Search

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., Author summary It is commonly thought that most people’s adaptive immune systems can recognise the same endemic pathogens, many of which invade our bodies daily. However, existing methods of antibody repertoire comparison (which focus on genetic relatedness) only predict a tiny number of functionally equivalent antibodies in the resting state repertoires of different individuals. Here, we propose a novel approach that predicts the structural diversity of antibody binding sites within a repertoire sequence dataset. This orthogonal methodology can be applied to pool together antibodies from different genetic lineages with topological potential to bind to the same pathogen surface, and that may be functionally equivalent if they share a sufficiently similar surface interaction profile. Our methodology finds that a much greater than random set of binding site geometries exist across resting-state repertoires and can detect binding site geometric convergence in response to vaccination, both of which are consistent with underlying functional commonality between individuals. We further show that knowledge of these geometries could be useful in therapeutic antibody drug discovery, through rational screening library design. Different repertoire sequencing datasets could be interrogated to achieve a more general set of topologies compatible with many pathogens or a tailored set bespoke to a single pathogen.

Most current analysis tools for antibody next-generation sequencing data work with primary sequence descriptors, leaving accompanying structural information unharnessed. We have used novel rapid methods to structurally characterize the complementary-determining regions (CDRs) of more than 180 million human and mouse B-cell receptor (BCR) repertoire sequences. These structurally annotated CDRs provide unprecedented insights into both the structural predetermination and dynamics of the adaptive immune response. We show that B-cell types can be distinguished based solely on these structural properties. Antigen-unexperienced BCR repertoires use the highest number and diversity of CDR structures and these patterns of naïve repertoire paratope usage are highly conserved across subjects. In contrast, more differentiated B-cells are more personalized in terms of CDR structure usage. Our results establish the CDR structure differences in BCR repertoires and have applications for many fields including immunodiagnostics, phage display library generation, and “humanness” assessment of BCR repertoires from transgenic animals. The software tool for structural annotation of BCR repertoires, SAAB+, is available at https://github.com/oxpig/saab_plus., Author summary B-cell receptors (BCR) are the major components of the adaptive immune system. These are immunoglobulin molecules that bind to foreign substances known as antigens. Each individual has a huge BCR repertoire, where each individual BCR has a specific binding site composed of the complementary-determining regions (CDRs) capable of recognising a specific antigen. Drug discovery and immunodiagnostics inspired by the adaptive immune system rely on our ability to accurately interrogate the structural diversity of the binding sites of the BCR repertoire. Here we report our novel rapid pipeline, SAAB+, which has enabled us to interrogate how the structure of the CDR changes in BCR repertoires along the B-cell differentiation axis. By analysing human and mouse BCR repertoires at an unprecedented scale, we observed species-specific structural predetermination and detected CDR dynamics across multiple stages of B-cell differentiation. We showed that naïve repertoires share the highest number and diversity of CDR structures, a pattern which was highly conserved in all B-cell donors. Our results suggest that increased B-cell differentiation is associated with a personalization of CDR structure usages. Finally, we established the differences in CDR usages between humans and mice, analysis with immediate relevance for BCR repertoire “humanness” assessment and rational immunotherapeutic engineering.