using cyclosporine a; autoimmune disorder, transplant rejection; Transforming Growth Factor- beta (TGF- beta )
Inventors
Khanna, Ashwani K. • Ledbetter, Steven
Assignees
Genzyme Corp • National Institutes of Health NIH • Medical College of Wisconsin Research Foundation Inc
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Publication Number
US-7867496-B2
Publication Date
2011-01-11
Expiration Date
2025-09-22
Abstract
The disclosure relates to methods of ameliorating nephrotoxic side effects of immunosuppressive agents whose immunosuppressive activity is mediated via upregulation of TGF-β such as, for example, cyclosporine (CsA). The disclosure provides treatment modalities for use in patients that require immunosuppression, e.g., patients at risk of transplant rejection or having an autoimmune disease. In the methods of the invention, a TGF-β antagonist, e.g., an anti-TGF-β antibody, is administered to a patient treated with an immunosuppressive agent. Such a TGF-β antagonist is administered in a therapeutically effective amount sufficient to alleviate the nephrotoxic effects of the immunosuppressive agent without substantially interfering with immunosuppressive activity of the agent.
Core Innovation
The invention provides methods and compositions for reducing nephrotoxicity caused by immunosuppressive agents that mediate their immunosuppressive activity at least in part via upregulation of Transforming Growth Factor-beta (TGF-β), such as cyclosporine, tacrolimus, and sirolimus. It involves administering a TGF-β antagonist, e.g., an anti-TGF-β antibody, to a patient treated with an immunosuppressive agent in a therapeutically effective amount sufficient to alleviate nephrotoxic effects without substantially interfering with the immunosuppressive activity.
The invention addresses the problem that immunosuppressive agents like cyclosporine A, while effective for preventing organ transplant rejection and treating autoimmune diseases, are associated with serious nephrotoxicity including acute and chronic renal dysfunction leading to renal failure. Prior approaches to mitigate nephrotoxicity either did not adequately preserve immunosuppressive efficacy or were incomplete. The challenge was to reduce nephrotoxicity mediated by TGF-β upregulation without diminishing the therapeutic immunosuppressive effects.
This invention is based on the discovery that low doses, but not high doses, of anti-TGF-β antibody can mitigate nephrotoxicity induced by cyclosporine A without substantially interfering with graft survival and immunosuppressive efficacy. Experimental data showed that administering a low dose of anti-TGF-β antibody to cyclosporine-treated rats reduced nephrotoxic effects such as fibrosis markers, renal dysfunction indicators, and histopathological changes, while maintaining immunosuppressive activity. Conversely, higher doses abolished immunosuppression, indicating a dose-dependent balance.
Claims Coverage
The patent contains one independent claim focused on a method of treating nephritis induced by an immunosuppressive agent, covering several main inventive features related to the therapeutically effective administration of a TGF-β antagonist and specifying dosing and antibody characteristics.
Administration of TGF-β antagonist to alleviate nephrotoxic effects without impairing immunosuppression
A method of treating nephritis caused by an immunosuppressive agent that induces TGF-β expression by administering a TGF-β antagonist in a therapeutically effective amount sufficient to reduce TGF-β-mediated nephrotoxicity without substantially interfering with the immunosuppressive activity mediated by TGF-β.
Use of specific immunosuppressive agents and patient types
The immunosuppressive agent is selected from cyclosporine, tacrolimus, and sirolimus. The method applies to mammals in need of immunosuppression, including humans with autoimmune disorders or receiving transplants such as allografts of heart, kidney, lung, liver, cornea, bone marrow, blood vessels, or islet cell transplants.
Dose control of TGF-β antagonist to balance efficacy and safety
The TGF-β antagonist is administered at a dose at or below about 2 mg/kg body weight of the antibody 1D11 in rats, with specific mention of 1 mg/kg as an effective dose to reduce nephrotoxicity while preserving immunosuppression.
Characteristics of TGF-β antagonists, especially antibodies
The TGF-β antagonist may be the monoclonal antibody 1D11 or its humanized or chimeric derivatives, with an affinity constant of at least 10^8 M^−1, and may be an anti-TGF-β antibody binding TGF-β1, TGF-β2, and TGF-β3 (pan-specific). The antibody formats include a human pan-specific IgG4 antibody with variable heavy and light chain domains as defined by SEQ ID NOs: 13–18.
The claims cover a method of treating immunosuppressant-induced nephritis by administering a controlled dose of a TGF-β antagonist, specifically antibodies like 1D11 or derivatives thereof, to mitigate nephrotoxicity without compromising immunosuppressive efficacy, applicable to various immunosuppressants and transplant or autoimmune patient populations.
Stated Advantages
The invention reduces nephrotoxic side effects of immunosuppressive agents while maintaining their immunosuppressive activity.
Low doses of anti-TGF-β antibody mitigate nephrotoxicity without substantially interfering with graft survival.
The treatment decreases intrarenal fibrosis markers and improves renal function indicators (e.g., creatinine and BUN levels).
Documented Applications
Treatment of patients in need of immunosuppression, including those undergoing organ or tissue transplantation to prevent graft rejection.
Treatment of autoimmune diseases requiring immunosuppressive therapy.
Method for detecting nephrotoxicity induced by immunosuppressive agents and evaluating compounds for reduction of such nephrotoxicity.
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