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  1. Thesis ; Online: Synthetic selection and engineering of antibodies

    Ehling, Roy A.

    2022  

    Keywords info:eu-repo/classification/ddc/570 ; Life sciences
    Language English
    Publisher ETH Zurich
    Publishing country ch
    Document type Thesis ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Immune Literacy: Reading, Writing, and Editing Adaptive Immunity.

    Csepregi, Lucia / Ehling, Roy A / Wagner, Bastian / Reddy, Sai T

    iScience

    2020  Volume 23, Issue 9, Page(s) 101519

    Abstract: Advances in reading, writing, and editing DNA are providing unprecedented insights into the complexity of immunological systems. This combination of systems and synthetic biology methods is enabling the quantitative and precise understanding of molecular ...

    Abstract Advances in reading, writing, and editing DNA are providing unprecedented insights into the complexity of immunological systems. This combination of systems and synthetic biology methods is enabling the quantitative and precise understanding of molecular recognition in adaptive immunity, thus providing a framework for reprogramming immune responses for translational medicine. In this review, we will highlight state-of-the-art methods such as immune repertoire sequencing, immunoinformatics, and immunogenomic engineering and their application toward adaptive immunity. We showcase novel and interdisciplinary approaches that have the promise of transforming the design and breadth of molecular and cellular immunotherapies.
    Keywords covid19
    Language English
    Publishing date 2020-09-01
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 2589-0042
    ISSN (online) 2589-0042
    DOI 10.1016/j.isci.2020.101519
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Immune Literacy

    Lucia Csepregi / Roy A. Ehling / Bastian Wagner / Sai T. Reddy

    iScience, Vol 23, Iss 9, Pp 101519- (2020)

    Reading, Writing, and Editing Adaptive Immunity

    2020  

    Abstract: Summary: Advances in reading, writing, and editing DNA are providing unprecedented insights into the complexity of immunological systems. This combination of systems and synthetic biology methods is enabling the quantitative and precise understanding of ... ...

    Abstract Summary: Advances in reading, writing, and editing DNA are providing unprecedented insights into the complexity of immunological systems. This combination of systems and synthetic biology methods is enabling the quantitative and precise understanding of molecular recognition in adaptive immunity, thus providing a framework for reprogramming immune responses for translational medicine. In this review, we will highlight state-of-the-art methods such as immune repertoire sequencing, immunoinformatics, and immunogenomic engineering and their application toward adaptive immunity. We showcase novel and interdisciplinary approaches that have the promise of transforming the design and breadth of molecular and cellular immunotherapies.
    Keywords Immunology ; Systems Biology ; Science ; Q
    Language English
    Publishing date 2020-09-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Synthetic coevolution reveals adaptive mutational trajectories of neutralizing antibodies and SARS-CoV-2

    Ehling, Roy A. / Minot, Mason / Overath, Max D. / Sheward, Daniel J. / Han, Jiami / Gao, Beichen / Taft, Joseph M. / Pertseva, Margarita / Weber, Cédric R. / Frei, Lester / Bikias, Thomas / Murrell, Ben / Reddy, Sai T.

    bioRxiv

    Abstract: The Covid-19 pandemic showcases a coevolutionary race between the human immune system and SARS-CoV-2, mirroring the Red Queen hypothesis of evolutionary biology. The immune system generates neutralizing antibodies targeting the SARS-CoV-2 spike protein9s ...

    Abstract The Covid-19 pandemic showcases a coevolutionary race between the human immune system and SARS-CoV-2, mirroring the Red Queen hypothesis of evolutionary biology. The immune system generates neutralizing antibodies targeting the SARS-CoV-2 spike protein9s receptor binding domain (RBD), crucial for host cell invasion, while the virus evolves to evade antibody recognition. Here, we establish a synthetic coevolution system combining high-throughput screening of antibody and RBD variant libraries with protein mutagenesis, surface display, and deep sequencing. Additionally, we train a protein language machine learning model that predicts antibody escape to RBD variants. Synthetic coevolution reveals antagonistic and compensatory mutational trajectories of neutralizing antibodies and SARS-CoV-2 variants, enhancing the understanding of this evolutionary conflict.
    Keywords covid19
    Language English
    Publishing date 2024-04-01
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2024.03.28.587189
    Database COVID19

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  5. Article ; Online: Evasion of neutralising antibodies by omicron sublineage BA.2.75.

