COMPOSITIONS AND METHODS FOR IDENTIFYING AGENTS THAT MODULATE IGE PRODUCTION AND MAST CELL DEGRANULATION
(SF00-074 SF98-005)

BACKGROUND: Of the approximately 40 million allergy sufferers in the US, about 9.9 million have asthma. Asthma is the most frequent chronic condition for those under 18. B lymphocytes in allergic individuals synthesize IgE in response to foreign substances (allergens). The IgE antibodies are specific to the allergen to which they are elicited. The IgE antibodies bind to IgE receptors on the surface of mast cells in tissues and basophilic granulocytes in the blood. A polyvalent allergen can crosslink the surface-bound IgE to activate signaling pathways that trigger degranulation of mast cells and the release of multiple pro-inflammatory mediators (eg. histamines and prostaglandins), which in turn cause the allergic symptoms in the target organ. In case of asthma, degranulation of mast cells causes bronchospasm.

DESCRIPTION: Investigators at UCSF have discovered the protein SWAP-70, a component of an enzyme complex that in B cells is involved in Ig switch recombination, specifically to the IgE isotype. SWAP-70 is also expressed in mast cells and regulates mast cell development and degranulation. Therefore SWAP-70 is an attractive target for the treatment of allergy conditions, including asthma.

The investigators discovered that SWAP-70 homozygous knockout mice are healthy but have specific, allergy-related phenotypes. Among them impaired switching to IgE in B cells and strongly reduced degranulation of mast cells. Specifically, the requirements for SWAP-70 in vivo, as delineated from these studies, are in the following processes:

1. CD40-induced production of IgE in B cells



2. IgE-triggered degranulation of mast cells



3. IgE-triggered expression of specific cytokines in mast cells



4. SCF-triggered mast cell migration and integrin-dependent adhesion

The invention provides screening methods to identify agents that modulate and reduce the level or activity of a SWAP-70 protein in IgE production in B lymphocytes, and in degranulation competent cells. The invention further provides methods for reducing IgE production in B cells and degranulation in a degranulation competent cell, such as a mast cell or basophil, for the treatment of B cell- and/or mast cell-mediated disorders.

ADVANTAGES: There is ongoing need in the field for therapeutic agents and methods to combat allergies. Unlike current medications that generally block the response of pro-inflammatory mediators such as anti-histamines, therapeutics that target SWAP-70 can potentially block allergic reactions at their origin by reducing IgE production and preventing the release of pro-inflammatory mediators from the mast cells. Such therapeutics should be able to significantly alleviate symptoms of allergy, and have beneficial effects in cases of anaphylaxis.

APPLICATIONS: Therapeutics targeting SWAP-70 would be useful in the treatment of allergies such as asthma, and other mast cell-mediated disorders.

REFERENCES:
Borggrefe, T., M. Wabl, A. T. Akhmedov, and Jessberger, R. A B-cell-specific DNA recombination complex. Journ. Biol. Chem., 273, 17025-17037 (1998)

Borggrefe, T., L. Masat, M. Wabl, B. Riwar, G. Cattoretti, and R. Jessberger: Cellular, intracellular, and developmental expression patterns of murine SWAP-70. Europ. J. Immunol. 29, 1812-1822 (1999).

Masat, L., J. Caldwell, R. Jessberger, B. Herndier, M. Wabl, and D. Ferrick: SWAP-70 associates with the B cell antigen receptor complex. Proc. Natl. Acad. Sci. USA, 97, 2180-2184 (2002).

Borggrefe, T., S. Keshavarzi, B. Gross, M. Wabl, and Jessberger, R. Impaired IgE Response in SWAP-70 Deficient Mice. Europ. J. Immunol., 31, 2467-2475 (2001).

Borggrefe, T., M. Wabl, B. Gross, M. Bennett, A. B. Rossi, and Jessberger, R.: SWAP-70 Deficient Immature Mast Cells Are Blocked in IgE-Mediated Degranulation. European J. Immunol., 32, 1121-1128 (2002).

Shinohara, M., Y. Terada, A. Iwamatsu, A. Shinohara, N. Mochizuki, S. Ihara, S. Nagata, H. Itoh, Y. Fukui, and R. Jessberger, R. SWAP-70 is a new type guanine nucleotide exchange factor that mediates signaling of membrane ruffling. Nature, 416, 759-763 (2002)

Sivalenka, R.R. and R. Jessberger: SWAP-70 is required for c-kit induced mast cell activation, aggregation, and migration. (2004) Submitted.

PATENT STATUS: The Regents of the University of California has an issued US patent application and several pending foreign patent applications claiming composition of matter for SWAP-70 (US Patent Application No. 20030143611). The Regents has also filed a patent application claiming methods for screening and identifying agents that regulate SWAP-70 and modulate mast cell degranulation (US Patent Application No. 20030166018). Worldwide patent rights are available.

If you would like to receive further information about this technology and potential licensing opportunities, please contact:

Sunita Rajdev, Ph.D.
Licensing Officer
Phone: (415) 353-4470
Fax: (415) 348-1579
Sunita.rajdev@ucsf.edu

Reference: OTM Case #SF00-074, SF98-005