Methods of administering immunosuppressants having a specified pharmacodynamic effective life and therapeutic macromolecules for the induction of immune tolerance

Abstract

This invention relates to methods that provide immunosuppressants and therapeutic macromolecules that are administered within a pharmacodynamically effective window of the immunosuppressants to induce immune tolerance to the therapeutic macromolecules. The methods allow shifting the immune response in favor of tolerogenic immune response development specific to the therapeutic macromolecule.

1 . A method comprising:
 administering an immunosuppressant to a subject in a first class of subjects at an administration dose that provides an administration pharmacodynamic effective-life, with respect to a therapeutic macromolecule, the duration of which pharmacodynamic effective-life ranges from a minimum of 20 hours to a maximum of 1 month; and   administering the therapeutic macromolecule to the subject within the duration of the administration pharmacodynamic effective-life of the immunosuppressant;   wherein the therapeutic macromolecule and immunosuppressant are not attached to one another, and the therapeutic macromolecule is not attached to a synthetic nanocarrier.   
     
     
         2 . The method of  claim 1 , wherein the method further comprises:
 determining the administration dose of the immunosuppressant based on a test dose of the immunosuppressant;   wherein the test dose possesses a test pharmacodynamic effective-life with respect to the therapeutic macromolecule the duration of which pharmacodynamic effective-life ranges from a minimum of 20 hours to a maximum of 1 month in a second class of subjects.   
     
     
         3 . An immunosuppressant for use in a method of inducing tolerance to a therapeutic macromolecule, said method comprising: (a) administering the immunosuppressant to a subject at a dose sufficient to elicit a pharmacodynamic effective-life the duration of which pharmacodynamic effective-life is between 20 hours to 1 month; and (b) administering the therapeutic macromolecule to said subject within the duration of said pharmacodynamic effective-life, wherein the therapeutic macromolecule and immunosuppressant are not attached to one another, and the therapeutic macromolecule is not attached to a synthetic nanocarrier. 
     
     
         4 . Use of an immunosuppressant for the manufacture of a medicament for use in a method comprising: (a) administering the immunosuppressant to a subject at a dose sufficient to elicit a pharmacodynamic effective-life the duration of which pharmacodynamic effective-life ranges is between 20 hours to 1 month; and (b) administering the therapeutic macromolecule to said subject within the duration of said pharmacodynamic effective-life, wherein the therapeutic macromolecule and immunosuppressant are not attached to one another, and the therapeutic macromolecule is not attached to a synthetic nanocarrier. 
     
     
         5 . The method of  claim 1 , wherein the immunosuppressant comprises synthetic nanocarriers that comprise a synthetic nanocarrier-attached immunosuppressant, implantable osmotic pumps, bi-specific antibodies, or implantable polymeric depot materials. 
     
     
         6 . The method of  claim 1 , wherein the immunosuppressant comprises a synthetic nanocarrier-attached immunosuppressant. 
     
     
         7 . The method of  claim 1 , wherein the synthetic nanocarrier comprises lipid nanoparticles, polymeric nanoparticles, metallic nanoparticles, surfactant-based emulsions, dendrimers, buckyballs, nanowires, virus-like particles, protein particles, or nanoparticles that comprise a combination of nanomaterials, optionally, wherein such nanoparticles are lipid-polymer nanoparticles. 
     
     
         8 . The method of  claim 1 , wherein the immunosuppressant comprises statins; mTOR inhibitors; TGF-β signaling agents; TGF-β receptor agonists; histone deacetylase inhibitors; corticosteroids; inhibitors of mitochondrial function; P38 inhibitors; NF-κβ inhibitors, Dexamethasone; TCPA-1; IKK VII; adenosine receptor agonists; prostaglandin E2 agonists; phosphodiesterase inhibitors; proteasome inhibitors; kinase inhibitors; G-protein coupled receptor agonists; G-protein coupled receptor antagonists; glucocorticoids; retinoids; cytokine inhibitors; cytokine receptor inhibitors; cytokine receptor activators; peroxisome proliferator-activated receptor antagonists; peroxisome proliferator-activated receptor agonists; histone deacetylase inhibitors; calcineurin inhibitors; phosphatase inhibitors; PI3KB inhibitors; autophagy inhibitors; aryl hydrocarbon receptor inhibitors; proteasome inhibitor I (PSI); oxidized ATPs; IDO, vitamin D3; cyclosporins; aryl hydrocarbon receptor inhibitors; resveratrol; azathiopurine; 6-mercaptopurine; 6-thioguanine; FK506; sanglifehrin A; salmeterol; mycophenolate mofetil; aspirin and other COX inhibitors; niflumic acid; estriol; or triptolide. 
     
     
         9 - 10 . (canceled) 
     
     
         11 . The method of  claim 1 , wherein a loading of the immunosuppressant in the synthetic nanocarriers ranges between 0.0001 wt % and 50 wt %, based on the total dry recipe weight of materials in the synthetic nanocarrier (weight/weight). 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 1 , wherein the therapeutic macromolecule comprises a therapeutic protein or a therapeutic polynucleotide. 
     
     
         14 . (canceled) 
     
     
         15 . The method of  claim 1 , wherein the administration pharmacodynamic effective-life has a duration that ranges from a minimum of 20 hours to a maximum of 2 weeks. 
     
     
         16 . The method of  claim 15 , wherein the administration pharmacodynamic effective-life has a duration that ranges from a minimum of 20 hours to a maximum of 1 week. 
     
     
         17 . (canceled) 
     
     
         18 . The method of  claim 1 , wherein the test pharmacodynamic effective-life has a duration that ranges from a minimum of 20 hours to a maximum of 2 weeks. 
     
     
         19 . The method of  claim 18 , wherein the test pharmacodynamic effective-life has a duration that ranges from a minimum of 20 hours to a maximum of 1 week. 
     
     
         20 . The method of  claim 19 , wherein the test pharmacodynamic effective-life has a duration that ranges from a minimum of 24 hours to a maximum of 2 days. 
     
     
         21 . The method of  claim 1 , wherein the administration dose of the immunosuppressant is determined based on the test dose of the immunosuppressant, together with use of allometric or isometric scaling techniques. 
     
     
         22 . The method of  claim 1 , wherein the first class of subjects and the second class of subjects are a same class of subjects. 
     
     
         23 . The method of  claim 1 , wherein the first class of subjects and the second class of subjects are different classes of subjects. 
     
     
         24 - 33 . (canceled) 
     
     
         34 . The method of  claim 1 , wherein the mean of a particle size distribution obtained using dynamic light scattering of the synthetic nanocarriers is a diameter greater than 100 nm. 
     
     
         35 - 38 . (canceled) 
     
     
         39 . The method of  claim 1 , wherein an aspect ratio of the synthetic nanocarriers is greater than 1:1, 1:1.2, 1:1.5, 1:2, 1:3, 1:5, 1:7 or 1:10.