Learning from B Cell Evolution: Adaptive Multi-Expert Diffusion for Antibody Design via Online Optimization

TL;DR

This paper introduces an adaptive, biologically-inspired framework for antibody design that uses online meta-learning and multiple specialized experts to optimize antibodies for specific antigens, surpassing traditional uniform strategies.

Contribution

It presents the first biologically-motivated, online meta-learning approach employing multiple experts for personalized antibody optimization, inspired by B cell affinity maturation.

Findings

Discoveries of personalized guidance strategies for different antigen classes.

Enhanced hotspot coverage and interface quality in antibody design.

Effective generalization across diverse antigen types.

Abstract

Recent advances in diffusion models have shown remarkable potential for antibody design, yet existing approaches apply uniform generation strategies that cannot adapt to each antigen's unique requirements. Inspired by B cell affinity maturation, where antibodies evolve through multi-objective optimization balancing affinity, stability, and self-avoidance, we propose the first biologically-motivated framework that leverages physics-based domain knowledge within an online meta-learning system. Our method employs multiple specialized experts (van der Waals, molecular recognition, energy balance, and interface geometry) whose parameters evolve during generation based on iterative feedback, mimicking natural antibody refinement cycles. Instead of fixed protocols, this adaptive guidance discovers personalized optimization strategies for each target. Our experiments demonstrate that this approach: (1) discovers optimal SE(3)-equivariant guidance strategies for different antigen classes without pre-training, preserving molecular symmetries throughout optimization; (2) significantly enhances hotspot coverage and interface quality through target-specific adaptation, achieving balanced multi-objective optimization characteristic of therapeutic antibodies; (3) establishes a paradigm for iterative refinement where each antibody-antigen system learns its unique optimization profile through online evaluation; (4) generalizes effectively across diverse design challenges, from small epitopes to large protein interfaces, enabling precision-focused campaigns for individual targets.