Systemic Administration Of An Antibody/Rna Complex Results In Tumor Specific Delivery Of Immunostimulatory Rnas And Tumor Growth Suppression In A Mouse Model Of Melanoma.

Abstract There is intense interest in the development of nucleic acid ligands for immune stimulation of the tumor microenvironment via pattern recognition receptors, especially for the treatment of “cold” tumors. However, delivery of these ligands in a tumor-specific manner to avoid systemic toxicity has been a challenge. Many current efforts rely on direct intra-tumoral injection of RNAs or other stimulatory immune ligands, which is therapeutically sub-optimal, especially for metastatic disease. Here we report studies evaluating the utility of a lupus-derived, cell-penetrating antibody, to deliver nucleic acids including mRNA to tumors in vivo. This antibody, a modified version of 3E10-D31N, forms non-covalent complexes with RNAs and can mediate highly specific delivery broadly into tumors via intravenous injection by targeting the nucleoside transporter ENT2. Studies with labeled RNAs and with mRNAs expressing a GFP reporter gene show tumor specific delivery and functional expression by imaging, with minimal delivery to healthy tissues. Cell culture studies show antibody-mediated delivery of a series of RIG-I ligands, including hairpin RNAs and poly(I:C), resulting in robust RIG-I stimulation and induction of type-1 interferon signaling. Using mouse B16 melanoma tumors as a model, we observe substantial tumor growth suppression upon i.v. injection of a combination of 3E10 complexed with poly(I:C) (synthetic double-stranded RNA). These results highlight a novel approach for the systemic delivery of immunostimulatory RNAs in a targeted manner that may offer treatment advantages over current approaches. Citation Format: Elias Quijano, Yanfeng Liu, Stephen Squinto, Bruce C. Turner, Peter M. Glazer. Systemic Administration of an antibody/RNA complex results in tumor specific delivery of immunostimulatory RNAs and tumor growth suppression in a mouse model of melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB169.