Multidimensional development of high-affinity anti-glycan antibodies to fight deadly bacterial infections

摘要 针对细菌表面多糖的免疫疗法的发展被认为是一种 在与威胁生命和抗药性细菌的斗争中潜在的范式转变，一种新兴的和 在治疗选择有限的情况下，人们日益关注健康。我们的PO1团队将利用化学反应 在人工平台上解构和展示细菌多糖结构，使其具有免疫原性和 被免疫系统识别。免疫反应将由细菌学家分析和解剖，细胞 和结构免疫学家来确定疫苗或抗体的特性 多糖作为一种抗生素有效，可在临床前研究中部署。这个程序汇编了一些 世界上在各自领域的专家都雄心勃勃，打算开创免疫疗法的先河。 仅次于化疗，用于治疗细菌感染。我们独特的化学-免疫学组合- 细菌学-结构生物学将提供必要的机制理解什么是合格的疫苗 或在免疫治疗中有效的抗体。这个团队已经很有成效了，并且已经发表了这些证据 这一应用的科学依据的方法的原理：非常高亲和力的抗体可以 针对暴露在抗生素耐药细菌表面的细菌多糖而生产，对 抗击传染性挑战。我们将把我们的策略扩展到三种细菌病原体的表面多糖 世卫组织将金黄色葡萄球菌、肺炎克雷伯氏菌和奈瑟氏菌列为“危急”或“高度”优先事项 淋病。我们将从我们的研究中获得的基本知识应该建立一个非常详细的 免疫系统对多糖和糖肽的免疫识别蓝图。整合了 该项目的化学、免疫学和结构生物学方面直接进入细菌学和活体 将确定葡聚糖的目标和策略，以启动临床前研究。

Abstract The development of immunotherapies focused on the surface glycans of bacteria is hypothesized to be a potential paradigm shift in the fight against life-threatening and antibiotic-resistant bacteria, an emerging and increasing health concern for which therapeutic options are limited. Our PO1 team will use chemistry to deconstruct and display bacterial glycan structures on an artificial platform to make them immunogenic and recognized by the immune system. Immune responses will be analyzed and dissected by bacteriologists, cellular and structural immunologists to determine the characteristics of what makes a vaccine or an antibody against glycans effective as an antibiotic and deployable in pre-clinical studies. This program that assembles some of the world experts in their respective fields is ambitious and intends to pioneer the effort of placing immunotherapy next to chemotherapy for the treatment of bacterial infections. Our unique combination of chemistry-immunology- bacteriology-structural biology will provide the necessary mechanistic understanding of what qualifies a vaccine or an antibody to be effective in immunotherapy. The team is already productive and has published the proofs of principle of the approach on which the science of this application is based: very high affinity antibodies can be produced against bacterial glycans exposed at the surface of antibiotic resistant bacteria and are effective at combating infectious challenges. We will expand our strategy to the surface glycans of three bacterial pathogens listed by WHO as “critical” or “high” priority: Staphylococcus aureus, Klebsiella pneumoniae, and Neisseria gonorrhea. The fundamental knowledge that we will gain from our studies should establish a very detailed blueprint of the immune recognition of glycans and glycopeptides by the immune system. The integration of the chemistry, immunology, and structural biology facets of the project directly into the bacteriology and in vivo models, will identify glycans targets and strategies to initiate pre-clinical studies.