MXPA06009362A - Use for interleukin-33 (il33) and the il-33 receptor complex - Google Patents
Use for interleukin-33 (il33) and the il-33 receptor complexInfo
- Publication number
- MXPA06009362A MXPA06009362A MXPA/A/2006/009362A MXPA06009362A MXPA06009362A MX PA06009362 A MXPA06009362 A MX PA06009362A MX PA06009362 A MXPA06009362 A MX PA06009362A MX PA06009362 A MXPA06009362 A MX PA06009362A
- Authority
- MX
- Mexico
- Prior art keywords
- cells
- nucleic acid
- antibody
- cell
- disorder
- Prior art date
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Abstract
Provided are methods of modulating cytokine activity, e.g., for the purpose of treating immune and inflammatory disorders, including tumors and cancer. Also provided are methods of administering agonists or antagonists of IL-33 and IL-33 receptor.
Description
USE OF INTERLEUC1NA-33 AND THE RECEPTOR 1NTERLEUCINE-33 COMPLEX
FIELD OF THE INVENTION
The present invention relates generally to the uses of mammalian cytokines. More specifically, the invention describes methods for using IL-33, and a receptor for IL-33.
BACKGROUND OF THE INVENTION
The immune system protects individuals from infectious agents, for example, bacteria, multicellular organisms, as well as cancer. The system includes several types of lymphoid and myeloid cells such as itosin, macrophages, dendritic cells (DCs), eosinophils, T cells, B cells, and neutrophils. These lymphoid and myeloid cells usually produce signaling proteins known as cytokines. The immune response includes inflammation, that is, the accumulation of immune cells systematically or at a particular location in the body. In response to an infectious agent or a foreign substance, immune cells secrete cytokines which, in turn, modulate cell proliferation, development, differentiation, or migration. The immune response sometimes results in pathological consequences, i.e., inflammatory disorders. These inflammatory disorders, which involve immune cells and cytokines, include, for example, psoriasis, rheumatoid arthritis, Crohn's disease, multiple sclerosis, and atherosclerosis (see, eg, Abbas, et al. (Eds.) (2000). Cellular and Molecular Immunology, WB Saunders Co., Philadelphia, PA; Oppenheim and Feldmann (eds.) (2001) Cytokine Reference, Academic Press, San Diego, CA; Kaufmann, et al. (2001) Immunobiol., 204: 603-613 Saurez and Schultz-Cheery (2000) Dev. Comp.Immunol.24: 269-283; van Reeth and Nauwynck (2000) Vet. Res. 31: 187-213; Garcia-Sastre (2001) Virology 279: 375-384; Katze, et al. (2002) Nat. Rev. Immunol., 2: 675-687; van Reeth (2000) Vet. Microbiol. 74: 109-116; Tripp (2003) Curr. Pharm., Des. 9: 51- 59). The family of interleukin-1 (IL-1) of cytokines contributes to the pathology of inflammatory disorders and proliferative conditions, for example, arthritis and cancer. The cytokines of the IL-1 family include IL-1 alpha, IL-1 beta, IL-1 delta, IL-1 epsilon, basic fibroblast growth factor, IL-18, CREG and CREG2. IL-1 alpha and IL-1 beta are bio-synthesized as 31 kDa polypeptides that are further processed to mature 17 kDa forms, while IL-1 delta and IL-1 epsilon do not appear to have a different pro-form (see , for example, Debets, et al (2001) J. Immunol., 167: 1440-1446, McMahon, et al. (1997) J. Biol. Chem. 272: 28202-28205, Irikura, et al. (2002). New Engl. J. Med. 169: 393-398; Kim, et al. (2002) J. Biol. Chem. 277: 10998-11003). The IL-1 family also includes the IL-1 receptors, i.e., IL-1 RI, IL-1 RII, and the accessory protein IL-1 R (aka IL-1 R1, IL-1 R2, and IL - 1 R3, respectively). IL-1 alpha and IL-1 beta activate cell signaling through the binding to IL-1 R1, while IL-1 RII can function as a molecule that absorbs ligand circulation. The IL-1 receptor antagonist (IL-1 Ra), another protein of the IL-1 family, binds to the IL-1 receptor without transmitting a signal and serves as an inhibitor of IL-1. IL-1 ra and IL-1 delta play similar roles in the antagonism of signaling through receptors, ie, IL-1 antagonist IL-1 R1 through signaling mediated by IL-1alpha, while IL- 1 delta IL-1 R6 antagonist through signaling mediated by IL-1 epsilon (see, for example, You, et al. (2001) New Engl. J. Med. 193: 101-109) Debets, et al. (2001) J. Immunol. 167: 1440-1446; Apte and Voronov (2002) Sem. Cancer Biol. 12: 277-290; Wong, et al. (1997) Proc. Nati Acad. Sci. USA 94: 227-232). Members of the IL-1 family play a role in inflammatory conditions, for example, rheumatoid arthritis, psoriasis, asthma, chronic obstructive pulmonary disorder (COPD), sepsis, and inflammatory bowel disorder (IBD). Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by the degradation of joints, for example, the synovial membrane, cartilage and bone. The disorder affects approximately 1% of the population and can not be cured. IL-1 stimulates a number of cells involved in arthritic inflammation, fibroblasts, osteoclasts, itosine, and neutrophils, which may show abnormal proliferation and release of enzymes causing the destruction of the joint (see, for example, , et al. (1997) J. Immunol.
158: 2955-2963; Lacey, et al. (2003) Arthritis Rheum. 48: 103-109; Cheng (2001) Eur. Resp. J. Suppl. 3. 4; 50s-59s; Freeman and Buchman (2001) Expert Opin. Biol. Ther. 1: 301-308; Dinarello (2000) Chest 118: 503-508). Krause, et al. (2002) J. Immunol. 169: 6610-6616; Choy and Panayi (2001) New Engl. J. Med. 344: 907-916; Woolley (2003) New Engl. J. Med 348: 1709-1711; Williams, et al (2000) New Engl. J. Med. 164: 7240-7245; Feldmann and Maini (2001) Annu. Rev. Immunol. 19: 163-196; Lacey, et al., Supra; Niki, et al. (2001) J. Clin. Invest. 107: 1127-1135; Attur, et al. (2000) J. Biol Chem. 51: 40307-40315). Proliferative disorders are the second most common cause of death in the United States (Anderson (2002) itosina Vital Statistics Reports 50: 1-86; Toribara and Sleisenger (2003) New Engl J Med 332: 861-867; Janne.. and Mayer (2000) New Engl. J. Med. 342: 1960-1968, Fuchs and Mayer (1995) New Engl. J. Med 333: 32-41). The cytokines of the IL-1 family have been implicated in the control and pathology of proliferative disorders, i.e., cancer. IL-1 modulates the progression through the cell cycle, for example, by changing the expression of cyclin-dependent kinases and cyclin-dependent kinase inhibitors. High doses of beta IL-1 promote tumor invasion, while low doses can promote the immune eradication of tumors (see, eg, Zeisler, et al (1998) Eur. J. Cancer 34: 931-933; Yoshida, et al (2002) Brit J. Cancer 86:... 1396-1400; Nesbit, et al (1999) Oncogene 18: 6469-6476; Dinarello, et al (1998) J. Biol 63 Leuko... 658-664; Apte and Voronov, supra; Saijo, et al (2002) New Engl J. Med. 169: 469-475; Murai, et al (2001) J. Biol Chem. 276: 6797-6806;... Koudssi, et al, (1998) J. Biol Chem 273: 25796-25803; Zeki, et al (1999) J. Endocrinol. 160:. 67-73; Osawa, et al (2000) J. Biochem.... 127: 883-893). There is an unmet need to treat inflammatory and immune disorders. The present invention satisfies this need by providing methods of use for IL-33 agonists and antagonists, or the IL-33 receptor.
BRIEF DESCRIPTION OF THE INVENTION
The present invention is based, in part, on the discovery of an IL-33 agonist or antagonist or the IL-33 receptor (previously known as IL-100 and IL-100 receptor) that modulates the response of a number of immune and inflammatory conditions. The present invention provides a method for modulating an immune disorder or condition, comprising administering an effective amount of an IL-33 agonist or antagonist, or the IL-33R complex. The above method is also provided wherein the condition condition comprises: a) an innate response; b) asthma or allergy; c) multiple sclerosis; d) an inflammatory bowel disorder; e) arthritis; f) infection; g) a cancer or tumor. In addition, the above method is provided wherein the infection comprises: a) an intracellular pathogen; b) a bacterium; c) a parasite; or d) a virus; and the above method wherein the intracellular pathogen is: a) Leishmania sp .; b) Mycobacterium sp .; c) Listeria sp .; d) Toxoplasma sp .; e) Schistosoma; or f) a respiratory virus. In addition, the present invention provides the above method wherein the disorder or immune conditions comprise the TH1-type response or the TH2-type response; and the above method wherein the TH2 type response comprises an early event in the TH2 type response; as well as the above method wherein arthritis comprises rheumatoid arthritis; osteoarthritis; or psoriatic arthritis. In another embodiment, the present invention provides the above method wherein the agonist comprises IL-33 or a nucleic acid; as well as the above method wherein the nucleic acid encodes IL-33; and the above method wherein the antagonist comprises a binding composition of an antibody that specifically binds to IL-33 or a complex of IL-33, T1 / ST2 and SIGIRR (IL-33R). In another embodiment, the present invention provides the above method wherein the binding composition of an antibody comprises a polyclonal antibody; a monoclonal antibody; a humanized antibody, or a fragment thereof; a Fab, Fv, or F (ab ') 2 fragment; a peptide mimetic of an antibody; or a detectable label. It is also provided in the above method, wherein the agonist comprises: a) a soluble IL-33R; b) a small molecule; or c) a nucleic acid; and the above method wherein the nucleic acid specifically hybridizes to a polynucleotide encoding IL-33; as well as the above method wherein the nucleic acid comprises an anti-sense nucleic acid or a low interference RNA (siRNA).
In another aspect, the present invention provides a method for modulating blood cell counts comprising administering an effective amount of a 1L-33 agonist or antagonist; and the previous method wherein the agonist IL-33 increases the counts of the total white blood cells; neutrophils; lymphocytes; or eosinophils; as well as the previous method wherein the IL-33 antagonist increases the platelet count; and the previous method in which the IL-33 antagonist decreases the counts of the total white blood cells; neutrophils, lymphocytes; or eosinophils. Yet another aspect of the present invention provides a method for diagnosing the condition or immune disorder observed above, comprising contacting a binding composition with a biological sample, wherein the binding composition specifically binds to IL-33, and measured determine the specific binding of the binding composition to the biological sample. Also provided is a kit for diagnosing the immune condition or disorder of claim 1, comprising a compartment and a binding composition that specifically binds to: IL-33; an IL-33R complex; a complex of IL-33 and IL-33R; or a nucleic acid encoding IL-33.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows the production of IL-5 in mice treated with IL-33 + anti-IL-33 antibody against IL-33 alone and mice treated with the isotype control antibody. Figure 2 shows the CIA disease scores for anti-IL-33 and mice treated with isotype control. Figure 3 shows the incidence of CIA in anti-IL-33 and mice treated with isotype control. Figure 4 shows the average number of arthritic legs in mice treated with the IL-33 antibody or isotype control antibody. Figure 5 shows EAE disease scores of anti-IL-33 and mice treated with isotype control. Figure 6 shows the incidence of EAE in anti-IL-33 and mice treated with isotype control.
