Compositions and methods to mitigate or prevent an immune response to an immunogenic therapeutic molecule in non-human primates

Abstract

Methods and compositions for preventing an immune response to an immunogenic therapeutic agent [i.e. anti-drug antibody (ADA), a.k.a. anti-therapeutic antibody (ATA)] are disclosed. One of the disclosed methods comprises administering an effective amount of an immunosuppressant such as an IL-2 signaling pathway inhibitor, including an antagonist, super agonist or partial agonist to the cytokine IL-2, to the IL-2 receptor (IL-2R), or to IL-2R signal transduction molecules. Inhibitors can be in the form of antibodies or antibody fragments, peptide inhibitors, fusion molecule, small molecules, antibody/small molecule conjugates. Administration of a given inhibitor can decrease the incidence and/or magnitude of an immune response or prevent an immune response, including an antibody response, to a potentially immunogenic therapeutic agent in a non-human primate (NHP). Some of the disclosed methods produce a tolerizing effect in NHPs.

1 . A method of mitigating formation of anti-drug antibodies (ADA) to an immunogenic therapeutic protein in a non-human primate (NHP), the method comprising administering an effective amount of an IL-2 pathway inhibitor to the NHP,
 wherein the inhibitor is selected from the group consisting of an IL-2 cytokine antagonist, an IL-2 cytokine partial agonist, an IL-2 cytokine super agonist, an IL-2 cytokine-chimeric fusion molecule, and an IL-2 cytokine toxic small molecule conjugate, and   wherein administration of the inhibitor decreases the incidence or intensity of an immune reaction caused by the immunogenic therapeutic protein in the NHP.   
     
     
         2 . The method of  claim 1 , wherein the inhibitor binds human or NHP IL-2R. 
     
     
         3 .- 5 . (canceled) 
     
     
         6 . The method of  claim 1  wherein inhibitor is a variant of cytokine IL-2 that binds the IL-2R, wherein such binding does not induce signaling, or induces partial signaling, that prevents or inhibits the formation of ADA. 
     
     
         7 . The method of  claim 1  wherein inhibitor is a variant of a cytokine IL-2-chimeric fusion molecule which binds the IL-2R, wherein such binding does not induce IL-2R signaling, or induces partial signaling, that prevents or inhibits formation of ADA. 
     
     
         8 . The method of  claim 1  wherein the inhibitor is a variant of cytokine IL-2 or a cytokine IL-2 conjugate molecule that binds the IL-2R wherein such binding induces deletion of the IL-2R bearing cell through apoptosis, necrosis, autophagy or other mechanism leading to partial, transient or permanent elimination of IL-2R bearing cells from the animal. 
     
     
         9 . The method of  claim 1  wherein the inhibitor is an antagonist, super agonist or partial agonist of the alpha chain of the IL-2R. 
     
     
         10 . The method of  claim 1  wherein the inhibitor is an antagonist, super agonist or partial agonist of the beta chain of the IL-2R. 
     
     
         11 . The method of  claim 1  wherein the inhibitor is an antagonist, super agonist or partial agonist of the gamma chain of the IL-2R. 
     
     
         12 .- 17 . (canceled) 
     
     
         18 . The method of  claim 1  wherein the inhibitor is a fully human recombinant protein. 
     
     
         19 . The method of  claim 1  wherein the inhibitor is a fully primate recombinant protein. 
     
     
         20 . The method of  claim 1  wherein the inhibitor is a human recombinant protein and at least a portion of the protein comprises an NHP sequence. 
     
     
         21 . The method of  claim 1  wherein the inhibitor is a NHP recombinant protein and at least a portion of the protein comprises a human sequence. 
     
     
         22 . The method of  claim 1  wherein the inhibitor is a human recombinant protein and at least a portion of the protein comprises a mouse sequence. 
     
     
         23 . The method of  claim 1  wherein the inhibitor is a NHP recombinant protein and at least a portion of the protein comprises a mouse sequence. 
     
     
         24 .- 25 . (canceled) 
     
     
         26 . The method of  claim 1 , wherein the inhibitor is administered as a nucleic acid, either alone or as part of a natural, synthetic or viral particulate, or cell. 
     
     
         27 . The method of  claim 1  wherein the effective amount of the inhibitor is from about 0.1 mg/kg to about 100 mg/kg of the body weight of the NHP. 
     
     
         28 .- 29 . (canceled) 
     
     
         30 . The method of  claim 1 , wherein the administering is performed before, during, and/or after administration of the immunogenic therapeutic protein. 
     
     
         31 . The method of  claim 1 , wherein the administering is performed once a day. 
     
     
         32 . The method of  claim 1 , wherein the administering is performed once a week. 
     
     
         33 . The method of  claim 1 , wherein the administering is performed once every 7-14 days. 
     
     
         34 .- 47 . (canceled)