    Sheward, Daniel J / Kim, Changil / Fischbach, Julian / Muschiol, Sandra / Ehling, Roy A / Björkström, Niklas K / Karlsson Hedestam, Gunilla B / Reddy, Sai T / Albert, Jan / Peacock, Thomas P / Murrell, Ben

    The Lancet. Infectious diseases

    2022  Volume 22, Issue 10, Page(s) 1421–1422

    MeSH term(s) Antibodies, Neutralizing ; Antibodies, Viral ; Humans
    Chemical Substances Antibodies, Neutralizing ; Antibodies, Viral
    Language English
    Publishing date 2022-09-01
    Publishing country United States
    Document type Letter
    ZDB-ID 2061641-7
    ISSN 1474-4457 ; 1473-3099
    ISSN (online) 1474-4457
    ISSN 1473-3099
    DOI 10.1016/S1473-3099(22)00524-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Omicron sublineage BA.2.75.2 exhibits extensive escape from neutralising antibodies.

    Sheward, Daniel J / Kim, Changil / Fischbach, Julian / Sato, Kenta / Muschiol, Sandra / Ehling, Roy A / Björkström, Niklas K / Karlsson Hedestam, Gunilla B / Reddy, Sai T / Albert, Jan / Peacock, Thomas P / Murrell, Ben

    The Lancet. Infectious diseases

    2022  Volume 22, Issue 11, Page(s) 1538–1540

    MeSH term(s) Humans ; Antibodies, Neutralizing ; Antibodies, Viral
    Chemical Substances Antibodies, Neutralizing ; Antibodies, Viral
    Language English
    Publishing date 2022-10-14
    Publishing country United States
    Document type Letter
    ZDB-ID 2061641-7
    ISSN 1474-4457 ; 1473-3099
    ISSN (online) 1474-4457
    ISSN 1473-3099
    DOI 10.1016/S1473-3099(22)00663-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Generation of a single-cell B cell atlas of antibody repertoires and transcriptomes to identify signatures associated with antigen specificity.

    Agrafiotis, Andreas / Neumeier, Daniel / Hong, Kai-Lin / Chowdhury, Tasnia / Ehling, Roy / Kuhn, Raphael / Sandu, Ioana / Kreiner, Victor / Cotet, Tudor-Stefan / Shlesinger, Danielle / Laslo, Daria / Anzböck, Stine / Starkie, Dale / Lightwood, Daniel J / Oxenius, Annette / Reddy, Sai T / Yermanos, Alexander

    iScience

    2023  Volume 26, Issue 3, Page(s) 106055

    Abstract: Although new genomics-based pipelines have potential to augment antibody discovery, these methods remain in their infancy due to an incomplete understanding of the selection process that governs B cell clonal selection, expansion, and antigen specificity. ...

    Abstract Although new genomics-based pipelines have potential to augment antibody discovery, these methods remain in their infancy due to an incomplete understanding of the selection process that governs B cell clonal selection, expansion, and antigen specificity. Furthermore, it remains unknown how factors such as aging and reduction of tolerance influence B cell selection. Here we perform single-cell sequencing of antibody repertoires and transcriptomes of murine B cells following immunizations with a model therapeutic antigen target. We determine the relationship between antibody repertoires, gene expression signatures, and antigen specificity across 100,000 B cells. Recombinant expression and characterization of 227 monoclonal antibodies revealed the existence of clonally expanded and class-switched antigen-specific B cells that were more frequent in young mice. Although integrating multiple repertoire features such as germline gene usage and transcriptional signatures failed to distinguish antigen-specific from nonspecific B cells, other features such as immunoglobulin G (IgG) subtype and sequence composition correlated with antigen specificity.
    Language English
    Publishing date 2023-01-25
    Publishing country United States
    Document type Journal Article
    ISSN 2589-0042
    ISSN (online) 2589-0042
    DOI 10.1016/j.isci.2023.106055
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Neutralisation sensitivity of the SARS-CoV-2 omicron (B.1.1.529) variant: a cross-sectional study.