DETAILED DESCRIPTION OF THE PREFERRED MODALITIES
As used herein, including the appended claims, the singular forms of words such as "a," "an," and "the," include the corresponding plural references unless the context clearly dictates otherwise.
All references cited herein are incorporated herein by reference to the same degree as if each individual publication or patent application was specifically and individually indicated as being incorporated by reference.
I Definitions "Activation", "stimulation", and "treatment", as applied to cells or receptors, may have the same meaning, for example, activation, stimulation, or treatment of a cell or receptor with a ligand, unless otherwise indicated by context or explicitly. "Ligand" encompasses natural and synthetic ligands, for example, cytokines, itosine variants, analogs, itosine, and antibody derived binding compositions. "Ligand" also encompasses small molecules, for example, peptide mimetics of cytokines and peptide mimetics of antibodies. "Activation" can refer to the activation of the cell as regulated by internal mechanisms as well as by external or environmental factors. "Response", for example of a cell, tissue, organ, or organism, encompasses a change in biochemical or physiological behavior, for example, concentration, density, adhesion, or migration within a biological compartment, the degree of excretion of the gene , or the state of differentiation, where the change is correlated with activation, stimulation, or treatment, or with internal mechanisms such as genetic programming.
"Activity" of a molecule can describe or refer to the binding of the molecule with a ligand or a receptor, to the catalytic activity; to the ability to stimulate the expression of the gene or the signaling, differentiation, or maturation of the cell; to the antigenic activity; the modulation of the activities of other molecules, and the like. "Activity" of a molecule can also refer to activity in the modulation or maintenance of cell-to-cell interactions, for example, adhesion, or activity in the maintenance of a cell structure, for example, membranes or cytoskeletons of cell. "Activity" can also mean the specific activity, for example, [catalytic activity] / [mg protein], or [immunological activity] / [mg protein], concentration in a biological compartment, or the like. "Proliferative activity" encompasses an activity that promotes, if necessary to, or specifically associated with, for example, the division of the normal cell, as well as cancer, tumors, dysplasia, cell transformation, metastasis, and angiogenesis. "Administration" and "treatment", as applied to the administration of an IL-33 agonist and antagonist, for example, to an animal, human being, experimental subject, cell, tissue, organ, or biological fluid, refers to the contact of an exogenous pharmaceutical, a therapeutic, a diagnostic agent, a compound, or a composition with the animal, human, subject, cell, tissue, organ, or biological fluid. "Administration" and
"treatment" can refer, for example, to a therapeutic, placebo, isosin es ca, diagnosis, research, and experimental methods.
"Treatment of a cell" covers the contact of a reagent with the cell, as well as the contact of a reagent with a fluid, where the fluid is in contact with the cell. "Administration" and "treatment" also means in vivo and ex vivo treatments, for example, of a cell, through a reagent, diagnostic, binding composition, or through another cell. "Treatment" as applied to a human being, veterinarian, or research subject, refers to therapeutic treatment, prophylactic or preventive measures, for research and diagnostic applications. "Treatment", as applied to a human, veterinarian, or research subject, or cell, tissue, or organ, encompasses the contact of an IL-33 agonist or IL-33 antagonist with a human or animal subject, a cell, tissue, physiological compartment, or physiological fluid. "Treatment of a cell" also encompasses situations in which the IL-33 agonist or the IL-33 antagonist is contacted with the IL-33 receptor (T1 / ST2), for example, in the fluid phase or in the phase colloidal, as well as in situations where the agonist or antagonist is contacted with a fluid, for example, when the fluid is in contact with a cell or receptor, but it has not been demonstrated that the agonist or antagonist is contacted with the cell or the receiver. "Link composition" refers to a molecule, a small molecule, a macro-molecule, an antibody, a fragment or analogue thereof, or a soluble receptor, capable of binding to a target, where the objective is, for example , IL-33 or IL-33R. "Linkage composition" can also refer to a complex of molecules, for example, a non-covalent complex, or a non-ionized molecule, and to a molecule covalently or non-covalently modified, for example, modified through phosphorylation, acylation, interlace , cyclization, or limited division, which is capable of linking to an objective. "Link composition" can also refer to a molecule in combination with a stabilizer, excipient, salt, Ph regulator, solvent, or additive, capable of binding to a target. "Link" can be defined as an association of the link composition with an objective where the association results in the reduction in normal Brownian movement of the linkage composition, in cases where the link composition can be dissolved or suspended in the solution. "Conservatively modified variants" apply to both amino acid and nucleic acid sequences. With respect to particular nucleic acid sequences, conservatively modified variants refer to those nucleic acids that encode identical or essentially identical amino acid sequences or, where the nucleic acid does not encode an amino acid sequence, to essentially identical nucleic acid sequences. Due to the degeneracy of the genetic code, a large number of functionally identical nucleic acids can encode any given protein. According to the amino acid sequences, one skilled artisan will recognize that an individual substitution to a nucleic acid, peptide, polypeptide or protein sequence that substitutes a percentage of amino acid or small percentages of amino acid in the sequence encoded for a conserved amino acid is a "conservatively modified variant". " The conservative substitution tables provide functionality similar to amino acids that are well known in the art. An example of a conservative substitution is the exchange of an amino acid in one of the following groups for another amino acid of the same group (U.S. Patent No. 5,767,063, issued to Lee, et al., Kyte and Doolittle (1982) J. Mol. Biol. 157: 105-132): (1) Hydrophobic: Norleucine, Lie, Val, Leu, Phe, Cys, or Met; (2) Neutral hydrophilic: Cys, Ser, Thr; (3) Acid: Asp, Glu; (4) Basic: Asn, Gln, His, Lys, Arg; (5) Residues that have influence on the chain orientation: Gly, Pro; (6) Aromatic: Trp, Tyr, Phe; (7) Small amino acids: Gly, Ala, Ser. "Derivative" can be used to describe, for example, the derivation of the structure of a peptide, oligopeptide, or polypeptide from a peptide, oligopeptide, or mother polypeptide such as an antibody . In this context, derivative encompasses, for example, peptide structures wherein the peptide has the same sequence as the sequence found within the mother, for example, wherein the peptide is identical to the mother but with a truncation at the N-terminus. , the term C or both in the term N as the term C of the mother, or with a truncation and a merger, or with a merger only. Derivative also encompasses a peptide having the same sequence found in the mother, but with conservative amino acid changes, or with deletions or insertions, wherein the deletions or insertions retain the biological property in the peptide that is inherent in the mother. "Derivative" encompasses situations wherein the peptide or polypeptide is synthesized using the mother as the starting compound, and wherein the peptide or polypeptide is synthesized de novo, using the structure of the mother as a guide. "Effective amount" or "therapeutically effective amount" of the IL-33 agonist or antagonist of the present invention means an amount sufficient to ameliorate a symptom or sign of a physiological disorder or condition, or an amount sufficient to allow or facilitate the diagnosis of a disorder or physiological condition. An effective amount for a particular patient, or veterinary subject may vary depending on such factors, the condition being treated, the general health of the patient, the route of the method and the dose of administration and the severity of side effects (see, for example, U.S. Patent No. 5,888,530 issued to NET, et al.). An effective amount may be the maximum dose or dosing protocol that avoids significant side effects or toxic effects. The effect will result in an improvement of the diagnostic measurement, parameter, or detectable signal by at least 5%, usually at least 10%, more usually at least 20%, more usually at least 30%, preferably at least 40%, more preferably at least 50%, more preferably at least 60%, ideally at least 70%, more ideally at least 80%, and most ideally at least 90%, wherein 100% is defined as the diagnostic parameter displayed by a subject normal (see, for example, Maynard, et al. (1996) A Handbook of SOPs for Good Clinical Practice, Interpharm Press, Boca Raton, FL; Dent (2001) Good Laboratory and Good Clinical Practice, Urch Publ., London, UK ). "Exogenous" refers to substances that are produced outside of an organism, cell, or human body, depending on the context. "Endogenous" refers to the substances that are produced within a cell, organism, or human body, depending on the context. "Disorder" refers to a pathological state, or a condition that is correlated or predisposed to a pathological state. "Infectious disorder" refers, for example, to a disorder resulting from a microbe, bacteria, parasite, virus, and the like, as well as to a naive, ineffective, or pathological immune response to the disorder. "Oncogenic disorder" encompasses a cancer, a transformed cell, a tumor, a dysplasia, an angiogenesis, a metastasis, and the like, as well as an inappropriate, ineffective, or pathological immune response to the disorder. "Effective amount" means, for example, an amount of an IL-33 agonist, an IL-33 antagonist, a binding compound or binding composition, sufficient to ameliorate a symptom or signal of a disorder, condition, or pathological condition. "Effective amount" also refers to an amount of an IL-33 agonist, antagonist, or composition of link or composition, sufficient to allow or facilitate the diagnosis of a symptom or sign of a disorder, condition, or pathological condition. "Inhibitors" and "antagonists" or "activators" and "agonists" refers to the inhibitory or activation molecules, respectively, for example, for the activation of, for example, a ligand, a receptor, a cofactor, a gene, a cell, a tissue, or organ. A modulator of, for example, a gene, a receptor, a ligand, or a cell, is a molecule that alters an activity of the gene, receptor, ligand, or cell, wherein the activity can be activated, inhibited, or altered in its regulatory properties. The modulator can act alone, or a cofactor, for example, a protein, a metal ion, or a small molecule can be used. Inhibitors are compounds that decrease, block, prevent, delay activation, inactivate, desensitize, or down-regulate, for example, a gene, a protein, a ligand, a receptor, or a cell. Activators are compounds that increase, activate, facilitate, enhance activation, sensitize, or upregulate, for example, a gene, a protein, a ligand, a receptor, or a cell. An inhibitor can also be defined as a composition that reduces, blocks, or inactivates a constitutive activity. An "agonist" is a compound that interacts with a target to cause or promote an increase in target activation. An "antagonist" is a compound that opposes the sections of an agonist. An antagonist prevents, reduces, inhibits, or neutralizes the activation of an agonist. An antagonist can also prevent, inhibit, or reduce the constitutive activity of an objective, for example, a target receptor, even where the agonist is not identified. To examine the degree of inhibition, for example, samples or assays comprising one, eg, protein, gene, cell, or given organism, are treated with a potential activator or inhibitor and compared to control samples without the inhibitor . The control samples, that is, not treated with antagonist, are assigned a relative activity value of 100% >; Inhibition is achieved when the activity value relative to the control is about 90% or less, typically 85% or less, more typically 80% or less, more typically 75% > or less, generally 70% or less, more generally 65% or less, more generally 60% or less, typically 55% or less, usually 50% > or less, more usually 45% > or less, more usually 40% > or less, preferably 35% or less, more preferably 30% or less, even more preferably 25% > or less, and preferably less than 25% > . The activation is achieved when the value of the activity relative to the control is about 110%, generally at least 120%, more generally at least 140% or, more generally at least 160%, usually at least 180%, by general at least 2 times, more generally at least 2.5 times, usually at least 5 times, more usually at least 10 times, preferably at least 20 times, more preferably at least 40 times and more preferably above 40 times higher.
