Novel scFv-Antibody Fusion siRNA Carrier Protein for Macroglobulinemia Treatment

该项目的目标是开发一种创新的流程，用于治疗患有 Waldenstr？m‘m’s巨球蛋白血症通过抑制IgM的产生。 沃尔登斯特姆的巨球蛋白血症是无法治愈的，而且是致命的。这一点的表现 由于高浓度的单抗IgM引起的疾病具有高粘滞性 头痛、疲劳、认知受损、神志不清、中风、周围神经病和 可能导致死亡的全身性淀粉样变性。我们假设生产的 使用RNA干扰可以阻止恶性浆细胞产生的IgM，这种干扰可以 系统地和特定地针对产生IgM的浆细胞给药。 这将通过使用一种创新的重组融合蛋白来实现，该融合蛋白针对 恶性浆细胞通过其抗原结合部分并递送RNA 通过自然内化干扰进入浆细胞。该融合蛋白包括 用于细胞特异性靶向的抗体片段和人类 鱼精蛋白将短的干扰RNA携带到组织和浆细胞中。 这种治疗方法将在沃尔登斯特姆巨球蛋白血症的小鼠模型上进行测试。 我们的具体目标是1.创造维持细胞结合的融合蛋白， 被恶性浆细胞内化，进而抑制IgM的产生；2.优化 融合蛋白的功能行为；3.体内抗癌实验 融合蛋白的行为。我们的方法将克服 系统地使用RNA干扰，即目前的方法无法传递RNA 全身给药对特定靶向细胞和组织传递的干扰。 我们的第二阶段目标将包括优化剂量和评估Side 使用这种疾病的动物模型的效果。

This goal of this project is to develop an innovative process for treating patients with Waldenstr¿m's macroglobulinemia by suppressing the production of IgM. Waldenstr¿m's macroglobulinemia is incurable and fatal. The manifestations of this disease that are due to high concentrations of monoclonal IgM are hyperviscosity with headache, fatigue, impaired cognition, confusion, and stroke, peripheral neuropathy and systemic amyloidosis which may result in death. We hypothesize that the production of IgM by malignant plasma cells can be stopped by using RNA interference which can be administered systemically and specifically targets the plasma cells which produce IgM. This will be accomplished by using an innovative recombinant fusion protein that targets the malignant plasma cells by its antigen binding portion and delivers the RNA interference into the plasma cells by natural internalization. The fusion protein consists of an antibody fragment for cell specific targeting and a modified version of human protamine for carrying the short interfering RNA to the tissue and into the plasma cells. This treatment will be tested in a mouse model of Waldenstr¿m's macroglobulinemia. Our Specific Aims are 1. Create fusion proteins that maintain cell binding, are internalized by the malignant plasma cells and then inhibit IgM production; 2. Optimize the functional behavior of the fusion proteins; 3. Demonstrate the in vivo anti- malignant behavior of the fusion proteins. Our method will overcome the major impediment to the use of RNA interference systemically, i.e. inability of present methods to deliver RNA interference by systemic administration with specific targeted cellular and tissue delivery. Our Phase II objectives will include optimization of dosage and assessment of side effects using an animal model of this disease.