Targeting aberrant glycopeptide tumor antigens for generation of novel cancer therapeutics with enhanced selectivity and utility

项目摘要 单克隆抗体（mAb）用于癌症治疗已经取得了相当大的成功， 在治疗多种癌症方面取得突破。在大多数情况下，癌症mAb通过区分 正常细胞和肿瘤细胞通过靶蛋白在肿瘤细胞上的表达升高的程度来确定。由于 在正常和肿瘤细胞上观察到的结合表位没有结构差异，mAb仍然能够结合， 影响正常细胞，即使靶蛋白以低水平表达。因此， 市场上可能有显着的副作用，这使得许多患者无法使用。发展众多 由于脱靶效应，针对新型肿瘤靶点的mAb已经遇到了难以克服的障碍。 本项目的目标是开发具有上级选择性和有效性的单克隆抗体治疗药物 通过联合靶向癌细胞过度表达的蛋白质和肿瘤的存在， 相关异常糖基化。为了实现肿瘤特异性靶向的目标，我们专注于开发 一种在大多数实体瘤（包括乳腺肿瘤）的细胞表面上发现的特定聚糖结构， 肺和结肠。这种异常的聚糖暴露了癌细胞上的蛋白质表位，而这些表位通常被癌细胞上的蛋白质表位所屏蔽。 健康的组织有许多细胞表面蛋白具有展示这些蛋白的高潜力。 异常聚糖，并且已知在主要癌症中过度表达。 对于这项建议，我们专注于市场上目前治疗的目标，虽然非常 有效的，可在许多患者中引起显著的副作用。我们将生成一个基于抗体的 该治疗剂解决了与现有治疗剂相关的有问题的毒性。 我们将使用一种新的免疫原平台和方法，称为GTI，以产生具有高表达的mAb。 对蛋白质的亲和力和特异性。这些单克隆抗体将被开发，使得它们仅识别靶点。 当用肿瘤特异性异常聚糖修饰时，不仅新的和改进的治疗方法 本项目的结果，将作为采用肿瘤特异性异常糖基化 在过度表达肿瘤相关蛋白的背景下， 肿瘤特异性治疗剂。

Project Summary The use of monoclonal antibodies (mAbs) for cancer therapy has achieved considerable success, leading to breakthroughs in the treatment of many types of cancer. In most cases cancer mAbs act by distinguishing normal and tumor cells by the extent of elevated expression of the target protein on the tumor cell. As there is no structural difference in the binding epitopes seen on normal and tumor cells, mAbs are still able to bind and effect normal cells, even if the target protein is expressed at low levels. As a result existing mAbs on the market can have significant side effects which disallows use for many patients. Development of numerous mAbs against novel tumor targets have incurred insurmountable hurdles due to off-target effects. The goal of this project is develop mAb-based therapeutics that exhibit superior selectivities and efficacies by combined targeting of proteins that are overexpressed by cancer cells and the presence of tumor- associated aberrant glycosylation. To achieve the goal of tumor specific targeting, we are focused on exploiting a specific glycan structure that is found on the cell surface of most solid tumors including those of the breast, lung and colon. This aberrant glycan exposes protein epitopes on cancer cells that are normally shielded on healthy tissues. There are numerous cell surface proteins that have a high potential of displaying these aberrant glycans and are known to be over-expressed on major cancers. For this proposal we are focusing on a target of a current therapeutic on the market that, while very effective, can cause significant side effects in a number of patients. We will generate an antibody-based therapeutic that addresses problematic toxicity associated with the existing therapeutic. We will use a novel immunogen platform and methodology, termed GTI, to generate mAbs with high affinity and specificity for proteins. These mAbs will be developed in such that they only recognize target proteins when modified with the tumor-specific aberrant glycans. Not only will novel and improved therapeutics result from this project, it will serve as proof of a principle that employing tumor-specific aberrant glycosylation in the context of over-expressed tumor-associated proteins is a defining methodology for the generation of truly tumor-specific therapeutic agents.