High-Affinity IgG Antibodies Develop Naturally in Ig-Knockout Rats Carrying Germline Human IgH/Igκ/Igλ Loci Bearing the Rat CH Region

Osborn, Michael J.; Ma, Biao; Avis, Suzanne; Binnie, Ashleigh; Dilley, Jeanette; Yang, Xi; Lindquist, Kevin C.; Ménoret, Séverine; Iscache, Anne-Laure; Ouisse, Laure-Hélène; Rajpal, Arvind; Anegón, Ignacio; Neuberger, Michael S.; Buelow, Roland; Brüggemann, Marianne

doi:10.4049/jimmunol.1203041

Cited by 82 publications

(84 citation statements)

References 55 publications

(60 reference statements)

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“…Large-scale production of therapeutic proteins that are of interest for the pharmaceutical industry can be produced in a time-and cost-efficient manner. Another human health-related application is creation of transgenic chickens expressing human antibodies, similar to "humanized" mice, rats, and cattle (11)(12)(13)(14). Such chickens would take advantage of the phylogenetic distance between chickens and humans for the discovery of human therapeutic antibodies against targets that are highly conserved between mice and humans but immunogenic in avian species.…”

mentioning

confidence: 99%

Immunoglobulin knockout chickens via efficient homologous recombination in primordial germ cells

Schusser

Collarini²,

Yi³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

128

134

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Gene targeting by homologous recombination or by sequencespecific nucleases allows the precise modification of genomes and genes to elucidate their functions. Although gene targeting has been used extensively to modify the genomes of mammals, fish, and amphibians, a targeting technology has not been available for the avian genome. Many of the principles of humoral immunity were discovered in chickens, yet the lack of gene targeting technologies in birds has limited biomedical research using this species. Here we describe targeting the joining (J) gene segment of the chicken Ig heavy chain gene by homologous recombination in primordial germ cells to establish fully transgenic chickens carrying the knockout. In homozygous knockouts, Ig heavy chain production is eliminated, and no antibody response is elicited on immunization. Migration of B-lineage precursors into the bursa of Fabricius is unaffected, whereas development into mature B cells and migration from the bursa are blocked in the mutants. Other cell types in the immune system appear normal. Chickens lacking the peripheral B-cell population will provide a unique experimental model to study avian immune responses to infectious disease. More generally, gene targeting in avian primordial germ cells will foster advances in diverse fields of biomedical research such as virology, stem cells, and developmental biology, and provide unique approaches in biotechnology, particularly in the field of antibody discovery.B-cell development | avian immunology | genome editing T he chicken has historically been an important model vertebrate organism in the fields of developmental biology and immunology and has contributed a number of basic tenets to these fields. For example, B lymphocytes were first recognized in chickens as the antibody-producing cells and are named after the bursa of Fabricius, a gut-associated lymphoid tissue (GALT) that is required for B-cell development in chickens (1). Graft-versushost response was first described in chicken embryos (2), and the first attenuated vaccine was developed by Louis Pasteur against fowl cholera caused by Pasteurella multocida. Nevertheless, the lack of a robust genome editing technology including knockouts has put the chicken at a distinct disadvantage to mammalian species, especially the mouse, as a vertebrate animal model. The discovery of ES cells provided a powerful method to make desired changes to genes of interest in the mouse using homologous recombination, but interestingly, ES cells have not been as easily derived from other species. In the case of chickens, ES cells can contribute to all somatic lineages in high-grade chimeras, but germ-line transmission has not yet been demonstrated, precluding their use in creating fully transgenic chickens (3). Although ES cells are not germ line competent in chickens, embryo-derived primordial germ cells (PGCs) can be cultured indefinitely, transfected, clonally selected, and reintroduced into the embryo where they colonize the gonad and give rise to fully transgenic progeny ...

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mentioning

confidence: 99%

Immunoglobulin knockout chickens via efficient homologous recombination in primordial germ cells

Schusser

Collarini²,

Yi³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

128

134

View full text Add to dashboard Cite

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“…The introduced light chains were fully human. In animals with knocked-out endogenous Ig loci and integrated large IgH loci, containing many human Vs, all D and all J segments expressed as chimeric H-chains with endogenous C-genes, as well as the light chains, highly diverse human antibody production similar to normal animals was obtained (Osborn et al 2013) (OmniRat). Recently developed rat lines expressing IgG with fixed L-chain (OmniFlic rat) or, separately, heavychain-only IgG (UniRat) have been generated.…”

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confidence: 96%

Transgenic animals and genetic engineering techniques. Nantes, France, 2–3 July, 2015

et al. 2015

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“…Factors that can favor recovery of internalized phage include high abundance of the target on the cell surface, rapid constitutive target internalization, high affinity, accessible epitope, and multivalent phage (Burris et al 2011;. While multivalent display (usually five copies per phage) allows greater recovery of lower affinity clones than does monovalent display (Burris et al 2011), and, therefore, is likely to lead to pools of higher diversity, numerous examples exist of monovalent phagemid systems giving rise to internalizing clones from naïve human scfv library selections (McDonagh et al 2008;Osborn et al 2013;Sapra et al 2013).…”

Section: �3 Agnostic Approach To Antibody Productionmentioning

confidence: 99%

“…Human immunoglobulin transgenic rodents provide a method of obtaining fully human monoclonal antibodies using conventional hybridoma technology (Fishwild et al 1996;Mendez et al 1997;Osborn et al 2013;Ma et al 2013). Transgenic rodents offer a powerful way to generate antibodies to validated targets relatively rapidly without the need for humanization.…”

Section: Approaches To Antibody Isolationmentioning

confidence: 99%

Selecting an Optimal Antibody for Antibody- Drug Conjugate Therapy

Ritchie

Bloom

Carven

et al. 2015

Antibody-Drug Conjugates

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Selection of appropriate targets is likely the most important consideration for the success of an antibody-drug conjugate (ADC) development program. Target selection for ADCs can be classified into two principal approaches: target-first and antibody-first approach or agnostic approach (Fig. 3.1). In the target-first approach, a target is chosen based on a set of factors, including expression pattern, abundance and internalization properties, and an antibody-generation campaign is focused on isolation of antibodies against this target. In the agnostic approach, antibodies capable of binding to and internalizing in tumor cells are isolated, followed by retrospective identification of their targets. While the target-first approach may have the advantage of a higher degree confidence in the suitability and novelty of the target based on prior knowledge of target properties, it requires significant work before internalizing antibodies become available. By contrast, the agnostic approach leads quickly to reagents suitable for testing hypotheses directly, although this strategy tends to favor highly expressed surface antigens, which are likely to have been described previously.

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High-Affinity IgG Antibodies Develop Naturally in Ig-Knockout Rats Carrying Germline Human IgH/Igκ/Igλ Loci Bearing the Rat CH Region

Cited by 82 publications

References 55 publications

Immunoglobulin knockout chickens via efficient homologous recombination in primordial germ cells

Immunoglobulin knockout chickens via efficient homologous recombination in primordial germ cells

Transgenic animals and genetic engineering techniques. Nantes, France, 2–3 July, 2015

Selecting an Optimal Antibody for Antibody- Drug Conjugate Therapy

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