Quijano, Martinez-Saucedo, and Ianniello et al. showed that the mAb TMAB3 noncovalently bound to 3p-hpRNA to form stable antibody/RNA complexes that delivered 3p-hpRNA specifically to premalignant and malignant cells. Intravenously administered TMAB3/ 3p-hpRNA complexes enhanced survival and suppressed tumor growth in orthotopic pancreatic cancer and medulloblastoma mouse models. Single-cell RNAseq showed that TMAB3/3p-hpRNA treatment promoted cytotoxic T cell infiltration and RIG-I activation. T cell activation mediated by TMAB3/3p-hpRNA was dependent on ENT2 and RIG-I expression on PDAC cells.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info: (1) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. Department of Genetics, Yale University School of Medicine, New Haven, CT 065
Author Info: (1) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA. (2) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. (3) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. (4) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. (5) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA. (6) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. (7) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. (8) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. (9) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. (10) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. (11) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. (12) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA. (13) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. (14) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA. (15) Gennao Bio, Hopewell, NJ 08525, USA. (16) Gennao Bio, Hopewell, NJ 08525, USA. (17) Gennao Bio, Hopewell, NJ 08525, USA. (18) Department of Medicine (Medical Oncology), Yale University School of Medicine, New Haven, CT 06520, USA. Department of Urology, Akita University School of Medicine, Akita, 010-8543, Japan. (19) Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA. (20) Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA. Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA. (21) Gennao Bio, Hopewell, NJ 08525, USA. (22) Gennao Bio, Hopewell, NJ 08525, USA. (23) Gennao Bio, Hopewell, NJ 08525, USA. (24) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA. (25) Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA. (26) Department of Medicine (Medical Oncology), Yale University School of Medicine, New Haven, CT 06520, USA. (27) Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA. Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA. Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA. (28) Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA. (29) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. Department of Medicine (Medical Oncology), Yale University School of Medicine, New Haven, CT 06520, USA. Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA. (30) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
