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NK-Cell-Mediated Targeting of Various Solid Tumors Using a B7-H3 Tri-Specific Killer Engager In Vitro and In Vivo

SIMPLE SUMMARY: B7-H3 costimulatory ligand has sparked tremendous interest as a target for antibody-directed therapy of solid tumors. This is attributed to high expression of B7-H3 on the surface of tumor and low expression on normal tissues. Natural killer cells are known as key effectors of the in...

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Autores principales: Vallera, Daniel A., Ferrone, Soldano, Kodal, Behiye, Hinderlie, Peter, Bendzick, Laura, Ettestad, Brianna, Hallstrom, Caroline, Zorko, Nicholas A., Rao, Arpit, Fujioka, Naomi, Ryan, Charles J., Geller, Melissa A., Miller, Jeffrey S., Felices, Martin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564091/
https://www.ncbi.nlm.nih.gov/pubmed/32961861
http://dx.doi.org/10.3390/cancers12092659
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author Vallera, Daniel A.
Ferrone, Soldano
Kodal, Behiye
Hinderlie, Peter
Bendzick, Laura
Ettestad, Brianna
Hallstrom, Caroline
Zorko, Nicholas A.
Rao, Arpit
Fujioka, Naomi
Ryan, Charles J.
Geller, Melissa A.
Miller, Jeffrey S.
Felices, Martin
author_facet Vallera, Daniel A.
Ferrone, Soldano
Kodal, Behiye
Hinderlie, Peter
Bendzick, Laura
Ettestad, Brianna
Hallstrom, Caroline
Zorko, Nicholas A.
Rao, Arpit
Fujioka, Naomi
Ryan, Charles J.
Geller, Melissa A.
Miller, Jeffrey S.
Felices, Martin
author_sort Vallera, Daniel A.
collection PubMed
description SIMPLE SUMMARY: B7-H3 costimulatory ligand has sparked tremendous interest as a target for antibody-directed therapy of solid tumors. This is attributed to high expression of B7-H3 on the surface of tumor and low expression on normal tissues. Natural killer cells are known as key effectors of the innate immune system against cancer and are being explored clinically in a number of immunotherapy settings. Here, we describe a unique platform technology incorporating a cytokine as a bispecific antibody cross-linker to create a tri-specific NK cell engager, or TriKE, directed against the antigen B7-H3. The data shows this immunotherapeutic construct promotes specific natural killer cell expansion. It also induces antibody-dependent cellular cytotoxicity due to simultaneous recognition of both natural killer cells and B7-H3-expressing cancer cells. Finally, using a xenogeneic mouse model, the data shows that the TriKE induces better natural killer cell-mediated control of ovarian cancer. Taken together, the findings presented here indicate that a B7-H3-targeted TriKE has the potential to enhance natural killer cell immunotherapy in solid tumor settings and supports further development. ABSTRACT: We improved the bispecific antibody platform that primarily engages natural killer (NK) cells to kill cancer cells through antibody-dependent cellular cytotoxicity (ADCC) by adding IL-15 as a crosslinker that expands and self-sustains the effector NK cell population. The overall goal was to target B7-H3, an established marker predominantly expressed on cancer cells and minimally expressed on normal cells, and prove that it could target cancer cells in vitro and inhibit tumor growth in vivo. The tri-specific killer engager (TriKE(TM)) was assembled by DNA shuffling and ligation using DNA encoding a camelid anti-CD16 antibody fragment, a wild-type IL-15 moiety, and an anti-B7-H3 scFv (clone 376.96). The expressed and purified cam1615B7H3 protein was tested for in vitro NK cell activity against a variety of tumors and in vivo against a tagged human MA-148 ovarian cancer cell line grafted in NSG mice. cam1615B7H3 showed specific NK cell expansion, high killing activity across a range of B7-H3+ carcinomas, and the ability to mediate growth inhibition of aggressive ovarian cancer in vivo. cam1615B7H3 TriKE improves NK cell function, expansion, targeted cytotoxicity against various types of B7-H3-positive human cancer cell lines, and delivers an anti-cancer effect in vivo in a solid tumor setting.