The end points in the activation or inhibition can be monitored as follows. Activation, inhibition, and response to treatment, for example, of a cell, physiological fluid, tissue, organ, and an animal subject or human being can be monitored through an endpoint. The end point may comprise a predetermined amount or percentage of, for example, an indication of inflammation, oncogenicity, or degranulation or cell secretion, such as the release of an itosine, toxic oxygen, or a protease. The end point may comprise, for example, a predetermined amount of ion flow or transport, cell migration; cell adhesion; cell proliferation; potential for metastasis; cell differentiation; and change in phenotype, eg, change in gene expression in relation to inflammation, apoptosis, transformation, cell cycle, or metastasis (see, for example, Knight (2000) Ann. Clin. Lab. Sci. : 145-158; Hood and Cheresh (2002) Nature Rev. Cancer 2: 91-100; Timme, et al. (2003) Curr. Drug Targets 4: 251-261; Robbins and Itzkowitz (2002) Med. Clin. Am. 86: 1467-1495; Grady and Markowitz (2002) Annu., Rev. Genomics Hum. Genet., 3: 101-128; Bauer, et al. (2001) Glia 36: 235-243; Stanimirovic and Satoh (2000) Brain Pathol 10: 113-126). An inhibition endpoint is generally 75% > of control or less, preferably 50% of the control or less, more preferably 25% > of control or less, and more preferably 10% > of control or less. Generally, an activation endpoint is at least 150% > of control, preferably at least 2 times the control, more preferably at least 4 times the control, and more preferably at least 10 times the control. "Expression" refers to a measure of mRNA or polypeptide encoded by a specific gene. Expression units can be measured from, for example, the number of mRNA or polypeptide / mg protein molecules, the number of mRNA or polypeptide / cell molecules, in measurements of expression through the cell, tissue, cell extract , or tissue extract. The expression units may be relative, for example, a comparison of signal against control and experimental mammals or a comparison of signal with a reagent that is specific for the mRNA or polypeptide against a reagent that is not specific. "Hybridization" that is specific or selective typically occurs when there is at least 55% or homology on a stretch of at least 30 nucleotides, preferably at least about 75% on stretch of about 25 nucleotides, and more preferably at least 90 % > about 20 nucleotides, see, for example, Kanehisa (1984) Nucleic Acids Res. 12: 203-213. Hybridization under stringent conditions, for example, from a first nucleic acid to a second nucleic acid are those that: (1) use a low ionic strength and high temperature for washing, for example, 0.015 M sodium chloride / 0.0015 M sodium citrate / 0.1% > of sodium dodecyl sulfate at 50 ° C; (2) using during the hybridization a denaturing agent, such as formamide, for example 50% or (vol / vol) of formamide with 0.1% bovine serum albumin / 0.1% > from Ficolle (Sigma-Aldrich, St. Louis, MO) /0.1% polyvinylpyrrolidone / 50 Mm Ph regulator sodium phosphate at pH 6.5 with 750 Mm sodium chloride, 75 Mm sodium citrate at 42 ° C; (3) use 50% 0 formamide, 5 X SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 Mm sodium phosphate (Ph 6.8), 0.1% sodium pyrophosphate, 5 X Denhardt's solution , Sonicated salmon sperm DNA (50 ng / ml), 0.1% SDS, and 10% dextran sulfate at 42 ° C, washed at 42 ° C in 0.2 X SSC and 0.1% SDS; or (4) used Ph regulator of 10% dextran sulfate, 2 X SSC (sodium chloride / sodium citrate), and 50% formamide at 55 ° C, followed by a high severity wash consisting of 0.1% > X SSC containing EDTA at 55 ° C (patent of E. U. A. No. 6, 387,657 issued to Botstein, et al). The stringent conditions for nucleic acid hybridization are a function of salt, temperature, organic solvents, and chaotropic agents. Severe temperature conditions will usually include temperatures in excess of about 30 ° C, more usually in excess of about 37 ° C, typically in excess of about 45 ° C, more typically in excess of about 50 ° C, preferably in excess of about 65 ° C and more preferably in excess of about 70 ° C. Strict salt conditions will ordinarily be less than about 1 M, more ordinarily less than about 500 mm, usually less than about 400 mm, more usually less than about 300 mm, typically less than about 200 mm, preferably less than about 100 mm, and more preferably less than about 80 mm, still below less than about 20 mm. However, the combination of parameters is more important than the measurement of any individual parameter (Wetmur and Davidson (1968) J. Mol. Biol. 31: 349-370). "Immune condition" or "immune disorder" encoses, for example, pathological inflammation, an inflammatory disorder, and an autoimmune disorder or disease. "Immune condition" also refers to infections, persistent infections, and proliferative conditions, such as cancer, tumors, and angiogenesis, including infections, tumors, and cancers that resist eradication through the immune system. "Cancer condition" includes for example, cancer, cancer cells, tumors, angiogenesis, and precancerous conditions, such as dysplasia. "Inflammatory disorder" means a disorder or pathological condition wherein the pathology results, in whole or in part, from for example, a change in number, change in the degree of migration, or change in the activation of cells of the immune system. Cells of the immune system include, for example, T cells, D cells, itosin or macrophages, antigen presenting cells (APCs), dendritic cells, microglia, NK cells, NKT cells, neutrophils, eosinophils, mast cells, and any other cell specifically associated with immunology for example, endothelial or epithelial cells that produce itosine.
"Inflammatory disorder" means a disorder or pathological condition wherein the pathology results, in whole or in part, from an increase in the number and / or decrease in the activation of cells of the immune system, eg, T cells, B cells , itosine or macrophages, alveolar macrophages, dendritic cells, NK cells, NKT cells, neutrophils, eosinophils, or mast cells. "IL-33 Receptor", "IL-33R" or "IL-33R Complex", as used herein, shall mean the association of two members of the IL-1 R, T1 / ST2 and SIGIRR family to form the sensitive receptor complex to stimulation with IL-33. "Ligand" refers, for example, to a small molecule, a peptide, a polypeptide, an associated membrane or a membrane-bound molecule or complex thereof, which may act as an agonist or antagonist of a receptor. "Ligand" also encompasses an agent that is not an agonist or antagonist, but that can bind to the receptor without significantly influencing its biological properties, for example, signaling or adhesion. In addition, "ligand" includes a membrane-linked ligand that has been changed, for example, through chemical or recombinant methods, or a soluble version of the membrane-bound ligand. By agreement, when a ligand is a membrane bound in the first cell, the receptor usually occurs in the second cell. The second cell may have the same or different identity as the first cell. A ligand or receptor can be completely intracellular, that is, it can reside in the cytosol, nucleus, or some other intracellular compartment. The ligand or receptor can change its location, for example, from an intracellular compartment to the outer face of the plasma membrane. The complex of a ligand and the receptor are referred to as a "ligand receptor complex". When a ligand and receptor are involved in a signaling path, the ligand exists in an upstream position and the receiver exists in a downstream position of the signaling path. A "first polypeptide chain" and a "second polypeptide chain" refers to two polypeptide chains not linked together via a classical peptide bond. Typically, the first polypeptide chain comprises one N-terminus and one C-terminus and the second polypeptide-chain comprises another N-terminus and another C-terminus, that is, in total there are two N-terminuses and two-C-termini. The first polypeptide chain is it can encode through a first vector, while the second polypeptide chain can be encoded through a second vector. The first polypeptide chain and the second polypeptide chain can be encoded by a vector, wherein a first promoter can be operably linked to the first polypeptide chain and a second promoter can be operably linked to the second polypeptide chain or, at another embodiment, the expression of both, the first and second polypeptide chains may be operably linked to the same promoter. "Sensitivity", for example receptor sensitivity to a ligand, means that the binding of a ligand to the receptor results in a detectable change in the receptor, or in events or molecules specifically associated with the receptor, for example, change in conformation, phosphorylation, nature or quantity of proteins associated with the receptor, or change in gene expression mediated by or associated with the receptor. "Small molecules" are provided for the treatment of physiology and disorders and tumors and cancers. "Small molecule" is defined as a molecule with a molecular weight that is less than 10 Kd, typically less than 2 Kd, and preferably less than 1 Kd. Small molecules include, but are not limited to, inorganic molecules, organic molecules, organic molecules that contain an inorganic component, molecules that comprise a radioactive atom, synthetic molecules, peptide mimetics, and antibody mimetics. As a therapeutic, a small molecule may be more permeable to cells, less susceptible to degradation, and less apt to elicit an immune response than large molecules. Small molecules, such as peptide mimetics of antibodies and cytokines, as well as small molecule toxins are described (see, for example, Casset, et al. (2003) Biochem. Biophys. Res.
cough. 307: 198-205; Muyldermans (2001) J. Biotechnol. 74: 277-302; Li (2000)
Nat. Biotechnol. 18: 1251-1256; Apostolopoulos, et al. (2002) Curr. Med. Chem. 9: 411-420; Monfardini, et al. (2002) Curr. Pharm. Des. 8: 2185-2199; itosina, et al. (1999) Nat. Struct. Biol. 6: 652-656; Sato and Soné (2003) Biochem. J. 371: 603-608; U.A. Patent No. 6,326, 482 issued to Stewart, et al).
