Cargando…
Expression of a Recombinant High Affinity IgG Fc Receptor by Engineered NK Cells as a Docking Platform for Therapeutic mAbs to Target Cancer Cells
Anti-tumor mAbs are the most widely used and characterized cancer immunotherapy. Despite having a significant impact on some malignancies, most cancer patients respond poorly or develop resistance to this therapy. A known mechanism of action of these therapeutic mAbs is antibody-dependent cell-media...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291448/ https://www.ncbi.nlm.nih.gov/pubmed/30574146 http://dx.doi.org/10.3389/fimmu.2018.02873 |
_version_ | 1783380247739105280 |
---|---|
author | Snyder, Kristin M. Hullsiek, Robert Mishra, Hemant K. Mendez, Daniel C. Li, Yunfang Rogich, Allison Kaufman, Dan S. Wu, Jianming Walcheck, Bruce |
author_facet | Snyder, Kristin M. Hullsiek, Robert Mishra, Hemant K. Mendez, Daniel C. Li, Yunfang Rogich, Allison Kaufman, Dan S. Wu, Jianming Walcheck, Bruce |
author_sort | Snyder, Kristin M. |
collection | PubMed |
description | Anti-tumor mAbs are the most widely used and characterized cancer immunotherapy. Despite having a significant impact on some malignancies, most cancer patients respond poorly or develop resistance to this therapy. A known mechanism of action of these therapeutic mAbs is antibody-dependent cell-mediated cytotoxicity (ADCC), a key effector function of human NK cells. CD16A on human NK cells has an exclusive role in binding to tumor-bound IgG antibodies. Though CD16A is a potent activating receptor, it is also a low affinity IgG Fc receptor (FcγR) that undergoes a rapid downregulation in expression by a proteolytic process involving ADAM17 upon NK cell activation. These regulatory processes are likely to limit the efficacy of tumor-targeting therapeutic mAbs in the tumor environment. We sought to enhance NK cell binding to anti-tumor mAbs by engineering these cells with a recombinant FcγR consisting of the extracellular region of CD64, the highest affinity FcγR expressed by leukocytes, and the transmembrane and cytoplasmic regions of CD16A. This novel recombinant FcγR (CD64/16A) was expressed in the human NK cell line NK92 and in induced pluripotent stem cells from which primary NK cells were derived. CD64/16A lacked the ADAM17 cleavage region in CD16A and it was not rapidly downregulated in expression following NK cell activation during ADCC. CD64/16A on NK cells facilitated conjugation to antibody-treated tumor cells, ADCC, and cytokine production, demonstrating functional activity by its two components. Unlike NK cells expressing CD16A, CD64/16A captured soluble therapeutic mAbs and the modified NK cells mediated tumor cell killing. Hence, CD64/16A could potentially be used as a docking platform on engineered NK cells for therapeutic mAbs and IgG Fc chimeric proteins, allowing for switchable targeting elements and a novel cancer cellular therapy. |
format | Online Article Text |
id | pubmed-6291448 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-62914482018-12-20 Expression of a Recombinant High Affinity IgG Fc Receptor by Engineered NK Cells as a Docking Platform for Therapeutic mAbs to Target Cancer Cells Snyder, Kristin M. Hullsiek, Robert Mishra, Hemant K. Mendez, Daniel C. Li, Yunfang Rogich, Allison Kaufman, Dan S. Wu, Jianming Walcheck, Bruce Front Immunol Immunology Anti-tumor mAbs are the most widely used and characterized cancer immunotherapy. Despite having a significant impact on some malignancies, most cancer patients respond poorly or develop resistance to this therapy. A known mechanism of action of these therapeutic mAbs is antibody-dependent cell-mediated cytotoxicity (ADCC), a key effector function of human NK cells. CD16A on human NK cells has an exclusive role in binding to tumor-bound IgG antibodies. Though CD16A is a potent activating receptor, it is also a low affinity IgG Fc receptor (FcγR) that undergoes a rapid downregulation in expression by a proteolytic process involving ADAM17 upon NK cell activation. These regulatory processes are likely to limit the efficacy of tumor-targeting