Genetic background and immunological status influence B cell repertoire diversity in mice

Chaaya, Nancy; Shahsavarian, M.; Maffucci, Irene; Friboulet, Alain; Offmann, Bernard; Léger, Jean-Benoist; Rousseau, Sylvain; Avalle, Bérangère; Padiolleau-Lefèvre, Séverine

doi:10.1038/s41598-019-50714-y

Cited by 6 publications

(4 citation statements)

References 37 publications

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“…A review of the lead candidate sequences further underscores the importance of risk mitigation in antibody discovery through the use of multiple strains of mice for added diversity. It is well documented that genetic backgrounds heavily influence the B cell repertoire diversity [ 24 , 25 ]. Therefore, in cases where rapid discovery is imperative, starting with multiple strains can improve the diversity in gene usage for V(D)J recombination.…”

Section: Discussionmentioning

confidence: 99%

Accelerated antibody discovery targeting the SARS-CoV-2 spike protein for COVID-19 therapeutic potential

Mullen¹,

Abdullah²,

Boucher³

et al. 2021

Antibody Therapeutics

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Background: Rapid deployment of technologies capable of high-throughput and high-resolution screening is imperative for timely response to viral outbreaks. Risk mitigation in the form of leveraging multiple advanced technologies further increases the likelihood of identifying efficacious treatments in an aggressive timeline. Methods: In this study, we describe two parallel, yet distinct, in vivo approaches for accelerated discovery of antibodies targeting the SARS-CoV-2 spike protein. Working with human transgenic Alloy-GK mice, we detail a single B-cell discovery workflow to directly interrogate antibodies secreted from plasma cells for binding specificity and ACE2 receptor blocking activity. Additionally, we describe a concurrent accelerated hybridoma-based workflow utilizing a DiversimAb™ mouse model for increased diversity. Results: The panel of antibodies isolated from both workflows revealed binding to distinct epitopes with both blocking and non-blocking profiles. Sequence analysis of the resulting lead candidates uncovered additional diversity with the opportunity for straightforward engineering and affinity maturation. Conclusions: By combining in vivo models with advanced integration of screening and selection platforms, lead antibody candidates can be sequenced and fully characterized within one to three months.

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Section: Discussionmentioning

confidence: 99%

Accelerated antibody discovery targeting the SARS-CoV-2 spike protein for COVID-19 therapeutic potential

Mullen¹,

Abdullah²,

Boucher³

et al. 2021

Antibody Therapeutics

View full text Add to dashboard Cite

show abstract

“…It is well documented that genetic backgrounds heavily influence the B cell repertoire diversity. 20,21 Therefore, in cases where rapid discovery is imperative, starting with multiple strains can improve the diversity in gene usage for V(D)J recombination. In the case of the Abveris DiversimAb mice, two separate background strains were leveraged (DiversimAb vs. DivergimAb) to further increase the output sequence diversity.…”

Section: Discussionmentioning

confidence: 99%

Accelerated Antibody Discovery Targeting the SARS-CoV-2 Spike Protein for COVID-19 Therapeutic Potential

Mullen

Abdullah

Boucher

et al. 2021

Preprint

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Rapid deployment of technologies capable of high-throughput and high-resolution screening is imperative for timely response to viral outbreaks. Risk mitigation in the form of leveraging multiple advanced technologies further increases the likelihood of identifying efficacious treatments in an aggressive timeline. In this study, we describe two parallel, yet distinct, in vivo approaches for accelerated discovery of antibodies targeting the SARS-CoV-2 spike protein. Working with human transgenic Alloy-GK mice, we detail a single B-cell discovery workflow to directly interrogate antibodies secreted from plasma cells for binding specificity and ACE2 receptor blocking activity. Additionally, we describe a concurrent accelerated hybridoma-based workflow utilizing a DiversimAb mouse model for increased diversity. The panel of antibodies isolated from both workflows revealed binding to distinct epitopes with both blocking and non-blocking profiles. Sequence analysis of the resulting lead candidates uncovered additional diversity with the opportunity for straightforward engineering and affinity maturation. By combining in vivo models with advanced integration of screening and selection platforms, lead antibody candidates can be sequenced and fully characterized within one to three months.

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“…To confirm and better characterize the advantage of Tg animals, we also performed immunoglobulin repertoire analysis with NGS (Rep-seq), which yields a higher resolution survey of the antibody repertoire ( 19 , 24 , 34 , 35 ). Rep-seq is a powerful tool for obtaining vast amounts of information about the antibody repertoire and it's utilization is emerging in various fields, for example analyzing the effects of vaccinations ( 34 , 36 ), aging ( 37 ), hematological malignancies ( 38 ), autoimmune diseases ( 39 ) or simply the normal repertoire ( 40 ), either in humans or in mice ( 41 ).…”

Section: Discussionmentioning

confidence: 99%

FcRn Overexpression Expands Diversity of the Humoral Immune Response in bFcRn Transgenic Mice

et al. 2020

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The neonatal Fc receptor (FcRn) plays key roles in IgG and albumin homeostasis, maternal IgG transport, and antigen presentation of IgG-opsonized antigens. Previously, we reported that transgenic (Tg) mice that overexpress bovine FcRn (bFcRn) have augmented T-dependent humoral immune response with increased IgG protection, higher level of antigen-specific antibodies, greater number of antigen-specific B cells, and effective immune response even against weakly immunogenic epitopes. In this study we analyzed the diversity of the humoral immune response of bFcRn Tg mice, using a length distribution analysis (spectratyping) and next generation sequencing (NGS) of the immunoglobulin heavy chain variable regions. Our analysis showed that in response to immunization with ovalbumin or transfected cells that expressed a unique membrane protein, our Tg animals developed a more diverse plasma cell repertoire than controls, which manifested in greater numbers of different clones, and clusters with fewer highly expanded large clones, as identified by the variable region (CDR3) of the immunoglobulin heavy chain. The increased antibody diversity in Tg mice after immunization was observed at both IgM and IgG levels, indicating that the increased humoral immune diversity in Tg mice is due to a higher number of both activated, antigen-specific naïve and isotype switched B cells. We thus demonstrated that the BCR repertoire of the immunized bFcRn Tg animals is more diverse compared to wild type mice, which likely makes these Tg mice a better choice for monoclonal antibody production against challenging antigens, including the extracellular regions of cell membrane proteins.

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Genetic background and immunological status influence B cell repertoire diversity in mice

Cited by 6 publications

References 37 publications

Accelerated antibody discovery targeting the SARS-CoV-2 spike protein for COVID-19 therapeutic potential

Accelerated antibody discovery targeting the SARS-CoV-2 spike protein for COVID-19 therapeutic potential

Accelerated Antibody Discovery Targeting the SARS-CoV-2 Spike Protein for COVID-19 Therapeutic Potential

FcRn Overexpression Expands Diversity of the Humoral Immune Response in bFcRn Transgenic Mice

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