Generative neural networks for structure-based antibody design

数据摘要/摘要 抗体作为一种分子检测平台，在现代医学中的重要性日益凸显 技术，从诊断测试，到成像，再到治疗。目前的市场规模为 抗体及其相关产品的销售额估计约为2000亿美元。日益增长的 对具有定制特异性的抗体的需求为工程化努力提供了丰富的环境。 近年来，计算蛋白质设计取得了快速进展。许多方法已经 以满足抗体工程的需求。研究人员希望，通过 通过建模和设计，可以降低抗体开发和改进的成本， 可以加快产生新靶向分子的速度。近年来，实验 管道已经精简，但即使如此，广泛的图书馆和屏幕活动通常是 需要获得初始绑定信号。一个主要的进步将是直接设计一个活页夹 从头开始，为人工进化的潜在优化提供了信号。电流 然而，计算方法由于许多缺点而没有发挥主导作用 目前的建模方法。我们在蛋白质设计方面拥有丰富的专业知识， 近年来，他率先将生成神经网络模型用于蛋白质结构。我们 已经观察到神经网络方法相对于现有方法的几个关键优势： 也就是说，他们的推理能力，插值，纳入拓扑信息， 加速采样。这些优点可以单独开发，也可以结合使用 与现有的方法，他们可以显着提高蛋白质设计的性能。这 该项目旨在利用我们迄今为止开发的几项新进展， 应对抗体工程挑战的策略，或基于AI的蛋白质设计， 将军我们将开发新的工具和设计管道，以扩大多个领域的特殊性， 特异性抗体和定制表位特异性抗体（使用蛇毒和CXCR 4 作为目标）。这个项目将提供计算方法和结构，可以 部署在临床环境中。这项研究的结果将具有很大的影响力。

PROGRAM SUMMARY/ABSTRACT As a molecular detection platform, antibodies have growing importance in modern medical technology, ranging from diagnostic tests, to imaging, to therapeutics. The current market size for antibodies and their related products is estimated to be around $200 billion USD. The growing need for antibodies with customized specificity provides a rich environment for engineering efforts. Computational protein design has seen rapid progress in recent years. Many methods have been developed to address antibody engineering needs. Researchers have hoped that, through modeling and design, the cost for antibody development and improvements can be reduced and the pace for creating new targeting molecules can be expedited. In recent years, the experimental pipeline has been streamlined, but even so, extensive libraries and screen campaigns are usually required to get an initial binding signal. A major advancement would be to directly design a binder from scratch, providing a signal for potential optimization by artificial evolution. Current computational methods, however, have not taken a leading role due to a number of shortcomings with the current modeling approach. We have extensive expertise in protein design and have pioneered the use of generative neural network models for protein structures in recent years. We have observed several key advantages in neural network approaches over existing methods: namely, their ability to make inferences, interpolate, incorporate topological information, and accelerate sampling. These advantages can be developed independently or used in conjunction with existing methods, and they can significantly boost the performance of protein design. This project aims at leveraging several new advances we have developed to date to inspire new strategies in response to the challenges in antibody engineering, or AI-based protein design in general. We will develop new tools and design pipelines for expanding the specificities for multi- specific antibodies and customizing epitope-specific antibodies (using snake venoms and CXCR4 as targets). This project will deliver both computational methods and constructs that can be deployed in clinical settings. The results from this research will be highly impactful.