Using an RNA-binding antibody for tumor-directed immunogenic RNA delivery
The inability to selectively deliver therapeutic RNAs within target cells currently hinders the development of novel treatments for cancer and other disorders. Here, we report that a tumor-targeting, cell-penetrating, and RNA-binding antibody, TMAB3, can form non-covalent antibody/RNA complexes that mediate highly specific and functional delivery of RNAs into tumors. We observed a robust anti-tumor efficacy of systemically administered 3p-hpRNA, an agonist of viral RNA sensor RIG-I, in complex with TMAB3 in animal models of pancreatic cancer, medulloblastoma, and melanoma. In pancreatic cancer models, treatment with TMAB3/3p-hpRNA tripled animal survival, decreased tumor growth, and specifically targeted malignant cells, with a 1500-fold difference in RNA delivery into tumor cells versus non-malignant cells within the tumor mass. Single-cell RNA-sequencing (scRNA-seq) and flow cytometry demonstrated that TMAB3/3p-hpRNA treatment elicited anti-tumoral immune responses against tumor cells. These studies establish that TMAB3/3p-hpRNA complexes can effectively deliver RNA payloads to malignant cells in hard-to-treat tumors to achieve anti-tumor efficacy, providing an antibody-based platform to advance RNA therapies for cancer. Overall design: Mice with the KPC orthotopic model were treated with an RNA-binding antibody, TMAB3, to deliver an immunogenic RNA, 3p-hpRNA, into the tumor. The mice received three doses on days 10, 13, and 16 post-tumor implantation. Mice were sacrificed at 1 day (D+1) and 7 days (D+7) post-final treatment. Tumors were harvested and dissociated, and dead cells were discarded before scRNA-seq analysis