Incorporation of a Novel CD16-Specific Single-Domain Antibody into Multispecific Natural Killer Cell Engagers With Potent ADCC
| Autor: | Seung-Hwan Lee, Michael J. Lowden, Dong-Hyeon Jo, Shannon Ryan, Greg Hussack, Henk van Faassen, Shalini Raphael, Kevin A. Henry, C. Roger MacKenzie |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_treatment
Pharmaceutical Science 02 engineering and technology 030226 pharmacology & pharmacy Jurkat Cells Mice 0302 clinical medicine Cancer immunotherapy Neoplasms Antibodies Bispecific Drug Discovery Antibody-dependent cell-mediated cytotoxicity biology Chemistry Degranulation hemic and immune systems 021001 nanoscience & nanotechnology Killer Cells Natural medicine.anatomical_structure bispecific NK cell engager Molecular Medicine Biological Assay Immunotherapy Antibody 0210 nano-technology Camelids New World CD16 Recombinant Fusion Proteins Primary Cell Culture VHH chemical and pharmacologic phenomena GPI-Linked Proteins CD19 Natural killer cell 03 medical and health sciences Protein Domains Antigen Antigens Neoplasm medicine Animals Humans single-domain antibody cancer immunotherapy Receptors IgG Antibody-Dependent Cell Cytotoxicity Single-Domain Antibodies natural killer cell Molecular biology Macaca fascicularis nanobody Single-domain antibody biology.protein |
| Zdroj: | Molecular Pharmaceutics. 18:2375-2384 |
| ISSN: | 1543-8392 1543-8384 |
| DOI: | 10.1021/acs.molpharmaceut.1c00208 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|