Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
1996-04-22
2002-01-22
Gambel, Phillip (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S130100, C424S133100, C424S135100, C424S141100, C424S143100, C424S144100, C424S153100, C424S173100, C530S387100, C530S387300, C530S388100, C530S388220, C530S388700, C530S388730, C530S388750, C530S388200, C435S007100, C435S007200, C435S007210, C435S007240
Reexamination Certificate
active
06340459
ABSTRACT:
Throughout this application, various references are referred to within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Full bibliographic citation for these references may be found in the text or at the end of this application, preceding the sequence listing and claims.
BACKGROUND OF THE INVENTION
CD40 is a 50 kDa cell surface molecule originally described as being expressed on B cells and some epithelial carcinomas (1, 2). CD40 interacts with CD40L (T-BAM, gp39, TRAP), a 30 kDa cell surface molecule transiently expressed on activated CD4
+
T cells (3-8). CD40L-CD40 interactions have been extensively studied in the context of T cell-B cell interactions. CD40 ligation plays key roles in B cell activation, proliferation, differentiation, Ig production and rescue from apoptotic signals (9-11). The critical in vivo role of CD40 ligation in B cell differentiation is highlighted by the hyper-IgM syndrome, a humoral immunodeficiency due to mutations in the gene encoding CD40L (12-16). Murine CD40 (17) or CD40L (18) “knockouts” have similar phenotypes to patients with the hyper-IgM syndrome.
Interestingly, recent studies indicate that CD40 expression has a broader cellular distribution than originally described. CD40 has been shown to be expressed on monocytes (19), dendritic cells (22), epithelium (23, 21), basophils (24), and Hodgkin's tumor cells (25). Moreover, various cytokines can regulate CD40 expression on non-B cells. CD40 expression on thymic epithelial cells is upregulated by IL-1&agr;, TNF-&agr; or INF-&ggr; (21). INF-&ggr;, in addition to IL-3 or GM-CSF, similarly upregulates CD40 expression on monocytes (19). Ligation of CD40 in the presence of INF-&ggr; and IL-1&agr; stimulates GM-CSF production by thymic epithelial cells (21). In addition, CD40L expressing transfectants induce tumoricidal activity by monocytes and, in the presence of INF-&ggr;, GM-CSF or IL-3, stimulate monocytes to secrete TNF-&ggr;, IL-6 or IL-8 (19).
CD40 is also expressed on cells found within synovial membrane (SM) in patients afflicted with rheumatoid, arthritis (RA). An immunohistological survey of cell surface molecules expressed in RA SM found that CD40 was expressed on a variety of cell types, including cells with fibroblast-like morphology (26). In this report it is shown by FACS analysis that CD40 is expressed on cultured synovial membrane (SM) fibroblasts isolated from patients with RA, non-RA inflammatory arthritis (IA) or osteoarthritis (OA). In addition, dermal fibroblasts isolated from normal donors also express CD40. Moreover, CD40 ligation by CD40L
+
cells induces fibroblast activation and proliferation.
Endothelial cells express surface molecules, such as CD54 (ICAM-1), CD62E (E-selectin) and CD106 (VCAM-1), that mediate adhesive interactions with leukocytes (27-35). The expression of endothelial cell surface adhesion molecules orchestrates recruitment of leukocytes to sites of inflammation and therefore is subject to tight regulation (27, 28). Resting endothelial cells express low levels of CD54 and minimal or no CD62E or CD106. Following activation with IL-1, TNF&agr;, or LPS, endothelial cells rapidly upregulate CD54, CD62E and CD106 expression (27, 28). CD4
+
T cells may contribute to upregulation of endothelial cell surface adhesion molecules by inducing endothelial cells or other target cells to secrete IL-1 or TNF&agr; (36). However, the molecular details involved in CD4
+
T cell-endothelial cell interactions that induce endothelial cell activation have not been completely delineated.
It can now be reported that normal human endothelial cells also express CD40 in situ and CD40L-CD40 interactions induce endothelial cell activation in vitro. Frozen sections from normal spleen, thyroid, skin, muscle, kidney, lung or umbilical cord were studied for CD40 expression by immunohistochemistry. Endothelial cells from all tissues studied express CD40 in situ. Moreover, human umbilical vein endothelial cells (HUVEC) express CD40 in vitro and rIFN-&ggr; induces HUVEC CD40 upregulation. CD40 expression on HUVEC is functionally significant because CD40L
+
Jurkat T cells upregulate HUVEC CD54 (ICAM-1), CD62E (E-selectin) and CD106 (VCAM-1) expression in vitro in a manner inhibited by anti-CD40L mAb 5C8. Additionally, CD40L expressing 293 kidney cell transfectants, but not control transfectants, also upregulate CD54, CD62E and CD106 expression on HUVEC. These results demonstrate that CD40L-CD40 interactions induce endothelial cell activation in vitro. It is shown for the first time that CD40L expressed on the surface of T cells induces activation of CD40
+
endothelial cells and that this activation is inhibited by an anti-CD40L monoclonal antibody. Moreover, these results demonstrate a mechanism by which activated CD4
+
T cells augment inflammatory responses in vivo by upregulating the expression of endothelial cell surface adhesion molecules.
SUMMARY OF THE INVENTION
This invention provides a method of inhibiting activation by CD40 ligand of cells bearing CD40 on the cell surface, comprising contacting the cells with an agent capable of inhibiting interaction between CD40 ligand and the cells, in an amount effective to inhibit activation of the cells.
This invention provides a method of inhibiting activation by CD40 ligand of cells bearing CD40 on the cell surface, in a subject, comprising administering to the subject an agent capable of inhibiting interaction between CD40 ligand and the cells, in an amount effective to inhibit activation of the cells in the subject.
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Press Release from IDEC Pharmaceuticals, Inc. (Apr. 20, 2000).
Press Release from IDEC Pharmaceuticals, Inc. (Jan. 29, 2001).
Press Release from Biogen website (www.prnewswire.com), “Biogen Says it Has Halted Several Trials of Anti-CD40 Ligand Monoclonal Antibody”, Oct. 21, 1999.
Press Release from Biogen website (www.prnewswire.com), “Biogen Says it Has Stopped Ongoing Trials of Anti-CD40 Ligand Monoclonal Antibody”, Nov. 2, 1999.
Bajorath J. et al. “Identification of Residues on CD40 and Its Ligand Which Are Critical for the Receptor-Ligand Interaction”,Biochemistry34:1833-1844 (1995).
Banchereau J. et al. “The CD40 Antigen and its Ligand”,Annual Rev. Immunol.12:881-922 (1994).
Cleary, A. M. et al. “Opposing roles of CD95 (Fas/APO-1) and CD40 in the Death and Rescue of Human Low Density Tonsillar B Cells”,J. Immunol.155:3329-3337 (1995).
Fanslow W. C. et al. “Soluble Forms of CD40 Inhibit Biologic Responses of Human B Cells”,J. Immunol.149:655
Chess Leonard
Lederman Seth
Yellin Michael J.
Cooper & Dunham LLP
Gambel Phillip
The Trustees of Columbia University in the City of New York
White John P.
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