In vivo targeting of hematopoetic cells with glycan ligands of siglecs

描述（由申请方提供）：CD 22是一种B淋巴细胞特异性聚糖结合蛋白，参与B细胞受体信号传导的调节。细胞外结构域识别含有唾液酸的聚糖作为配体，所述配体在B细胞活化和分化期间调节其活性。因为它在B细胞上特异性表达，所以CD22也是用于治疗B细胞淋巴瘤和炎性自身免疫疾病的基于抗体的细胞耗竭疗法的临床靶标。我们已经开发了一种使用CD 22的多价聚糖配体靶向B细胞的方法。在这个项目中，我们将使用CD 22的聚糖配体开发B细胞靶向脂质体，并测试它们在小鼠疾病模型中消除B细胞的效用。本课题的主要目标是：1）研制高效特异性靶向杀伤B细胞的人CD 22配体脂质体。2)在人B细胞淋巴瘤的鼠模型中评估靶向CD 22的脂质体制剂的体内功效。3)测试CD22靶向脂质体与人B细胞白血病和非霍奇金B细胞淋巴瘤患者血液中癌细胞结合的能力。4)确定用靶向CD22的化疗脂质体去除B细胞是否在自身免疫性疾病的鼠模型中表现出功效。如果成功的话，这些结果可能会导致细胞靶向疗法的发展，用于治疗B细胞恶性肿瘤和由B细胞介导的炎性自身免疫性疾病。

DESCRIPTION (provided by applicant): CD22 is a B lymphocyte specific glycan binding protein that participates in regulation of B cell receptor signaling. The extra-cellular domain recognizes sialic acid containing glycans as ligands that regulate its activity during B cell activation and differentiation. Because it is specifically expressed on B cells, CD22 is also a clinical target for antibody based cell depletion therapies for treatment of B cell lymphoma and inflammatory autoimmune disease. We have developed an approach for targeting B cells using multivalent glycan ligands of CD22. In this project we will develop B cell targeted liposomes using glycan ligands of CD22, and test their utility for depletion of B cells in murine models of disease. The major objectives of the project are: 1) Develop chemotherapeutic loaded liposomes displaying ligands of human CD22 that efficiently and specifically target and kill B cells. 2) Assess the in vivo efficacy of CD22 targeted liposome formulations in a murine model of human B cell lymphoma. 3) Test the ability of CD22 targeted liposomes to bind to cancer cells in the blood of human B cell leukemia and non-Hodgkin's B cell lymphoma patients. 4) Determine if B cell depletion with CD22 targeted chemotherapeutic liposomes exhibit efficacy in a murine model of autoimmune disease. If successful, the results may lead to the development of cell-targeted therapies for treatment of B cell malignancies and inflammatory autoimmune diseases mediated by B cells.