Monoclonal lamprey VLR antibodies specific for mucin-type O-linked glycan core 1 - 4 structures

项目摘要 我们将开发和商业化的研究社区一类新的聚糖特异性 结合可变淋巴细胞受体识别功能的结合试剂 VLR是无颌脊椎动物、七鳃鳗、巨噬细胞和巨噬细胞的适应性免疫系统的抗原受体。 还有盲鳗这些试剂对于检测、定位、定量和建立 正常和疾病细胞和组织中特定聚糖的生物学功能，并且可以 此外，还导致新的诊断和治疗方式的发展。当前 缺乏这样的试剂是进一步推进理解这种作用的一个重大障碍， 对健康和疾病的影响。VLRs由串联排列的高度多样化的 富含亮氨酸重复序列（LRR）的结构基序，其多样性与人类相似 免疫球蛋白（IG）抗体库，并具有独特的更刚性的结合位点 几何结构相对于完全包含在单个多肽结构内的IG抗体。 大约5.5亿年前，脊椎动物分裂成无颌和有颌脊椎动物谱系。 前无颌脊椎动物与人类和其他哺乳动物的进化分离， VLR独特结合位点几何结构潜在地提供了新的特异性和功能 不与IG抗体接触。这一预期得到了VLRs发现的支持， 以上级通常用IG实现的亲和力和特异性结合糖类抗原 抗体，并表明VLR是唯一适合结合和区分聚糖 结构.七鳃鳗基于VLR的免疫系统是一种潜在的变革性技术 用于快速、高通量地生产针对不同聚糖的特异性结合试剂 构成人类糖组的结构。通过第一阶段的STTR应用，我们将启动 这种应用的七鳃鳗VLR为基础的免疫系统，通过证明七鳃鳗可以 免疫以产生特异性结合并区分四种最常见的 人类中常见的粘蛋白型O-连接聚糖核心结构。在接下来的第二阶段 研究中，我们将表达这些VLRs的形式，有利于用于检测，定量和 调节四种粘蛋白型O-连接聚糖核心结构的功能，并提供 将这些试剂提供给研究界。

PROJECT SUMMARY We will develop and commercialize to the research community a new class of glycan-specific binding reagents that incorporate the recognition function of variable lymphocyte receptors (“VLRs”), the antigen receptors of the adaptive immune system of jawless vertebrates, lamprey and hagfish. Such reagents are essential to detecting, localizing, quantifying, and establishing biological function(s) of specific glycans in normal and disease cells and tissues, and may additionally lead to development of new diagnostic and therapeutic modalities. The current absence of such reagents is a significant barrier to further advancing an understanding the role of glycans in health and disease. VLRs are composed of tandemly arranged highly diverse leucine-rich repeat (LRR) structural motifs with diversity comparable to the human immunoglobulin (Ig) antibody repertoire, and possess a distinctive more rigid binding site geometry vs Ig antibodies that is entirely contained within a single polypeptide structure. Vertebrates split into jawless and jawed vertebrate lineages approximately 550 million years ago. The evolutionary separation of jawless vertebrates from humans and other mammals, and the distinctive binding site geometry of VLRs potentially provide novel specificities and functions not accessed with Ig antibodies. This expectation is supported by the discovery of VLRs that bind carbohydrate antigens with affinity and specificity superior to that typically achieved with Ig antibodies and indicate that VLRs are uniquely well-suited to binding and discriminating glycan structures. The lamprey VLR-based immune system is potentially a transformative technology for the rapid, high throughput production of specific binding reagents for the diverse glycan structures that comprise the human glycome. With this phase 1 STTR application we will initiate this application of the lamprey VLR-based immune system by demonstrating that lamprey can be immunized to produce VLRs that specifically bind and discriminate each of the four most common mucin-type O-linked glycan core structures in humans. In our follow-on phase 2 studies we will express these VLRs in a form that facilitates use for detecting, quantifying and modulating the functions of the four mucin-type O-linked glycan core structures and provide these reagents to the research community.