Biochemical patterns of antibody polyreactivity revealed through a bioinformatics-based analysis of CDR loops

To defend itself against bacteria and viruses, the body depends on a group of proteins known as antibodies. Each subset of antibodies undergoes a rigorous training regimen to ensure it recognizes a single epitope well – that is, one specific region on the surface of foreign, harmful organisms.

Most antibodies stick extremely tightly to their one unique epitope, but some can also weakly bind to molecules that are vastly different from their main trained targets. This feature – known as polyreactivity – can in some cases help the immune system fight against multiple strains of viruses. On the other hand, when antibodies are designed in the laboratory to treat diseases, this characteristic can sometimes lead to the failure of pre-clinical trials. Yet it is currently unclear why some antibodies are polyreactive when others are not.

To investigate this question, Boughter et al. compared over 1,000 polyreactive and non-polyreactive antibody sequences from a large database, revealing differences in the physical properties of the region of the antibodies that attaches to epitopes. Using these defining features, Boughter et al. went on to design a new piece of freely available, automated software that could predict which antibodies would be polyreactive more than 75% of the time.

Such software could ultimately help to guide the design of antibody-based treatments, while bypassing the need for costly laboratory tests.

Antibodies are immunogenic proteins expressed by B cells that play a major role in the adaptive immune response against non-self. Upon recognition of target epitopes, these antibodies undergo multiple rounds of somatic hypermutation and affinity maturation inside a germinal center, whereby the amino acid sequence of the epitope-binding surface is selected for optimal binding to the target (Victora and Nussenzweig, 2012; Eisen and Siskind, 1964; McKean et al., 1984). The longer this affinity maturation process extends, the higher the affinity and specificity of the antibodies toward their target antigen, primarily through mutagenesis of the six complementarity determining region (CDR) loops of the antibody (Victora and Nussenzweig, 2012). Using a combination of affinity matured CDR loops, these antibodies bind strongly to the target and aid in invader neutralization. While the process of affinity maturation and somatic hypermutation of antibodies results in high-affinity and incredibly specific binders to a particular epitope, some antibodies have been shown to display signs of reactivity toward diverse off-target epitopes. This broad but low-affinity binding has been termed ‘polyreactivity’.

Antibody polyreactivity has been hypothesized to be beneficial in the early stages of antibody maturation, acting as a pool of diverse binders ready to recognize novel antigens and initiate the more stringent selection process (Dimitrov et al., 2013). To this end, a majority of B cell receptors and antibodies which have not undergone somatic hypermutation, including those on immature B cells and early ‘natural’ antibodies, have been found to be polyreactive to some extent and are suggested to have an innate-like response to pathogens (Ochsenbein et al., 1999; Wardemann et al., 2003). While these mostly unmutated polyreactive antibodies remain at low frequency in antigen-experienced individuals, a distinct population of polyreactive antibodies that have undergone selection are still expressed by mature B cells that circulate in blood (Tiller et al., 2007). In fact, some studies have found that the polyreactivity status of an antibody is mostly independent of the number of somatic hypermutations in the antibody sequence (Mouquet et al., 2010; Prigent et al., 2016). In line with this finding, only 5–10% of the repertoire of naive B cells circulating in the periphery are polyreactive, but this increases to 20–30% in the memory B cell compartment, showing a distinct capability of polyreactivity to survive selection (Tiller et al., 2007; Koelsch et al., 2007). These results suggest that polyreactivity can persist, or perhaps even be selected for during the selection process within the germinal center.

In a few notable cases, polyreactivity may in fact augment the efficacy of a given immune response. Polyreactive IgA antibodies have been shown to have an inherent reactivity to microbiota in the mouse gut, with a predicted role in host homeostasis (Bunker et al., 2017). These previously identified antibodies so far have no known primary ligands, yet play a key role in facilitating the gut immune response to the plethora of exogenous antigens encountered in the dynamic dietary and microbial environment of the gut. This implies the existence of antibodies whose primary function is to act as polyreactive sentries in the gut, yet the downstream effects of polyreactive antibodies coating commensal bacteria is so far unclear. Similar polyreactive IgA and IgG mucosal antibodies were found in the gut of human immunodeficiency virus (HIV)-infected patients, but these antibodies either had low affinity to the virus or lacked neutralization capabilities (Planchais et al., 2019). The benefit of singular antibody sequences with the ability to sample large portions of the commensal population may represent an improvement in efficiency of the homeostatic machinery of the gut.