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spelling pubmed-75640912020-10-27 NK-Cell-Mediated Targeting of Various Solid Tumors Using a B7-H3 Tri-Specific Killer Engager In Vitro and In Vivo Vallera, Daniel A. Ferrone, Soldano Kodal, Behiye Hinderlie, Peter Bendzick, Laura Ettestad, Brianna Hallstrom, Caroline Zorko, Nicholas A. Rao, Arpit Fujioka, Naomi Ryan, Charles J. Geller, Melissa A. Miller, Jeffrey S. Felices, Martin Cancers (Basel) Article SIMPLE SUMMARY: B7-H3 costimulatory ligand has sparked tremendous interest as a target for antibody-directed therapy of solid tumors. This is attributed to high expression of B7-H3 on the surface of tumor and low expression on normal tissues. Natural killer cells are known as key effectors of the innate immune system against cancer and are being explored clinically in a number of immunotherapy settings. Here, we describe a unique platform technology incorporating a cytokine as a bispecific antibody cross-linker to create a tri-specific NK cell engager, or TriKE, directed against the antigen B7-H3. The data shows this immunotherapeutic construct promotes specific natural killer cell expansion. It also induces antibody-dependent cellular cytotoxicity due to simultaneous recognition of both natural killer cells and B7-H3-expressing cancer cells. Finally, using a xenogeneic mouse model, the data shows that the TriKE induces better natural killer cell-mediated control of ovarian cancer. Taken together, the findings presented here indicate that a B7-H3-targeted TriKE has the potential to enhance natural killer cell immunotherapy in solid tumor settings and supports further development. ABSTRACT: We improved the bispecific antibody platform that primarily engages natural killer (NK) cells to kill cancer cells through antibody-dependent cellular cytotoxicity (ADCC) by adding IL-15 as a crosslinker that expands and self-sustains the effector NK cell population. The overall goal was to target B7-H3, an established marker predominantly expressed on cancer cells and minimally expressed on normal cells, and prove that it could target cancer cells in vitro and inhibit tumor growth in vivo. The tri-specific killer engager (TriKE(TM)) was assembled by DNA shuffling and ligation using DNA encoding a camelid anti-CD16 antibody fragment, a wild-type IL-15 moiety, and an anti-B7-H3 scFv (clone 376.96). The expressed and purified cam1615B7H3 protein was tested for in vitro NK cell activity against a variety of tumors and in vivo against a tagged human MA-148 ovarian cancer cell line grafted in NSG mice. cam1615B7H3 showed specific NK cell expansion, high killing activity across a range of B7-H3+ carcinomas, and the ability to mediate growth inhibition of aggressive ovarian cancer in vivo. cam1615B7H3 TriKE improves NK cell function, expansion, targeted cytotoxicity against various types of B7-H3-positive human cancer cell lines, and delivers an anti-cancer effect in vivo in a solid tumor setting. MDPI 2020-09-18 /pmc/articles/PMC7564091/ /pubmed/32961861 http://dx.doi.org/10.3390/cancers12092659 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Vallera, Daniel A.
Ferrone, Soldano
Kodal, Behiye
Hinderlie, Peter
Bendzick, Laura
Ettestad, Brianna
Hallstrom, Caroline
Zorko, Nicholas A.
Rao, Arpit
Fujioka, Naomi
Ryan, Charles J.
Geller, Melissa A.
Miller, Jeffrey S.
Felices, Martin
NK-Cell-Mediated Targeting of Various Solid Tumors Using a B7-H3 Tri-Specific Killer Engager In Vitro and In Vivo
title NK-Cell-Mediated Targeting of Various Solid Tumors Using a B7-H3 Tri-Specific Killer Engager In Vitro and In Vivo
title_full NK-Cell-Mediated Targeting of Various Solid Tumors Using a B7-H3 Tri-Specific Killer Engager In Vitro and In Vivo
title_fullStr NK-Cell-Mediated Targeting of Various Solid Tumors Using a B7-H3 Tri-Specific Killer Engager In Vitro and In Vivo
title_full_unstemmed NK-Cell-Mediated Targeting of Various Solid Tumors Using a B7-H3 Tri-Specific Killer Engager In Vitro and In Vivo
title_short NK-Cell-Mediated Targeting of Various Solid Tumors Using a B7-H3 Tri-Specific Killer Engager In Vitro and In Vivo
title_sort nk-cell-mediated targeting of various solid tumors using a b7-h3 tri-specific killer engager in vitro and in vivo
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564091/
https://www.ncbi.nlm.nih.gov/pubmed/32961861
http://dx.doi.org/10.3390/cancers12092659
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