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T-cell ligands modulate the cytolytic activity of the CD33/CD3 BiTE antibody construct, AMG 330
Preclinical and emerging clinical studies demonstrate that bispecific T-cell engaging (BiTE) antibody constructs can potently lyse targeted tumor cells, but the determinants for their activity remain incompletely understood. Using human acute myeloid leukemia (AML) cell lines engineered to overexpre...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558592/ https://www.ncbi.nlm.nih.gov/pubmed/26295610 http://dx.doi.org/10.1038/bcj.2015.68 |
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author | Laszlo, G S Gudgeon, C J Harrington, K H Walter, R B |
author_facet | Laszlo, G S Gudgeon, C J Harrington, K H Walter, R B |
author_sort | Laszlo, G S |
collection | PubMed |
description | Preclinical and emerging clinical studies demonstrate that bispecific T-cell engaging (BiTE) antibody constructs can potently lyse targeted tumor cells, but the determinants for their activity remain incompletely understood. Using human acute myeloid leukemia (AML) cell lines engineered to overexpress individual T-cell ligands, we found that expression of the inhibitory ligands, PD-L1 and PD-L2, reduced the cytolytic activity of the BiTE antibody construct targeting CD33, AMG 330; conversely, expression of the activating ligands, CD80 and CD86, augmented the cytotoxic activity of AMG 330. Consistent with these findings, treatment with an activating antibody directed at the co-stimulatory T-cell receptor, CD28, significantly increased AMG 330-induced cytotoxicity in human AML cell lines. Using specimens from 12 patients with newly diagnosed or relapsed/refractory AML, we found that activation of CD28 also increased the activity of AMG 330 in primary human AML cells (P=0.023). Together, our findings indicate that T-cell ligands and co-receptors modulate the anti-tumor activity of the CD33/CD3 BiTE antibody construct, AMG 330. These findings suggest that such ligands/co-receptors could serve as biomarkers of response and that co-treatment strategies with pharmacological modulators of T-cell receptor signaling could be utilized to further enhance the activity of this targeted therapeutic. |
format | Online Article Text |
id | pubmed-4558592 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-45585922015-09-14 T-cell ligands modulate the cytolytic activity of the CD33/CD3 BiTE antibody construct, AMG 330 Laszlo, G S Gudgeon, C J Harrington, K H Walter, R B Blood Cancer J Original Article Preclinical and emerging clinical studies demonstrate that bispecific T-cell engaging (BiTE) antibody constructs can potently lyse targeted tumor cells, but the determinants for their activity remain incompletely understood. Using human acute myeloid leukemia (AML) cell lines engineered to overexpress individual T-cell ligands, we found that expression of the inhibitory ligands, PD-L1 and PD-L2, reduced the cytolytic activity of the BiTE antibody construct targeting CD33, AMG 330; conversely, expression of the activating ligands, CD80 and CD86, augmented the cytotoxic activity of AMG 330. Consistent with these findings, treatment with an activating antibody directed at the co-stimulatory T-cell receptor, CD28, significantly increased AMG 330-induced cytotoxicity in human AML cell lines. Using specimens from 12 patients with newly diagnosed or relapsed/refractory AML, we found that activation of CD28 also increased the activity of AMG 330 in primary human AML cells (P=0.023). Together, our findings indicate that T-cell ligands and co-receptors modulate the anti-tumor activity of the CD33/CD3 BiTE antibody construct, AMG 330. These findings suggest that such ligands/co-receptors could serve as biomarkers of response and that co-treatment strategies with pharmacological modulators of T-cell receptor signaling could be utilized to further enhance the activity of this targeted therapeutic. Nature Publishing Group 2015-08 2015-08-21 /pmc/articles/PMC4558592/ /pubmed/26295610 http://dx.doi.org/10.1038/bcj.2015.68 Text en Copyright © 2015 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Original Article Laszlo, G S Gudgeon, C J Harrington, K H Walter, R B T-cell ligands modulate the cytolytic activity of the CD33/CD3 BiTE antibody construct, AMG 330 |
title | T-cell ligands modulate the cytolytic activity of the CD33/CD3 BiTE antibody construct, AMG 330 |
title_full | T-cell ligands modulate the cytolytic activity of the CD33/CD3 BiTE antibody construct, AMG 330 |
title_fullStr | T-cell ligands modulate the cytolytic activity of the CD33/CD3 BiTE antibody construct, AMG 330 |
title_full_unstemmed | T-cell ligands modulate the cytolytic activity of the CD33/CD3 BiTE antibody construct, AMG 330 |
title_short | T-cell ligands modulate the cytolytic activity of the CD33/CD3 BiTE antibody construct, AMG 330 |
title_sort | t-cell ligands modulate the cytolytic activity of the cd33/cd3 bite antibody construct, amg 330 |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558592/ https://www.ncbi.nlm.nih.gov/pubmed/26295610 http://dx.doi.org/10.1038/bcj.2015.68 |
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