| Autor: |
Claudia Augusta Di Trani, Assunta Cirella, Leire Arrizabalaga, Maite Alvarez, Ángela Bella, Myriam Fernandez-Sendin, Joan Salvador Russo-Cabrera, Celia Gomar, Nuria Ardaiz, Alvaro Teijeira, Elixabet Bolaños, José González-Gomariz, Itziar Otano, Fernando Aranda, Belén Palencia, Aina Segués, Shuyu Huang, Sander M.J. van Duijnhoven, Andrea van Elsas, Ignacio Melero, Pedro Berraondo |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
|
| Zdroj: |
Molecular Therapy: Nucleic Acids, Vol 33, Iss , Pp 599-616 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2162-2531 |
| DOI: |
10.1016/j.omtn.2023.07.020 |
| Popis: |
IL-12 is a potent cytokine for cancer immunotherapy. However, its systemic delivery as a recombinant protein has shown unacceptable toxicity in the clinic. Currently, the intratumoral injection of IL-12-encoding mRNA or DNA to avoid such side effects is being evaluated in clinical trials. In this study, we aimed to improve this strategy by further favoring IL-12 tethering to the tumor. We generated in vitro transcribed mRNAs encoding murine single-chain IL-12 fused to diabodies binding to CSF1R and/or PD-L1. These targeted molecules are expressed in the tumor microenvironment, especially on myeloid cells. The binding capacity of chimeric constructs and the bioactivity of IL-12 were demonstrated in vitro and in vivo. Doses as low as 0.5 μg IL-12-encoding mRNA achieved potent antitumor effects in subcutaneously injected B16-OVA and MC38 tumors. Treatment delivery was associated with increases in IL-12p70 and IFN-γ levels in circulation. Fusion of IL-12 to the diabodies exerted comparable efficacy against bilateral tumor models. However, it achieved tethering to myeloid cells infiltrating the tumor, resulting in nearly undetectable systemic levels of IL-12 and IFN-γ. Overall, tethering IL-12 to intratumoral myeloid cells in the mRNA-transferred tumors achieves similar efficacy while reducing the dangerous systemic bioavailability of IL-12. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
|
