The Pipeline Repertoire for Ig-Seq Analysis

López-Santibáñez-Jácome, Laura; Avendaño‐Vázquez, S. Eréndira; Flores-Jasso, C. Fabián

doi:10.3389/fimmu.2019.00899

Cited by 39 publications

(33 citation statements)

References 93 publications

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“…Raw nucleotide sequences of variable regions can be translated into amino acids by aligning them to germline sequences, thus identifying the V, D and J regions. This can be achieved by programs such as IgBLAST [ 68 ] or IMGT V-Quest [ 69 ] and multiple other tools aimed at processing raw antibody data ( Table 2A , reviewed in [ 150 ]). Similarities between antibody amino acid sequences further allow for the creation of a standardized reference framework, or numbering scheme, giving each variable region amino acid an identifier [ 151 ].…”

Section: Computational Characterization Of Antibodiesmentioning

confidence: 99%

Computational approaches to therapeutic antibody design: established methods and emerging trends

Norman

Ambrosetti

Bonvin

et al. 2019

Briefings in Bioinformatics

155

130

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Antibodies are proteins that recognize the molecular surfaces of potentially noxious molecules to mount an adaptive immune response or, in the case of autoimmune diseases, molecules that are part of healthy cells and tissues. Due to their binding versatility, antibodies are currently the largest class of biotherapeutics, with five monoclonal antibodies ranked in the top 10 blockbuster drugs. Computational advances in protein modelling and design can have a tangible impact on antibody-based therapeutic development. Antibody-specific computational protocols currently benefit from an increasing volume of data provided by next generation sequencing and application to related drug modalities based on traditional antibodies, such as nanobodies. Here we present a structured overview of available databases, methods and emerging trends in computational antibody analysis and contextualize them towards the engineering of candidate antibody therapeutics.

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Section: Computational Characterization Of Antibodiesmentioning

confidence: 99%

Computational approaches to therapeutic antibody design: established methods and emerging trends

Norman

Ambrosetti

Bonvin

et al. 2019

Briefings in Bioinformatics

155

130

View full text Add to dashboard Cite

show abstract

“…Clonotyping is commonly used in antibody drug discovery to identify 'expanded clones'novel genetic lineages present after vaccination/infection but that were absent, or low concentration, beforehand [14]. Often these expanded lineages are seen across many different individuals after vaccination, implying particular pathogenic epitopes are 'immunodominant' â€" more susceptible to immune recognition [39][40][41].…”

Section: Structurally Profiling a Flu Vaccine Responsementioning

confidence: 99%

“…Since most publicly-available Ig-seq data covers only the VH domain, the vast majority of whole-repertoire analysis has been performed over this region alone. The primary analytical method is currently 'clonotyping' [14][15][16]. Clonotyping is a computational technique used to sort sequencing datasets into sets of functionally similar chains based on sequence features, and can be performed in several ways.…”

Section: Introductionmentioning

confidence: 99%

Public Baseline and shared response structures support the theory of antibody repertoire functional commonality

et al. 2021

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The naïve antibody/B-cell receptor (BCR) repertoires of different individuals ought to exhibit significant functional commonality, given that most pathogens trigger an effective antibody response to immunodominant epitopes. Sequence-based repertoire analysis has so far offered little evidence for this phenomenon. For example, a recent study estimated the number of shared (‘public’) antibody clonotypes in circulating baseline repertoires to be around 0.02% across ten unrelated individuals. However, to engage the same epitope, antibodies only require a similar binding site structure and the presence of key paratope interactions, which can occur even when their sequences are dissimilar. Here, we search for evidence of geometric similarity/convergence across human antibody repertoires. We first structurally profile naïve (‘baseline’) antibody diversity using snapshots from 41 unrelated individuals, predicting all modellable distinct structures within each repertoire. This analysis uncovers a high (much greater than random) degree of structural commonality. For instance, around 3% of distinct structures are common to the ten most diverse individual samples (‘Public Baseline’ structures). Our approach is the first computational method to find levels of BCR commonality commensurate with epitope immunodominance and could therefore be harnessed to find more genetically distant antibodies with same-epitope complementarity. We then apply the same structural profiling approach to repertoire snapshots from three individuals before and after flu vaccination, detecting a convergent structural drift indicative of recognising similar epitopes (‘Public Response’ structures). We show that Antibody Model Libraries derived from Public Baseline and Public Response structures represent a powerful geometric basis set of low-immunogenicity candidates exploitable for general or target-focused therapeutic antibody screening.

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“…Clonotyping is commonly used in antibody drug discovery to identify 'expanded clones' -novel genetic lineages present after vaccination/infection but that were absent, or low concentration, beforehand (14). Here, we applied our repertoire characterisation method to investigate whether we could identify an analogous structural response to vaccination.…”

Section: Structurally Profiling a Flu Vaccine Responsementioning

confidence: 99%

Evidence of Antibody Repertoire Functional Convergence through Public Baseline and Shared Response Structures

Raybould¹,

Marks²,

Kovaltsuk³

et al. 2020

Preprint

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The antibody repertoires of different individuals ought to exhibit significant functional commonality, given that most pathogens trigger a successful immune response in most people. Sequence-based approaches have so far offered little evidence for this phenomenon. For example, a recent study estimated the number of shared ('public') antibody clonotypes in circulating baseline repertoires to be around 0.02% across ten unrelated individuals. However, to engage the same epitope, antibodies only require a similar binding site structure and the presence of key paratope interactions, which can occur even when their sequences are dissimilar. Here, we investigate functional convergence in human antibody repertoires by comparing the antibody structures they contain. We first structurally profile baseline antibody diversity (using snapshots from 41 unrelated individuals), predicting all modellable distinct structures within each repertoire. This analysis uncovers a high degree of structural commonality. For instance, around 3% of distinct structures are common to the ten most diverse individual samples ('Public Baseline' structures). Our approach is the first computational method to provide support for the long-assumed levels of baseline repertoire functional commonality. We then apply the same structural profiling approach to repertoire snapshots from three individuals before and after flu vaccination, detecting a convergent structural drift indicative of recognising similar epitopes ('Public Response' structures). Antibody Model Libraries (AMLs) derived from Public Baseline and Public Response structures represent a powerful geometric basis set of low-immunogenicity candidates exploitable for general or target-focused therapeutic antibody screening. antibody repertoire | structural profiling | public structures | antibody model libraries | antibody screening Correspondence: deane@stats.ox.ac.uk

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The Pipeline Repertoire for Ig-Seq Analysis

Cited by 39 publications

References 93 publications

Computational approaches to therapeutic antibody design: established methods and emerging trends

Computational approaches to therapeutic antibody design: established methods and emerging trends

Public Baseline and shared response structures support the theory of antibody repertoire functional commonality

Evidence of Antibody Repertoire Functional Convergence through Public Baseline and Shared Response Structures

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