Evaluation of the Ability of Immune Humanized Mice to Demonstrate CD20‐Specific Cytotoxicity Induced by Ofatumumab

CD20 monoclonal antibodies are well‐established therapeutics for the treatment of B‐cell malignancies. Several mechanisms of target cell killing occur from anti‐CD20 therapy, including complement‐dependent cytotoxicity (CDC) cell lysis and antibody‐dependent cell‐mediated cytotoxicity. Human Fc rece...

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Main Authors:	Kenrick M. Semple, Carlos M. Gonzaléz, Melissa Zarr, José R. Austin, Vikram Patel, Kristina E. Howard
Format:	Article
Language:	English
Published:	Wiley 2019-05-01
Series:	Clinical and Translational Science
Online Access:	https://doi.org/10.1111/cts.12613

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spelling	doaj-42101265439442b59af085088b6bc82f2020-11-24T22:19:42ZengWileyClinical and Translational Science1752-80541752-80622019-05-0112328329010.1111/cts.12613Evaluation of the Ability of Immune Humanized Mice to Demonstrate CD20‐Specific Cytotoxicity Induced by OfatumumabKenrick M. Semple0Carlos M. Gonzaléz1Melissa Zarr2José R. Austin3Vikram Patel4Kristina E. Howard5Division of Applied Regulatory Sciences Office of Translational Sciences Center for Drug Evaluation and Research US Food and Drug Administration Silver Spring Maryland USADivision of Applied Regulatory Sciences Office of Translational Sciences Center for Drug Evaluation and Research US Food and Drug Administration Silver Spring Maryland USADivision of Pharmaceutical Analysis II Office of Testing and Research Center for Drug Evaluation and Research US Food and Drug Administration Silver Spring Maryland USADivision of Applied Regulatory Sciences Office of Translational Sciences Center for Drug Evaluation and Research US Food and Drug Administration Silver Spring Maryland USADivision of Applied Regulatory Sciences Office of Translational Sciences Center for Drug Evaluation and Research US Food and Drug Administration Silver Spring Maryland USADivision of Applied Regulatory Sciences Office of Translational Sciences Center for Drug Evaluation and Research US Food and Drug Administration Silver Spring Maryland USACD20 monoclonal antibodies are well‐established therapeutics for the treatment of B‐cell malignancies. Several mechanisms of target cell killing occur from anti‐CD20 therapy, including complement‐dependent cytotoxicity (CDC) cell lysis and antibody‐dependent cell‐mediated cytotoxicity. Human Fc receptors (FcRs) are required to mediate these functions and are either not present or not cross‐reactive in mice and most animal species. In contrast, some nonhuman primates have cross‐reactive FcR; however, their cellular expression and function may differ from humans. Therefore, we tested bone marrow‐liver‐thymus (BLT) humanized mice to determine if they could recapitulate the pharmacokinetics (PKs), pharmacodynamics, and potential toxicities of ofatumumab, for which CDC is the predominant mechanism of action. Ofatumumab‐treated BLT mice depleted B cells in a dose‐dependent manner in all tissues sampled and recapitulated the PKs observed in humans, suggesting that BLT mice can mediate the CDC effector mechanism associated with biological drug products.https://doi.org/10.1111/cts.12613
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Kenrick M. Semple Carlos M. Gonzaléz Melissa Zarr José R. Austin Vikram Patel Kristina E. Howard
spellingShingle	Kenrick M. Semple Carlos M. Gonzaléz Melissa Zarr José R. Austin Vikram Patel Kristina E. Howard Evaluation of the Ability of Immune Humanized Mice to Demonstrate CD20‐Specific Cytotoxicity Induced by Ofatumumab Clinical and Translational Science
author_facet	Kenrick M. Semple Carlos M. Gonzaléz Melissa Zarr José R. Austin Vikram Patel Kristina E. Howard
author_sort	Kenrick M. Semple
title	Evaluation of the Ability of Immune Humanized Mice to Demonstrate CD20‐Specific Cytotoxicity Induced by Ofatumumab
title_short	Evaluation of the Ability of Immune Humanized Mice to Demonstrate CD20‐Specific Cytotoxicity Induced by Ofatumumab
title_full	Evaluation of the Ability of Immune Humanized Mice to Demonstrate CD20‐Specific Cytotoxicity Induced by Ofatumumab
title_fullStr	Evaluation of the Ability of Immune Humanized Mice to Demonstrate CD20‐Specific Cytotoxicity Induced by Ofatumumab
title_full_unstemmed	Evaluation of the Ability of Immune Humanized Mice to Demonstrate CD20‐Specific Cytotoxicity Induced by Ofatumumab
title_sort	evaluation of the ability of immune humanized mice to demonstrate cd20‐specific cytotoxicity induced by ofatumumab
publisher	Wiley
series	Clinical and Translational Science
issn	1752-8054 1752-8062
publishDate	2019-05-01
description	CD20 monoclonal antibodies are well‐established therapeutics for the treatment of B‐cell malignancies. Several mechanisms of target cell killing occur from anti‐CD20 therapy, including complement‐dependent cytotoxicity (CDC) cell lysis and antibody‐dependent cell‐mediated cytotoxicity. Human Fc receptors (FcRs) are required to mediate these functions and are either not present or not cross‐reactive in mice and most animal species. In contrast, some nonhuman primates have cross‐reactive FcR; however, their cellular expression and function may differ from humans. Therefore, we tested bone marrow‐liver‐thymus (BLT) humanized mice to determine if they could recapitulate the pharmacokinetics (PKs), pharmacodynamics, and potential toxicities of ofatumumab, for which CDC is the predominant mechanism of action. Ofatumumab‐treated BLT mice depleted B cells in a dose‐dependent manner in all tissues sampled and recapitulated the PKs observed in humans, suggesting that BLT mice can mediate the CDC effector mechanism associated with biological drug products.
url	https://doi.org/10.1111/cts.12613
work_keys_str_mv	AT kenrickmsemple evaluationoftheabilityofimmunehumanizedmicetodemonstratecd20specificcytotoxicityinducedbyofatumumab AT carlosmgonzalez evaluationoftheabilityofimmunehumanizedmicetodemonstratecd20specificcytotoxicityinducedbyofatumumab AT melissazarr evaluationoftheabilityofimmunehumanizedmicetodemonstratecd20specificcytotoxicityinducedbyofatumumab AT joseraustin evaluationoftheabilityofimmunehumanizedmicetodemonstratecd20specificcytotoxicityinducedbyofatumumab AT vikrampatel evaluationoftheabilityofimmunehumanizedmicetodemonstratecd20specificcytotoxicityinducedbyofatumumab AT kristinaehoward evaluationoftheabilityofimmunehumanizedmicetodemonstratecd20specificcytotoxicityinducedbyofatumumab
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Evaluation of the Ability of Immune Humanized Mice to Demonstrate CD20‐Specific Cytotoxicity Induced by Ofatumumab

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