Bonobo: Efficient Library-Scale Generation for De Novo Antibody Design

Recently several methods have shown promise for purely in silico “de novo” design of antibodies which bind to drug targets. The methods which have shown success in vitro propose candidates via either a generative diffusion model or hallucination-based sequence optimization, and then filter these candidates with a structure predictor model. Hallucination methods rely on compute-intensive backpropagation through a structure predictor model for each candidate, and the generative methods require expensive structure re-prediction and filtering of many (often mostly non-passing) candidates, limiting their application to test-time generation of large libraries. Given the highly variable per-drug-target hit rates of current methods, screening large libraries is a well established route to improved antibody candidate discovery. Thus, we propose an alternative approach, Bonobo, which instead formulates this problem as black-box optimization of a per-drug-target generative model, amortizing candidate generation into training. This is accomplished by using a structure predictor as a reward signal to directly train a GFlowNet generative model. We show that this approach can match or exceed the in silico metrics of state-of-the-art approaches, while allowing for dramatically more efficient generation of diverse and arbitrarily large numbers of antibody binder candidates.