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

项目总结 我们将向研究界开发并商业化一类新的葡聚糖专属化合物 结合可变淋巴细胞受体识别功能的结合试剂 无颌脊椎动物适应性免疫系统的抗原受体(VLR)，七鳃鳗 还有八目鳗鱼。这种试剂对于检测、定位、量化和建立 特定糖链在正常和疾病细胞和组织中的生物学功能(S)，并可能 此外，还导致开发新的诊断和治疗模式。海流 缺乏这样的试剂是进一步促进对其作用的理解的重大障碍 多糖在健康和疾病中的作用。VLR是由高度不同排列的卷曲组成的 富含亮氨酸重复序列(LRR)的结构基序具有与人类相似的多样性 免疫球蛋白(Ig)抗体库，并具有独特的更严格的结合部位 几何VS Ig抗体，完全包含在单一的多肽结构中。 脊椎动物大约在5.5亿年前分裂成无颌骨和有颌骨的脊椎动物谱系 那是以前的事了。无颌脊椎动物与人类和其他哺乳动物的进化分离，以及 VLRs独特的结合部位几何结构可能提供新的特异性和功能 不能用免疫球蛋白抗体访问。VLRS的发现支持了这种预期 结合碳水化合物抗原的亲和力和特异性优于通常的免疫球蛋白 抗体，并表明VLRs是唯一非常适合结合和区分多糖的 结构。基于七鳃鳗VLR的免疫系统是一项潜在的变革性技术 用于快速、高通量地生产各种糖链的特定结合试剂 构成人类糖类的结构。通过此第1阶段STTR应用程序，我们将启动 本文通过对七鳃鳗基于VLR免疫系统的应用演示了七鳃鳗可以 进行免疫以产生VLRs，该VLRs能特异性地结合和区分四种最 人类常见的粘蛋白O型连接的葡聚糖核心结构。在我们的后续阶段2 研究我们将以一种便于检测、量化和 调节四种粘蛋白O型连接的糖链核心结构的功能，并提供 这些试剂带给了研究界。

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.