While the precise role of these primarily polyreactive gut antibodies is still a topic of debate, polyreactivity has been suggested to augment the immune response in other immunological niches. Broadly neutralizing antibodies (bnAbs), which bind robustly to conserved epitopes on the surface glycoproteins of influenza viruses or HIV are more likely to be polyreactive (Haynes et al., 2005; Mouquet et al., 2011; Andrews et al., 2015). In one study of HIV-binding antibodies, over half of all tested bnAbs were found to be polyreactive (Prigent et al., 2018). These bnAbs have been the subject of intense study for their potential as the central components of an HIV treatment or as the byproduct of an immune response to a universal Influenza vaccine (Andrews et al., 2015; Haynes et al., 2019; Crowell et al., 2019; Li et al., 2012). One hypothesized mechanism for the capability of polyreactive antibodies to confer this broad neutralization in the face of a changing viral epitope is heteroligation, the ability of a single antibody to bind the primary target with one binding domain and use the other binding domain to bind in a polyreactive manner (Mouquet et al., 2010). This heteroligation allows the antibody to take advantage of the significant avidity increase afforded by bivalent binding, despite the low envelope protein density of HIV or a geometry which does not readily lend itself to bivalent binding on the surface of influenza viruses (Klein and Bjorkman, 2010).

Although polyreactivity may play a positive role in natural immune responses, oftentimes this same property is considered undesirable from the point of view of generating therapeutic antibodies with high specificity. Antibody-based treatments, which generally take the form of an intravenous transfusion, are sensitive to the accelerated systemic clearance of polyreactive antibodies (Hötzel et al., 2012; Kelly et al., 2015; Kelly et al., 2018; Datta-Mannan et al., 2015). In general, much work has focused on attempting to answer the question of optimizing ‘developability’ of a given antibody. These efforts have been dedicated to determining the most critical components of developability through a large array of experimental assays, in silico structural prediction-based methods, sequence-based analysis and their correlations with clearance, sequence-based SASA predictions, and sequence-based aggregation propensity predictors (Jain et al., 2017b; Raybould et al., 2019; Sharma et al., 2014; Jain et al., 2017a; Obrezanova et al., 2015). In many of these studies, polyreactivity or non-specificity in general was seen to be a negative indicator of the developability of a drug, suggesting that therapeutic antibodies should strive toward a drug-like specificity (Starr and Tessier, 2019).

In line with this goal of understanding the predominant factors involved in the specificity of therapeutic antibodies, many researchers have worked to identify the biophysical underpinnings of polyreactivity in natural immune responses. The most popular hypotheses for the primary biophysical predictors of polyreactivity have included CDR3 length (Prigent et al., 2016), CDR3 flexibility (Prigent et al., 2018), net hydrophobicity (Lecerf et al., 2019), and net charge (Rabia et al., 2018). More observational studies have found an increased prevalence of arginine and tyrosine in polyreactive antibodies (Kelly et al., 2018; Birtalan et al., 2008). While these previous studies represent substantial advances in the study of polyreactivity, they have often been limited in scope, focusing on a singular antibody source and primarily focused on CDR3H. Comparing across these individual antibody sources highlights discrepancies between the proposed predictors of polyreactivity. The aforementioned properties determined to be key to polyreactivity in previous studies were found to be statistically insignificant in studies of HIV-binding and mouse gut polyreactive antibodies (Bunker et al., 2017; Mouquet et al., 2010).

Clearly, a computational framework that would enable us to predict the polyreactivity of a given antibody a priori, whether evaluating the efficacy of a natural immune response or the potential fate of a therapeutic antibody, would be tremendously useful. Such a framework, for example, could be used to assist in the isolation of broadly neutralizing antiviral antibodies, or speed up the process of therapeutic antibody screening. To achieve this goal, a thorough understanding of the molecular features behind polyreactive binding interactions is critical. Experimental approaches utilizing next-generation sequencing and ELISA allow for the identification of hundreds of polyreactive antibody sequences. However, the systematic characterization of these antibodies is difficult. Issues immediately arise when defining the conditions by which we determine an antibody to be polyreactive. While polyreactivity may exist on some continuous spectrum, we are inclined to frame the problem as binary. This binary discretization is useful for the identification of meaningful differences, yet must be recognized as an imperfect assumption. In addition to this more philosophical challenge, experimental efforts must also overcome significant hurdles. Detailed biochemical studies of polyreactive antibodies via protein crystallography, quantitative binding experiments, and mutagenesis provide exceptional insight but are inherently low throughput. Structural modeling of these polyreactive antibodies represent a high-throughput approach, but models of flexible loops are relatively unreliable, and are unlikely to capture nuances in side-chain placement (Karami et al., 2019). A bioinformatics-based approach, centered around high-throughput analysis that minimizes structural assumptions while maintaining positional context of amino acid sequences would provide a thorough, unbiased analysis of existing data and create a powerful pipeline for future studies.

