Method of reducing titers of antibodies specific for a therapeutic agent
The present invention relates, in general, to a method of treating patients undergoing enzyme replacement therapy (ERT) or other therapy involving the administration of a proteinaceous therapeutic agent as well gene replacement therapy with non-viral or viral vectors, or other therapeutic modality or modalities, used alone or in combination, which involve the administration of exogenous substances for potential therapeutic benefit, including, but not limited to DNA vaccines, siRNA, splice-site switching oligomers (SSOs) as well as RNA-based nanoparticles (RNPs) and nanovaccines. The invention further relates to compounds and compositions suitable for use in such methods.
1. A method for reducing titers of antibodies against a therapeutic protein in a patient treated with the therapeutic protein by administration of a nucleic acid comprising a nucleotide sequence encoding the therapeutic protein in expressible form, said administration able to elicit said antibodies, wherein the therapeutic protein is a proteinaceous replacement for acid alpha-glucosidase (GAA), comprising administering to the patient a proteasome inhibitor in an amount and under conditions that the antibody titers are reduced.
2. The method of claim 1 , wherein the nucleic acid is present in a vector.
3. The method of claim 2 , wherein the vector is a viral vector.
4. A method for reducing titers of antibodies elicited by administration of a viral vector comprising a nucleotide sequence encoding a therapeutic protein in expressible form in a patient treated with the viral vector comprising administering to the patient a proteasome inhibitor in an amount and under conditions that the antibody titers are reduced.
5. The method of claim 1 , wherein the patient suffers from Pompe disease, a mucopolysaccharide storage disorder, Fabry disease, Gaucher disease, gangliosidosis, alkaline hypophosphatasia, cholesterol ester storage disease, hyperuricemia, hemophilia, diabetes, growth hormone deficiency, or renal anemia.
6. The method of claim 1 , wherein the patient suffers from Pompe disease and the therapeutic protein is acid alpha-glucosidase (GAA).
7. The method of claim 1 , wherein the method further comprises administering to the patient a compound that targets or alters antigen presentation or humoral or cell mediated immune response.
8. The method of claim 1 , wherein the method further comprises administering to the patient a compound that exerts a therapeutic effect against B cells and a compound that targets or alters antigen presentation or humoral or cell mediated immune response.
9. The method of claim 1 , wherein the proteosome inhibitor is bortezomib.
10. The method of claim 1 , wherein the method further comprises administering to said patient rituximab, methotrexate, and intravenous gamma globulin.
11. The method of claim 3 , wherein the viral vector is an adenovirus vector or an adeno-associated virus vector.
12. A method to reduce or prevent the production of antibodies elicited against a therapeutic agent in a patient treated with the therapeutic agent, wherein the therapeutic agent is a viral vector, wherein the viral vector comprises a nucleic acid encoding a therapeutic protein in expressible form, said treatment comprising administration of said therapeutic agent, and said therapeutic agent able to elicit said antibodies, the method comprising administering to the patient, prior to administration of the therapeutic agent, an amount of a proteasome inhibitor sufficient to effect said reduction or prevention.
13. The method of claim 12 , wherein the method further comprises administering to the patient a compound that targets or alters antigen presentation or humoral or cell mediated immune response.
14. The method of claim 12 , wherein the patient suffers from Pompe disease, a mucopolysaccharide storage disorder, Fabry disease, Gaucher disease, gangliosidosis, alkaline hypophosphatasia, cholesterol ester storage disease, hyperuricemia, hemophilia, diabetes, growth hormone deficiency, or renal anemia.
15. The method of claim 12 , wherein the method further comprises administering to said patient rituximab, methotrexate, and intravenous gamma globulin.
16. The method of claim 12 , wherein the viral vector is an adenovirus vector or an adeno-associated virus vector.
17. The method of claim 4 , wherein the viral vector is an adenovirus vector or an adeno-associated virus vector.