Efficient Generation of Bispecific Murine Antibodies for Pre-Clinical Investigations in Syngeneic Rodent Models

Abstract Therapeutic concepts exploiting tumor-specific antibodies are often established in pre-clinical xenograft models using immuno-deficient mice. More complex therapeutic paradigms, however, warrant the use of immuno-competent mice, that more accurately capture the relevant biology that is bein...

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Autores principales:	Aran F. Labrijn, Joyce I. Meesters, Matthew Bunce, Anthony A. Armstrong, Sandeep Somani, Tom C. Nesspor, Mark L. Chiu, Işil Altintaş, Sandra Verploegen, Janine Schuurman, Paul W. H. I. Parren
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bbef8d706f08451bb51dc1be0939cbc2
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spelling	oai:doaj.org-article:bbef8d706f08451bb51dc1be0939cbc22021-12-02T16:06:36ZEfficient Generation of Bispecific Murine Antibodies for Pre-Clinical Investigations in Syngeneic Rodent Models10.1038/s41598-017-02823-92045-2322https://doaj.org/article/bbef8d706f08451bb51dc1be0939cbc22017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02823-9https://doaj.org/toc/2045-2322Abstract Therapeutic concepts exploiting tumor-specific antibodies are often established in pre-clinical xenograft models using immuno-deficient mice. More complex therapeutic paradigms, however, warrant the use of immuno-competent mice, that more accurately capture the relevant biology that is being exploited. These models require the use of (surrogate) mouse or rat antibodies to enable optimal interactions with murine effector molecules. Immunogenicity is furthermore decreased, allowing longer-term treatment. We recently described controlled Fab-arm exchange (cFAE) as an easy-to-use method for the generation of therapeutic human IgG1 bispecific antibodies (bsAb). To facilitate the investigation of dual-targeting concepts in immuno-competent mice, we now applied and optimized our method for the generation of murine bsAbs. We show that the optimized combinations of matched point-mutations enabled efficient generation of murine bsAbs for all subclasses studied (mouse IgG1, IgG2a and IgG2b; rat IgG1, IgG2a, IgG2b, and IgG2c). The mutations did not adversely affect the inherent effector functions or pharmacokinetic properties of the corresponding subclasses. Thus, cFAE can be used to efficiently generate (surrogate) mouse or rat bsAbs for pre-clinical evaluation in immuno-competent rodents.Aran F. LabrijnJoyce I. MeestersMatthew BunceAnthony A. ArmstrongSandeep SomaniTom C. NessporMark L. ChiuIşil AltintaşSandra VerploegenJanine SchuurmanPaul W. H. I. ParrenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Aran F. Labrijn Joyce I. Meesters Matthew Bunce Anthony A. Armstrong Sandeep Somani Tom C. Nesspor Mark L. Chiu Işil Altintaş Sandra Verploegen Janine Schuurman Paul W. H. I. Parren Efficient Generation of Bispecific Murine Antibodies for Pre-Clinical Investigations in Syngeneic Rodent Models
description	Abstract Therapeutic concepts exploiting tumor-specific antibodies are often established in pre-clinical xenograft models using immuno-deficient mice. More complex therapeutic paradigms, however, warrant the use of immuno-competent mice, that more accurately capture the relevant biology that is being exploited. These models require the use of (surrogate) mouse or rat antibodies to enable optimal interactions with murine effector molecules. Immunogenicity is furthermore decreased, allowing longer-term treatment. We recently described controlled Fab-arm exchange (cFAE) as an easy-to-use method for the generation of therapeutic human IgG1 bispecific antibodies (bsAb). To facilitate the investigation of dual-targeting concepts in immuno-competent mice, we now applied and optimized our method for the generation of murine bsAbs. We show that the optimized combinations of matched point-mutations enabled efficient generation of murine bsAbs for all subclasses studied (mouse IgG1, IgG2a and IgG2b; rat IgG1, IgG2a, IgG2b, and IgG2c). The mutations did not adversely affect the inherent effector functions or pharmacokinetic properties of the corresponding subclasses. Thus, cFAE can be used to efficiently generate (surrogate) mouse or rat bsAbs for pre-clinical evaluation in immuno-competent rodents.
format	article
author	Aran F. Labrijn Joyce I. Meesters Matthew Bunce Anthony A. Armstrong Sandeep Somani Tom C. Nesspor Mark L. Chiu Işil Altintaş Sandra Verploegen Janine Schuurman Paul W. H. I. Parren
author_facet	Aran F. Labrijn Joyce I. Meesters Matthew Bunce Anthony A. Armstrong Sandeep Somani Tom C. Nesspor Mark L. Chiu Işil Altintaş Sandra Verploegen Janine Schuurman Paul W. H. I. Parren
author_sort	Aran F. Labrijn
title	Efficient Generation of Bispecific Murine Antibodies for Pre-Clinical Investigations in Syngeneic Rodent Models
title_short	Efficient Generation of Bispecific Murine Antibodies for Pre-Clinical Investigations in Syngeneic Rodent Models
title_full	Efficient Generation of Bispecific Murine Antibodies for Pre-Clinical Investigations in Syngeneic Rodent Models
title_fullStr	Efficient Generation of Bispecific Murine Antibodies for Pre-Clinical Investigations in Syngeneic Rodent Models
title_full_unstemmed	Efficient Generation of Bispecific Murine Antibodies for Pre-Clinical Investigations in Syngeneic Rodent Models
title_sort	efficient generation of bispecific murine antibodies for pre-clinical investigations in syngeneic rodent models
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/bbef8d706f08451bb51dc1be0939cbc2
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Efficient Generation of Bispecific Murine Antibodies for Pre-Clinical Investigations in Syngeneic Rodent Models

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