Systemic administration of an RNA binding and cell-penetrating antibody targets therapeutic RNA to multiple mouse models of cancer
Menée à l'aide de modèles murins de cancers (cancer du pancréas, médulloblastome et mélanome), cette étude met en évidence l'intérêt d'un anticorps monoclonal capable de délivrer des ARNs thérapeutiques dans les cellules cancéreuses
There is intense interest in the advancement of RNAs as rationally designed therapeutic agents, especially in oncology, where a major focus is to use RNAs to stimulate pattern recognition receptors to leverage innate immune responses. However, the inability to selectively deliver therapeutic RNAs within target cells after intravenous administration now hinders the development of this type of treatment for cancer and other disorders. Here, we found that a tumor-targeting, cell-penetrating, and RNA binding monoclonal antibody, TMAB3, can form stable, noncovalent antibody/RNA complexes of a discrete size that mediate highly specific and functional delivery of RNAs into tumors. Using 3p-hpRNA, an agonist of the pattern recognition receptor retinoic acid–inducible gene-I (RIG-I), we observed robust antitumor efficacy of systemically administered TMAB3/3p-hpRNA complexes in mouse models of pancreatic cancer, medulloblastoma, and melanoma. In the KPC syngeneic, orthotopic pancreatic cancer model in immunocompetent mice, 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 nonmalignant cells within the tumor mass. Single-cell RNA sequencing (scRNA-seq) and flow cytometry demonstrated that TMAB3/3p-hpRNA treatment elicited a potent antitumoral immune response characterized by RIG-I activation and increased infiltration and activity of cytotoxic T cells. These studies established that TMAB3/RNA complexes can deliver RNA payloads specifically to hard-to-treat tumor cells to achieve antitumor efficacy, providing an antibody-based platform to advance the study of RNA therapies for the treatment of patients with cancer. A cell-penetrating and RNA binding antibody forms noncovalent complexes with an immunogenic RNA to target tumors and achieve antitumor efficacy. RNA therapeutics hold promise for treating diseases such as cancer, but translation of these therapeutics has been hindered by issues including cell penetration and target cell specificity. Here, Quijano and colleagues engineered a mouse DNA binding monoclonal antibody to noncovalently bind therapeutic RNA, forming complexes that penetrate tumor cells by engaging the equilibrative nucleoside transporter 2 (ENT2). Intravenous administration of this engineered antibody, called tumor-targeting monoclonal antibody (TMAB3), complexed with the retinoic acid–inducible gene I (RIG-I) agonist 3p-hpRNA, specifically targeted orthotopic pancreatic and medulloblastoma tumors in immunocompetent mice and led to reduced tumor growth and improved survival through increased cytotoxic T cell infiltration and activation. These studies support TMAB3 as a platform to advance the study of RNA therapeutics and their translation into the clinic. —Melissa L. Norton
Science Translational Medicine , article en libre accès, 2025