Use of TGF-β antagonists to limit nephrotoxicity of...

Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof

Reexamination Certificate

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C424S133100, C424S141100, C424S142100, C424S158100, C530S317000, C530S350000, C530S387300, C530S388100, C530S388150, C530S388240, C530S389100, C530S389200, C514S021100

Reexamination Certificate

active

07867496

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.

REFERENCES:
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patent: 2003/0069248 (2003-04-01), Chakravarty et al.
patent: WO 2004/060362 (2004-07-01), None
International Search Report and Written Opinion for PCT/US2005/033942, mailed May 30, 2006 from the International Searching Authority of the European Patent Office.
Islam et al., “Effect of Anti-Transforming Growth Factor-β Antibodies in Cyclosporine-Induced Renal Dysfunction,” Kidney International, 59:498-506, (2001).
Khanna et al., “Anti-Transforming Growth Factor Antibody at Low but Not High Doses Limits Cyclosporine-Mediated Nephrotoxicity Without Altering Rat Cardiac Allograft Survival,” Circulation, 110:3822-3829 (2004).
Khanna et al., “Transforming Growth Factor (TGF)-β Mimics and Anti-TGF-β Antibody Abrogates the In Vivo Effects of Cyclosporine: Demonstration of a Direct Role of TGF-β in Immunosuppression and Nephrotoxicity of Cyclosporine,” Transplantation, 67:882-889 (1999).
Ling et al., “Therapeutic Role of TGF-β-Neutralizing Antibody in Mouse Cyclosporine A Nephropathy: Morphologic Improvement Associated with Functional Preservation,” J. Am. Soc. Nephrol., 14:377-388 (2003).
Ninova et al. “Acute Nephrotoxicity of Tacrolimus and Sirolimus in Renal Isografts: Differential Intragraft Expression of Transforming Growth Factor-β1 and α-Smooth Muscle Actin,” Transplantation, 78:338-344 (2004).
Shihab et al., “Sirolimus Increases Transforming Growth Factor-β1 Expression and Potentiates Chronic Cyclosporine Nephrotoxicity,” Kidney International, 65:1262-1271 (2004).
Xin et al., “Suppression of Cyclosporine A Nephrotoxicity In Vivo by Transforming Growth Factor β Receptor-Immunoglobulin G Chimeric Protein,” Transplantation, 77:1433-1442 (2004).

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