Methods related to administering immunosuppressants and therapeutic macromolecules at a reduced pharmacodynamically effective dose

Abstract

Disclosed are compositions and methods that provide pharmacodynamic effects specific to therapeutic macromolecules. The effects may result from reduced doses of therapeutic macromolecules in combination with immunosuppressant doses. The effects may also be enhanced with such compositions.

1 . A method comprising:
 providing an immunosuppressant dose, wherein the immunosuppressant dose is attached to synthetic nanocarriers; and   administering a reduced pharmacodynamically effective dose of a therapeutic macromolecule concomitantly with the immunosuppressant dose to a subject in which an anti-therapeutic macromolecule antibody response is expected to occur;   wherein the concomitant administration is according to a protocol that has been demonstrated to result in a pharmacodynamic effect with the reduced pharmacodynamically effective dose of the therapeutic macromolecule upon concomitant administration with the immunosuppressant dose, as compared to administration of the therapeutic macromolecule when not administered concomitantly with the immunosuppressant dose and in the presence of an anti-therapeutic macromolecule antibody response; or   wherein the reduced pharmacodynamically effective dose of the therapeutic macromolecule is less than a pharmacodynamically effective dose of the therapeutic macromolecule that: (A) is administered in the presence of an anti-therapeutic macromolecule antibody response, and (B) is not administered concomitantly with the immunosuppressant dose; or   wherein the concomitant administration is according to a protocol that has been demonstrated to enhance a pharmacodynamic effect of the therapeutic macromolecule upon concomitant administration with the immunosuppressant dose, as compared to administration of the therapeutic macromolecule when not administered concomitantly with the immunosuppressant dose, and each in the presence of an anti-therapeutic macromolecule antibody response.   
     
     
         2 . The method of  claim 1 , wherein the method further comprises determining the protocol. 
     
     
         3 . The method of  claim 1 , wherein the method further comprises determining the reduced pharmacodynamically effective dose. 
     
     
         4 . The method of  claim 1 , wherein the method further comprises assessing the pharmacodynamic effect in the subject prior to and/or after the administration. 
     
     
         5 - 14 . (canceled) 
     
     
         15 . The method of  claim 1 , further comprising:
 recording an enhanced pharmacodynamic effect following the concomitant administration.   
     
     
         16 - 18 . (canceled) 
     
     
         19 . A method comprising:
 providing therapeutic macromolecules that cause or are expected to cause anti-therapeutic macromolecule antibodies upon repeated dosing in one or more subjects;   providing an immunosuppressant dose, wherein the immunosuppressant dose is attached to synthetic nanocarriers; and   repeatedly dosing at the same or a lower dose a subject with the therapeutic macromolecules concomitantly with the immunosuppressant dose.   
     
     
         20 . The method of  claim 19 , wherein the concomitant administration is according to a protocol that has been demonstrated to result in maintenance of a pharmacodynamic effect of the therapeutic macromolecule over two or more doses of the therapeutic macromolecules to a subject. 
     
     
         21 . The method of  claim 20 , wherein the method further comprises determining the protocol. 
     
     
         22 . The method of  claim 19 , wherein the method further comprises assessing a pharmacodynamic effect in the subject prior to and/or after the administration of the two or more doses. 
     
     
         23 . (canceled) 
     
     
         24 . A composition or kit comprising:
 an immunosuppressant dose wherein the immunosuppressant is attached to synthetic nanocarriers; and   a reduced pharmacodynamically effective dose of a therapeutic macromolecule.   
     
     
         25 - 28 . (canceled) 
     
     
         29 . The method of  claim 1 , wherein the therapeutic macromolecule is not attached to the synthetic nanocarriers. 
     
     
         30 . The method of  claim 1 , wherein the therapeutic macromolecule is attached to the synthetic nanocarriers. 
     
     
         31 - 33 . (canceled) 
     
     
         34 . The method of  claim 1 , wherein the reduced pharmacodynamically effective dose of the therapeutic macromolecule is at least 30% less than a pharmacodynamically effective dose of the therapeutic macromolecule that: (A) is administered in the presence of an anti-therapeutic macromolecule antibody response, and (B) is not administered concomitantly with the immunosuppressant dose. 
     
     
         35 . The method of  claim 34 , wherein the reduced pharmacodynamically effective dose is at least 40% less. 
     
     
         36 . (canceled) 
     
     
         37 . The method of  claim 1 , wherein the immunosuppressant dose comprises a statin, an mTOR inhibitor, a TGF-β signaling agent, a corticosteroid, an inhibitor of mitochondrial function, a P38 inhibitor, an NF-κβ inhibitor, an adenosine receptor agonist, a prostaglandin E2 agonist, a phosphodiesterase 4 inhibitor, an HDAC inhibitor or a proteasome inhibitor. 
     
     
         38 - 40 . (canceled) 
     
     
         41 . The method of  claim 1 , wherein the therapeutic macromolecule comprises a/an infusible or injectable therapeutic protein, enzyme, enzyme cofactor, hormone, blood or blood coagulation factor, cytokine, interferon, growth factor, monoclonal antibody, polyclonal antibody or protein associated with Pompe's disease. 
     
     
         42 - 50 . (canceled) 
     
     
         51 . The method of  claim 1 , wherein a load of immunosuppressant attached to the synthetic nanocarriers, on average across the synthetic nanocarriers, is between 0.1% and 50%. 
     
     
         52 . (canceled) 
     
     
         53 . The method of  claim 1 , wherein the synthetic nanocarriers comprise lipid nanoparticles, polymeric nanoparticles, metallic nanoparticles, surfactant-based emulsions, dendrimers, buckyballs, nanowires, virus-like particles or peptide or protein particles. 
     
     
         54 - 63 . (canceled) 
     
     
         64 . 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. 
     
     
         65 - 68 . (canceled) 
     
     
         69 . 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.