In this study, we show that using just the amino acid sequences of antibodies from a database of over 1000 sequences tested for polyreactivity, unifying biophysical properties that distinguish polyreactive antibodies from non-polyreactive antibodies can be identified. We find that, while charge and hydrophobicity are in fact important determinants of polyreactivity, the characteristic feature of polyreactive antibodies appears to be a shift toward neutrality of the binding interface. In addition, loop crosstalk is more prevalent in the heavy chain of polyreactive antibodies than non-polyreactive antibodies. From these properties, a machine learning-based classification software was developed with the capability to determine the polyreactivity status of a given sequence. This software is generalizable and can be retrained on any binary classification problem and identify the key differences between two distinct populations of antibodies, T cell receptors, or MHC-like molecules at the amino acid level.

Previous research has highlighted the importance of hydrophobicity, charge, and CDR loop flexibility on antibody specificity. In this work, we expand upon these previous results with a new bioinformatic and biophysical characterization of polyreactive antibodies. The software generated for this study provides a powerful computational tool which can be utilized by researchers interested in discerning differences between populations of adaptive immune molecules in broad contexts. Building off of the efforts of our own work and that of experimental collaborators, we were able to aggregate to date one of the largest publicly available datasets of antibodies tested for polyreactivity. Differences in the germline gene frequency and amino acid frequencies show there exists some underlying differences between polyreactive and non-polyreactive antibodies. A surface level analysis of this dataset is able to discriminate certain features of polyreactive and non-polyreactive antibodies, namely that on average, polyreactive antibodies are less strongly negatively charged, less hydrophilic, and have a higher prevalence of antibodies with longer CDR loops of the heavy chain. Importantly, however, these binding surfaces do not have a net positive charge nor are they net hydrophobic.

Our results highlight an increase in $V_{H}1\text{-}69$ gene usage in polyreactive antibodies, an interesting finding given the substantial literature outlining its importance in diverse immune environments. In addition to the aforementioned role of $V_{H}1\text{-}69$ in broadly neutralizing anti-influenza and anti-HIV antibodies (Haynes et al., 2005; Mouquet et al., 2011; Andrews et al., 2015; Prigent et al., 2018), autoreactive chronic lymphocytic leukemic B cells commonly express receptors bearing $V_{H}1\text{-}69$ (Sasso et al., 1993; Forconi et al., 2010), and anti-HIV antibodies which target the membrane-proximal external region of HIV-1 envelope glycoproteins frequently utilize $V_{H}1\text{-}69$ (IAVI Protocol G Investigators et al., 2019). While previous reports suggest that the key feature permitting these auto-reactive or polyreactive interactions of $V_{H}1\text{-}69$ is an exceptionally hydrophobic CDR2H loop (Chen et al., 2019) our results suggest this does not explain the over-representation of this antibody in the polyreactive dataset, as on average the CDR2H of polyreactive antibodies is strongly hydrophilic. Instead, certain structural or dynamic features of the antibody may contribute to its out-sized role in critical biological contexts.

To dig deeper into the biophysical differences between polyreactive and non-polyreactive antibodies, we created an adaptable software for the automated analysis of large antibody datasets and the application of a new analysis pipeline for the study of polyreactive antibodies. Overall, the improvements of this software to the current state of antibody sequence analysis are sufficient to highlight key differences in the two populations with improved spatial resolution. The position sensitive sequence alignment is able to further parse through the genetic differences and show that in general, polyreactive antibodies have a tendency to have more hydrophobic residues in CDR2H, and a decreased preference for phenylalanine in CDR1H. While these observational differences provided some initial insight, a more rigorous biophysical treatment was necessary. With the addition of 62 biophysical properties analyzed using the position sensitive alignment, significant differences between the CDR3H loops in polyreactive and non-polyreactive antibodies become immediately evident, providing a more detailed depiction of the antigen binding surface of polyreactive antibodies.

