Advanced cutaneous T-cell lymphoma (CTCL) remains an unmet medical need, which lacks effective targeted therapies. In this study, we report the development of IPH4102, a humanized monoclonal antibody that targets the immune receptor KIR3DL2, which is widely expressed on CTCL cells but few normal immune cells. Potent antitumor properties of IPH4102 were documented in allogeneic human CTCL cells and a mouse model of KIR3DL2⁺ disease. IPH4102 antitumor activity was mediated by antibody-dependent cell cytotoxicity and phagocytosis. IPH4102 improved survival and reduced tumor growth in mice inoculated with KIR3DL2⁺ tumors. Ex vivo efficacy was further evaluated in primary Sézary patient cells, sorted natural killer–based autologous assays, and direct spiking into Sézary patient peripheral blood mononuclear cells. In these settings, IPH4102 selectively and efficiently killed primary Sézary cells, including at unfavorable effector-to-target ratios characteristic of unsorted PBMC. Together, our results offer preclinical proof of concept for the clinical development of IPH4102 to treat patients with advanced CTCL. Cancer Res; 74(21); 6060–70. ©2014 AACR.

Purpose: KIR3DL2 is a recently discovered marker of the malignant clonal cell population in Sézary syndrome. We intended to evaluate the expression of KIR3DL2 on blood T cells as a diagnostic, prognostic, and follow-up marker of Sézary syndrome. Experimental Design: Sixty-four patients diagnosed with Sézary syndrome were included in this monocentric study. We collected the percentage of KIR3DL2⁺ cells among CD3⁺ T cells, obtained by flow cytometry, and other classical diagnostic criteria for Sézary syndrome at diagnosis and during the follow-up. Results: Compared with the classical diagnostic factors, KIR3DL2 was the most sensitive diagnostic factor for Sézary syndrome. Univariate and multivariate analyses established that an eosinophil cell count >700/mm³ and a percentage of KIR3DL2⁺ cells within the CD3⁺ T cells >85% at diagnosis were associated with a significantly reduced disease-specific survival. Moreover, KIR3DL2 immunostaining allowed the assessment of treatment efficiency and specificity toward tumor cells, the detection of the residual disease following treatment, and the occurrence of relapse, even though patients clinically experienced complete remission and/or undetectable circulating Sézary cells by cytomorphologic analysis. Conclusions: We show that KIR3DL2 expression is the most sensitive diagnostic criterion of Sézary syndrome when compared with all other available biological criteria. It also represents the best independent prognostic factor for Sézary syndrome–specific death and the most relevant feature for the follow-up of Sézary syndrome, showing the invasion of the functional lymphocytes pool by Sézary cells. KIR3DL2 therefore represents a valuable tool for routine use as a clinical parameter at diagnosis, for prognosis and during patient follow-up. Clin Cancer Res; 23(14); 3619–27. ©2017 AACR.

KIR3DL2 is a member of the killer cell immunoglobulin-like receptor (KIR) family that was initially identified at the surface of natural killer (NK) cells. KIR3DL2, also known as CD158k, is expressed as a disulfide linked homodimer. Each chain is composed of three immunoglobulin-like domains and a long cytoplasmic tail containing two immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Beside its expression on NK cells it is also found on rare circulating T lymphocytes, mainly CD8+. Although the KIR gene number varies between haplotype, KIR3DL2 is a framework gene present in all individuals. Together with the presence of genomic regulatory sequences unique to KIR3DL2, this suggests some particular functions for the derived protein in comparison with other KIR family members. Several ligands have been identified for KIR3DL2. As for other KIRs, binding to HLA class-I molecules is essential for NK development by promoting phenomena such as licensing or driving NK cell maturation. For KIR3DL2 this includes binding to HLA-A3 and -A11 and to the free heavy chain form of HLA-B27. In addition KIR3DL2 also binds to CpG oligonucleotides (ODN) and ensures their transport to endosomal TLR9 receptors that promote cell activation. These characteristics have implicated KIR3DL2 in several pathologies: ankylosing spondylitis and cutaneous T cell lymphomas such as Sézary syndrome, CD30+ cutaneous lymphoma and transformed mycosis fungoides. Consequently, a new generation of humanized monoclonal antibodies directed against KIR3DL2 has been helpful in the diagnosis, follow-up and treatment of these diseases. In addition, preliminary clinical studies of a novel targeted immunotherapy for cutaneous T cell lymphomas using the anti-KIR3DL2 mAb IPH4102 are now underway. In this review we discuss the various aspects of KIR3DL2 on the functions of CD4+ T cells and how targeting this receptor helps to develop innovative therapeutic strategies.

Gabrielle Sonigo, Alizée Bozonnat, Maëlle Dumont, Nicolas Thonnart, Caroline Ram-Wolff, Adèle de Masson, Martine Bagot, Armand Bensussan, Anne Marie-Cardine; In

We previously identified the NK cell receptor KIR3DL2 as a valuable diagnostic and prognostic marker for the detection of the tumoral T cell burden of Sézary syndrome (SS) patients. However, the function of this receptor on the malignant T lymphocyte population remained unexplored. We here demonstrate that engagement of KIR3DL2 by its recently identified ligand CpG oligodeoxynucleotide (ODN) induces the internalization of the receptor and leads to a caspase-dependent apoptosis of malignant T cells. This process of cellular death is correlated to a dephosphorylation of the transcription factor STAT3 (signal transducer and activator of transcription 3), which is found constitutively phosphorylated and activated in Sézary cells. Our results indicate that KIR3DL2 can directly promote SS malignant cell death through the use of CpG ODN.