Antibody-Mediated Delivery of Anti- @entity11518 -siRNA In Vivo Overcomes Therapy Resistance in XXXX .

@entity12841 @entity5 @entity19 @entity11518 @entity694 @entity420
PURPOSE: @entity11518 mutations are frequent driver mutations in multiple @entity5 . @entity11518 mutations also induce anti- @entity12841 antibody resistance in @entity420 such as @entity694 . The aim of this study was to overcome anti- @entity12841 antibody resistance by coupling the antibody to @entity11518 -specific siRNA. EXPERIMENTAL DESIGN: The anti- @entity12841 antibody was chemically coupled to siRNA. The resulting complex was tested for antibody binding efficiency, serum stability and ability to deliver siRNA to @entity12841 -expressing cells. Western blotting, viability, apoptosis, and colony formation assays were performed for efficacy evaluation in vitro. Furthermore, therapeutic activity of the antibody- @entity11518 -siRNA complexes was examined in in vivo xenograft @entity19 @entity5 models. RESULTS: Antibody-siRNA complexes were targeted and internalized via the @entity12841 receptor. Upon internalization, target gene expression was strongly and specifically repressed, followed by a reduced proliferation and viability, and induced apoptosis of the cells in vitro. Clonogenic growth of mutant @entity11518 -bearing cells was suppressed by @entity11518 -siRNA-anti- @entity12841 antibody complexes. In xenograft mouse models, anti- @entity12841 antibody- @entity11518 -siRNA complexes significantly slowed @entity5 growth in anti- @entity12841 -resistant cells. CONCLUSIONS: The coupling of siRNA against @entity11518 to anti- @entity12841 antibodies provides a novel therapy approach for @entity11518 -mutated @entity12841 -positive @entity5 cells in vitro and in vivo. These findings provide an innovative approach for @entity5 -specific siRNA application and for enhanced therapeutic potential of monoclonal antibody therapy and personalized treatment of @entity5 entities. Clin Cancer Res; 21(6); 1383-94.   2015 AACR.
