arXiv subjects

Nick Bhattacharya

Publications and source records attributed to Nick Bhattacharya.

4 recordsLinked to original sources

arXiv2026

Probabilistic Steering of Generative Priors for Lab-in-the-Loop Antibody Optimization

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.

cs.LG↗

arXiv2026

How to make the most of your masked language model for protein engineering

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.

cs.LG↗

arXiv2026

Can agents reliably design therapeutic antibodies?

Recent work has demonstrated agents driving protein design workflows, either through orchestration of specialized tools or direct manipulation of sequences. Yet the fidelity with which agents follow protein design instructions and the factors contributing to their effectiveness remain understudied. We examine agentic antibody design under two settings: when explicit molecular-editing instructions are provided and when agents receive only previously-scored sequences and are prompted to propose improvements. We call the first task-guided and the second black-box design. For the task-guided setting, we curate ten expert-validated affinity-improvement tasks and show that LLM judges closely reproduce programmatic evaluations of instruction following. We then study two augmentations: access to antibody-relevant tools and to previously scored design history. Tools improve instruction following (IF) and sequence space exploration while reducing optimization performance, whereas design history reduces IF but improves optimization performance at the expense of exploration. Finally, we combine taskguided and black-box design within an in silico optimization loop and show that our agentic optimizer performs comparably to an established Bayesian optimization baseline.

q-bio.QM↗

arXiv2025

Improved Therapeutic Antibody Reformatting through Multimodal Machine Learning

Modern therapeutic antibody design often involves composing multi-part assemblages of individual functional domains, each of which may be derived from a different source or engineered independently. While these complex formats can expand disease applicability and improve safety, they present a significant engineering challenge: the function and stability of individual domains are not guaranteed in the novel format, and the entire molecule may no longer be synthesizable. To address these challenges, we develop a machine learning framework to predict "reformatting success" -- whether converting an antibody from one format to another will succeed or not. Our framework incorporates both antibody sequence and structural context, incorporating an evaluation protocol that reflects realistic deployment scenarios. In experiments on a real-world antibody reformatting dataset, we find the surprising result that large pretrained protein language models (PLMs) fail to outperform simple, domain-tailored, multimodal representations. This is particularly evident in the most difficult evaluation setting, where we test model generalization to a new starting antibody. In this challenging "new antibody, no data" scenario, our best multimodal model achieves high predictive accuracy, enabling prioritization of promising candidates and reducing wasted experimental effort.

cs.LG↗