Key Points
• Conclusion/Relevance: “While significant amount of work is required to enter clinical phase for the technology including formulation development, consistency batches, detailed physicochemical characterization, and in vivo efficacy studies, we believe GADS technology to be a potential ARC platform for gene therapy.”
• The investigators developed a delivery technology based on the antibody–siRNA conjugate (ARC) platform for the stable delivery of siRNA, which they call the Gelatin-Antibody Delivery System (GADS). In this system, positively charged gelatin acts as a linker between antibody–siRNA and facilitates the endosomal escape of siRNA for gene silencing following cellular internalization. They formulated a scalable GADS conjugate consisting of Cetuximab (CTB), cationized gelatin (cGel) and NSCLC KRASG12C-specific siRNA, as proof of concept.
• “The POC used for demonstrating the technology shows KRASG12C knockdown and subsequently, sensitization of NSCLC cells toward small molecule TKI [tyrosine kinase inhibitor]. The CTB component targets overexpressed EGFR of NSCLC cells enabling receptor-mediated endocytosis while the cGel [cationized gelatin] acts as a linker and aides in endosomal escape. The process for generating GADS molecule requires formulation and stability only for thiol-reactive antibody-linker intermediate, since siRNA can be conjugated prior to dosing,” the authors wrote.
• The investigators noted that the model is designed to remove impurities secondary to extant monoclonal antibody purification methodology, thus permitting operations to readily be scaled up.