Monte Carlo Thompson sampling-guided design for antibody engineering.

Antibodies are one of the predominant treatment modalities for various diseases. To improve the characteristics of a lead antibody, such as antigen-binding affinity and stability, we conducted comprehensive substitutions and exhaustively explored their sequence space. However, it is practically unfeasible to evaluate all possible combinations of mutations owing to combinatorial explosion when multiple amino acid residues are incorporated. It was recently reported that a machine-learning guided protein engineering approach such as Thompson sampling (TS) has been used to efficiently explore sequence space in the framework of Bayesian optimization. For TS, over-exploration occurs when the initial data are biasedly distributed in the vicinity of the lead antibody. We handle a large-scale virtual library that includes numerous mutations. When the number of experiments is limited, this over-exploration causes a serious issue. Thus, we conducted Monte Carlo Thompson sampling (MTS) to balance the exploration-exploitation trade-off by defining the posterior distribution via the Monte Carlo method and compared its performance with TS in antibody engineering. Our results demonstrated that MTS largely outperforms TS in discovering desirable candidates at an earlier round when over-exploration occurs on TS. Thus, the MTS method is a powerful technique for efficiently discovering antibodies with desired characteristics when the number of rounds is limited.

Antibody design using LSTM based deep generative model from phage display library for affinity maturation.

Molecular evolution is an important step in the development of therapeutic antibodies. However, the current method of affinity maturation is overly costly and labor-intensive because of the repetitive mutation experiments needed to adequately explore sequence space. Here, we employed a long short term memory network (LSTM)-a widely used deep generative model-based sequence generation and prioritization procedure to efficiently discover antibody sequences with higher affinity. We applied our method to the affinity maturation of antibodies against kynurenine, which is a metabolite related to the niacin synthesis pathway. Kynurenine binding sequences were enriched through phage display panning using a kynurenine-binding oriented human synthetic Fab library. We defined binding antibodies using a sequence repertoire from the NGS data to train the LSTM model. We confirmed that likelihood of generated sequences from a trained LSTM correlated well with binding affinity. The affinity of generated sequences are over 1800-fold higher than that of the parental clone. Moreover, compared to frequency based screening using the same dataset, our machine learning approach generated sequences with greater affinity.