Combination immunomodulation and uses thereof
A composition and a technology of combining fragments, applied in the field of combined immune regulation and its use, can solve the problems of insufficient immune response and the like
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Embodiment 1
[0152] Example 1. Nanoparticle (NP)-OX40 mRNA induces increased expression levels of OX40
[0153] Characterization of OX40 expression in EG.7-OVA cells. Nanoparticle (NP)-OX40 mRNA induced much higher OX40 expression compared to the control group ( figure 1 ). 5'UTR and 3'UTR modifications are broadly applicable to mRNAs encoding cytokines and immune checkpoint regulators (such as ICOS, 4-1BB, GITR, CD40, etc.). Nanoparticles were formulated with lipids, DOPE, cholesterol, DMG-PEG, and mRNA (see Li, B et al., An Orthogonal array optimization of lipid-like nanoparticles for mRNA delivery in vivo. Nano Lett. 2015, 15, 8099-8107 ).
Embodiment 2
[0154] Example 2. Combination therapy of NP / OX40 mRNA + anti-OX40 antibody improves tumor therapy in a B16 melanoma tumor model.
[0155] A mouse tumor model of B16 melanoma was established (Triplett, TA et al., Reversal of IDO-mediated cancer immunopression by systemic kynurenine depletion with treatment enzyme, Nat Biotechnol. 2018 Sep;36(8):758-764). Mice were treated with PBS, NP+anti-OX40 antibody (InVivoPlus anti-mouse OX40 (clone OX-86) (company: BioXcell, catalog: BP0031)) or NP / OX40 mRNA+anti-OX40 antibody. In this mouse tumor model, the combination of these mRNAs and their associated antibodies significantly improved tumor therapy ( Figure 2A ) and prolonged overall survival ( Figure 2B ).
Embodiment 3
[0156] Example 3. Combination therapy of NP / OX40 mRNA + anti-OX40 antibody improves tumor therapy in CT26 tumor model.
[0157] A CT26 mouse tumor model was established (Malvicini, M et al., Tumor Microenvironment Remodeling by 4-Methylumbelliferone Boosts the Antitumor Effect of Combined Immunotherapy in Murine Colorectal Carcinoma, Molecular Therapy. Vol. 23 No. 9, 1444-1455, September 2015). Mice were treated with PBS, nanoparticles (NP)+anti-OX40 antibody, nanoparticles (NP) / OX40 mRNA+anti-OX40 antibody, and nanoparticles (NP) / OX40 mRNA+anti-OX40 antibody together. Nanoparticles (NP) / OX40 mRNA+anti-OX40 antibody (injection interval: 6 hours); and nanoparticles (NP) / OX40 mRNA+anti-OX40 antibody together (injection interval: 0 hours). The OX40 antibody used was InVivoPlus anti-mouse OX40 (clone OX-86) (company: BioXcell, catalog: BP0031)). The combination of these mRNAs and their associated antibodies significantly prolonged overall survival and improved tumor therapy in th...
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