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PEDS Advance Access originally published online on September 11, 2008
Protein Engineering Design and Selection 2008 21(11):665-672; doi:10.1093/protein/gzn047
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Redirecting NK cells mediated tumor cell lysis by a new recombinant bifunctional protein

Claire Germain1,3, Emmanuelle Campigna1, Imed Salhi1, Sébastien Morisseau1, Isabelle Navarro-Teulon1, Jean-Pierre Mach2, André Pèlegrin1 and Bruno Robert1,4

1IRCM, Institut de Recherche en Cancérologie de Montpellier; INSERM U896; Université Montpellier1; CRLC Val d'Aurelle Paul Lamarque, Montpellier F-34298, France 2Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland

4 To whom correspondence should be addressed. E-mail: brobert{at}valdorel.fnclcc.fr

Natural killer (NK) cells are at the crossroad between innate and adaptive immunity and play a major role in cancer immunosurveillance. NK cell stimulation depends on a balance between inhibitory and activating receptors, such as the stimulatory lectin-like receptor NKG2D. To redirect NK cells against tumor cells, we designed bifunctional proteins able to specifically bind tumor cells and to induce their lysis by NK cells, after NKG2D engagement. To this aim, we used the ‘knob into hole’ heterodimerization strategy, in which ‘knob’ and ‘hole’ variants were generated by directed mutagenesis within the CH3 domain of human IgG1 Fc fragments fused to an anti-CEA or anti-HER2 scFv or to the H60 murine ligand of NKG2D, respectively. We demonstrated the capacity of the bifunctional proteins produced to specifically coat tumor cells surface with H60 ligand. Most importantly, we demonstrated that these bifunctional proteins were able to induce an NKG2D-dependent and antibody-specific tumor cell lysis by murine NK cells. Overall, the results show the possibility to redirect NK cytotoxicity to tumor cells by a new format of recombinant bispecific antibody, opening the way of potential NK cell-based cancer immunotherapies by specific activation of the NKG2D receptor at the tumor site.

Keywords: bifunctional proteins/‘knob into hole’ strategy/natural killer cells/NKG2D/tumor targeting

Received April 18, 2008; revised July 16, 2008; accepted August 12, 2008.

3 Present address: IPMC, Institut de Pharmacologie Moléculaire et Cellulaire; CNRS/UNSA UMR 6097, Valbonne, 06560, France


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