Abstract 2473: KIR3DL2 is a novel target for antibody-therapy of T cell lymphomas
Authors: Chester Cariad , Lim Sean , Marie-Cardine Anne , Rajasekaran Naren , Sicard Hélène , Kim Youn , Kohrt Holbrook 
Published: August 2015

Intro:

The killer immunoglobulin-like receptor, three domains, long cytoplasmic tail 2 (KIR3DL2) is a transmembrane glycoprotein expressed by natural killer (NK) cells and subsets of T cells. On NK cells, KIRD3L2 modulates NK cell activation by transducing inhibitory signals upon ligation by human leukocyte antigen (HLA) class I molecules. Interestingly, KIR3DL2 is also expressed on several subtypes of T cell lymphomas/leukemias, such as Sézary Syndrome and transformed Mycosis Fungoides. This expression pattern provides a promising target for antibody-based therapy. Recently, antibody-based therapies have been shown to synergize with co-stimulatory immunomodulation via agonistic immunotherapeutic antibodies, such as anti-CD137.

Methods:

We evaluated the efficacy of an anti-KIR3DL2 monoclonal antibody, IPH4102 (Innate Pharma S.A.), in inducing effector cell cytotoxicity of KIR3DL2+ tumors. In vitro experiments utilized primary samples and three KIR3DL2+ cell lines: HUT78, a Sézary cell line with constitutive KIR3DL2 expression; a RAJI-KIR3DL2 high-expression sub clone with ∼28,000 KIR3DL2 antigen sites per cell; and a RAJI-KIR3DL2 low-expression sub clone with ∼ 6,000 antigens sites per cell. All antibody-mediated cell cytotoxicity (ADCC) experiments used 7-AAD and Annexin-V to identify apoptotic cells.

Results:

In a CD107a /IFN-γ assay, NK cells co-cultured with IPH4102-coated HUT78 cells demonstrated increased activation profiles relative to NK cells co-cultured with untreated HUT78 cells. Activated NK cells displayed elevated expression of CD137, OX40, and CD69 and produced more CD107a and IFN-γ. In allo-ADCC assays using HUT78 cells at varying target to effector ratios, IPH4102 treatment induced more target apoptosis than treatment with positive control anti-CD52 alemtuzumab. In additional allo-ADCC assays, RAJI-KIR3DL2 high-expression tumors demonstrated more apoptosis than RAJI-KIR3DL2 low-expression tumors. The IPH4102-mediated cytotoxicity could be enhanced by the concurrent administration of an agonistic anti-CD137 monoclonal antibody. In ADCC assays of primary Sézary cells with autologous NK cells, we confirmed the upregulation of KIR3DL2 and observed enhanced NK cytotoxicity following tumor treatment with IPH4102. Again, the combination of anti-KIR3DL2 and anti-CD137 therapy proved synergistic leading to increased tumor eradication relative to either therapy alone.

Conclusion:

Our findings support a role for anti-KIR3DL2 monoclonal antibodies in the treatment of KIR3DL2+ tumors. IPH4102 effectively increased ADCC of KIR3DL2+ tumors by NK cells. The addition of agonistic anti-CD137 antibodies will further augment the anti-tumor efficacy of this therapeutic strategy.

Citation Format: Cariad Chester, Sean Lim, Anne Marie-Cardine, Naren Rajasekaran, Hélène Sicard, Youn Kim, Holbrook Kohrt. KIR3DL2 is a novel target for antibody-therapy of T cell lymphomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2473. doi:10.1158/1538-7445.AM2015-2473