Biology subjects

Mehta, B. B.

Publications and source records attributed to Mehta, B. B..

3 recordsLinked to original sources

bioRxiv2021

In silico proof of principle of machine learning-based antibody design at unconstrained scale

Generative machine learning (ML) has been postulated to be a major driver in the computational design of antigen-specific monoclonal antibodies (mAb). However, efforts to confirm this hypothesis have been hindered by the infeasibility of testing arbitrarily large numbers of antibody sequences for their most critical design parameters: paratope, epitope, affinity, and developability. To address this challenge, we leveraged a lattice-based antibody-antigen binding simulation framework, which incorporates a wide range of physiological antibody binding parameters. The simulation framework enables both the computation of antibody-antigen 3D-structures as well as functions as an oracle for unrestricted prospective evaluation of the antigen specificity of ML-generated antibody sequences. We found that a deep generative model, trained exclusively on antibody sequence (1D) data can be used to design native-like conformational (3D) epitope-specific antibodies, matching or exceeding the training dataset in affinity and developability variety. Furthermore, we show that transfer learning enables the generation of high-affinity antibody sequences from low-N training data. Finally, we validated that the antibody design insight gained from simulated antibody-antigen binding data is applicable to experimental real-world data. Our work establishes a priori feasibility and the theoretical foundation of high-throughput ML-based mAb design. HighlightsO_LIA large-scale dataset of 70M [3 orders of magnitude larger than the current state of the art] synthetic antibody-antigen complexes, that reflect biological complexity, allows the prospective evaluation of antibody generative deep learning C_LIO_LICombination of generative learning, synthetic antibody-antigen binding data, and prospective evaluation shows that deep learning driven antibody design and discovery at an unconstrained level is feasible C_LIO_LITransfer learning (low-N learning) coupled to generative learning shows that antibody-binding rules may be transferred across unrelated antibody-antigen complexes C_LIO_LIExperimental validation of antibody-design conclusions drawn from deep learning on synthetic antibody-antigen binding data C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/451480v1_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@1d947bcorg.highwire.dtl.DTLVardef@1f4c51corg.highwire.dtl.DTLVardef@b8df67org.highwire.dtl.DTLVardef@1530ea5_HPS_FORMAT_FIGEXP M_FIG We leverage large synthetic ground-truth data to demonstrate the (A,B) unconstrained deep generative learning-based generation of native-like antibody sequences, (C) the prospective evaluation of conformational (3D) affinity, paratope-epitope pairs, and developability. (D) Finally, we show increased generation quality of low-N-based machine learning models via transfer learning. C_FIG

immunology↗

bioRxiv2021

A billion synthetic 3D-antibody-antigen complexes enable unconstrained machine-learning formalized investigation of antibody specificity prediction

Machine learning (ML) is a key technology for accurate prediction of antibody-antigen binding. Two orthogonal problems hinder the application of ML to antibody-specificity prediction and the benchmarking thereof: The lack of a unified ML formalization of immunological antibody specificity prediction problems and the unavailability of large-scale synthetic benchmarking datasets of real-world relevance. Here, we developed the Absolut! software suite that enables parameter-based unconstrained generation of synthetic lattice-based 3D-antibody-antigen binding structures with ground-truth access to conformational paratope, epitope, and affinity. We formalized common immunological antibody specificity prediction problems as ML tasks and confirmed that for both sequence and structure-based tasks, accuracy-based rankings of ML methods trained on experimental data hold for ML methods trained on Absolut!-generated data. The Absolut! framework thus enables real-world relevant development and benchmarking of ML strategies for biotherapeutics design. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/451258v3_ufig1.gif" ALT="Figure 1"> View larger version (86K): org.highwire.dtl.DTLVardef@4c3a6aorg.highwire.dtl.DTLVardef@8f1deborg.highwire.dtl.DTLVardef@1f55ec6org.highwire.dtl.DTLVardef@2135dd_HPS_FORMAT_FIGEXP M_FIG The software framework Absolut! enables (A,B) the generation of virtually arbitrarily large numbers of synthetic 3D-antibody-antigen structures, (C,D) the formalization of antibody specificity as machine learning (ML) tasks as well as the exploration of ML strategies for real-world antibody-antigen binding or paratope-epitope prediction. C_FIG HighlightsO_LISoftware framework Absolut! to generate an arbitrarily large number of synthetic 3D-antibody-antigen structures that contain biological layers of antibody-antigen binding complexity that render ML predictions challenging C_LIO_LIImmunological antibody specificity prediction problems formalized as machine learning tasks for which the in silico complexes are immediately usable as benchmark datasets C_LIO_LIExploration of machine learning prediction accuracy as a function of architecture, dataset size, choice of negatives, and sequence-structure encoding C_LIO_LIRelative ML performance learnt on Absolut! datasets transfers to experimental datasets C_LI

immunology↗

bioRxiv2021

Individualized VDJ recombination predisposes the available Ig sequence space

The process of recombination between variable (V), diversity (D), and joining (J) immunoglobulin (Ig) gene segments determines an individuals naive Ig repertoire, and consequently (auto)antigen recognition. VDJ recombination follows probabilistic rules that can be modeled statistically. So far, it remains unknown whether VDJ recombination rules differ between individuals. If these rules differed, identical (auto)antigen-specific Ig sequences would be generated with individual-specific probabilities, signifying that the available Ig sequence space is individual-specific. We devised a sensitivity-tested distance measure that enables inter-individual comparison of VDJ recombination models. We discovered, accounting for several sources of noise as well as allelic variation in Ig sequencing data, that not only unrelated individuals but also human monozygotic twins and even inbred mice possess statistically distinguishable immunoglobulin recombination models. This suggests that, in addition to genetic, there is also non-genetic modulation of VDJ recombination. We demonstrate that population-wide individualized VDJ recombination can result in orders of magnitude of difference in the probability to generate (auto)antigen-specific Ig sequences. Our findings have implications for immune receptor-based individualized medicine approaches relevant to vaccination, infection, and autoimmunity.

immunology↗