"Soluble receptor" refers to receptors that are soluble in water and exist, for example, in extracellular fluids, intracellular fluids, or weakly associated with a membrane. The soluble receptor also refers to receptors that are engineered to be soluble in water. For T1 / ST2, the soluble or extracellular domain is defined as residues 1-337 of SEQ ID NO: 6 (human) and residues 1-342 of SEQ ID NO: 8 (mouse). For SIGIRR, the soluble or extracellular domain is defined as residues 1-119 of SEQ ID NO: 10 (human) and residues 1-117 of SEQ ID NO: 12 (mouse). "Link specificity", "link selectivity", and the like, refer to the binding interaction between a predetermined ligand and a predetermined receptor that enables the distinction between the predetermined ligand and other ligands, or between the predetermined receptor and other receptors . It binds "specifically" or "selectively", when it refers to a ligand / receptor, antibody / antigen, or other binding pair, it indicates a binding version that is determinative for the presence of the protein in a heterogeneous population of proteins and other biological Thus, under designated conditions, a specified ligand binds to a particular receptor and does not bind in a significant amount to other proteins present in the sample. The antibody, or the binding composition derived from the antigen binding site of an antibody, binds to its antigen with an affinity that is at least twice as large, preferably at least 10 times as large, more preferably at least less than 20 times larger, and more preferably at least 10 times larger than the affinity to any other antigen. In a preferred embodiment, the antibody will have an affinity that is greater than about 109 liters / moles (see, for example, Munsen, et al (1980) Analyt. Biochem. 107: 220-239).
II. General The present invention provides methods for the modulation or treatment of a number of immune conditions and disorders. In particular, the present invention provides IL-33 agonists and antagonists for the treatment and diagnosis of, for example, asthma, allergies, arthritis, and response to intracellular pathogens such as parasites, and response to disorders involving granulomas, e.g., tuberculosis. , sarcoidosis, and Crohn's disease. The inexperienced T cells do not seem to express T1 / ST2 on their surface, whereas the expression is induced after contact with antigens in itosin cells is TH2 differentiated. T1 / ST2 has been used as a marker for the TH2 type T cell. T1 / ST2 is also expressed in mast cells and fibroblasts. Studies with knocked out T1 / ST2 mice seem to suggest that T1 / ST2 does not play a part in the differentiation of inexperienced CD4 + T cells for TH2-type T cells, although these results appear to be a function of the nature of the assay used , for example, with organism whose pathogenic organism is used in the attack studies, or whose phase of response to TH2 is studied. The evidence also suggests a role for T1 / ST2 in previous events in response to TH2 (see, for example, Kropf, et al. (2002) Infect. Immunity 70: 5512-5520; Hoshino, et al. (1999) J Exp. Med. 190: 1541-1547; Senn, et al. (2000) Eur. J. Immunol., 30: 1929-1938; Townsend, et al. (2000) J. Exp. Med. 191: 1069-1075. ). Anti-T1 / ST2 antibodies have been used in a number of studies that direct the role of T1 / ST2 in an immune function, while other studies have examined the expression of T1 / ST2 in animal models for immune response. Treatment with anti-T1 / ST2 antibodies resulted in the decrease of TH2-type immune responses. The antibody inhibited the infiltration of eosinophils, the production of IL-5, and the production of IgE. Schistosome infections caused by ascending T1 / ST2 regulation, for example, as determined by the evaluation of expression in lung and liver granulomas. Animal models for asthma, for example, treatment with house dust mite extract or with ovalbumin, resulted in an increased expression of T1 / ST2 in CD4 + T cells indicating the role for T1 / ST2 in allergic or asthmatic responses. Studies with BALB / c mice revealed that treatment with the anti-T1 / ST2 antibody induced a higher TH1 response, improving the ability of CD4 + T cells to respond to IL-12. Anti-T1 / ST2 antibodies also reduce lesions due to infections with major Leishmania, and reduced expression of TH2-type cytokines. An animal model of arthritis (collagen-induced arthritis); CÍA) was exacerbated by anti-T1 / ST2 antibodies. In particular, the functions of T1 / ST2 in the early events in the generation of TH2 type responses. Chronic exposure to several allergens resulted in increased expression of T1 / ST2 in T cells of CD40 T1 / ST2 plays a role in mediating the innate response, such as anti-T1 / ST2 antibodies that exacerbate the toxic effects of lipopolysaccharides ( LPS). Antibodies to T1 / ST2 also modulate the immune response to viruses, for example, the respiratory syncytial virus (see, for example, Xu, et al (1998) J. Exp. Med. 187: 787-794; Lohning, et. al. (1998) Proc. Nati, Acad. Sci. USA 95: 6930-6935; Coyle, et al. (1999) J. Exp. Med. 190: 895-902; Lohning, et al. (1999) J. Immunol., 162: 3882-3889; Johnson, et al. (2003) Am. J. Respir. Crit. Care Med. 169: 378-385; Kropf, et al. (2003) Infect. Immunity 71: 1961-1971; Xu, et al (1998) J. Exp. Med. 187: 787-794; Kropf, et al. (2002) Eur. J. Immunol., 32: 2450-2459; Swirski, et al. (2002) J. Immunol., 169: 3499-3506; Sweet, et al. (2001) J. Immunol., 166: 6633-6639; Walzl, et al. (2001) J. Exp. Med. 193: 785-792. The members of the IL-1 family typically bind to heterodimeric members of the IL-1 receptor family It has been shown that other members of the known IL-1 R family, SIGIRR (protein related to the individual Ig IL-1 receptor), are they form in complexes with T 1 / ST2 to form the functional receptor complex for IL-33. SIGIRR was originally found as an IL-1 R member (see, for example, Garlanda, et al. (2004) Proc. Nati, Acad. Sci. 101: 3522-3526; Clark, et al.
(2003) Genome Res. 13: 2265-2270; Thomassen et al. (1999) Cytokme 11: 389-399; GenBank access number NP_068577; Access number of GenBank NM 021805; GenBank access number NP_075546; and access number of GenBank NM_0230459). SIGIRR is a widely expressed IL-1 R member. In the precipitation experiments using biotinylated mature human IL-33 (residues 112-270 of SEQ ID NO: 2), the T1 / ST2-Fc fusion, and the SIGIRR-Fc fusion, demonstrated that IL-33 can bind to both receptor fusion proteins, however, the binding of IL-33 to SIGIRR was weaker as compared to the binding of IL-33 and T1 / ST2. To test the signaling capabilities of either or both receptors, a NF-kB-dependent assay was run. The co-expression of both T1 / ST2 and SIGIRR was necessary and sufficient to activate NF-kB and MAP kinase signaling after stimulation with IL-33. Activation of JNK kinases was also observed.
III. Agonists, antagonists, and binding compositions. The present invention provides IL-33 agonists and antagonists, including binding compositions that specifically bind IL-33 or the IL-33 receptor complex (T1 / ST2 and SIGIRR). The binding compositions include antibodies, antibody fragments, and soluble receptors. The present invention contemplates blocking antibodies that bind to IL-33 or IL-33R, or agonistic antibodies that stimulate signaling through the IL-33R complex. The binding compositions of the present invention also include nucleic acids that specifically hybridize to nucleic acids encoding IL-33 or IL-33R, for example, anti-sense nucleic acids and low interference RNA (siRNA). Anti-idiotypic antibodies can also be used. Human IL-33 is described by means of GenBank NM_033439. Regions of increased antigenicity, suitable for preparing anti-IL-33 antibodies, occur in, for example, amino acids 1-23; 30-38; 61-78; 84-93; 99-106; 127-133; 139-144; 148-158; 166-180; 196-204; 231-237; And 252-257, from GenBank NM_033439, according to a Parker plot using Vector NTI® Suite (Informax, Inc. Bethesda, MD). The receptors based on these extracellular regions are not limited by these exact N-itosine and C-terminal amino acids, but may be longer or shorter, for example, through one, two, three, or more amino acids, while the ligand binding properties are substantially maintained. Fusion proteins based on soluble receptors are also contemplated, for example, to facilitate purification and stability or to provide a functional domain, for example, a toxic polypeptide. Antibodies, monoclonal, polyclonal, and humanized can be prepared (see, for example, Sheperd and Dean (eds.) (2000) Monoclonal Antibodies, Oxford Univ. Press, New York, NY; Kontermann and Dubel (eds.) (2001). ) Antibody Engineering, Springer-Verlag, New York, Harlow and Lane (1988) Antibodies A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp. 139-243; Carpenter, et al. (2000) J. Immunol., 165: 6205; He, et al. (1998) J. Immunol., 160: 1029; Tang, et al. (1999) J. Biol. Chem. 274: 27371-27378; Baca, et al. (1997). J. Biol. Chem. 272: 10678-10684; Chothia, et al. (1989) Nature 342: 877-883; Foote and Winter (1992) J. Mol. Biol. 224: 487-499; US Patent No. 6,329,511 issued to Vasquez, et al.). The itosine and variants of the antibodies and the soluble receptors are contemplated, for example, pegylation or mutagenesis to remove or replace the deamidation of the Asn residues. Purification of the antigen is not necessary for the generation of antibodies. Immunization can be carried out through immunization of the DNA vector, see, for example, Wang, et al. (1997) Virology 228: 278-284. Alternatively, the animals can be immunized with cells carrying the antigen of interest. Splenocytes can then be isolated from immunized animals, and splenocytes can be fused with a myeloma cell line to produce a hybridoma (Meyaard, et al. (1997) Immunity 7: 283-290; Wright, et al. (2000) Immunity 13: 233-242; Preston, et al. (1997) Eur. J. Immunol. 27: 1911-1918). The resulting hybridomas can be classified for the production of the desired antibody through functional assays or biological assays, ie assays that do not depend on the possession of the purified antigen. Immunization with cells may prove to be superior for the generation of antibodies than immunization with the purified antigen (Kaithamana, et al (1999) J. Immunol. 163: 5157-5164).
Antibodies will usually bind to at least one KD of about 10"3 M, more usually at least 10" 6 M, typically at least 10"7 M, more typically at least 10" 8 M, preferably at least 10"9 M, and more preferably at least 10"10 M, and more preferably at least 10" 11 M (see, for example, Presta, et al. (2001) Thromb. Haemost., 85: 379-389; Yang, et. al. (2001) Crit. Rev. Oncol.Hematol.38: 17-23; Camahan, et al. (2003) Clin. Cancer Res. (Suppl.) 9: 3982s- 3990s.) The appropriate receptors comprising the domains extracellular for the IL-33 receptor complex (T1 / ST2 and SIGIRR) can be prepared, as transmembrane cytoplasmic regions, and extracellular from each of the subunits that have been identified (see, for example, Lecart, et al. 2002) Eur. J. Immunol., 32: 2979-2987, Mitcham, et al. (1996) J. Biol. Chem. 271: 5777-5783, and the following Sequence List.) Soluble receptors can be prepared and used. according to n standard methods (see, for example, Jones, et al. (2002) Biochim. Biophys. Acta 1592: 251-263; Prudhomme, et al. (2001) Expert OpinionBiol. Ther. 1: 359-373; Fernandez-Botran (1999) Crit. Rev. Clin. Lab Sci. 36: 165-224). Compounds for siRNA interference are also provided (see, for example, Arenz and Schepers (2003) Naturwissenschaften 90: 345-359; Sazani and Kole (2003) J. Clin.Research 112: 481-486; Pirollo, et al. (2003) Pharmacol. Therapeutics 99: 55-77; Wang, et al. (2003) Antisense Nuci, Acid Drug Devel., 13: 169-189).
