Abstract 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. Highlights A 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 Combination 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 Transfer learning (low-N learning) coupled to generative learning shows that antibody-binding rules may be transferred across unrelated antibody-antigen complexes Experimental validation of antibody-design conclusions drawn from deep learning on synthetic antibody-antigen binding data Graphical abstract 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.

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