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Isolation and characterization of anti-Fc{gamma}RIII (CD16) llama single-domain antibodies that activate natural killer cells.

Abstract : FcgammaRIII (CD16) plays an important role in the anti-tumor effects of therapeutic antibodies. Bi-specific antibodies (bsAbs) targeting FcgammaRIII represent a powerful alternative to the recruitment of the receptor via the Fc fragment, but are not efficiently produced. Single-domain antibodies (sdAbs) endowed with many valuable structural features might help to bypass this problem. In the present work, we have isolated anti-FcgammaRIII sdAbs (C21 and C28) from a phage library generated from a llama immunized with FcgammaRIIIB extra-cellular domains. These sdAbs bind FcgammaRIIIA(+) NK cells and FcgammaRIIIB(+) polymorphonuclear cells, but not FcgammaRI(+) or FcgammaRII(+) cells, as detected by indirect immunofluorescence. Competition experiments showed that C21 and C28 sdAbs bind different FcgammaRIII epitopes, with C21 recognizing a linear and C28 a conformational epitope of the receptor. Surface plasmon resonance experiments showed that C21 and C28 sdAbs bind FcgammaRIII with a K(D) in the 10 and 80 nM range, respectively. Importantly, the engagement by both molecules of FcgammaRIIIA expressed by transfected Jurkat T cells or by NK cells derived from peripheral blood induced a strong IL-2 and IFN-gamma production, respectively. These anti-FcgammaRIII sdAbs represent versatile tools for generating bsAbs under various formats, able to recruit FcgammaRIII killer cells to target and destroy tumor cells.
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https://hal.archives-ouvertes.fr/hal-00258940
Contributor : Nathalie Pasqualini Connect in order to contact the contributor
Submitted on : Tuesday, February 26, 2008 - 10:19:12 AM
Last modification on : Thursday, October 14, 2021 - 12:04:02 PM

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Ghislaine Behar, Sophie Sibéril, Agnès Groulet, Patrick Chames, Martine Pugnière, et al.. Isolation and characterization of anti-Fc{gamma}RIII (CD16) llama single-domain antibodies that activate natural killer cells.. Protein Engineering, Design and Selection, Oxford University Press (OUP), 2008, 21 (1), pp.1-10. ⟨10.1093/protein/gzm064⟩. ⟨hal-00258940⟩

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