Incorporation of a novel CD16-specific single-domain antibody into multispecific natural killer cell engagers with potent ADCC

Par Conseil national de recherches du Canada

DOITrouver le DOI : https://doi.org/10.1021/acs.molpharmaceut.1c00208
AuteurRechercher : 1; Rechercher : ; Rechercher : 1; Rechercher : 1; Rechercher : 1; Rechercher : 1; Rechercher : ; Rechercher : 1; Rechercher : 1Identifiant ORCID : https://orcid.org/0000-0003-0477-0558
Affiliation
  1. Conseil national de recherches du Canada. Thérapeutique en santé humaine
Bailleur de fondsRechercher : National Research Council of Canada
FormatTexte, Article
Sujetsingle-domain antibody; VHH; nanobody; CD16; natural killer cell; bispecific NK cell engager; cancer immunotherapy
Date de publication
Maison d’éditionAmerican Chemical Society
Condition d’accès
  • Multispecific antibodies that bridge immune effector and tumor cells have shown promising preclinical and clinical efficacies. Here, we isolated and characterized novel llama single-domain antibodies (sdAbs) against CD16. One sdAb, NRC-sdAb048, bound recombinant human and cynomolgus monkey CD16 ectodomains with equivalent affinity (KD: 1 nM) but did not recognize murine CD16. Binding was similar for human CD16a expressed on NK cells and CD16b (NA2) expressed on neutrophils but dramatically weaker (KD: ∼6 μM) for the CD16b (NA1) allotype. The sdAb stained primary human peripheral blood NK cells. Irrespective of fusion orientation and linker length, bispecific sdAb–sdAb and sdAb–scFv dimers (anti-CD16/EGFR, anti-CD16/HER2, and anti-CD16/CD19) retained full binding affinity for each target, coengaged both antigens simultaneously, elicited ADCC against target antigen-expressing tumor cells in a reporter bioassay, and triggered target-specific activation and degranulation of primary NK cells as measured via interferon-γ and CD107a expression. These molecules may have applications in cancer immunotherapy.
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Langueanglais
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Identificateur de l’enregistrement5bb9162d-a754-4dd8-9abd-5a2db5bba67b
Enregistrement créé2023-01-20
Enregistrement modifié2023-03-16
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