用神经网络预言抗体开发性,可大幅降低实验筛选成本。
Biologically-Grounded Multi-Encoder Architectures as Developability Oracles for Antibody Design

- 用冻结蛋白语言模型+可调注意力解码器预测抗体性质
- 在5项测试中3项超越基线12%~20%,表达量与稳定性表现优异
- 发现重链主导聚集,轻重链协同影响稳定性的关键机制
生成模型可提出数千条全新抗体序列,但其转化为有效治疗药物仍受限于生物物理表征的高成本。本文提出CrossAbSense框架,通过系统超参数搜索(每项性质超200次运行)构建属性专用神经预言器,结合冻结蛋白语言模型编码器与可配置注意力解码器。在包含242种治疗性IgGs的GDPa1基准上,其在五项开发性评估中的三项表现优于现有基线12%~20%,其余两项表现相当。核心发现为最优解码架构反向验证初始生物学假设:仅自注意力即可充分捕捉聚集相关性质(如疏水相互作用色谱、多反应性),因60亿参数编码器已完整解析单链嵌入中的关键序列特征(如CDR-H3疏水斑块)。而表达量与热稳定性则需双向跨链注意力,因涉及重链与轻链的兼容性。学习到的链融合权重进一步证实重链在聚集中占主导(w_H=0.62),而稳定性呈均衡贡献(w_H=0.51)。通过在100个IgLM生成的抗体设计上部署,验证了该框架可显著降低实验筛选成本。
原文摘要 · Abstract (English)
Generative models can now propose thousands of \emph{de novo} antibody sequences, yet translating these designs into viable therapeutics remains constrained by the cost of biophysical characterization. Here we present CrossAbSense, a framework of property-specific neural oracles that combine frozen protein language model encoders with configurable attention decoders, identified through a systematic hyperparameter campaign totaling over 200 runs per property. On the GDPa1 benchmark of 242 therapeutic IgGs, our oracles achieve notable improvements of 12--20\% over established baselines on three of five developability assays and competitive performance on the remaining two. The central finding is that optimal decoder architectures \emph{invert} our initial biological hypotheses: self-attention alone suffices for aggregation-related properties (hydrophobic interaction chromatography, polyreactivity), where the relevant sequence signatures -- such as CDR-H3 hydrophobic patches -- are already fully resolved within single-chain embeddings by the high-capacity 6B encoder. Bidirectional cross-attention, by contrast, is required for expression yield and thermal stability -- properties that inherently depend on the compatibility between heavy and light chains. Learned chain fusion weights independently confirm heavy-chain dominance in aggregation ($w_H = 0.62$) versus balanced contributions for stability ($w_H = 0.51$). We demonstrate practical utility by deploying CrossAbSense on 100 IgLM-generated antibody designs, illustrating a path toward substantial reduction in experimental screening costs.
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