Preclinical characterization of 1-7F9, a novel human anti-KIR receptor therapeutic antibody that augments natural killer-mediated killing of tumor cells.
Inhibitory-cell killer immunoglobulin-like receptors (KIR) negatively regulate natural killer (NK) cell-mediated killing of HLA class I-expressing tumors. Lack of KIR-HLA class I interactions has been associated with potent NK-mediated antitumor efficacy and increased survival in acute myeloid leukemia (AML) patients upon haploidentical stem cell transplantation from KIR-mismatched donors. To exploit this pathway pharmacologically, we generated a fully human monoclonal antibody, 1-7F9, which cross-reacts with KIR2DL1, -2, and -3 receptors, and prevents their inhibitory signaling. The 1-7F9 monoclonal antibody augmented NK cell-mediated lysis of HLA-C-expressing tumor cells, including autologous AML blasts, but did not induce killing of normal peripheral blood mononuclear cells, suggesting a therapeutic window for preferential enhancement of NK-cell cytotoxicity against malignant target cells. Administration of 1-7F9 to KIR2DL3-transgenic mice resulted in dose-dependent rejection of HLA-Cw3-positive target cells. In an immunodeficient mouse model in which inoculation of human NK cells alone was unable to protect against lethal, autologous AML, preadministration of 1-7F9 resulted in long-term survival. These data show that 1-7F9 confers specific, stable blockade of KIR, boosting NK-mediated killing of HLA-matched AML blasts in vitro and in vivo, providing a preclinical basis for initiating phase 1 clinical trials with this candidate therapeutic antibody.
Romagné
Francois
F
Innate-Pharma SA, Marseille, France. Francois.romagne@innate-pharma.fr
André
Pascale
P
Spee
Pieter
P
Zahn
Stefan
S
Anfossi
Nicolas
N
Gauthier
Laurent
L
Capanni
Marusca
M
Ruggeri
Loredana
L
Benson
Don M
DM
Blaser
Bradley W
BW
Della Chiesa
Mariella
M
Moretta
Alessandro
A
Vivier
Eric
E
Caligiuri
Michael A
MA
Velardi
Andrea
A
Wagtmann
Nicolai
N
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D054340:Receptors, KIR / Q000037:antagonists & inhibitors / Q000276:immunology*; D054342:Receptors, KIR2DL1 / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D054343:Receptors, KIR2DL2 / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D054344:Receptors, KIR2DL3 / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C093100:KIR2DL1 protein, human; D054340:Receptors, KIR; D054342:Receptors, KIR2DL1; D054343:Receptors, KIR2DL2; D054344:Receptors, KIR2DL3