Modular Particulars for Immunotherapy

Abstract

Nanoparticulate compositions are disclosed. The nanoparticulate compositions typically include at least one, preferably two or more, active agent(s), one of which is an immunomodulatory compound, loaded into, attached to the surface of and/or enclosed within a delivery vehicle. The delivery vehicles can be nanolipogels including a polymeric core and a lipid shell or a biodegradable polymeric nanoparticle such as a PLGA nanoparticle. Typically, at least one of the active agents is an immunomodulator that increases an immune stimulatory response or decreases an immune suppressive response. In some embodiments, the particle includes both an immunomodulator that increases an immune stimulatory response and an immunomodulator that decreases an immune suppressive response. The particles can be decorated with a targeting moiety that improves delivery to a target cell. Methods of using the compositions to enhance an immune response and treat diseases such as cancer are also disclosed.

1 .- 20 . (canceled) 
     
     
         21 . A nanoparticulate composition comprising a delivery vehicle selected from the group consisting of a nanolipogel comprising a polymeric core and a lipid shell; a polymeric nanoparticle; and a liposome; wherein the delivery vehicle is decorated with IL-15; which composition does not comprise a nanolipogel formulation comprising IL-2 and losartan or structural analogs or salts thereof. 
     
     
         22 . The nanoparticulate composition of  claim 21 , wherein the delivery vehicle is decorated with IL-15/IL-15Rα complex. 
     
     
         23 . The nanoparticulate composition of  claim 22 , wherein the IL-15/IL-15Rα complex is attached to the surface of the delivery vehicle. 
     
     
         24 . The nanoparticulate composition of  claim 23 , wherein the IL-15/IL-15Rα complex is attached to the surface of the delivery vehicle by PEGylation or by an avidin-biotin link. 
     
     
         25 . The nanoparticulate composition of  claim 21 , wherein the delivery vehicle is loaded with at least one immunomodulator. 
     
     
         26 . The nanoparticulate composition of  claim 25 , wherein the at least one immunomodulator includes a cytokine, a chemokine, and/or a TGF-β inhibitor. 
     
     
         27 . The nanoparticulate composition of  claim 25 , wherein the at least one immunomodulator includes IL-2, IFN-γ, losartan, SB505124 or any combination thereof, excluding the combination of IL-2 and losartan. 
     
     
         28 . The nanoparticulate composition of  claim 21 , comprising a cytokine and a TGFβ inhibitor each loaded into, attached to the surface of, and/or enclosed within the delivery vehicle; wherein the cytokine is selected from the group consisting of an interferon, a macrophage colony stimulating factor, a granulocyte colony stimulating factor, a tumor necrosis factor, a Leukocyte Inhibitory Factor (LIF), a chemokine, SDF-1α and a member of the CXC family of cytokines. 
     
     
         29 . The nanoparticulate composition of  claim 27 , wherein the cytokine is IFN-γ. 
     
     
         30 . The nanoparticulate composition of  claim 28 , wherein the TGFβ inhibitor is losartan or a pharmaceutical salt, imidazole derivative or metabolite thereof. 
     
     
         31 . The nanoparticulate composition of  claim 28 , wherein the cytokine is IFN-γ and the TGFβ inhibitor is losartan. 
     
     
         32 . The nanoparticulate composition of  claim 21 , wherein the delivery vehicle is a nanolipogel comprising a polymeric core formed of non-crosslinkable polymers. 
     
     
         33 . The nanoparticulate composition of  claim 21 , wherein the delivery vehicle is a nanolipogel comprising a polymeric core formed of one or more crosslinkable polymers. 
     
     
         34 . The nanoparticulate composition of  claim 33 , wherein the polymers in the polymeric core are cross-linked by way of one or more photo-polymerizable groups 
     
     
         35 . The nanoparticulate composition of  claim 21 , wherein the delivery vehicle is a nanolipogel comprising a polymeric core formed of a block copolymer containing one or more poly(alkylene oxide) segments selected from polyethylene glycol, polypropylene, 1,2-glycol, poly(propylene oxide) and/or polypropylene 1,3-glycol segments; and/or one or more aliphatic polyester segments selected from polylactic acid (PLA), polyglycolic acid (PGA), and/or polylactide-coglycolide (PLGA) segments. 
     
     
         36 . The nanoparticulate composition of  claim 35 , wherein the block copolymer is a tri-block copolymer containing a central poly(alkylene oxide) segment and adjoining aliphatic polyester segments attached to either end of the central poly(alkylene oxide) segment. 
     
