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Human Antibody Production in Transgenic Animals

Fully human antibodies from transgenic animals account for an increasing number of new therapeutics. After immunization, diverse human monoclonal antibodies of high affinity can be obtained from transgenic rodents, while large animals, such as transchromosomic cattle, have produced respectable amoun...

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Autores principales: Brüggemann, Marianne, Osborn, Michael J., Ma, Biao, Hayre, Jasvinder, Avis, Suzanne, Lundstrom, Brian, Buelow, Roland
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Basel 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359279/
https://www.ncbi.nlm.nih.gov/pubmed/25467949
http://dx.doi.org/10.1007/s00005-014-0322-x
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author Brüggemann, Marianne
Osborn, Michael J.
Ma, Biao
Hayre, Jasvinder
Avis, Suzanne
Lundstrom, Brian
Buelow, Roland
author_facet Brüggemann, Marianne
Osborn, Michael J.
Ma, Biao
Hayre, Jasvinder
Avis, Suzanne
Lundstrom, Brian
Buelow, Roland
author_sort Brüggemann, Marianne
collection PubMed
description Fully human antibodies from transgenic animals account for an increasing number of new therapeutics. After immunization, diverse human monoclonal antibodies of high affinity can be obtained from transgenic rodents, while large animals, such as transchromosomic cattle, have produced respectable amounts of specific human immunoglobulin (Ig) in serum. Several strategies to derive animals expressing human antibody repertoires have been successful. In rodents, gene loci on bacterial artificial chromosomes or yeast artificial chromosomes were integrated by oocyte microinjection or transfection of embryonic stem (ES) cells, while ruminants were derived from manipulated fibroblasts with integrated human chromosome fragments or human artificial chromosomes. In all strains, the endogenous Ig loci have been silenced by gene targeting, either in ES or fibroblast cells, or by zinc finger technology via DNA microinjection; this was essential for optimal production. However, comparisons showed that fully human antibodies were not as efficiently produced as wild-type Ig. This suboptimal performance, with respect to immune response and antibody yield, was attributed to imperfect interaction of the human constant region with endogenous signaling components such as the Igα/β in mouse, rat or cattle. Significant improvements were obtained when the human V-region genes were linked to the endogenous C(H)-region, either on large constructs or, separately, by site-specific integration, which could also silence the endogenous Ig locus by gene replacement or inversion. In animals with knocked-out endogenous Ig loci and integrated large IgH loci, containing many human Vs, all D and all J segments linked to endogenous C genes, highly diverse human antibody production similar to normal animals was obtained.
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spelling pubmed-43592792015-03-18 Human Antibody Production in Transgenic Animals Brüggemann, Marianne Osborn, Michael J. Ma, Biao Hayre, Jasvinder Avis, Suzanne Lundstrom, Brian Buelow, Roland Arch Immunol Ther Exp (Warsz) Review Fully human antibodies from transgenic animals account for an increasing number of new therapeutics. After immunization, diverse human monoclonal antibodies of high affinity can be obtained from transgenic rodents, while large animals, such as transchromosomic cattle, have produced respectable amounts of specific human immunoglobulin (Ig) in serum. Several strategies to derive animals expressing human antibody repertoires have been successful. In rodents, gene loci on bacterial artificial chromosomes or yeast artificial chromosomes were integrated by oocyte microinjection or transfection of embryonic stem (ES) cells, while ruminants were derived from manipulated fibroblasts with integrated human chromosome fragments or human artificial chromosomes. In all strains, the endogenous Ig loci have been silenced by gene targeting, either in ES or fibroblast cells, or by zinc finger technology via DNA microinjection; this was essential for optimal production. However, comparisons showed that fully human antibodies were not as efficiently produced as wild-type Ig. This suboptimal performance, with respect to immune response and antibody yield, was attributed to imperfect interaction of the human constant region with endogenous signaling components such as the Igα/β in mouse, rat or cattle. Significant improvements were obtained when the human V-region genes were linked to the endogenous C(H)-region, either on large constructs or, separately, by site-specific integration, which could also silence the endogenous Ig locus by gene replacement or inversion. In animals with knocked-out endogenous Ig loci and integrated large IgH loci, containing many human Vs, all D and all J segments linked to endogenous C genes, highly diverse human antibody production similar to normal animals was obtained. Springer Basel 2014-12-03 2015 /pmc/articles/PMC4359279/ /pubmed/25467949 http://dx.doi.org/10.1007/s00005-014-0322-x Text en © The Author(s) 2014 https://creativecommons.org/licenses/by/4.0/ Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
spellingShingle Review
Brüggemann, Marianne
Osborn, Michael J.
Ma, Biao
Hayre, Jasvinder
Avis, Suzanne
Lundstrom, Brian
Buelow, Roland
Human Antibody Production in Transgenic Animals
title Human Antibody Production in Transgenic Animals
title_full Human Antibody Production in Transgenic Animals
title_fullStr Human Antibody Production in Transgenic Animals
title_full_unstemmed Human Antibody Production in Transgenic Animals
title_short Human Antibody Production in Transgenic Animals
title_sort human antibody production in transgenic animals
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359279/
https://www.ncbi.nlm.nih.gov/pubmed/25467949
http://dx.doi.org/10.1007/s00005-014-0322-x
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