Novel scFv-Antibody Fusion siRNA Carrier Protein for Macroglobulinemia Treatment

该项目的目标是开发一种创新的治疗方法， Waldenstr m巨球蛋白血症通过抑制IgM的产生。 瓦尔登斯特伦巨球蛋白血症是无法治愈和致命的。这种现象的表现形式 由于高浓度的单克隆IgM引起的疾病是高粘滞性， 头痛、疲劳、认知受损、意识模糊和中风、周围神经病变和 可能导致死亡的系统性淀粉样变性。我们假设， 恶性浆细胞的IgM可以通过使用RNA干扰来阻止， 全身性地施用并且特异性地靶向产生IgM的浆细胞。 这将通过使用一种创新的重组融合蛋白来实现， 恶性浆细胞通过其抗原结合部分并递送RNA 通过自然内化进入浆细胞的干扰。融合蛋白由以下组成： 用于细胞特异性靶向的抗体片段和修饰形式的人源化抗体片段。 鱼精蛋白用于将短干扰RNA携带到组织中并进入浆细胞。 该治疗将在Waldenstr？m巨球蛋白血症小鼠模型中进行测试。 我们的具体目标是1。产生维持细胞结合的融合蛋白， 由恶性浆细胞内化，然后抑制IgM产生; 2.优化 融合蛋白的功能行为; 3.证明体内抗恶性肿瘤 融合蛋白的行为。我们的方法将克服 RNA干扰的系统性使用，即本方法不能递送RNA 通过特异性靶向细胞和组织递送的全身施用的干扰。 我们的第二阶段目标将包括优化剂量和评估副作用。 使用这种疾病的动物模型。

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.