These data suggest a movement toward neutrality or ‘inoffensive’ residues in the CDR loops of polyreactive antibodies: amino acids that are neither exceptionally hydrophobic nor hydrophilic and with a net charge close to 0. Previous studies have suggested that polyreactive antibodies tend to have more hydrophobic CDR loops, such that low-affinity Van der Waals interactions might be the primary means of polyreactive interactions (Prigent et al., 2018; Starr and Tessier, 2019). However, these studies counted the number of hydrophobic residues per sequence or averaged the hydrophobicity of all six CDR loops. While our results partially agree with these previous findings, our analysis extends much further into defining the biophysical basis of this phenomenon. For example, while our position sensitive representation of the sequences shows that CDR3H does become more hydrophobic in polyreactive sequences, it is still net hydrophilic on average. A highly hydrophobic binding surface would provide an avenue for non-specific interactions with other hydrophobic proteins, but it would occlude binding to highly hydrophilic ligands like DNA. A slightly hydrophilic, neutral-charged binding surface would permit weak interactions with a wide range of ligands.

Using these and other biophysical properties as input feature vectors, we were able to generate a generalizable protocol for binary comparisons between two distinct populations of Ig-domain sequences. This framework is able to successfully split all tested polyreactive and non-polyreactive antibody datasets. Care was taken to not overfit these data and a preliminary classifier built from this algorithm was able to identify the proper number of input vectors for each LDA application. While there are general features which best split the polyreactive and non-polyreactive antibodies in these datasets, including charge, hydrophobicity, and α-helix propensity, these features alone are not sufficient to discriminate between the two populations. Instead, 75 vectors taken from the position-sensitive biophysical property matrix are necessary to properly split the groups, including both simple properties like charge, hydrophobicity, flexibility, and bulkiness and more carefully curated properties like the often used Kidera factors and the hotspot detecting variables of Liu et al. (Kidera et al., 1985; Liu et al., 2018; Vihinen et al., 1994). The inability to arrive at a core few biophysical properties that could effectively distinguish polyreactive and non-polyreactive antibodies necessitated the application of further approaches, namely information theory.

The tools provided by information theory proved to be effective in the present study. The classic approach to information theory considers some input, communication of this input across a noisy channel, and then reception of a meaningful message from the resultant output. We can think of the analogous case for these antibodies, whereby the sequence and structure of the antibodies can be seen as our input, the thermal noise inherent to biological systems can complicate biochemical interactions, and the necessary output is antigen recognition, i.e. binding between the antibody and the ligand. Focusing just on the antibody side of this communication channel, we determined the underlying loop diversity through the Shannon entropy of the polyreactive and non-polyreactive datasets. This diversity was found to be nearly equivalent while the mutual information, a metric of ‘crosstalk’ across populations, between and within CDR loops was found to be increased in the heavy chain and decreased in the light chain of polyreactive antibodies. What this loop crosstalk entails physically is not immediately clear from these measurements.

The mutual information increase could come from gene usage being somehow coupled, amino acid usage coupling with the cognate ligand, or the amino acids directly interacting physically with each other. In some way, this crosstalk appears to be selected for in the polyreactive population. If this increase in mutual information manifests as an increase of charge-charge interactions, this could explain why there is a minimal change in net charge of antibodies between the two groups, yet a significant move toward neutrality in the CDR loops of polyreactive antibodies. The pairing of two charged groups would help move the binding surface of polyreactive antibodies toward a more ‘inoffensive’ binding surface. A binding surface that is neither exceptionally hydrophobic nor hydrophilic, and lacks a significant positive or negative charge, would represent a relatively appealing binding interface for a low-affinity interaction with a large array of diverse ligands. A patchwork of hydrophobic and hydrophilic non-charged residues exposed to potential ligands would provide an ideal candidate polyreactive surface. The corresponding decrease in the mutual information between the light chain CDR loops of polyreactive antibodies could be caused by a de-emphasis in the involvement of these loops due to differential binding configurations of polyreactive ligands, as has been previously hypothesized (Dimitrov et al., 2013; Sethi et al., 2006).

While further crystallographic, biochemical, and dynamic studies are necessary to identify the true source of this increase in mutual information across polyreactive antibodies, we can speculate what these results may mean in the context of the results obtained using linear discriminant analysis. In addition to standard side chain properties, many of the most important features for splitting polyreactive and non-polyreactive antibodies were structural in nature. Specifically, hotspot variables 6, 24, 25, and 41 all correspond to the structural tendencies of a given amino acid. Coupled with the increase in side chain interactions that may be implied by the increased mutual information across the loops of polyreactive antibodies, this potential for increased loop structure may suggest more rigid CDR loops in polyreactive antibodies.

