Application of a newly-developed cynomolgus macaque BiTE-mediated cytotoxic T-lymphocyte activity assay to various immunomodulatory agents in vitro

The immunotoxic potential of drug candidates is assessed through the examination of results from a variety of in vitro and in vivo immunophenotyping and functional study endpoints in pre-clinical studies. CD8+ cytotoxic T-lymphocyte (CTL) activity impairment by immunosuppressive agents is recognized...

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Autores principales:	Brendon Frank, Hao Guo, Hervé Lebrec, Xiaoting Wang
Formato:	article
Lenguaje:	EN
Publicado:	Taylor & Francis Group 2021
Materias:	bite immunomodulation; in vitro ctl activity cynomolgus Immunologic diseases. Allergy RC581-607 Toxicology. Poisons RA1190-1270
Acceso en línea:	https://doaj.org/article/e0ce9dcc7d614ab5b9780e895fd53896
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spelling	oai:doaj.org-article:e0ce9dcc7d614ab5b9780e895fd538962021-11-04T15:00:42ZApplication of a newly-developed cynomolgus macaque BiTE-mediated cytotoxic T-lymphocyte activity assay to various immunomodulatory agents in vitro1547-691X1547-690110.1080/1547691X.2021.1992687https://doaj.org/article/e0ce9dcc7d614ab5b9780e895fd538962021-01-01T00:00:00Zhttp://dx.doi.org/10.1080/1547691X.2021.1992687https://doaj.org/toc/1547-691Xhttps://doaj.org/toc/1547-6901The immunotoxic potential of drug candidates is assessed through the examination of results from a variety of in vitro and in vivo immunophenotyping and functional study endpoints in pre-clinical studies. CD8+ cytotoxic T-lymphocyte (CTL) activity impairment by immunosuppressive agents is recognized to be a potentiating factor for decreased antiviral defense and increased cancer risk. A bi-specific T-cell engager (BiTE®)-mediated CTL activity assay that applies to ex vivo experimentation in non-human primates in the context of toxicology studies was successfully developed and applied in cynomolgus monkey regulatory studies. While an ex vivo analysis conducted in the context of repeat-dose toxicology studies focuses on the long-term impact on CTL function, an in vitro assay with the same experimental design captures acute effects in the presence of the test article. Here, the in vitro assay was applied to a list of drugs with known clinical immunomodulatory impact to understand the applicability of the assay. The results showed this assay was sensitive to a wide range of immunosuppressants directly targeting cell-intrinsic signaling pathways in activated CTL. However, agents executing immuno-modulation through inhibiting cytokines/cytokine receptors, co-stimulatory molecules, and cell adhesion and migration pathways did not impair the CTL activity in this short-term in vitro culture. In addition, anti-PD-1/PD-L1 immune checkpoint blockers enhanced the CTL activity. Taken together, the results here demonstrate that in concordance with their mechanism of action, the in vitro BiTE®-mediated CTL assay is applicable and sensitive to immunomodulatory agents acting via a variety of mechanisms.Brendon FrankHao GuoHervé LebrecXiaoting WangTaylor & Francis Grouparticlebiteimmunomodulation; in vitroctl activitycynomolgusImmunologic diseases. AllergyRC581-607Toxicology. PoisonsRA1190-1270ENJournal of Immunotoxicology, Vol 18, Iss 1, Pp 154-162 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	bite immunomodulation; in vitro ctl activity cynomolgus Immunologic diseases. Allergy RC581-607 Toxicology. Poisons RA1190-1270
spellingShingle	bite immunomodulation; in vitro ctl activity cynomolgus Immunologic diseases. Allergy RC581-607 Toxicology. Poisons RA1190-1270 Brendon Frank Hao Guo Hervé Lebrec Xiaoting Wang Application of a newly-developed cynomolgus macaque BiTE-mediated cytotoxic T-lymphocyte activity assay to various immunomodulatory agents in vitro
description	The immunotoxic potential of drug candidates is assessed through the examination of results from a variety of in vitro and in vivo immunophenotyping and functional study endpoints in pre-clinical studies. CD8+ cytotoxic T-lymphocyte (CTL) activity impairment by immunosuppressive agents is recognized to be a potentiating factor for decreased antiviral defense and increased cancer risk. A bi-specific T-cell engager (BiTE®)-mediated CTL activity assay that applies to ex vivo experimentation in non-human primates in the context of toxicology studies was successfully developed and applied in cynomolgus monkey regulatory studies. While an ex vivo analysis conducted in the context of repeat-dose toxicology studies focuses on the long-term impact on CTL function, an in vitro assay with the same experimental design captures acute effects in the presence of the test article. Here, the in vitro assay was applied to a list of drugs with known clinical immunomodulatory impact to understand the applicability of the assay. The results showed this assay was sensitive to a wide range of immunosuppressants directly targeting cell-intrinsic signaling pathways in activated CTL. However, agents executing immuno-modulation through inhibiting cytokines/cytokine receptors, co-stimulatory molecules, and cell adhesion and migration pathways did not impair the CTL activity in this short-term in vitro culture. In addition, anti-PD-1/PD-L1 immune checkpoint blockers enhanced the CTL activity. Taken together, the results here demonstrate that in concordance with their mechanism of action, the in vitro BiTE®-mediated CTL assay is applicable and sensitive to immunomodulatory agents acting via a variety of mechanisms.
format	article
author	Brendon Frank Hao Guo Hervé Lebrec Xiaoting Wang
author_facet	Brendon Frank Hao Guo Hervé Lebrec Xiaoting Wang
author_sort	Brendon Frank
title	Application of a newly-developed cynomolgus macaque BiTE-mediated cytotoxic T-lymphocyte activity assay to various immunomodulatory agents in vitro
title_short	Application of a newly-developed cynomolgus macaque BiTE-mediated cytotoxic T-lymphocyte activity assay to various immunomodulatory agents in vitro
title_full	Application of a newly-developed cynomolgus macaque BiTE-mediated cytotoxic T-lymphocyte activity assay to various immunomodulatory agents in vitro
title_fullStr	Application of a newly-developed cynomolgus macaque BiTE-mediated cytotoxic T-lymphocyte activity assay to various immunomodulatory agents in vitro
title_full_unstemmed	Application of a newly-developed cynomolgus macaque BiTE-mediated cytotoxic T-lymphocyte activity assay to various immunomodulatory agents in vitro
title_sort	application of a newly-developed cynomolgus macaque bite-mediated cytotoxic t-lymphocyte activity assay to various immunomodulatory agents in vitro
publisher	Taylor & Francis Group
publishDate	2021
url	https://doaj.org/article/e0ce9dcc7d614ab5b9780e895fd53896
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Application of a newly-developed cynomolgus macaque BiTE-mediated cytotoxic T-lymphocyte activity assay to various immunomodulatory agents in vitro

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