category
bioRxiv
date
Feb 12, 2026
slug
status
Published
summary
提出TCRPPO2模型,整合强化学习与生成式AI批评机制,通过迭代突变策略优化TCR亲和力,结合物理建模与功能注释筛选,实现无需结构监督的TCR工程化设计,并在临床相关抗原验证中展示显著功能提升。
tags
蛋白质进化
合成生物学
type
Post
📄 原文题目
Generative AI Guided Design of High-Affinity T cell Receptors
🔗 原文链接
💡 AI 核心解读
提出TCRPPO2模型,整合强化学习与生成式AI批评机制,通过迭代突变策略优化TCR亲和力,结合物理建模与功能注释筛选,实现无需结构监督的TCR工程化设计,并在临床相关抗原验证中展示显著功能提升。
📝 英文原版摘要
Developing T cell receptors (TCRs) with sufficiently high affinity for tumor antigens (TAs) remains a fundamental challenge in TCR-T immunotherapy. Experimental methods such as affinity maturation and high-throughput screening have enabled the identification of TCRs with enhanced activity, but the efficiency of such methods is limited by throughput, coverage, and the generally lower affinities of naturally occurring TCRs towards TAs. To address these challenges, we present TCRPPO2, an integrated AI-driven, in silico affinity maturation model for peptide-specific TCR optimization. Using reinforcement learning, TCRPPO2 learns mutation policies that iteratively enhance the objective of the TCR binding affinity towards the target peptide, derived from predictive models trained on carefully curated interaction data. The model is further augmented by a generative AI critic model that discourages implausible designs to ensure the validity. The designs are further screened by robust post-screening methods that leverage diverse functional annotations and physical prior knowledge. We applied TCRPPO2 to the clinically relevant MART-1 antigen and experimentally validated the designed candidates in Jurkat cell-based functional assays. Among the five engineered TCRs all demonstrating positive cellular responses, three showed significantly increased activities relative to their templates and one with pronounced enhancement. These functional gains were consistent with improved interaction energy from structural and physical modeling. Together, our results support a generalizable paradigm for TCR engineering, in which learned mutation policies can efficiently navigate the peptide-specific binding landscape of TCRs and propose biologically enhanced candidates without explicit structural
supervision, offering a practical route for early-stage computational TCR optimization for challenging tumor antigens.
- 作者:NotionNext
- 链接:https://tangly1024.com/article/30648bd6-1f96-8180-8e87-f7b0c6e60450
- 声明:本文采用 CC BY-NC-SA 4.0 许可协议,转载请注明出处。
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