Method of reducing titers of antibodies specific for a therapeutic agent
Inventors
Kishnani, Priya S. • Banugaria, Suhrad G. • Koeberl, Dwight D. • Prater, Sean N.
Assignees
Publication Number
US-12290549-B2
Publication Date
2025-05-06
Expiration Date
2031-05-06
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Abstract
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.
Core Innovation
The present invention provides a method for reducing or preventing antibody titers in patients undergoing protein replacement therapy (PRT), gene replacement therapy with viral or non-viral vectors, or other therapeutic modalities involving the administration of exogenous substances for therapeutic benefit. The invention specifically focuses on the use of proteasome inhibitors, in particular bortezomib, to deplete plasma cells responsible for the production of antibodies against therapeutic agents or vectors, thereby overcoming immune responses that compromise the efficacy of such therapies.
The problem being addressed arises from the frequent development of robust and persistent immune responses, notably the formation of high sustained antibody titers (HSAT), in patients treated with proteinaceous therapeutic agents or undergoing gene therapy. These antibodies often neutralize therapeutic efficacy, cause adverse reactions, and lead to clinical decline. Existing immunomodulatory therapies, such as rituximab or cyclophosphamide, have shown limited success in reducing established antibody titers, particularly because they do not target long-lived plasma cells—the main source of ongoing antibody production.
The core solution offered by the invention is the administration of a proteasome inhibitor, such as bortezomib, as a way to eliminate both short- and long-lived plasma cells, thereby directly reducing antibody titers specific for a therapeutic agent or vector. This strategy can be used alone or in combination with other immunomodulatory agents and is applicable both prophylactically and therapeutically, for patients at risk of or already exhibiting high antibody titers that threaten the effectiveness of the administered therapy.
Claims Coverage
The patent includes two independent claims covering two inventive features relating to improving efficacy and reducing risk of high antibody titers in gene therapy for GSD II using bortezomib.
Method of improving efficacy of gene replacement therapy using bortezomib in GSD II patients
This inventive feature is directed to a method for improving the efficacy of gene replacement therapy comprising: - Administering to a treatment-naive patient with glycogen storage disease type II (GSD II) a viral vector encoding human acid glucosidase alfa (rhGAA). - Administering to the patient a therapeutically effective amount of bortezomib. - The reduction of antibody titers specific for the viral vector, the encoded rhGAA, or both, following bortezomib administration, thereby improving the efficacy of the gene replacement therapy.
Method of reducing the risk of developing high sustained antibody titers (HSAT) in GSD II gene therapy using bortezomib
This inventive feature encompasses a method of reducing the risk of developing high sustained antibody titers comprising: - Administering to a treatment-naive patient with glycogen storage disease type II (GSD II) gene replacement therapy with a viral vector encoding human acid glucosidase alfa (rhGAA). - Administering to the patient a therapeutically effective amount of bortezomib. - Where, after bortezomib administration, the patient's risk of developing HSAT to the viral vector, the encoded rhGAA, or both is reduced.
In summary, the independent claims provide coverage for methods using bortezomib to improve efficacy and reduce antibody titers or risk thereof in gene replacement therapy for GSD II patients.
Stated Advantages
The use of bortezomib enables a significant and rapid reduction in antibody titers, including high sustained antibody titers, thereby improving clinical outcomes in patients receiving therapeutic proteins or gene therapy.
The method directly targets long-lived plasma cells, the ultimate source of persistent antibody production, overcoming limitations of other immune suppressing therapies that fail to eliminate these cells.
Reduction or prevention of antibody titers allows continued and more effective use of life-saving therapeutic agents, resulting in clinical benefit and the potential for immune tolerance induction.
Combination therapy with bortezomib and other agents (e.g., rituximab, methotrexate, IVIG) is both safe and efficacious, targeting different parts of the immune response pathway leading to antibody production.
Documented Applications
Use in patients with glycogen storage disease type II (Pompe disease) undergoing protein or gene replacement therapy to reduce or prevent antibody titers and improve clinical outcomes.
Application in gene replacement therapy with viral or non-viral vectors, including treating antibody responses to vectors or expressed proteins such as rhGAA.
Use in treating other disorders where exogenous protein, enzyme, or gene therapies provoke problematic antibody responses, including mucopolysaccharidosis I, II, VI, Gaucher disease, Fabry disease, metachromatic leukodystrophy, primary immune deficiency, hemophilia A and B, growth hormone deficiency, IGF-1 deficiency, and conditions requiring exogenous insulin.
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