Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
2001-04-02
2004-08-03
Spector, Lorraine (Department: 1646)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C435S344000
Reexamination Certificate
active
06770745
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to compounds which specifically interfere with the function of the common gamma chain of cytokine receptors and which are able to block cytokine responses. It also relates to cell lines which produce such compounds, compositions comprising such compounds, methods of blocking the effects of cytokines on cells, and methods of treating immunological diseases by treating patients with the compounds.
BACKGROUND OF THE INVENTION
Cytokines are important molecules produced by cells of the immune system. Cellular responses to cytokines are regulated by cell surface receptors, polypeptide chains that individually and/or coordinately bind cytokines and transmit signals that regulate activation of cellular genes. The affinities of these receptors regulate the magnitude of the cellular response, which can impact the pattern and determine the physiologic outcome. Regulation of cytokine responses can therefore determine if a cell is activated, divides, differentiates, becomes tolerant or dies. Regulation of cytokine response can also determine if auto-immune cells are permitted to survive and proliferate.
Each cytokine receptor contains one or more cytokine-specific polypeptide chains. As discussed below, when cytokines bind to their cognate receptors, signals through these multiple cell surface polypeptide chains of cytokine receptors control cell growth, activation and differentiation, and appear to be critical in regulating the generation and maintenance of immune responses (Sugamura et al.,
Adv. Immunol.
59:225-277 (1995)).
Briefly, immune responses are initiated by antigen presenting cells (APC) which display peptide fragments of processed foreign antigen in association with MHC class II molecules on their surfaces to CD4+ helper T lymphocytes (T helper cells or Th cells) which interact with these APC's. The Th cells are activated when they recognize particular epitopes of a foreign antigen displayed on the appropriate APC surface for which the Th cells express a specific T cell receptor (TcR). In addition to the TcR interaction with a peptide/MHC complex, T cells require a second cognate costimulatory signal, usually through a cell surface receptor, for eg. CD28 (Harding,
Nature
356:607-609 (1992) interacting with ligands for CD28 expressed on APC including B7-1 and B7-2 (Bluestone,
Immunity
2:555-559 (1995). Productive engagement of these two types of cell surface receptors primes the T cells to make and to respond to one or more cytokines secreted or released by activated cells. A key cytokine is interleukin-2 (IL-2), which stimulates and supports cell division, increasing the number of interacting cell types and hence the magnitude of the immune response.
In addition to regulating the magnitude of immune responses, the pattern of cytokines released at the onset of an immune challenge affects the subsequent choice of which immune effector pathways are activated (Paul and Seder,
Cell
76:241-251 (1993). These cytokines are released by several cell types involved in initiating the immune response, including APC and CD4+ helper Th cells which interact with the APCs. Activated Th cells secrete cytokines which, together with the APC-derived cytokines, direct their differentiation into one of several types of Th cells. These different types of Th cells are then responsible for activating diverse effector mechanisms including killer T cell activation, B cell antibody production and macrophage activation. The choice between effector mechanisms is mediated largely by which cytokines are produced by the activated Th cells.
Th cells can be divided into three subgroups based on their cytokine secretion patterns (Fitch et al.,
Ann. Rev. Immunol.,
11, pp. 2948 (1993); Mosmann and Sad,
Immunol. Today
17:138-146 (1996)). These subgroups are called Th0, Th1 and Th2. In humans, the Th1 pattern of cytokine secretion has been generally associated with cellular immunity and resistance to infection with viruses and intracellular parasites. The Th1 cytokines such as IFN &ggr; and IL-2 tend to activate macrophages, natural killer cells and cytotoxic T cells. Other cytokines produced by APCs, such as IL-7 and IL-15, may also participate in the activation of these cytotoxic functions. In addition to their protective functions, Th1 cytokines promote deleterious inflammatory responses such as delayed type hypersensitivity. Pathological Th1 responses are also associated with a number of organ-specific and systemic autoimmune conditions and with chronic inflammatory diseases, and play an important role in cellular rejection of tissue grafts and organ transplants. In contrast, the Th2 pattern of cytokine secretion (IL-4, IL-5, IL-6, IL-9 and IL-10) promotes the fill expansion and maturation of B cells thereby providing humoral protection, for example, against extracellular pathogens (Howard et al., “T cell-derived cytokines and their receptor”,
Fundamental Immunology,
3d ed., Raven Press, New York (1993)). Th2 cytokines such as IL-4 and IL-9 also increase eosinophil and mast cell production. But like Th1 responses, deleterious Th2 responses can lead to pathologic conditions, including IgE antibodies associated with allergic responses, autoimmune antibodies such as those in idiopathic thrombocytopenia, myasthenia gravis, and systemic lupus erythematosus, and anti-graft antibodies.
The pattern and magnitude of cytokine responses can also be used to negatively regulate activated cells. The absence of appropriate cytokine dependent signaling to activated cells (physiologically, an inadequate or temporally discordant signal) usually results in their death. In some circumstances it can lead to a so called tolerant state, also called unresponsiveness or anergy, where cells survive but fail to respond to subsequent stimuli (Schwartz,
Science,
248, 1349-1356 (1990); Jenkins et al.,
J. Immunol.,
140, 3324-3330 (1988). Thus, inhibition of cytokine signaling to activated cells may represent a physiological means of regulating for eg. autoreactive cells. It also may be therapeutically useful in treating autoimmune and inflammatory diseases.
One way to block cytokine responses is to target the receptor. In the case of IL-2, the receptor is composed of three distinct polypeptide chains: alpha, beta and &ggr; common (hereinafter “gc”). The alpha chain specifically binds to IL-2 but has no capacity to signal the cell which expresses it. The beta chain binds IL-2 poorly (K
D
=1 micromolar), but with the alpha chain creates a two chain receptor with an affinity that exceeds that of either chain alone. The gc chain binds IL-2 very weakly, if at all, but combines with the alpha and beta chains to create a three chain receptor with very high affinity [10 picomolar] for IL-2 (Sugamura et al.,
Adv. Immunol.
59:225-277(1995)). Other combinations of the IL-2 receptor chains are also possible. For example, on NK cells the beta and gc chains combine to form an IL-2 receptor of intermediate affinity (K
D
=1 nanomolar).
The gc chain is a cell surface polypeptide component of cytokine receptors and forms part of the receptors for several other interleukins besides IL-2 such as IL-4, 7, 9, and 15. The extracellular region of the gc chain of these IL receptors (IL-R) is composed of 2 FNIII type domains, each comprised of 7 strands connected by loop sequences which are presumed to form intermolecular contacts (see structural model derived for the IL-4/IL-4 chain gc chain complex, Gustchina et al., Proteins: Structure, Function and Genetics 21:140 (1995)), and for the IL-2/IL-2R complex, Bamborough et al.,
Structure
2:839-851(1994)).
In the case of the IL-4 receptor, the gc chain is paired only with a cytokine binding alpha chain; no additional beta chain has been identified to date. The same is true for the IL-7 and IL-9 receptors; each brings its own cytokine binding alpha chain to combine with the gc chain to create a complete cooperating two chain receptor. The receptor for IL-15 is composed of an alpha chain specific for IL-15 together wit
Benjamin Christopher D.
Burkly Linda C.
Hession Catherine
Biogen Idec MA Inc.
Biogen Idec MA Inc.
O'Hara Eileen
Spector Lorraine
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