2022-04-04, Akbar, Rahmad, Robert, Philippe A., Weber, Cédric R., Widrich, Michael, Frank, Robert, Pavlović, Milena, Scheffer, Lonneke, Chernigovskaya, Maria, Snapkov, Igor, Slabodkin, Andrei, Mehta, Brij Bhushan, Miho, Enkelejda, Lund-Johansen, Fridtjof, Andersen, Jan Terje, Hochreiter, Sepp, Hobæk Haff, Ingrid, Klambauer, Günter, Sandve, Geir Kjetil, Greiff, Victor

Generative machine learning (ML) has been postulated to become 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 the computation of synthetic antibody-antigen 3D-structures, and it functions as an oracle for unrestricted prospective evaluation and benchmarking of antibody design parameters of ML-generated antibody sequences. We found that a deep generative model, trained exclusively on antibody sequence (one dimensional: 1D) data can be used to design conformational (three dimensional: 3D) epitope-specific antibodies, matching, or exceeding the training dataset in affinity and developability parameter value variety. Furthermore, we established a lower threshold of sequence diversity necessary for high-accuracy generative antibody ML and demonstrated that this lower threshold also holds on experimental real-world data. Finally, we show that transfer learning enables the generation of high-affinity antibody sequences from low-N training data. Our work establishes a priori feasibility and the theoretical foundation of high-throughput ML-based mAb design.