Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-09-17
2004-01-20
Mertz, Prema (Department: 1646)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C435S069520, C435S071100, C435S071200, C435S471000, C435S325000, C435S320100, C435S348000, C435S252300, C435S254110, C435S254200
Reexamination Certificate
active
06680380
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compositions and methods for affecting mammalian physiology, including morphogenesis or immune system function. In particular, it provides nucleic acids, proteins, and antibodies which regulate development and/or the immune system. Diagnostic and therapeutic uses of these materials are also disclosed.
BACKGROUND OF THE INVENTION
Recombinant DNA technology refers generally to techniques of integrating genetic information from a donor source into vectors for subsequent processing, such as through introduction into a host, whereby the transferred genetic information is copied and/or expressed in the new environment. Commonly, the genetic information exists in the form of complementary DNA (cDNA) derived from messenger RNA (mRNA) coding for a desired protein product. The carrier is frequently a plasmid having the capacity to incorporate cDNA for later replication in a host and, in some cases, actually to control expression of the cDNA and thereby direct synthesis of the encoded product in the host.
For some time, it has been known that the mammalian immune response is based on a series of complex cellular interactions, called the “immune network”. Recent research has provided new insights into the inner workings of this network. While it remains clear that much of the immune response does, in fact, revolve around the network-like interactions of lymphocytes, macrophages, granulocytes, and other cells, immunologists now generally hold the opinion that soluble proteins, known as lymphokines, cytokines, or monokines, play critical roles in controlling these cellular interactions. Thus, there is considerable interest in the isolation, characterization, and mechanisms of action of cell modulatory factors, an understanding of which will lead to significant advancements in the diagnosis and therapy of numerous medical abnormalities, e.g., immune system disorders.
Lymphokines apparently mediate cellular activities in a variety of ways. They have been shown to support the proliferation, growth, and/or differentiation of pluripotent hematopoietic stem cells into vast numbers of progenitors comprising diverse cellular lineages which make up a complex immune system. Proper and balanced interactions between the cellular components are necessary for a healthy immune response. The different cellular lineages often respond in a different manner when lymphokines are administered in conjunction with other agents.
Cell lineages especially important to the immune response include two classes of lymphocytes: B-cells, which can produce and secrete immunoglobulins (proteins with the capability of recognizing and binding to foreign matter to effect its removal), and T-cells of various subsets that secrete lymphokines and induce or suppress the B-cells and various other cells (including other T-cells) making up the immune network. These lymphocytes interact with many other cell types.
Another important cell lineage is the mast cell (which has not been positively identified in all mammalian species), which is a granule-containing connective tissue cell located proximal to capillaries throughout the body. These cells are found in especially high concentrations in the lungs, skin, and gastrointestinal and genitourinary tracts. Mast cells play a central role in allergy-related disorders, particularly anaphylaxis as follows: when selected antigens crosslink one class of immunoglobulins bound to receptors on the mast cell surface, the mast cell degranulates and releases mediators, e.g., histamine, serotonin, heparin, and prostaglandins, which cause allergic reactions, e.g., anaphylaxis.
Research to better understand and treat various immune disorders has been hampered by the general inability to maintain cells of the immune system in vitro. Immunologists have discovered that culturing many of these cells can be accomplished through the use of T-cell and other cell supernatants, which contain various growth factors, including many of the lymphokines.
The interleukin-1 family of proteins includes the IL-1&agr;, the IL-1&bgr;, the IL-1RA (SEQ ID NOs:11 or 12), and recently the IL-1&ggr; (also designated Interferon-Gamma Inducing Factor, IGIF). This related family of genes have been implicated in a broad range of biological functions. See Dinarello (1994)
FASEB J
. 8:1314-1325; Dinarello (1991)
Blood
77:1627-1652; and Okamura, et al. (1995)
Nature
378:88-91.
In addition, various growth and regulatory factors exist which modulate morphogenetic development. This includes, e.g., the Toll ligands, which signal through binding to receptors which share structural, and mechanistic, features characteristic of the IL-1 receptors. See, e.g., Lemaitre, et al. (1996)
Cell
86:973-983; and Belvin and Anderson (1996)
Ann. Rev. Cell
&
Develop. Biol
. 12:393-416.