In addition to the insights into polyreactivity, the computational tools developed for this study are broadly applicable to future studies of large antibody or T cell receptor repertoires. One of the strengths of this approach is a decreased emphasis on structural information when crystal structures are unavailable. Computational prediction of loop conformation is difficult, and drawing inferences from incorrect models regarding side-chain interactions and positioning could be misleading. Reliable structural information on these polyreactive antibodies will be critical to a further understanding of the mechanisms of polyreactivity, including complex structures of antibodies bound to various ligands. In the high-throughput analysis of antibody sequences, our approach strikes a careful balance of the structural assumptions that should apply consistently across antibody populations.

Further experimental assays will be necessary to more comprehensively identify the underlying mechanisms of polyreactivity, including further sequencing and biochemical analysis of polyreactive and non-polyreactive antibodies. Antibodies specific to other pathogens or those from other organisms tested for polyreactivity will help form a more complete picture and improve the generality of the results. As with any machine learning based approach, the classification algorithm is only as good as the data it is trained on. Adding further data in the training set, including more mutations and germline reversions that turn a polyreactive antibody non-polyreactive or vice-versa, will be critical for a comprehensive analysis of polyreactivity. Additionally, a more robust assay for determining polyreactivity such as a chip based screen to test for binding to many diverse targets, would greatly broaden our perspective and help understand just how broadly reactive these polyreactive antibodies are. Lastly, a more complete understanding of the germinal center and the selection processes inherent to the affinity maturation process will assist in the determination of whether polyreactivity is a byproduct or a purposeful feature of the affinity maturation process.

The software generated for this study is publicly available as a python application (see Materials and methods). The unique aspect of this software is its hybrid approach to position-sensitive amino acid sequence analysis. Structural information is implicitly encoded by the alignment strategy employed, yet these assumptions are weaker than those imposed by explicit structural prediction. Downstream analysis from this positional encoder is streamlined and can be generalized to analyze any binary or higher order classification problems. This streamlined analysis allows for the generation of each figure in this study to be applied to thousands of sequences in a matter of minutes. The classification capabilities of the software could prove particularly useful when comparing binary classes, such as T cell receptors or antibody sequences derived from healthy and diseased tissue samples. Acceptable inputs are not restricted to CDR loops of immunoglobulins, and we have shown that the software can be adapted for the analysis of MHC-like molecules. Moving forward, this MHC analysis has the potential to classify the antigen binding properties of highly-divergent MHC sequences from a broad range of species, providing insights where phylogenetic approaches prove difficult. This software represents a strong addition to the existing toolkit for repertoire analysis of diverse molecular species.

All data generated and all code used for analysis in this study has been published on GitHub at http://github.com/ctboughter/AIMS (copy archived at https://archive.softwareheritage.org/swh:1:rev:f6c855ef4a7ce63f72dba6b34e9d0e9edd9200ce/).

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Author details

1. Christopher T Boughter

   Graduate Program in Biophysical Sciences, University of Chicago, Chicago, United States

   Contribution

   Conceptualization, Resources, Data curation, Software, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7106-4699

2. Marta T Borowska

   Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, United States

   Contribution

   Conceptualization, Data curation, Writing - review and editing

   Competing interests

   No competing interests declared

3. Jenna J Guthmiller

   Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, United States

   Contribution

   Resources, Data curation, Writing - review and editing

   Competing interests

   No competing interests declared

4. Albert Bendelac

   1. Committee on Immunology, University of Chicago, Chicago, United States
   2. Department of Pathology, University of Chicago, Chicago, United States

   Contribution

   Conceptualization, Resources, Data curation, Writing - review and editing

   Competing interests

   No competing interests declared

5. Patrick C Wilson

   1. Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, United States
   2. Committee on Immunology, University of Chicago, Chicago, United States

   Contribution

   Resources, Data curation, Writing - review and editing

   Competing interests

   No competing interests declared

6. Benoit Roux

   Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, United States

   Contribution

   Conceptualization, Resources, Data curation, Supervision, Funding acquisition, Project administration, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-5254-2712

7. Erin J Adams

   1. Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, United States
   2. Committee on Immunology, University of Chicago, Chicago, United States

   Contribution

   Conceptualization, Resources, Data curation, Supervision, Funding acquisition, Project administration, Writing - review and editing

   For correspondence

   ejadams@uchicago.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-6271-8574

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