IV. Therapeutic compositions, methods. The present invention provides methods to treat and diagnose innate response, asthma, and allergies, and arthritis. To prepare pharmaceutical or sterile compositions that include an IL-33 agonist or antagonist, the reagent is mixed with a pharmaceutically acceptable carrier or excipient. Formulations of therapeutic and diagnostic agents can be prepared through mixing with carriers, excipients, or physiologically acceptable stabilizers, in the form of, for example, lyophilized powders, slurries, aqueous solutions, lotions, or suspensions (see, for example, example, Hardman, et al. (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, NY; Gennaro (2000) Remington, The Science and Practice of Pharmacy, Lippincott, Williams, and Wiikins, New York, NY, Avis, et al. (Eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman, et al. (Eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; Lieberman, et al. (Eds.) (1990) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weiner and Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, NY). The selection of a regimen of administration for a therapeutic depends on several factors, including, the degree of rotation of the serum or tissue of the entity, the level of symptoms, the immunogenicity of the.
entity and the accessibility of target cells in the biological matrix. Preferably, the administration regimen maximizes the amount of therapeutic delivered to the patient consistent with an acceptable level of side effects. Therefore, the amount of the biological distributed depends in part on the particular entity and the severity of the condition being treated. Guidance on the selection of the estimated dose of antibodies, cytokines, and small molecules is available (see, for example, Wawrzynczak (1996) Antibody Therapy, Bios Scientific Pub. Ltd, Oxfordshire, UK; Kresina (ed.) (1991) Monoclonal Antibodies, Cytokines and Arthritis, Marcel Dekker, New York, NY, Bach (ed.) (1993) Monoclonal Antibodies and Peptide Therapy in Autoimmune Diseases, Marcel Dekker, New York, NY; Baert, et al. (2003) New Engl J. Med. 348: 601-608; Milgrom, et al. (1999) New Engl. J. Med. 341: 1966-1973; Slamon, et al. (2001) New Engl. J. Med. 344: 783 -792; Beniaminovitz, et al. (2000) NewEngl. J. Med. 342: 613-619; Ghosh, et al. (2003) New Engl. J. Med. 348: 24-32; Lipsky, et al. (2000) New Engl. J. Med. 343: 1594-1602). Antibodies, antibody fragments and cytokines can be provided through continuous infusion, or through doses at intervals of, for example, a day, a week, or 1 to 7 times per week. The doses may be provided intravenously, subcutaneously, topically, orally, nasally, rectally, intramuscularly, intracerebrally, or through inhalation. A preferred dose protocol in one that involves the maximum dose or dose frequency that avoids significantly undesirable side effects. A total weekly dose is generally at least 0.05 μg / kg body weight, more generally at least 0.2 μg / kg, more generally at least 0.5 μg / kg, typically at least 1 μg / kg, more typically at least 10 μg. / kg, more typically at least 100 μg / kg, preferably at least 0.2 mg / kg, more preferably at least 1.0 mg / kg, more preferably at least 2.0 mg / kg, optimally at least 10 mg / kg, more optimally at least 2.5 mg / kg, and more optimally at least 50 mg / kg (see, for example, Yang, et al. (2003) New Engl. J. Med. 349: 427-434; Herold, et al. 2002) New Engl. J. Med. 346: 1692-1698; Liu, et al. (1999) J. Neurol. Neurosurg., Psych 67: 451-456; Portielji, et al., (20003) Cancer Immunol. Immunother. 52: 133-144). The desired dose of a small molecule therapeutist, for example, a peptide mimetic, a natural product, or an organic chemical, is approximately the same as for an antibody or polypeptide, or on a mole / kg basis of body weight. The desired concentration in the plasma of a small-molecule therapeutic is approximately the same as for an antibody, on the basis of moles / kg of body weight. An effective amount for a particular patient may vary depending on factors such as the condition being treated, the general salute of the patient, the route of the method and the dose of administration and the severity of the side effects (see, for example, Maynard , et al. (1996) A Handbook of SOPs for Good Clinical Practice, Interpharm Press, Boca Raton, FL; Dent (2001) Good Laboratory and Good Clinical Practice, Urch Publ., London, UK). Typical veterinary, experimental or research subjects include monkeys, dogs, cats, rats, mice, rabbits, guinea pigs, horses and humans. The determination of the appropriate dose is made through the physician, for example, using parameters or factors known or suspected in the art to affect the treatment or that are predicted to affect the treatment. Generally, the dose starts with an amount of some form less than the optimal dose and is increased by small increments thereafter until the desired or optimum effect is achieved in relation to any negative side effects. Important diagnostic measures include those of symptoms of, for example, inflammation, or level of inflammatory cytokines produced. Preferably, a biological to be used is derived from the same species as the target animal for treatment, thereby minimizing a humoral response to the reagent. Methods for co-administration or treatment with a second therapeutic agent, eg, an itosine, a steroid, a chemotherapeutic agent, an antibiotic, or radiation, are well known in the art (see, for example, Hardman, et al. (eds.) (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed., McGraw-Hill, New York, NY; Poole and Peterson (eds.) (2001) Pharmacotherapeutics for Advanced Practice: A Practical Approach, Lippíncott , Williams &Wiikins, Phila., PA; Chabner and Longo (eds.) (2001) Cancer Chemotherapy and Biotherapy, Lippincott, Williams &Wiikins, Phila., PA). An effective amount of therapeutics will typically decrease symptoms by at least 10% >; usually by at least 20% >;; preferably at least about 30% 0; more preferably at least 40% >; and more preferably at least 50% > . The route of administration is through, for example, topical or cutaneous application, injection or infusion through the intravenous, intraperitoneal, intracerebral, intramuscular, infraocular, intraarterial, intracerebroespinal, intralesional, or pulmonary route, or through sustained release systems or an implant (see, for example, Sidman et al. (1983) Biopolymers 22: 547-556; Langer, et al. (1981) J. Biomed, Mater. Res. 15: 167-277; Langer (1982) Chem. Tech. 12: 98-105; Epstein, et al. (1985) Proc. Nati, Acad Sci USA 82: 3688-3692; Hwang, et al. (1980) Proc. Nati. Acad. Sci. USA 77 : 4030-4034; US Pat. Nos. 6,350,466 and 6,316,024).
V. Diagnostic kits and reagents. Diagnostic methods for inflammatory disorders for example, psoriasis, Crohn's disease, rheumatoid arthritis, asthma or allergy, atherosclerosis, and cancers, are based on antibodies, nucleic acid hybridization, and in the PCR method, are available.
This invention provides IL-33 polypeptides, fragments thereof, IL-33 nucleic acids, and fragments thereof, in a diagnostic kit, for example, for the diagnosis of viral disorders, including influenza A, and disorders of the respiratory tract and mucosal tissues. Linkage compassions are also provided, including antibodies or fragments of antibodies, for the detection of IL-33, and metabolites and disruption products thereof. Typically, the kit will have a compartment that contains either an IL-33 polypeptide, or an antigenic fragment thereof, a binding composition thereof, or a nucleic acid, such as a nucleic acid probe, primer, or molecular model ( see, for example, Rajendran, et al. (2003) Nucleic Acids Res. 31: 5700-5713; Cockerill (2003) Arch. Pathol. Lab. Med. 127: 1112-1120; Zammatteo, et al. (2002) Biotech Annu Rev. 8: 85-101; Klein (2002) itosi Mol. Med. 8: 257-260). A diagnostic method may comprise contacting a sample from a subject, eg, a test subject, with a binding composition that specifically binds to a polypeptide or nucleic acid of the IL-33 or IL-33 receptor. The method may further comprise contacting a sample from a control subject, a normal subject, or normal tissue, or fluid from the subject of the test subject, with the binding composition. In addition, the method may additionally comprise comparing the specific binding of the composition with the test subject with the specific binding of the composition to the normal subject, control subject, or normal tissue or fluids of the test subject. The expression or activity of the test sample or test subject can be compared to that of a control sample or control subject. A control sample may comprise, for example, a sample of unaffected or non-inflamed tissue in a patient suffering from an immune disorder. The expression or activity of a control subject or control sample can be provided with a predetermined value, for example, purchased from a statistically-appropriate group of control subjects. The kit may comprise, for example, a reagent, and a compartment, a reagent and instructions for its use, or a reagent with a compartment and instructions for its use. The reagent may comprise an IL-33 agonist or antagonist, or an antigenic fragment thereof, a binding composition, or a nucleic acid in a sense and / or anti-sense orientation. A kit for determining the binding of a test compound, eg, purchased from a biological sample or from a chemical collection, may comprise a control compound, a labeled compound, and a method for separating the free labeled compound from the bound labeled compound. . The control compound may comprise a segment of the IL-33 polypeptide or the IL-33 receptor or a nucleic acid encoding IL-33 or the IL-33 receptor. The segment may comprise zero, one, two, or more antigenic fragments. A composition that is "marked" is detectable, either directly or indirectly, through spectroscopic, photochemical, biochemical, immunochemical, isotopic or chemical methods. For example, useful labels include 32p, 33p, 35S, 14C, 3H, 125l, stable isotopes, fluorescent dyes, dense electron reagents, substrates, epitope tags, or enzymes, for example, as used in linked immunoassays. enzyme, or fluoretes (Rozinov and Nolan (1998) Chem. Biol. 5: 713-728). Diagnostic assays can be used with biological matrices such as living cells, cell extracts, cell lysates, fixed cells, cell cultures, body fluids or forensic samples. Conjugated antibodies useful for diagnostic or kit purposes include antibodies coupled to dyes, isotopes, enzymes, and metals, see, for example, Le Doussal, et al. (1991) New Engl. J. Med. 146: 169-175; Gibellini, et al. (1998) J. Immunol. 160: 3891-3898; Hsing and Bishop (1999) New Engl. J. Med. 162: 2804-2811; Everts, et al. (2002) New Engl. J. Med. 168: 883-889. There are several assay formats, such as radio immunoassays (RIA), EKISA, and on-chip laboratory (U.S. Patent Nos. 6,176,962 and 6,517,234). Gene expression data are a useful tool in the diagnosis of diseases and pathological conditions (see, for example, Li and Wong (2001) Genome Informatics 12: 3-13; Lockhart, et al. (1996) Nature Biotechnol 14: 1675-1680; Homey, et al (2000) J. Immunol. 165: 4950-4956).