    Sheward, Daniel J / Kim, Changil / Ehling, Roy A / Pankow, Alec / Castro Dopico, Xaquin / Dyrdak, Robert / Martin, Darren P / Reddy, Sai T / Dillner, Joakim / Karlsson Hedestam, Gunilla B / Albert, Jan / Murrell, Ben

    The Lancet. Infectious diseases

    2022  Volume 22, Issue 6, Page(s) 813–820

    Abstract: Background: The SARS-CoV-2 omicron (B.1.1.529) variant, which was first identified in November, 2021, spread rapidly in many countries, with a spike protein highly diverged from previously known variants, and raised concerns that this variant might ... ...

    Abstract Background: The SARS-CoV-2 omicron (B.1.1.529) variant, which was first identified in November, 2021, spread rapidly in many countries, with a spike protein highly diverged from previously known variants, and raised concerns that this variant might evade neutralising antibody responses. We therefore aimed to characterise the sensitivity of the omicron variant to neutralisation.
    Methods: For this cross-sectional study, we cloned the sequence encoding the omicron spike protein from a diagnostic sample to establish an omicron pseudotyped virus neutralisation assay. We quantified the neutralising antibody ID
    Findings: Neutralising antibody responses in reference sample pools sampled shortly after infection or vaccination were substantially less potent against the omicron variant than against wild-type SARS-CoV-2 (seven-fold to 42-fold reduction in ID
    Interpretation: These data highlight the extensive, but incomplete, evasion of neutralising antibody responses by the omicron variant, and suggest that boosting with licensed vaccines might be sufficient to raise neutralising antibody titres to protective levels.
    Funding: European Union Horizon 2020 research and innovation programme, European and Developing Countries Clinical Trials Partnership, SciLifeLab, and the Erling-Persson Foundation.
    MeSH term(s) Antibodies, Monoclonal ; Antibodies, Monoclonal, Humanized ; Antibodies, Neutralizing ; Antibodies, Viral ; COVID-19/epidemiology ; COVID-19 Vaccines ; Cross-Sectional Studies ; Humans ; SARS-CoV-2/genetics ; Spike Glycoprotein, Coronavirus/genetics
    Chemical Substances Antibodies, Monoclonal ; Antibodies, Monoclonal, Humanized ; Antibodies, Neutralizing ; Antibodies, Viral ; COVID-19 Vaccines ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; sotrovimab (1MTK0BPN8V) ; imdevimab (2Z3DQD2JHM) ; bamlanivimab (45I6OFJ8QH) ; casirivimab (J0FI6WE1QN) ; etesevimab (N7Q9NLF11I)
    Language English
    Publishing date 2022-03-17
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2061641-7
    ISSN 1474-4457 ; 1473-3099
    ISSN (online) 1474-4457
    ISSN 1473-3099
    DOI 10.1016/S1473-3099(22)00129-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Deep mutational learning predicts ACE2 binding and antibody escape to combinatorial mutations in the SARS-CoV-2 receptor-binding domain.

    Taft, Joseph M / Weber, Cédric R / Gao, Beichen / Ehling, Roy A / Han, Jiami / Frei, Lester / Metcalfe, Sean W / Overath, Max D / Yermanos, Alexander / Kelton, William / Reddy, Sai T

    Cell

    2022  Volume 185, Issue 21, Page(s) 4008–4022.e14

    Abstract: The continual evolution of SARS-CoV-2 and the emergence of variants that show resistance to vaccines and neutralizing antibodies threaten to prolong the COVID-19 pandemic. Selection and emergence of SARS-CoV-2 variants are driven in part by mutations ... ...

