Key Points• Blockade of inhibitory KIRs with MHC class I antigens on lymphoma cells by anti-KIR antibodies augments NK-cell spontaneous cytotoxicity.• In combination with anti-CD20 mAbs, anti-KIR induces enhanced NK cell-mediated, rituximab-dependent cytotoxicity against lymphoma.
Natural killer (NK) cells mediate anti-lymphoma activity by spontaneous cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) when triggered by rituximab, an anti-CD20 monoclonal antibody (mAb) used to treat patients with B cell lymphomas. The balance of inhibitory and activating signals determines the magnitude of NK cell's efficacy by spontaneous cytoxicity. Using a killer cell immunoglobulin-like receptor (KIR) transgenic murine model, we show that blockade of the interface of inhibitory KIRs with MHC class I antigens on lymphoma by anti-KIR antibodies prevents a tolerogenic interaction and augments NK cell spontaneous cytotoxicity. In combination with anti-CD20 mAbs, anti-KIR treatment induces enhanced NK cell-mediated, rituximab-dependent cytotoxicity against lymphoma in vitro and in vivo in syngeneic and KIR transgenic murine lymphoma models. Specifically targeting murine NK cells in vitro, anti-Ly49C/I F(ab')2 increased anti-CD20 mAb-mediated NK cell degranulation as measured by CD107a mobilization and interferon-γ release, as well as increased cytotoxicity as assessed by chromium release. In the syngeneic EL4-huCD20 lymphoma model, anti-Ly49C/I F(ab')2 enhanced the anti-lymphoma activity of anti-CD20 mAb in vivo (Fig 1A-1B) and was NK cell-dependent with efficacy abrogated by NK cell depletion with anti-Asialo-GM1. To validate these observations and the potential efficacy of a fully human anti-KIR mAb (IPH2101, lirilumab), we demonstrated, in vitro, dose-dependent KIR2DL3 saturation and tumor lysis following blockade of KIR2DL3/HLA-C with lirilumab. In the transgenic KIR murine model, lirilumab therapy improved survival in an NK cell-dependent manner in both a prophylactic and therapeutic HLA+ (221 HLA-Cw3) lymphoma model. In combination, lirilumab therapy synergistically enhanced rituximab's anti-lymphoma efficacy in vivo in an NK cell-dependent manner (Fig 2A-C). These results support a therapeutic strategy of combination, rituximab and KIR blockade through lirilumab, illustrating the potential efficacy of combining a tumor targeting therapy with an NK cell agonist thus stimulating the post-rituximab anti-lymphoma immune response. Disclosures: Thielens: Innate Pharma: Employment, Equity Ownership. Sola:Innate Pharma: Employment, Equity Ownership. Chanuc:Innate Pharma: Employment, Equity Ownership. Fuseri:Innate Pharma: Employment. Bonnafous:Innate Pharma: Employment, Equity Ownership. Vivier:Innate Pharma: Membership on an entity’s Board of Directors or advisory committees. Romagne:Innate Pharma: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Andre:Innate-Pharma: Employment, Equity Ownership. Blery:Innate Pharma: Employment, Equity Ownership.
MICA and MICB, along with ULPBs, are ligands for the activating receptor NKG2D expressed on NK cells and subsets of T cells in Human. NKG2D ligands are induced by cellular stress and pathogen infections. Their expression is tightly regulated by complex mechanisms both at the mRNA and protein levels. In the case of MICA and MICB, more than 65 and 30 alleles respectively were described with different properties regarding to their cellular location adding to the complexity of this recognition system. Nevertheless, as markers of cellular stress, in particular in tumorigenesis, MICA and the closely related MICB proteins are candidates of choice to be targeted by a cytotoxic therapeutic antibody. We first evaluated MICA/B expression by immunohistochemistry on healthy tissues and tumors to validate these antigens as therapeutic targets. Then, using mouse immunization, we generated a panel of chimeric human IgG1 monoclonal antibodies targeting MICA and MICB. These mAbs have the ability to bind to several structurally different alleles and to cross-react on MIC proteins from cynomolgus macaques. Their capacity to block the MICA/NKG2D interaction was assessed by surface plasmon resonance as well as by using cell-based assays. In vitro efficacy was measured by the capacity to mediate complement-dependent cytotoxicity (CDC) and antibody-dependent cell cytotoxicity (ADCC) towards MICA expressing cells. In vivo efficacy of the anti-MICA mAbs was measured in both a preventive and a curative setting using MICA expressing cell lines. Altogether, we have generated a panel of anti-MICA mAbs with diverse functional properties. Ongoing work aims to choose the best candidate for humanization and further clinical development. Citation Format: Mathieu Blery, Cécile Bonnafous, Valentine Peri, Sylvia Trichard, Ivan Perrot, Stéphanie Cornen, Ariane Thielens, Violette Breso, Yannis Morel, François Romagne, Benjamin Rossi, Carine Paturel, Laurent Gauthier. Targeting MICA with therapeutic antibodies for the treatment of cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5037. doi:10.1158/1538-7445.AM2014-5037
Natural Killer cells (NK cells) are lymphocytes able to recognize and kill tumors for which the expression of Major Histocompatibility Complex (MHC) class I molecules is altered. This “missing self” recognition is mediated in humans by the lack of engagement of MHC class I i.e. Human Leucocyte Antigens (HLA) molecules with NK cell inhibitory receptors that include Killer Immunoglobulin-like Receptors (KIR). Some tumors escape NK cell immune surveillance by increasing the expression of HLA molecules on their surface. Consequently, blocking interactions between KIR and HLA molecules constitutes an interesting therapeutic strategy. The anti-KIR2DL1/2/3-specific monoclonal antibody, BMS-986015/IPH2102, is a human IgG4 that is being developed for treating both hematologic malignancies and solid tumors. In rodents, the MHC class I inhibitory system regulating NK cell activation is based on lectin-like family Ly49 but the KIR molecules are not expressed. The objective of this study was to develop a preclinical model to assess the efficacy of the drug candidate used in clinical trials, BMS-986015/IPH2102. Mice expressing the human NK inhibitory KIR2DL3, on the surface of NK cells were generated on a RAG-1deficient background (KIRtgRAG mice). The human B cell lymphoma cell line, 721.221, transduced with HLA-Cw3 molecule, a ligand of KIR2DL3, was intra-venously engrafted in these mice. The expression of HLA-C by tumor cells was sufficient to allow them to escape control of NK cells, leading to mice death in around 30 days. IPH2102 treatment increased mice survival in a dose dependent manner when injected at the same time as the tumor challenge. This protective effect was NK cell mediated and directly correlated with the duration of KIR saturation. Interestingly, BMS-986015/IPH2102 treatment also improved survival in therapeutic conditions i.e. when the antibody was injected 5 days after the tumor, also in a NK cell dependent manner. In conclusion, this study showed efficacy of BMS-986015/IPH2102 as single agent in a HLA-Cw3-expressing tumor model and this xenogenic pre-clinical model will be an excellent tool to investigate the therapeutic benefits of combination treatments. Citation Format: Caroline Sola, Fabien Chanuc, Ariane Thielens, Nicolas Fuseri, Isabelle Palacios, Mathieu Blery, Pascale André, Eric Vivier, Sophie Ugolini, Robert Graziano, François Romagne, Cécile Bonnafous. Antitumoral efficacy of therapeutic human anti-KIR antibody (BMS-986015/IPH2102) in a preclinical xenograft tumor model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 493. doi:10.1158/1538-7445.AM2013-493
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