From the foregoing, it is evident that the discovery and development of new soluble proteins, including ones similar to lymphokines, should contribute to new therapies for a wide range of degenerative or abnormal conditions which directly or indirectly involve development, differentiation, or function, e.g., of the immune system and/or hematopoietic cells. In particular, the discovery and understanding of novel lymphokine-like molecules which enhance or potentiate the beneficial activities of other lymphokines would be highly advantageous. The present invention provides new interleukin-1 like compositions and related compounds, and methods for their use.
SUMMARY OF THE INVENTION
The present invention is based on the discovery, purification, and characterization of the biological activities of a novel mammalian, e.g., primate, interleukin-1 like molecule, designated interleukin-1&zgr; (IL-1&zgr;). IL-1&zgr; exhibits both structural and sequence similarity, e.g., by homology comparison, to known members of the IL-1 family of molecules.
In a first aspect, the invention provides an isolated or recombinant polypeptide that: specifically binds polyclonal antibodies generated against at least a 12 consecutive amino acid segment of SEQ ID NO: 2 or 4; and comprises at least one sequence selected from: GENSGVK (amino acids 5-11 of SEQ ID NO:2); EDWEKD (15-20, SEQ ID NO:2); CCLEDPA (24-30, SEQ ID NO:2); FVHTSR (45-50, SEQ ID NO:2); KKFSIHD (58-64, SEQ ID NO:2); VLVLDS (69-74, SEQ ID NO:2); NLIAVP (76-81, SEQ ID NO:2); FFALAS (91-96, SEQ ID NO:2); SSASAEK (99-105, SEQ ID NO:2); SLILLGV (107-113, SEQ ID NO:2); FCLYCDK (118-124, SEQ ID NO:2); PSLQLK (131-136, SEQ ID NO:2); KLMKLAAQ (139-146, SEQ ID NO:2); FIFYRAQ (154-160, SEQ ID NO:2); SRNMLES (163-169, SEQ ID NO:2); WFICTS (175-180, SEQ ID NO:2); EPVGVT (185-190, SEQ ID NO:2); or FSFQPVC (201-207, SEQ ID NO:2); or FVHTSP (amino acids 45-50, SEQ ID NO:4); SPILLGV (107-113, SEQ ID NO:4); or SWNMLES (163-169, SEQ ID NO:4). Certain embodiments include those: wherein the polypeptide comprises a plurality of the sequence; or which specifically bind to polyclonal antibodies generated against an immunogen selected from SEQ ID NO: 2 or 4. Other embodiments include those where the 12 consecutive amino acid segment is selected from: GVKMGSEDWEKD (amino acids 9-20, SEQ ID NO:2); AGSPLEPGPSLP (30-41, SEQ ID NO:2); SRKVKSLNPKKF (49-60, SEQ ID NO:2); HDQDHKVLVLDS (63-74, SEQ ID NO:2); NLIAVPDKNYIR (76-87, SEQ ID NO:2); FALASSLSSASA (92-103, SEQ ID NO:2); GQSHPSLQLKKE (127-138, SEQ ID NO:2); MKLAAQKESARR (141-152, SEQ ID NO:2); FYRAQVGSRNML (156-167, SEQ ID NO:2); TSCNCNEPVGVT (179-190, SEQ ID NO:2); FENRKHIEFSFQ (193-204, SEQ ID NO:2); or PVCKAEMSPSEV (205-216, SEQ ID NO:2); or AVSPLEPGPSLP (amino acids 30-41, SEQ ID NO:4); SPKVKNLNPKKF (49-60, SEQ ID NO:4); or FYRAQVGSWNML (156-167, SEQ ID NO:4). Certain preferred embodiments include those wherein the polypeptide: comprises a mature protein; lacks a post-translational modification; is from a primate, including a human; is a natural allelic variant of IL-1&zgr;; has a length at least about 30 amino acids; exhibits at least two non-overlapping epitopes that are specific for a primate IL-1&zgr;; exhibits a sequence identity over a leng
Brody Tom
Ching Edwin P.
Mertz Prema
Mohan-Peterson Sheela
Schering Corporation
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