therapeutic mAbs in the tumor environment. We sought to enhance NK cell binding to anti-tumor mAbs by engineering these cells with a recombinant FcγR consisting of the extracellular region of CD64, the highest affinity FcγR expressed by leukocytes, and the transmembrane and cytoplasmic regions of CD16A. This novel recombinant FcγR (CD64/16A) was expressed in the human NK cell line NK92 and in induced pluripotent stem cells from which primary NK cells were derived. CD64/16A lacked the ADAM17 cleavage region in CD16A and it was not rapidly downregulated in expression following NK cell activation during ADCC. CD64/16A on NK cells facilitated conjugation to antibody-treated tumor cells, ADCC, and cytokine production, demonstrating functional activity by its two components. Unlike NK cells expressing CD16A, CD64/16A captured soluble therapeutic mAbs and the modified NK cells mediated tumor cell killing. Hence, CD64/16A could potentially be used as a docking platform on engineered NK cells for therapeutic mAbs and IgG Fc chimeric proteins, allowing for switchable targeting elements and a novel cancer cellular therapy. Frontiers Media S.A. 2018-12-06 /pmc/articles/PMC6291448/ /pubmed/30574146 http://dx.doi.org/10.3389/fimmu.2018.02873 Text en Copyright © 2018 Snyder, Hullsiek, Mishra, Mendez, Li, Rogich, Kaufman, Wu and Walcheck. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Snyder, Kristin M. Hullsiek, Robert Mishra, Hemant K. Mendez, Daniel C. Li, Yunfang Rogich, Allison Kaufman, Dan S. Wu, Jianming Walcheck, Bruce Expression of a Recombinant High Affinity IgG Fc Receptor by Engineered NK Cells as a Docking Platform for Therapeutic mAbs to Target Cancer Cells |
title | Expression of a Recombinant High Affinity IgG Fc Receptor by Engineered NK Cells as a Docking Platform for Therapeutic mAbs to Target Cancer Cells |
title_full | Expression of a Recombinant High Affinity IgG Fc Receptor by Engineered NK Cells as a Docking Platform for Therapeutic mAbs to Target Cancer Cells |
title_fullStr | Expression of a Recombinant High Affinity IgG Fc Receptor by Engineered NK Cells as a Docking Platform for Therapeutic mAbs to Target Cancer Cells |
title_full_unstemmed | Expression of a Recombinant High Affinity IgG Fc Receptor by Engineered NK Cells as a Docking Platform for Therapeutic mAbs to Target Cancer Cells |
title_short | Expression of a Recombinant High Affinity IgG Fc Receptor by Engineered NK Cells as a Docking Platform for Therapeutic mAbs to Target Cancer Cells |
title_sort | expression of a recombinant high affinity igg fc receptor by engineered nk cells as a docking platform for therapeutic mabs to target cancer cells |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291448/ https://www.ncbi.nlm.nih.gov/pubmed/30574146 http://dx.doi.org/10.3389/fimmu.2018.02873 |
work_keys_str_mv | AT snyderkristinm expressionofarecombinanthighaffinityiggfcreceptorbyengineerednkcellsasadockingplatformfortherapeuticmabstotargetcancercells AT hullsiekrobert expressionofarecombinanthighaffinityiggfcreceptorbyengineerednkcellsasadockingplatformfortherapeuticmabstotargetcancercells AT mishrahemantk expressionofarecombinanthighaffinityiggfcreceptorbyengineerednkcellsasadockingplatformfortherapeuticmabstotargetcancercells AT mendezdanielc expressionofarecombinanthighaffinityiggfcreceptorbyengineerednkcellsasadockingplatformfortherapeuticmabstotargetcancercells AT liyunfang expressionofarecombinanthighaffinityiggfcreceptorbyengineerednkcellsasadockingplatformfortherapeuticmabstotargetcancercells AT rogichallison expressionofarecombinanthighaffinityiggfcreceptorbyengineerednkcellsasadockingplatformfortherapeuticmabstotargetcancercells AT kaufmandans expressionofarecombinanthighaffinityiggfcreceptorbyengineerednkcellsasadockingplatformfortherapeuticmabstotargetcancercells AT wujianming expressionofarecombinanthighaffinityiggfcreceptorbyengineerednkcellsasadockingplatformfortherapeuticmabstotargetcancercells AT walcheckbruce expressionofarecombinanthighaffinityiggfcreceptorbyengineerednkcellsasadockingplatformfortherapeuticmabstotargetcancercells |