Scientific publications
Intratumoral injection of IL-12-encoding mRNA targeted to CSFR1 and PD-L1 exerts potent anti-tumor effects without substantial systemic exposure
Claudia Augusta Di Trani 1 2 , Assunta Cirella 1 2 , Leire Arrizabalaga 1 2 , Maite Alvarez 1 2 3 , Ángela Bella 1 2 , Myriam Fernandez-Sendin 1 2 , Joan Salvador Russo-Cabrera 1 2 , Celia Gomar 1 2 , Nuria Ardaiz 1 2 , Alvaro Teijeira 1 2 3 , Elixabet Bolaños 1 2 , José González-Gomariz 1 2 , Itziar Otano 1 2 , Fernando Aranda 1 2 , Belén Palencia 1 , Aina Segués 4 5 , Shuyu Huang 4 5 , Sander M J van Duijnhoven 6 , Andrea van Elsas 7 , Ignacio Melero 1 2 3 8 9 , Pedro Berraondo 1 2 3
Abstract
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.
CITATION Mol Ther Nucleic Acids. 2023 Jul 19:33:599-616. doi: 10.1016/j.omtn.2023.07.020. eCollection 2023 Sep 12.
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