Method for preparing viral particles with cyclic dinucleotide and use of said particles for treating cancer
A technology of cyclic dinucleotides and particles, which is used in the fields of medicine, vaccines and oncology, and can solve the problem that cyclic dinucleotides cannot effectively pass through the plasma membrane of cells
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[0120] Formulations of the pharmaceutical compositions described herein may be prepared by any method known or later developed in the art of pharmacology. These preparation methods include the steps of combining the active ingredient with one or more excipients and / or one or more other auxiliary ingredients, and then, if necessary and / or desired, shaping and / or packaging the product into the desired single or multiple dosage units.
[0121] Pharmaceutical compositions according to the invention may be prepared, packaged and / or sold in bulk as a single unit dose and / or as a plurality of single unit doses.
[0122] The relative amount of active ingredients, pharmaceutically acceptable excipients and / or any other ingredients in the pharmaceutical composition according to the present invention can be adjusted according to the identity, stature and / or condition of the subject to be treated and / or according to the composition The route of administration varies. For example, the co...
Embodiment 1
[0127] The inventors have shown that cGAMP can be incorporated into lentiviral particles when they are produced in cGAS expressing cells. cGAMP is translocated into infected cells and triggers STING-dependent type I interferon (IFN) induction.
[0128] This effect is independent of reverse transcription and integration, and could accelerate antiviral responses and broaden the spectrum of cells in which IFN is induced.
[0129] result
[0130] Viruses that trigger cGAS-dependent IFN responses in infected cells include retroviruses, including human immunodeficiency virus (HIV). The response to HIV is thought to involve cGAS detection of viral cDNA produced after reverse transcription, resulting in IFN gene transcription in the same cells where cDNA detection occurs. However, it is conceivable that IFN induction after retroviral infection could also occur independently of retroviral or cGAS if the infectious virus carries the cGAMP second messenger within it. The inventors hyp...
Embodiment 2
[0171] result
[0172] In order to study cGAS function, the present inventors attempted to control its expression in DC (dendritic cells) derived from human monocytes. They generated a lentiviral vector expressing cGAS, produced lentiviral particles and infected monocytes with the cell-free viral supernatant, which were then differentiated in DCs. On day 4 of differentiation, most differentiated DCs exposed to cGAS virus expressed CD86 and were thus activated, but transduction efficiency was lower as indicated by the expression of the reporter fluorescent protein BFP ( Figure 6 A). In contrast, infection with lentiviruses encoding only BFP efficiently transduced monocytes but did not increase the percentage of activated DCs compared to cells not exposed to the virus ( Figure 6 A). This confirms that the general process of lentiviral vector infection is not sensed by monocytes and DC and that it cannot be responsible for inducing the activation observed in the case of cGAS...
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