title: KIR3DL2 (CD158k) is a potential therapeutic target in primary cutaneous anaplastic large-cell lymphoma.
abstract: BACKGROUND
  KIR3DL2, an inhibitory receptor expressed by natural killer cells and a subset of normal CD8(+) T cells, is aberrantly expressed in neoplastic cells in transformed mycosis fungoides and Sézary syndrome. Anti-KIR3DL2 targeted antibody therapy has shown potent activity in preclinical models for these diseases.
  
  
  OBJECTIVE
  To examine the expression of KIR3DL2 and its potential use as a therapeutic target in patients with primary cutaneous anaplastic large-cell lymphoma (pcALCL), the most aggressive cutaneous CD30(+) lymphoproliferative disease.
  
  
  METHODS
  Samples from 11 patients with pcALCL and three CD30(+) lymphoproliferative disease cell lines - Mac1, Mac2a and Mac2b - were used in KIR3DL2 expression studies using immunohistochemistry, flow cytometry and reverse-transcriptase quantitative polymerase chain reaction. The effect of IPH4102, a monoclonal humanized IgG1 targeting KIR3DL2, was assessed by in vitro cytotoxicity assays against Mac1, Mac2a and Mac2b using allogeneic peripheral blood mononuclear cells as effectors.
  
  
  RESULTS
  KIR3DL2 mRNA and protein were found in all human samples of pcALCL, and in the Mac2a and Mac2b cell lines. KIR3DL2 protein expression was present on 85·8 ± 14·0% of CD30(+) skin-infiltrating tumour cells. In vitro functional studies showed that KIR3DL2(+) Mac2a and Mac2b pcALCL lines are sensitive to antibody-derived cytotoxicity mediated by IPH4102, through activation of natural killer cells, in a concentration-dependent manner.
  
  
  CONCLUSIONS
  pcALCL tumour cells express KIR3DL2, and we provide preclinical proof of concept for the use of IPH4102, a humanized anti-KIR3DL2 antibody, to treat patients with primary cutaneous CD30(+) ALCL.
authors.affiliation: Département de Pathologie, AP-HP, Hôpital Saint-Louis, Paris, 75010, France.|Université Paris-Diderot, Sorbonne Paris Cité, Paris, 75010, France.|INSERM U1165, Paris, F-75010, France.
authors.forename: M
authors.initials: M
authors.lastname: Battistella
authors.affiliation: Département de Pathologie, AP-HP, Hôpital Saint-Louis, Paris, 75010, France.|Université Paris-Diderot, Sorbonne Paris Cité, Paris, 75010, France.|INSERM U1165, Paris, F-75010, France.
authors.forename: A
authors.initials: A
authors.lastname: Janin
authors.affiliation: INSERM U976, Centre de Recherche en Dermatologie, Paris, 75010, France.
authors.forename: F
authors.initials: F
authors.lastname: Jean-Louis
authors.affiliation: Innate Pharma, Marseille, F-13276, France.
authors.forename: C
authors.initials: C
authors.lastname: Collomb
authors.affiliation: Université Paris-Diderot, Sorbonne Paris Cité, Paris, 75010, France.|INSERM U1165, Paris, F-75010, France.
authors.forename: C
authors.initials: C
authors.lastname: Leboeuf
authors.affiliation: Innate Pharma, Marseille, F-13276, France.
authors.forename: H
authors.initials: H
authors.lastname: Sicard
authors.affiliation: Innate Pharma, Marseille, F-13276, France.
authors.forename: C
authors.initials: C
authors.lastname: Bonnafous
authors.affiliation: Innate Pharma, Marseille, F-13276, France.
authors.forename: A
authors.initials: A
authors.lastname: Dujardin
authors.affiliation: INSERM U976, Centre de Recherche en Dermatologie, Paris, 75010, France.|Département de Dermatologie, AP-HP, Hôpital Saint-Louis, Paris, 75010, France.
authors.forename: C
authors.initials: C
authors.lastname: Ram-Wolff
authors.affiliation: Roger Williams Medical Center, Providence, RI, U.S.A.|Boston University, Boston, MA, U.S.A.
authors.forename: M E
authors.initials: ME
authors.lastname: Kadin
authors.affiliation: Université Paris-Diderot, Sorbonne Paris Cité, Paris, 75010, France.|INSERM U976, Centre de Recherche en Dermatologie, Paris, 75010, France.
authors.forename: A
authors.initials: A
authors.lastname: Bensussan
authors.affiliation: Université Paris-Diderot, Sorbonne Paris Cité, Paris, 75010, France.|INSERM U976, Centre de Recherche en Dermatologie, Paris, 75010, France.|Département de Dermatologie, AP-HP, Hôpital Saint-Louis, Paris, 75010, France.
authors.forename: M
authors.initials: M
authors.lastname: Bagot
authors.affiliation: Université Paris-Diderot, Sorbonne Paris Cité, Paris, 75010, France.|INSERM U976, Centre de Recherche en Dermatologie, Paris, 75010, France.
authors.forename: L
authors.initials: L
authors.lastname: Michel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D017730:Ki-1 Antigen / Q000378:metabolism; D007694:Killer Cells, Natural / Q000502:physiology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D017728:Lymphoma, Large-Cell, Anaplastic / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D054343:Receptors, KIR2DL2 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy*; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C515077:KIR2DL2 protein, human; D017730:Ki-1 Antigen; D054343:Receptors, KIR2DL2