KIR showed weak activation and target cell depletion capacity when incubated with rituximab and KIR-ligand matched target B cells. In contrast, NK cells from individuals missing one or more KIR ligands activated more strongly and depleted KIR ligand-matched target B cells more efficiently in the presence of rituximab. NK cells expressing a KIR for which the ligand was absent were the main effectors of ADCC in these donors. Notably, the influence of KIR/HLA interactions on NK cell activation was synergistic with the effect of the V158F FCGR3A single nucleotide polymorphism. In contrast, GA101 induced activation of NK cells irrespective of inhibitory KIR expression, and efficiency of target cell depletion was not negatively affected by KIR/HLA interactions. These data show that modification of the Fc fragment to enhance ADCC can be an effective strategy to augment the efficacy of therapeutic mAbs by recruiting NK cells irrespective of their inhibitory KIR expression.
ISSN	00221767
e-ISSN	15506606
Journal	The Journal of Immunology
Issue Number	12
Volume Number	192
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2014-06-15
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Antibodies, Monoclonal, Humanized Pharmacology Antibodies, Monoclonal, Murine-derived Antibody-dependent Cell Cytotoxicity Drug Effects Antineoplastic Agents Hla Antigens Immunology Receptors, Kir Amino Acid Substitution Genetics Killer Cells, Natural Pathology Lymphocyte Activation Mutation, Missense Receptors, Igg Rituximab Clinical Trial Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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