    Abstract The continual evolution of SARS-CoV-2 and the emergence of variants that show resistance to vaccines and neutralizing antibodies threaten to prolong the COVID-19 pandemic. Selection and emergence of SARS-CoV-2 variants are driven in part by mutations within the viral spike protein and in particular the ACE2 receptor-binding domain (RBD), a primary target site for neutralizing antibodies. Here, we develop deep mutational learning (DML), a machine-learning-guided protein engineering technology, which is used to investigate a massive sequence space of combinatorial mutations, representing billions of RBD variants, by accurately predicting their impact on ACE2 binding and antibody escape. A highly diverse landscape of possible SARS-CoV-2 variants is identified that could emerge from a multitude of evolutionary trajectories. DML may be used for predictive profiling on current and prospective variants, including highly mutated variants such as Omicron, thus guiding the development of therapeutic antibody treatments and vaccines for COVID-19.
    MeSH term(s) Angiotensin-Converting Enzyme 2/chemistry ; Angiotensin-Converting Enzyme 2/genetics ; Angiotensin-Converting Enzyme 2/metabolism ; Antibodies, Neutralizing ; Antibodies, Viral ; COVID-19 ; COVID-19 Vaccines ; Humans ; Mutation ; Pandemics ; Protein Binding ; SARS-CoV-2/genetics ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/metabolism
    Chemical Substances Antibodies, Neutralizing ; Antibodies, Viral ; COVID-19 Vaccines ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
    Language English
    Publishing date 2022-08-31
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2022.08.024
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Phenotypic determinism and stochasticity in antibody repertoires of clonally expanded plasma cells.

    Neumeier, Daniel / Yermanos, Alexander / Agrafiotis, Andreas / Csepregi, Lucia / Chowdhury, Tasnia / Ehling, Roy A / Kuhn, Raphael / Cotet, Tudor-Stefan / Brisset-Di Roberto, Raphaël / Di Tacchio, Mariangela / Antonialli, Renan / Starkie, Dale / Lightwood, Daniel J / Oxenius, Annette / Reddy, Sai T

    Proceedings of the National Academy of Sciences of the United States of America

    2022  Volume 119, Issue 18, Page(s) e2113766119

    Abstract: The capacity of humoral B cell-mediated immunity to effectively respond to and protect against pathogenic infections is largely driven by the presence of a diverse repertoire of polyclonal antibodies in the serum, which are produced by plasma cells (PCs). ...

    Abstract The capacity of humoral B cell-mediated immunity to effectively respond to and protect against pathogenic infections is largely driven by the presence of a diverse repertoire of polyclonal antibodies in the serum, which are produced by plasma cells (PCs). Recent studies have started to reveal the balance between deterministic mechanisms and stochasticity of antibody repertoires on a genotypic level (i.e., clonal diversity, somatic hypermutation, and germline gene usage). However, it remains unclear if clonal selection and expansion of PCs follow any deterministic rules or are stochastic with regards to phenotypic antibody properties (i.e., antigen-binding, affinity, and epitope specificity). Here, we report on the in-depth genotypic and phenotypic characterization of clonally expanded PC antibody repertoires following protein immunization. We find that clonal expansion drives antigen specificity of the most expanded clones (top ∼10), whereas among the rest of the clonal repertoire antigen specificity is stochastic. Furthermore, we report both on a polyclonal repertoire and clonal lineage level that antibody-antigen binding affinity does not correlate with clonal expansion or somatic hypermutation. Last, we provide evidence for convergence toward targeting dominant epitopes despite clonal sequence diversity among the most expanded clones. Our results highlight the extent to which clonal expansion can be ascribed to antigen binding, affinity, and epitope specificity, and they have implications for the assessment of effective vaccines.
    MeSH term(s) Animals ; Antibodies/genetics ; Antibody Affinity ; Antigens ; Epitopes/genetics ; Mice ; Plasma Cells
    Chemical Substances Antibodies ; Antigens ; Epitopes
    Language English
    Publishing date 2022-04-29
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2113766119
    Database MEDical Literature Analysis and Retrieval System OnLINE

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