T Cell Receptor Ligands, And Methods For Use


T lymphocytes are key cellular elements of the immune system. The growth, effector functions (cytokine secretion, cytotoxicity), and survival of these cells are regulated by signals arising from the interaction of ligands consisting of polypeptide-MHC molecule complexes with specific receptors (TCR) on the cell membrane. All antigen-specific attempts at modulation of T-cell dependent immunity involve this key TCR-ligand interaction. This application describes a novel class of TCR ligands (called variant TCR ligands, sometimes referred to in the scientific literature as altered peptide ligands) with selective antagonist or mixed agonist-antagonist properties that can modulate the function of T cells in unique ways. For example, these compounds can induce T lymphocyte unresponsiveness while preventing T cell effector activity or can permit secretion of some cytokines while inhibiting the secretion of others typically produced upon exposure to the normal stimulatory ligand of the TCR in question. These effects can thus modulate in vivo immune responses by inactivating T cells or by changing the effector response of such cells from a damaging to a benign pattern. These properties should be extremely useful in the development of antigen-specific immunotherapies for various autoimmune diseases, including but not limited to diabetes, rheumatoid arthritis, and multiple sclerosis. These compounds could also be useful in modifying responses to tumor antigens, to vaccine components, or tissue transplants. Because these novel immunomodulatory compounds are produced by slight alteration of the normal peptide-MHC molecule ligand for the TCR, it is believed that all current attempts to modify such diseases using as antigen either species variants or synthetic variants rather than native, unmodified human self-antigens involve materials whose properties and mode of action fall within the scope of this patent application.

Potential Commercial Applications: Competitive Advantages:
* treatment of autoimmune disorders * graft rejection * vaccines * screening of drugs for autoimmune disorders * modulates T cell effector responses * TCR ligands are selective antagonists and mixed agonists-antagonists


Inventors:

Ronald Germain (NIAID)  ➽ more inventions...

Luigi Racioppi (NIAID)  ➽ more inventions...


Intellectual Property:
U.S. Pat: 5,837,477 issued 1998-11-17
U.S. Pat: 5,948,409 issued 1999-09-07
U.S. Pat: 5,958,712 issued 1999-09-28
U.S. Pat: 6,900,024 issued 2005-05-31
US Application No. 09/776,520
US Application No. 09/776,522
US Application No. 10/193,474
US Application No. 10/193,473
US Application No. 09/293,738

Publications:
Racioppi L; Ronchese F; Matis LA; Germain RN. Peptide-major histocompatibility complex class II complexes with mixed agonist/antagonist properties provide evidence for ligand-related differences in T cell receptor-dependent intracellular signaling. J Exp Med 1993 Apr 1;177(4):1047-60.

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OTT Reference No: E-188-1992-0
Updated: Jul 1, 1996