IPH2101, a novel anti-inhibitory KIR antibody, and lenalidomide combine to enhance the natural killer cell versus multiple myeloma effect
Open Access
- 8 December 2011
- journal article
- Published by American Society of Hematology in Blood
- Vol. 118 (24), 6387-6391
- https://doi.org/10.1182/blood-2011-06-360255
Abstract
Multiple myeloma (MM) patients who receive killer cell Ig–like receptor (KIR) ligand–mismatched, T cell–depleted, allogeneic transplantation may have a reduced risk of relapse compared with patients who receive KIR ligand–matched grafts, suggesting the importance of this signaling axis in the natural killer (NK) cell-versus-MM effect. Expanding on this concept, IPH2101 (1-7F9), an anti-inhibitory KIR mAb, enhances NK-cell function against autologous MM cells by blocking the engagement of inhibitory KIR with cognate ligands, promoting immune complex formation and NK-cell cytotoxicity specifically against MM cell targets but not normal cells. IPH2101 prevents negative regulatory signals by inhibitory KIR, whereas lenalidomide augments NK-cell function and also appears to up-regulate ligands for activating NK-cell receptors on MM cells. Lenalidomide and a murine anti-inhibitory NK-cell receptor Ab mediate in vivo rejection of a lenalidomide-resistant tumor. These mechanistic, preclinical data support the use of a combination of IPH2101 and lenalidomide in a phase 2 trial for MM.Keywords
This publication has 24 references indexed in Scilit:
- The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti–PD-1 antibodyBlood, 2010
- In vivo tumor cell rejection induced by NK cell inhibitory receptor blockade: Maintained tolerance to normal cells even in the presence of IL‐2European Journal of Immunology, 2010
- Dexamethasone Synergizes with Lenalidomide to Inhibit Multiple Myeloma Tumor Growth, But Reduces Lenalidomide-Induced Immunomodulation of T and NK Cell FunctionCurrent Cancer Drug Targets, 2010
- Infusion of haplo‐identical killer immunoglobulin‐like receptor ligand mismatched NK cells for relapsed myeloma in the setting of autologous stem cell transplantationBritish Journal of Haematology, 2008
- Human natural killer cellsBlood, 2008
- Roles for HLA and KIR polymorphisms in natural killer cell repertoire selection and modulation of effector functionThe Journal of Experimental Medicine, 2006
- MHC class I molecules and kirs in human history, health and survivalNature Reviews Immunology, 2005
- Molecular mechanisms whereby immunomodulatory drugs activate natural killer cells: clinical applicationBritish Journal of Haematology, 2004
- Evaluating the cytotoxicity of innate immune effector cells using the GrB ELISPOT assayJournal of Translational Medicine, 2004
- Anti‐myeloma activity of natural killer lymphocytesBritish Journal of Haematology, 2002