SAW. Uses The present invention provides methods for the treatment and diagnosis of inflammatory immune disorders, including the inappropriate or ineffective response to infection. Methods related to, for example, asthma, allergies, arthritis, disorders involving eosinophilic inflammation, and disorders involving the pathogenic and ineffective TH2 response are provided. The present invention provides methods for stimulating the immune defense against bacteria, parasites, and viruses, intracellular pathogens, and cancers and tumors. The method for the treatment of intracellular bacteria is provided. Intracellular bacterial species include Salmonella sp. Shigella sp., Rickettsia sp., Listeria sp., Francisella sp., Mycobacteria sp. (Tuberculosis, leprosy), Legionella sp., Rickettsia sp., Orienta sp., Ehrlichia sp. Anaplasma sp., Neorickettsia sp., Chlamydia sp., And Coxiella sp. Additionally IFNgamma mediates the response to parasites, for example Plasmodia sp., (Malaria), Toxoplasma sp., Leishmania sp., Tripanosoma sp. and Cryptosporidium sp. Methods are provided for treating viruses, for example, HIV orthopoxviruses, such as smallpox virus, and vaccinia virus (smallpox), and herpes viruses, including alphaherpes viruses, eg, Herpes itosin virus, and betaherpesviruses , for example., Cytomegalovirus. Methods for treating chronic inflammatory disorders are also provided (see, for example, Kent, et al. (2000) Vaccine 18: 2250-2256; Ismail, et al. (2002) FEMS Microbiol. Lett. 207: 111-120; Kaufmann; (2001) Nature Rev. Immunol., 1: 20-30, Goebel and Gross (2001) TRENDS Microbiol., 9: 267-273, Heussler, et al.
(2001) Int. J. Parasitol. 31: 1166-1176; Luder, et al. (2001) Carsten, et al (2001) TRENDS. Parasitol. 17: 480-486; Rook, et al. (2001) Eur. Resp. J. 17: 537-557; Stenger and Rollinghoff (2001) Ann. Rheum. Dis. 60: ¡ii43¡¡¡¡46; Haas, et al. (2002) Am. J. Dermatopathol. 24: 319-323; Dorman and Holland (2000) Cytokine Growth Factor Revs. 11: 321-333; Smith, et al. (2002) J. Gen. Virol. 83 (Pt. 12) 2915-2931; Cohrs and Gilden (2001) Brain Pathol. 11: 465-474; Tannenbaum and Hamilton (2002) Sem. Cancer Biol. 10: 113-123; Ikeda, et al.
(2002) Cytokine Growth Factor Revs. 13: 95-109; Klimp, et al. (2002) Crit. Rev. Oncol. Hematol. 44: 143-161; Frucht, et al. (2001) TRENDS Immunol. 22:
556-560). The present invention provides methods for treating or diagnosing a proliferative condition or disorder, for example, cancer in the uterus, cervix, breast, prostate, testes, penis, gastrointestinal tract, eg, esophagus, lower jaw, stomach, large and small intestine. , colon, rectum, kidney, renal cell, bladder, bones, spinal cord, skin, head or neck, liver, gallbladder, heart, lung, pancreas, salivary glands, adrenal gland, thyroid, brain, ganglia, central nervous system ( CNS) and peripheral nervous system (PNS), and immune system, for example, spleen and thymus. The present invention provides methods for treating, for example, immunogenic tumors, non-immunogenic tumors, inactive tumors, virus-induced cancers, for example, epithelial cell cancer, endothelial cell cancer, squamous cell carcinomas, papillomavirus, adenocarcinomas, lymphomas, carcinomas, melanomas, leukemias, myelomas, sarcomas, teratocarcinomas, chemically induced cancers, metastases, and angiogenesis. The invention also contemplates the reduction of tolerance to a tumor cell or a cancer cell antigen, for example, by modulating the activity of a regulatory T cell (Treg) (see, for example, Ramirez-Montagut, et al. (2003) Oncogene 22: 3180-3187; Sawaya, et al. (2003) NewEngl., J. Med. 349: 1501-1509; Farrar, et al. (1999) J. Immunol., 162: 2842-2849 Le, et al / (2001) J. Immunol 167: 6765-6772; Cannistra and Niloff (1996) New Engl. J. Med. 334: 1030-1038; Osbome (1998) New Engl. J. Med. 339 : 1609-1618; Lynch and Chapelle (2003) New Engl. J. Med. 348: 919-932; Enzinger and Mayer (2003) New Engl. J. Med. 349: 2241-2252; Forastiere, et al. (2001) New Engl. J. Med. 345: 1890-1900; Izbicki, et al. (1997) New Engl. J. Med. 337: 1188-1194; Holland, et al. (eds.) (1996) Cancer Medicine Encyclopedia of Cancer, 4a. ed., Academic Press, San Diego, CA). The present invention provides methods of treating a proliferative condition, cancer, tumor, or pre-cancerous condition, such as dysplasia, with an IL-33 agonist or antagonist, with at least one additional therapeutic or diagnostic agent. The at least one additional therapeutic or diagnostic agent may be, for example, an itosine, or an itosine antagonist, such as interferon-alpha, or an anti-epidermal growth factor receptor, doxorubicin, epirubicin, an anti-folate, example, methotrexate or fluorouracil, irinotecan, cyclophosphamide, radiotherapy, hormone, or anti-hormone therapy, for example, androgen, estrogen, anti-estrogen, flutamide, or diethylstibestrol, surgery, tamoxifen, phosphamide, mitolactol, and alkylating agent, example, melphalan or cis-platinum, etoposide, vinorelbine, vinblastine, vindesine, glucocorticoid, a histamine receptor antagonist, an inhibitor of angiogenesis, radiation, radiation sensitizer, anthracycline, vinca alkaloid, taxane, for example, paclitaxel and docetaxel, a cell cycle inhibitor, for example, a cyclin-dependent kinase inhibitor, a monoclonal antibody, a monoclonal antibody complex and toxin, an adjuvant e of T cell, a spinal cord transplant, or antigen presenting cells, e.g., dendritic cell therapy. Vaccines may be provided, for example, as a soluble protein or as a nucleic acid encoding the protein (see, for example, Le, et al., Supra; Greco and Zellefsky (eds.) (2000) Radiotherapy of Prostate Cancer , Harwood Academy, Amsterdam, Shapiro and Rect. (2001) New Engl. J. Med. 344: 1997-2008; Hortobagyi (1998) New Engl. J. Med. 339: 974-984; Catalona (1994) New Engl. J. Med 331: 996-1004; Naylor and Hadden (2003) Int. Immunopharmacol 3: 1205-1215; The Int Adjuvant Lung Cancer Trial Collaborative Group (2004) New Engl. J. Med 350-351-360; Slamon, et al. (2001) New Engl. J. Med. 344: 783-792; Kudelka, et al. (1998) New Engl. J. Med. 338: 991-992; van Netten, et al. (1996) New Engl J Med. 334: 920-921). A number of biomarkers and methods are available for classifying inflammatory disorders, for example, psoriasis, Crohn's disease, and rheumatoid arthritis, (see, for example, Bresnihan (2003) itosine Res.
Ther. 5: 271-278; Barnero and Delmas (2003) Curr. Opin. Rheumatol. 15: 641-646; Gionchetti, et al. (2003) Dig. Dis. 21: 157-167; Wiik (2002) Autoimmune Rev. 1: 67-72; Sostegni, et al. (2003) Aliment Pharmacol. Ther. 17 (Suppl 2): 11-17). Biomarkers and methods for classifying cancer are also described (see, for example, Alison (ed.) (2001) The Cancer Handbook, Grove's Dictionaries, Inc., St. Louis, MO; Oldham (ed.) (1998) Principles of Cancer Biotherapy, 3rd ed., Kluwer Academic Publ., Hingham, MA; Thompson, et al. (Eds.) (2001) Textbook of Melanoma, Martin Dunitz, Ltd., London, UK; Devita, et al. (Eds. .) (2001) Cancer: Principles and Practice of Oncology, 6th ed., Lippincott, Phila, PA; Holland, et al. (Eds.) (2000) Holland-Frei Cancer Medicine, BC Decker, Phila., PA; Garrett and Sell (eds.) (1995) Cellular Cancer Markers, Humana Press, Totowa, NJ; MacKie (1996) Skin Cancer, 2nd ed., Mosby, St. Louis; Moertel (1994) New Engl. J. Med. 330: 1136-1142; Engleman (2003) Semin Oncol. 30 (3 Suppl 8): 23-29; Mohr, et al. (2003) Onkologie 26: 227-233). The broad scope of this invention will be better understood with reference to the following examples, which do not intend to limit the inventions to the specific embodiments.
EXAMPLES
I. General Methods Standard methods in biochemistry and molecular biology are described (see, for example, Maniatis, et al. (1982) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Sambrook and Russell (2001) Molecular Cloning, 3rd ed, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, which describes cloning in bacterial cells and DNA mutagenesis (Vol. 1), cloning in mammalian and yeast cells (Vol. 2) glycoconjugates and protein expression (Vol. 3), and bioinformatics (Vol.4) Methods for protein purification include immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization are described in (Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 1, John Wiley and Sons, Inc., New York.) Clinical analyzes, chemical modification, post-translational modification, production of fusion proteins, gl protein icosylation (see, for example, Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 2, John Wiley and Sons, Inc., New York; Ausubel, et al. (2001) Current Protocols in Molecular Biology, Vol. 3, John Wiley and Sons, Inc., NY, NY, pp. 16.0. 5-16.22. 17; Sigma-Aldrich, Co. (2001) Products for Life Science Research, St. Louis, MO; pp. 45-89; Amersham Pharmacia Biotech (2001) BioDirectory, Piscataway, N.J., pp. 384-391). Methods for the production, purification, and fragmentation of polyclonal and monoclonal antibodies are described (Coligan, et al. (2001) Current Protocols Immunology, Vol. 4, John Wiley, Inc., New York; Harlow and Lane ( 1999) Using Antibodies, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Harlow and Lane, supra). Standard techniques for characterization of ligand / receptor interactions are available (see, for example, Coligan, et al (2001) Current Protocols in Immunology, Vol. 4, John Wiley, Inc., New York). Methods for flow cytometry are available, including the explanation of fluorescence activated cell (FACS), (see, for example, Owens, et al. (1994) Flow Cytometry Principles for Clinical Laboratory Practice, John Wiley and Sons, Hoboken, NJ; Givan (2001) Flow Cytometry, 2nd ed., Wiley-Liss, Hoboken, NJ; Shapiro (2003) Practical Flow Cytometry, John Wiley and Sons, Hoboken, NJ). Reagents are available. Itosine is suitable for modifying nucleic acids, including primers and nucleic acid probes, polypeptides, and antibodies, for use, for example, as diagnostic reagents, (see, for example, Molecular Probes (2003) Catalog, Molecular Probes, Inc., Eugene, OR; Sigma-Aldrich (2003) Catalog, St. Louis, MO). The standard methods of histology of the itosi system are described (see, for example, Muller-Harmelink (ed.) (1986) Human Thymus:
Histopathology and Pathology, Springer Verlag, New York, NY; Hiatt, et al.