     
         37 . The nanoparticulate composition of  claim 35 , wherein the polymeric core further comprises one or more photo-polymerisable groups. 
     
     
         38 . The nanoparticulate composition of  claim 21 , wherein the delivery vehicle is a nanolipogel comprising a polymeric matrix core containing one or more host molecules dispersed within or covalently bound to the polymeric matrix, and a lipid shell. 
     
     
         39 . The nanoparticulate composition of  claim 38 , wherein the host molecule is selected from the group consisting of polysaccharides, cyclodextrins, cryptands, cryptophanes, cavitands, crown ethers, dendrimers, catenanes, polycatenanes, carcerands, spherands, carbon nanotubes, fullerenes, inorganic phosphates, and silica. 
     
     
         40 . The nanoparticulate composition of  claim 38 , further comprising a cytokine and a TGFβ inhibitor each dispersed within the polymeric matrix core, dispersed within the lipid shell, and/or attached to the lipid shell. 
     
     
         41 . The nanoparticulate composition of  claim 39 , wherein the TGFβ inhibitor is associated with a host molecule and the cytokine is attached to the lipid shell. 
     
     
         42 . The nanoparticulate composition of  claim 38 , wherein the one or more host molecules comprise cyclodextrin which is unfunctionalised or is functionalized with one or more reactive functional groups that react with the polymeric matrix core and/or with one or more reactive functional groups that modify the solubility of the cyclodextrin. 
     
     
         43 . The nanoparticulate composition of  claim 21 , wherein the delivery vehicle is a nanolipogel comprising a lipid shell composed of a mixture of a phospholipid, a PEGylated phospholipid, and cholesterol. 
     
     
         44 . The nanoparticulate composition of  claim 21 , wherein the delivery vehicle is a polymeric nanoparticle formed of one or more polymers selected from polymers of hydroxyacids, and copolymers of the hydroxyacids with polyethylene glycol, polyanhydrides, poly(ortho)esters, polyurethanes, poly(butyric acid), poly(valeric acid), poly(lactide-co-caprolactone), and blends and copolymers thereof. 
     
     
         45 . The nanoparticulate composition of  claim 21 , further comprising at least one additional active agent which is an immune modulator or a chemotherapeutic agent, wherein the at least one additional active agent is not loaded into, attached to the surface of or enclosed within said delivery vehicle. 
     
     
         46 . The nanoparticulate composition of  claim 45 , wherein the immune modulator is an immune response stimulating agent; an agent that blocks immune suppression; or an agent that targets tumor checkpoint blockade or costimulatory molecules. 
     
     
         47 . The nanoparticulate composition of  claim 46 , wherein the immune response stimulating agent is a PD-1 antagonist, a CTLA4 antagonist or a combination thereof, or wherein the chemotherapeutic agent is doxorubicin. 
     
     
         48 . A method of increasing or improving an immune stimulating or immune enhancing effect of an immune response stimulating agent or an effect of a chemotherapeutic agent, the method comprising administering to a subject in need thereof an effective amount of the nanoparticulate composition according to  claim 21  in combination with an immune response stimulating agent or chemotherapeutic agent to increase an immune stimulating or immune enhancing effect of the immune response stimulating agent or an effect of the chemotherapeutic agent, wherein the nanoparticulate composition is to be administered to the subject together with or separately from said immune response stimulating agent or chemotherapeutic agent. 
     
     
         49 . The method of  claim 48 , wherein the composition and the immune response stimulating agent or the chemotherapeutic agent are administered to the subject together, or are administered to the subject separately and independently at the same time or at different times. 
     
     
         50 . The method of  claim 48 , wherein the immune response stimulating agent is an agent that targets tumor checkpoint blockade or costimulatory molecules. 
     
     
         51 . The method of  claim 48 , wherein the immune response stimulating agent is a PD-1 antagonist or a CTLA4 antagonist or a combination thereof. 
     
     
         52 . The method of  claim 48 , wherein the chemotherapeutic agent is doxorubicin. 
     
     
         53 . A method of treating an infectious disease or a cancer in a subject, including a cancer selected from the group consisting of: multiple myeloma and adenocarcinomas and sarcomas of the bone, bladder, brain, breast, cervix, colon, rectum, oesophagus, kidney, liver, lung, nasopharynx, pancreas, prostate, skin, stomach and uterus, the method comprising administering to the subject an effective amount of the composition of  claim 21  to reduce one or more symptoms of the infectious disease or the cancer.