Anti-ADAM17 monoclonal antibody MEDI3622 increases IFNγ production by human NK cells in the presence of antibody-bound tumor cells
Autor: | Emil Michelotti, Bruce Walcheck, Nabendu Pore, Hemant K. Mishra |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Cancer Research medicine.drug_class medicine.medical_treatment Immunology Cell ADAM17 Protein Monoclonal antibody Article Cell Line Interferon-gamma Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Leukocytes medicine Animals Humans Immunology and Allergy Cytotoxicity Mice Knockout biology Chemistry Receptors IgG Antibodies Monoclonal Immunotherapy Killer Cells Natural Mice Inbred C57BL 030104 developmental biology Cytokine medicine.anatomical_structure Oncology Cell culture 030220 oncology & carcinogenesis Cancer research biology.protein Antibody |
Zdroj: | Cancer Immunology, Immunotherapy. 67:1407-1416 |
ISSN: | 1432-0851 0340-7004 |
Popis: | Several clinically successful tumor-targeting mAbs induce NK cell effector functions. Human NK cells exclusively recognize tumor-bound IgG by the FcR CD16A (FcγRIIIA). Unlike other NK cell activating receptors, the cell surface density of CD16A can be rapidly downregulated in a cis manner by the metalloproteinase ADAM17 following NK cell stimulation in various manners. CD16A downregulation takes place in cancer patients and this may affect the efficacy of tumor-targeting mAbs. We examined the effects of MEDI3622, a human mAb and potent ADAM17 inhibitor, on NK cell activation by antibody-bound tumor cells. MEDI3622 effectively blocked ADAM17 function in NK cells and caused a marked increase in their production of IFNγ. This was observed for NK cells exposed to different tumor cell lines and therapeutic antibodies, and over a range of effector/target ratios. The augmented release of IFNγ by NK cells was reversed by a function-blocking CD16A mAb. In addition, NK92 cells, a human NK cell line that lacks endogenous FcγRs, expressing a recombinant non-cleavable version of CD16A released significantly higher levels of IFNγ than NK92 cells expressing equivalent levels of wildtype CD16A. Taken together, our data shows that MEDI3622 enhances the release of IFNγ by NK cells engaging antibody-bound tumor cells by blocking the shedding of CD16A. These findings support ADAM17 as a dynamic inhibitory checkpoint of the potent activating receptor CD16A, which can be targeted by MEDI3622 to potentially increase the efficacy of anti-tumor therapeutic antibodies. |
Databáze: | OpenAIRE |
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