(2000) Color Atlas of Histology, Lippincott, Williams, and Wiikins, Phila, PA;
Louis, et al. (2002) Basic Histology: Text and Atlas, McGraw-Hill, New York,
NY). Methods for using animal models, for example, annihilated mice, and cell-based assays for the testing, evaluation, and classification of diagnostic, therapeutic, and pharmaceutical itoses are available (see, for example, Car and Eng (2001). ) Vet Pathol 38: 20-30;
Kenyon, et al. (2003) Toxicol. Appl. Pharmacol. 186: 90-100; Deurloo, et al.
(2001) Am. J Respir. Cell Mol. Biol. 25: 751-760; Zuberi, et al. (2000) J.
Immunol. 164: 2667-2673; Temelkovski, et al. (1998) Thorax 53: 849-856; Horrocks, et al. (2003) Curr. Opin. Drug Discov. Devel. 6: 570-575; Johnston, et al. (2002) Drug Discov. Today 7: 353-363). Software packages and databases to determine, for example, antigenic fragments, leader sequences, protein folds, functional domains, glycosylation sites, and sequence alignments are available (see, for example, example,
GenBank, Vector NTI Suite (Informax, Inc., Bethesda, MD); GCG Wisconsin
Package (Accelrys, Inc., San Diego, CA); DeCyphert) (TimeLogic Corp., Itosin Bay, Nevada); Menne, et al. (2000) Bioinformatics 16: 741-742;
Menne, et al. (2000) Bioinformatics Applications Note 16: 741-742; Wren, et al. (2002) Comput. Methods Programs Biomed. 68: 177-181; von Heijne (1983)
Eur. J. Biochem. 133: 17-21; von Heijne (1986) Nucleic Acids Res. 14: 4683-4690).
II. Interleukin-100 The similarity of the amino acid sequence of human IL-33 with the other members of the IL-1 family are as follows. The similarity of IL-1 Ra is 34% or similarity; IL-1 delta is 36%; IL-1 F10 is 36%; IL-1zeta is 9%; IL-1 F8 is 32%; IL-1 epsilon is 40%; and IL-1 F9 is 31%. Interleukin-100 was discovered through the use of computational sequence analysis and was identified as a new member of the IL-1 family by comparing the secondary structure with members of the IL-1 family, respectively IL- 1 beta and IL-18. Members of the IL-1 family are highly inflammatory regulators of the immune system, released in response to pathogenic challenges. Human and mouse homologs of IL-33 were also identified as rat and dog IL-33. Analysis of gene expression showed that human IL-33 was expressed in epithelial cells, smooth muscle cells, and mesangial cells. After stimulation with IL-1β and TNF-α, human IL-33 mRNA levels are highly induced in dermal and lung fibroblasts of normal primary humans as well as bronchial smooth muscle cells. The expression of IL-33 mRNA in psoriatic skin samples as well as pulmonary alveolar lung proteinosis was significantly elevated. Similar to IL-1 and IL-18, IL-33 has no signal peptide. Rather, IL-33 is made and secreted as a large pre-protein that requires extensive processing to release the biologically active, mature form.
It is likely that prepro IL-33 is processed through a caspase. A caspase cleavage site was identified in the protein sequence and it was shown that translated human IL-33 was divided by recombinant constitutively active caspase-1. To investigate the putative biological role of IL-33, the recombinant proteins were expressed and purified in E. coli. Accordingly, the IL-33 gene was cloned into a bacterial expression vector Pet3a. The N-terminus of the recombinant protein was selected by comparing the mature sequence of IL-33 to IL-1β and IL-18 so that the mature, biologically active protein might lack pro-domain. The amino acid 112 of full-length protein was selected as the N-terminal amino acid. The recombinant protein was expressed and purified from E. coli. In vivo studies were carried out. Intraperitoneal (IP) injection of human IL-33 in mice (C57BL / 6J), with a dosage of either 5 ug / day or 50 ug / day, led to severe esopharyngeal and splenomegaly after 7 days. Serum levels of several cytokines were tested on day 3 and on day 7. An induction of IL-5 up to 10000 pg / ml in 50 ug of rhlL-33 / day group and up to 1000 pg / ml in 5 ug rhlL-33 / day group was observed on day 3. The serum levels of IL-5 were decreased to 1100 pg / ml at 50 ug rhlL-33 / day group and at 5 ug rhlL-33 / day group at 500pg / ml. Serum levels of IL-13 were also detected on day 7 after treatment with either 5ug or 50ug IL-33 / day at 30pg / ml and 100 pg / ml, respectively. It was not possible to detect if IL-5 and IL-13 in the control group treated with PBS. In addition, high levels of IFN-α, TNF-α, IL-12, IL-10, IL-6, IL-4, IL-2 or MCP-1 could not be detected in mice treated with IL-33 or in control group. After IP injection of 50 ug rhlL-33 / day for 2 days, liver lymphocytes were harvested. The cells were plated in culture dishes with 2x10e6 / ml culture medium and stimulated with 50 ng / ml PMA and 1 Um ionomycin for 4 hours. During the last two hours, the Brefelding A secretion inhibitor was added. The cells were stained on the surface for CD3 and NK1.1 and stained intracellularly for either IL-5 or I L-4, and analyzed by means of FACS. CD3 / NK1.1 positive lymphocyte cells were derived from mice treated for two days with IL-33 which showed an accumulation of IL-5 and IL-4. These results suggest that IL-33 activates NKT cells to secrete IL-4 and IL-5. To test whether IL-33 binds to NKT cells, biotinylated IL-33 was used for the binding experiment. Human NKT cells, derived from PBMCs, were incubated with either streptavidin-PE or biotinylated rhlL-33, and strepdavidin-PE. The stained cells were analyzed through FACS. This link could have been completed with rhlL-33 not stained. Members of the IL-1 family exerted their biological response through interaction with cell surface receptors. The ST2 / T1 receptor of orphan IL-1 was identified as the cellular receptor for IL-33. FACS staining of a mouse mast cell line with a specific monoclonal antibody ST2 / T1 showed that this mast cell line expresses the ST2 / T1 receptor. This staining could be specifically, and dose-dependently completed through incubation of the mast cell line with the IL-33 protein. NKT cells are essential for airway inflammation and the production of IL-4 and IL-13 reactivity in the allergen-induced airway hypereactivity in models of asthma mice. The induction of IL-5 and IL-13 through IL-33 in NKT cells suggests that IL-33 may play a role in the induction of these diseases. The generation of therapeutic antibodies that neutralize IL-33 may be beneficial in the treatment of these diseases. NKT cells have been implicated in many diseases. The identification of IL-33 as a modulator of NKT cells suggests that IL-33 can affect other diseases, such as lupus, multiple sclerosis, malignancies, airway inflammation and infectious diseases. The induction of Th2 cytokines through IL-33 such as IL-5 and IL-13, may help in protection against microbial infection or in protection against tumors. Members of the IL-1 family typically bind to two different members of the IL-1 receptor family to form a complete receptor complex. The identification of IL-33 and ST2 / T1 as one of the subunits that form the receptor for IL-33 makes it possible to identify the second subunit of the IL-33 receptor. The identification of the complete IL-33 receptor will allow the detailed identification of a biological response induced by IL-33.
Real-time PCR analysis using itosi revealed that IL-33 was expressed through a number of cells and tissues (Table 1). The present invention provides IL-33 agonists and antagonists for the modulation of inflammatory and auto immune conditions and disorders for example, psoriasis, asthma, allergies, and inflammatory bowel disease, eg, gastric inflammation, ulcerative colitis, Crohn's disease, celiac disease, and irritable bowel syndrome.
TABLE 1 Real-time PCR analysis of IL-33 expression, relative to ubiquitin Ii0)
The induction of IL-33 through IL-1β plus TNF-a (8 hours) was compared with the induction of IL-33 only with medium. The induction was studied in the type of cells indicated (Table 2).
TABLE 2 Induction of IL-33. ND media not detectable. The numbers are relative to ubiquitin (1.0)
Human IL-33 translated in itos was found to be divided through caspase-1. Without the caspase treatment, the analysis through
SDS PAGE revealed a band of approximately 32 kDa, corresponding to pro-human IL-33. Treatment with caspase-1 for one hour at 37 ° C resulted in two bands of approximately equal intensity, one corresponding to pro-IL-33, and the other migrated around 20-22 kDa (mature human IL-33). Treatment for two hours at 37 ° C resulted in the same two bands, but with approximately two thirds of the protein migrating around 22 kDa. Similar studies showed that a human IL-33 translated in itos can also be divided through elastase, or through cathepsin G, for species that migrate around 20-22 kDa, while treatment with MMP-3 did not give as the division results under the conditions used. The amino acid 112 of IL-33 is believed to be in the cleavage position, producing mature IL-33, due to homology with other members of the IL-1 family.
T1 / ST2 was identified as at least one receptor subunit for human IL-33. The expression of T1 / ST2 was as follows (Table 3).
TABLE 3 Expression of T1 / TS2 through human or mouse cells
Human IL-33 was cloned into a Pet3a vector, and expressed in E. coli. The cloned protein was started with the amino acid 112, and was 158 amino acids long (18kDa). IPTG was used to induce expression, and the protein was found to be soluble in water. The expressed protein was purified using a column A, and Sephadex gel filtration. The purified preparation was tested for endotoxin, where the results showed about 0.023 EU per microgram of protein. Analysis through SDS PAGE using non-reduction conditions revealed that at least 95% of the protein migrated to a single molecular weight of 18 kDa. IL-33 was injected intraperitoneally (i.p.) in B6 / Balb / c mice. Three groups of mice were used: (1) injection with salines regulated in their phosphate Ph (PBS); (2) hiL-33 (5 micrograms / day); and (3) h¡L-33 (50 nigrograms / day). The protocol also involved injections (i.p.) for 3 days, with sacrifice after 3 days of treatment, or injections (i.p.) for 7 days, with sacrifice after 7 days of treatment. Blood, serum, blood samples, white blood cell differentials, histology were made. The suspensions of thymus / spleen cells were analyzed through FACS analysis. The treatment of IL-33 induces IL-5 and IL-13 (Table 4). The cytokines IL-4, IL-5 and IL-13 were also measured in various organs with administration of IL-33. The organs were tested in thymus, lung, spleen, and liver. It was found that these three cytokines were induced, as determined after 7 days of treatment with IL-33. Increases were found in both levels of IL-33 (5 and 50 micrograms of IL-33). For example, in lung, the expression of IL-4, IL-5, and IL-13 with the saline treatment was approximately 1.0 or less. But with IL-33 (50 micrograms), the expression of IL-4 was 8.0; of IL-5 was 11.0; and of IL-13 was 41.0. The treatment of IL-33 also caused an increase in serum IgE and IgA. With 7 days of treatment, the IgE levels were 30 thousand ng / ml (PBS) and 17,000 ng / ml (50 micrograms of IL-33). With 7 days of treatment, the IgA levels were 90 ng / ml (PBS) and 420 ng / ml (50 grams of IL-33). Treatment of IL-33 also resulted in splenomegaly, where the mass of the spleen in mice treated with PBS (control) was approximately 80 mg, 5 micrograms with IL-33 for 7 days (150 mg of spleen) and 50 micrograms with IL-33 for 7 days (spleen 190 mg). The treatment with IL-33 also produced hematopoiesis extramadurally, in the spleen, and hypoplasia in the thymus (decreased in thymus size), and hypoplasia of the thymus cortex.
