The Brigham and Women's Hospital, Inc.

Massachusetts Institute of Technology

Chiron Corporation

Mount Sinai School of Medicine

Brigham and Women's Hospital Harvard Medical School

Harold A Chapman

Hidde L Ploegh

Matthew S Bogyo

Richard J Riese

Paula R Bryant

Steven Rosenberg

Michael V Doyle

Robert J Desnick

Daniel Simon

Bruce D Gelb

Guo-Ping Shi

Peter Libby

Galina K Sukhova

Methods and products for suppressing a class II MHC-restricted immune response in a mammal, or in mammalian cells, are described. The methods depend upon inhibiting invariant chain proteolysis by cathepsin S from class II MHC/invariant chain complexes, thereby reducing the competency of class II MHC molecules for binding antigenic peptides, reducing presentation of antigenic peptides by class II MHC molecules, and suppressing immune responses. The methods may be employed in the treatment of autoimmune diseases, allergic responses, and organ or tissue graft rejection. Pharmaceutical and therapeutic compositions which are peptide based inhibitors of cathepsin S are also described.

Suppression of immune response via inhibition of cathepsin S

Methods and products for suppressing a class II MHC-restricted immune response in a mammal, or in mammalian cells, are described. The methods depend upon inhibiting invariant chain proteolysis by cathepsin S from class II MHC/invariant chain complexes, thereby reducing the competency of class II MHC molecules for binding antigenic peptides, reducing presentation of antigenic peptides by class II MHC molecules, and suppressing immune responses. The methods may be employed in the treatment of autoimmune diseases, allergic responses, and organ or tissue graft rejection. Pharmaceutical and therapeutic compositions which are peptide-based inhibitors of cathepsin S are also described.

Novel peptides that are capable of binding to uPAR and inhibiting the binding of an integrin and vitronectin are described. Also provided are nucleic acid sequences encoding the novel peptides. Methods for screening for small molecules, other peptides, or peptoids that mimic the antagonistic function of the peptides of the invention are described. The invention has applications in design of therapeutics for treating disorders characterized by upregulation of uPA and uPAR, and cancer and chronic inflammation, cell migration or uPAR: integrin binding interactions, and diagnostical applications to such disorders.

Peptide ligands of the urokinase receptor

The invention provides methods of treating and preventing vascular diseases, by inhibiting cysteine proteases active at sites of vascular injury, particularly cathepsins K and S, by administering cystatin C or TGF-&bgr; . Cystatin C is severely reduced in both atherosclerotic and aneurysmal aortic lesions. Also provided is a method of diagnosing a patient at risk of, or with, vascular injury by detecting low levels of circulating cystatin C.

Methods of treating vascular disease associated with cystatin C deficiency

Methods and products for suppressing a class II MHC-restricted immune response in a mammal, or in mammalian cells, are described. The methods depend upon inhibiting invariant chain proteolysis by cathepsin S from class II MHC/invariant chain complexes, thereby reducing the competency of Class II MHC molecules for binding antigenic peptides, reducing presentation of antigenic peptides by class II MHC molecules, and suppressing immune responses. The methods may be employed in the treatment of autoimmune diseases, allergic responses, and organ or tissue graft rejection. Pharmaceutical and therapeutic compositions which are peptide-based inhibitors of cathepsin S are also described.

The present invention relates to methods and compositions for the amelioration of symptoms caused by bone resorption disorders, including but not limited to osteoporosis, arthritides and periodontal disease, and damage caused by macrophage-mediated inflammatory processes. In one embodiment, the methods and compositions of the invention include methods and compositions for the specific inhibition of cathepsin K activity. In an additional embodiment, the methods and compositions of the invention include methods and compositions for the specific inhibition of cathepsin K activity coupled with specific inhibition of at least a second activity involved in the bone resorption and/or macrophage-mediated inflammatory processes. In a particular embodiment, the methods and compositions of the invention include methods and compositions for the specific inhibition of cathepsin K and cathepsin S activity.

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Newton, MA, United States of America

Harold A Chapman