Anisha Parsan, Sebastian Ober, Calvin McCarter, Nick Bhattacharya, Hunter Elliott
原文摘要
Therapeutic antibody development is often framed as comprising two discrete stages: initial discovery of novel binders followed by iterative optimization to refine these hits into therapeutic-grade molecules. Models and methods often reflect these stages, with generative structure models applied to discovery and probabilistic black-box optimization methods applied to refinement. Here we propose to unify these stages by smoothly transitioning a generative discovery model into iterative optimization, allowing the handoff between the structure-based prior and supervision from wet lab data to be guided by the posterior uncertainty of a probabilistic surrogate. We show that this yields improvements in optimization efficiency in the low-N regime, as well as improved diversity amongst the optimized molecules.
Calvin McCarter, Nick Bhattacharya, Sebastian W. Ober, Hunter Elliott
原文摘要
A plethora of protein language models have been released in recent years. Yet comparatively little work has addressed how to best sample from them to optimize desired biological properties. We fill this gap by proposing a flexible, effective sampling method for masked language models (MLMs), and by systematically evaluating models and methods both in silico and in vitro on actual antibody therapeutics campaigns. Firstly, we propose sampling with stochastic beam search, exploiting the fact that MLMs are remarkably efficient at evaluating the pseudo-perplexity of the entire 1-edit neighborhood of a sequence. Reframing generation in terms of entire-sequence evaluation enables flexible guidance with multiple optimization objectives. Secondly, we report results from our extensive in vitro head-to-head evaluation for the antibody engineering setting. This reveals that the choice of sampling method can have a substantial impact, motivating future research into this under-explored area.