PO.BCS01.10 · 生物信息与计算
用于跨适应症多组学评估表面蛋白靶点的模块化计算机分诊流程
A modular in silico triage pipeline for multi omic evaluation of surface protein targets across indications
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
抗体-药物偶联物(ADC)通过将细胞毒性载荷与选择性靶向恶性细胞的抗体偶联,为肿瘤学带来了革命性变化。然而,在疗效与毒性之间取得平衡仍然是一个重大挑战,尤其是当健康组织中的脱靶表达导致不良副作用时。为解决这些局限性,我们开发了一个模块化的计算机分诊流程,整合多模态、多组学数据集,以系统评估用于靶向双特异性治疗的候选表面蛋白。我们的流程基于候选抗原在多种细胞群体与组织中基于质谱(MS)的组织蛋白表达模式对其进行评估,从而识别在癌细胞中主要上调、同时在关键正常组织中mRNA表达较低的标志物。这一全面的方法支持双特异性抗体的合理设计,此类抗体可通过同时结合两种不同抗原进一步增强特异性。通过简化靶点选择流程,该策略有望加速在一系列癌症适应症中开发更有效、更安全的治疗模式。在此,我们详述了该计算机框架的设计、实现与验证,为快速、灵活地评估ADC及其他领域潜在表面蛋白靶点提供了一个稳健的平台。
查看英文原文 English abstract
Antibody-Drug Conjugates (ADCs) have revolutionized oncology by coupling cytotoxic payloads with antibodies that selectively target malignant cells. However, balancing efficacy with toxicity continues to be a major challenge, especially when off-target expression in healthy tissues leads to adverse side effects. To address these limitations, we have developed a modular in silico triage pipeline that integrates multi-modal, multi-omic datasets to systematically evaluate candidate surface proteins for targeted bispecific therapy.Our pipeline evaluates candidate antigens based on their MS-based tissue protein expression patterns across diverse cell populations and tissues, enabling the identification of markers that are predominantly upregulated in cancer cells while maintaining low mRNA expression in critical normal tissues. This comprehensive approach supports the rational design of bispecific antibodies that can further enhance specificity by binding to two distinct antigens simultaneously. By streamlining the target selection process, this strategy promises to accelerate the development of more effective and safer therapeutic modalities across a range of cancer indications.Here, we detail the design, implementation, and validation of our in silico framework, providing a robust platform for rapid and flexible evaluation of potential surface protein targets for ADCs and beyond.
利益披露 Disclosure
S. Rajapurkar,
GSK Employment.
L. Eismann,
GSK Employment.
M. Pereira,
GSK Employment.
T. Groth,
GSK Employment.
M. Khaladkar,
GSK Employment.
K. Jansen,
GSK Employment.
E. Curry,
GSK Employment.
M. Speranza,
GSK Employment.