Internalizing human antibody-targeted nanosized siRNA therapeutics

描述(申请人提供)：该项目的目标是开发一种新型的人类单抗靶向小干扰RNA(SiRNA)疗法，该疗法有可能成为治疗肿瘤和转移的首个同类药物。我们之前已经确定了一个小组 快速内化针对临床表现的肿瘤细胞表面抗原的人单链抗体(ScFv)。这些单链抗体是通过激光捕获显微切割从噬菌体抗体展示文库中挑选出来的，因为它们能够与组织微环境中的肿瘤细胞原位结合，并介导有效的细胞内有效载荷传递到肿瘤细胞。此外，我们还鉴定了新的siRNA结合基序，这些基序可以与我们内化的scFv结合，并作为融合蛋白产生，从而获得肿瘤靶向的细胞内siRNA递送功能。我们建议开发一类新型的单链抗体靶向siRNA治疗药物，该药物基于我们快速内化的人单链抗体，通过新的siRNA结合基序连接到靶向肿瘤细胞生存关键基因的siRNA。

DESCRIPTION (provided by applicant): The goal of this project is to develop a novel human monoclonal antibody-targeted small interfering RNA (siRNA) therapeutic that has the potential to be first-in-its-kind for treating tumor and metastasis. We have previously identified a panel of rapidly internalizing human single chain antibodies (scFvs) that target clinically represented tumor cell surface antigens. These scFvs were selected from phage antibody display libraries using laser capture microdissection for their ability to bind to tumor cells in situ residing in thir tissue microenvironment, and to mediate efficient intracellular payload delivery to tumor cells. We have in addition identified novel siRNA binding motifs that can be joined with our internalizing scFv and produced as a fusion protein that gains the tumor-targeted intracellular siRNA delivery functions. We propose to develop a novel class of scFv-targeted siRNA therapeutics based on our rapidly internalizing human scFv linked via the novel siRNA binding motif to siRNAs that target genes critical for tumor cell survival.