Incorporation of a Novel CD16-Specific Single-Domain Antibody into Multispecific Natural Killer Cell Engagers With Potent ADCC.

Autor: van Faassen H; Human Health Therapeutics Research Centre, Life Sciences Division, National Research Council Canada, 100 Sussex Drive, Ottawa, Ontario K1A 0R6, Canada., Jo DH; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada., Ryan S; Human Health Therapeutics Research Centre, Life Sciences Division, National Research Council Canada, 100 Sussex Drive, Ottawa, Ontario K1A 0R6, Canada., Lowden MJ; Human Health Therapeutics Research Centre, Life Sciences Division, National Research Council Canada, 100 Sussex Drive, Ottawa, Ontario K1A 0R6, Canada., Raphael S; Human Health Therapeutics Research Centre, Life Sciences Division, National Research Council Canada, 100 Sussex Drive, Ottawa, Ontario K1A 0R6, Canada., MacKenzie CR; Human Health Therapeutics Research Centre, Life Sciences Division, National Research Council Canada, 100 Sussex Drive, Ottawa, Ontario K1A 0R6, Canada., Lee SH; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada., Hussack G; Human Health Therapeutics Research Centre, Life Sciences Division, National Research Council Canada, 100 Sussex Drive, Ottawa, Ontario K1A 0R6, Canada., Henry KA; Human Health Therapeutics Research Centre, Life Sciences Division, National Research Council Canada, 100 Sussex Drive, Ottawa, Ontario K1A 0R6, Canada.; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada.
Jazyk: angličtina
Zdroj: Molecular pharmaceutics [Mol Pharm] 2021 Jun 07; Vol. 18 (6), pp. 2375-2384. Date of Electronic Publication: 2021 May 17.
DOI: 10.1021/acs.molpharmaceut.1c00208
Abstrakt: 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 ( K D : 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 ( K D : ∼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.
Databáze: MEDLINE
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