TABLE 4
The transformed and untransformed cells were injected into the mice, followed by a period of incubation of the cells within the mouse, and the recovery and purification of the injected cells, with the evaluation of T1 / ST2 expression (Table 5). Untransformed mammary gland cells and ras-transformed mammary gland cells were used. With injection of the ras-transformed cells into a nude mouse immune deficient host, the ras-transformed cells expressed T1 / ST2 at increased levels, ie, the expression was 103 (Table 5). With injection of ras-transformed cells into a host mouse having an intact immune system, recovery of transformed cells, and Taqman® analysis revealed a larger increase in T1 / ST2 expression. It is believed that their increases in T1 / ST2 expression reflect increases in soluble T1 / ST2, where T1 / ST2 as a decoy. When T1 / ST2 acts as a decoy, it binds to IL-33, and inhibits the host from mounting a TH2-type immune response against the tumor cells. The host mice with intact immune systems that were used were Xtb mice and Xbalb mice (Table 6). The soluble version of T1 / ST2 (also known as Fit 1) is described (see, for example, Bergers, et al. (1994) EMBO J. 13: 1176-1188; Reikerstorfer, et al. (1995) J. Biol. Chem. 270: 17645-17648). IL-33 was administered to mice harboring breast cancer 4T1. The administered IL-33 was effective in reducing tumor size (Table 6). The present invention provides agonists of IL-33, for example, IL-33 or a nucleic acid encoding IL-33, for the treatment of proliferative conditions, including cancer and tumors.
TABLE 5 Injection of ras-transformed cells in nude mice and immunocompetent mice, followed by Taiman analysis of T1 / TS2 expression through recovered ras-transformed cells
TABLE 6 IL-33 administered reduced tumor size in mice
The itosi analysis of human tissue samples revealed a decreased expression of IL-33 in several cancers, for example, breast cancer, and ovarian cancer (Table 7). The results indicate that the tumor cells abstain from producing IL-33, in order to prevent the activation of the immune system to mount an anti-tumor response (Table 7).
TABLE 7 Real-time PCR analysis of IL-33 expression by human cancer tissues
Prolonged experimental autoimmune encephalitis of IL-33 treatment, an animal model for multiple sclerosis. EAE was induced through proteolipid protein (PLP) (Kjellen, et al (2001) J. Neuroimmunol 120: 25-33; Laman, et al. (2001) J. Neuroimmunol. 119: 124-130; Fife, et al. (2001) J. Immunol. 166: 7617-7624). The three groups of mice were used for injections of PBS, 0.5 micrograms of IL-33, or 2.0 micrograms of IL-33, with i.p. injections. daily from day 0 to day 12. The itosine is from the disease were evaluated on days 7 to 23 (Table 8). The results showed that in mice treated with PBS, the disease spontaneously resolved. However, with treatment with any dose of IL-33, the disease was prolonged, higher than that found with the PBS treatment, and remained the same with a disease score of between 2.5-3.0 (Table 8). The present invention provides an IL-33 antagonist for the treatment of autoimmune disorders, including autoimmune disorders of the central nervous system, for example, multiple sclerosis.
TABLE 8 Disease score EAE in mice on selected days after treatment with PBS or with IL-33
Treatment with IL-33 led to the induction of IL-5 in NKT cells. The NKT cells were identified by the presence of both the NK1.1 marker and the CD3 marker. Six black mice were treated for two days with PBS or 50 micrograms / day of IL-33. Liver hocytes were isolated, and they were again stimulated with PIC ionomycin for 3 hours and brefeldin for 1 hour. The results showed that IL-33 induced IL-5 in NKT cells. The anti-T1 / ST2 antibody was tested for its ability to bind wild-type mast cells (WTMC), and the influence of IL-33 added on the binding of this antibody to the mast cells. By adding IL-33, the ability of the anti-T1 / ST2 antibody to bind mast cells was abolished, demonstrating that the IL-33 receptor is T1 / ST2.
III. In vivo effects of the il-33 antibody treatment. A mouse monoclonal antibody against human IL-33 was raised using methods well known in the art (see above). To test the ability of this antibody to antagonize the activity of IL-33, Balb / c mice were injected subcutaneously with 0.2 mg of anti-IL-33 antibody on day 0. On day 1 the mice were injected intraperitoneally with 100 ng of Mil-33. The serum was collected on day 2, and the levels of IL-5 were measured. Treatment with the anti-IL-33 antibody resulted in little or no IL-5 production when compared to mice treated with IL-33 and mice treated with the isotype control antibody and IL-33 (See Figure 1 ).
IV. Treatment of collagen-induced arthritis (CIA). B10.RIII mice known to be susceptible to the development of CIA, were injected with bovine type II collagen (bovine CU, Sigma) in itos adjuvant (itos). Mice were injected above the base of the tail with 100 ul of a 1 mg / ml emulsion of bovine CU. A second dose burst was administered on day 21. Mice were evaluated by the following clinical scale: 0 = normal; 1 = red coloration and / or swelling of the entire leg in more than one joint / site; 2 = red coloration and / or swelling in more than one joint / site; and 3 = a reddish color and / or swelling of the entire leg. Mice induced with CIA had a disease onset percentage of 70-90% or. The mice were treated on day 23 with one mg of the anti-IL-33 antibody or isotype control antibody. The antibodies were administered every 7 days during two or more treatments. Mice treated with anti-IL-33 showed a decrease in disease scores as well as a lower percentage of incidence of onset of the disease (See Figures 2 and 3). Mice treated with anti-IL-33 also had a lower average number of arthritic legs (see Figure 4).
V. Treatment of experimental autoimmune encephalitis (EAE) C57BL / 6 mice were immunized with 50 ug of myelin oligodendrocyte glycoprotein (MOG) peptide to induce EAE. The clinical evaluation of the disease was evaluated as follows: 1 = a flaccid tail; 2 = posterior flaccid weakness; 3 = disability to the right + individual posterior flaccid weakness; 4 = disability to the right + individual posterior flaccid paralysis; 5 = bilateral posterior flaccid paralysis; 6 = a bilateral posterior flaccid paralysis + collapse of the abdomen; 7 = 6 + dying. The EAE mice were tested subcutaneously with either 100 mg of the anti-IL-33 antibody or with isotype control antibody. Mice treated with anti-IL-33 showed lower disease scores and lower disease incidence of the control group (see figures 5 and 6).
SAW. Downward displacement test to identify the II-33R complex. IL-33 was biotinylated with EX-LINK Supho-NHS-Biotin (Pierce). The slide down of 2 μg of biotinylation of IL-33 in 500 μl RIPA-Ph-regulator of Lysis (upstate cell signaling solution) was performed with 50 μl of 50%, of bound slurry of itosin D of Azarosa ( Vector
Laborities). We used 5μ of either recombinant extracellular ST2-Fc (R &D)
Systems) or SIGIRR-Fc (R &D Systems). After incubation overnight at 4 ° C, the precipitates were washed 3x with 500 μl RIPA-Ph-regulator of Lysis. The precipitated proteins were separated through SDS-Page, electrographed, and visualized through the Western blot / ECL reaction with antibodies specific against ST2 (R & D Systems) or SIGIRR (R &D;
Systems). The downward displacement of IL-33 biotinylated with ST2-Fc or
SIGIRR-Fc was carried out in the same manner as above, only G-Sepharose protein (Amersham Bioscience) was used in place of itosin D linked to itosin. The IL-33 was visualized through the conjugate
Streptavidin-HRP (Pierce) and the ECL reaction.
vii. Phosphorylation of nf-kb and map kinases The WTMC mast cell line was previously described
(see, for example, Wright, et al (2003) J. Immunol 171: 3034-3036). The cells were lysed with Ph-lysis buffer RIPA (Upstate) containing the Mini Complete Protease inhibitor cocktail (Roche) and 10 Mm Na3 V04. The proteins were separated through SDS-Page, transferred to Immobilon-P membranes (Millipore) and immunostained using antibodies to phosphorylate p65 NF-kB, p65 NF-kB, phosphorylated p44 / 42 MAP kinases, p44 / 42 kinases MAP, phosphorylated p38MAP kinase, and p38 MAP kinase (all antibodies of Cell Signaling Technology).
VIII. Temporary transfection and reporter gene assay HEK293FT cells were seeded before transfection with a NF-kB reporter gene construct driven by GFP (Pnf-kB-hr GFP; Stratagene) and with a combination of plasmids coding for ST2, or SIGIRR or both, as indicated with Fugene-6 (Roche) according to the manufacturer's recommendations. The cells were divided 24 hours before transfection. After 24 hours the cells were either left untreated, or stimulated with mouse IL-33 at a concentration of 50 ng / ml. Sixteen hours after the stimulation, the cells were analyzed for GFP- expression through FACS.
TABLE 9 Sequence identifiers
All citations herein are incorporated herein by reference to the same degree as if each individual publication, patent application, or patent was specifically and individually indicated as being incorporated by reference including all figures. Many modifications and variations of this invention, as will be apparent to one skilled in the art can be made to suit a particular situation, material, composition of matter, procedure, step or procedural steps, to preserve the purpose, spirit and scope of the invention. the invention. All said modifications are intended to be within the scope of the appended claims thereof without departing from the spirit and scope of the invention. The specific embodiments described herein are offered by way of example only and the invention will be limited by the terms of the appended claims, together with the full scope of the equivalents to which said claims are entitled; and the invention will not be limited by the specific embodiments that have been presented here by way of example.
Claims (20)
1. - The use of an agonist or antagonist of IL-33 or of the IL-33 receptor complex (IL-33R) in the preparation of a medicament for modulating an immune disorder or condition.
2. The use claimed in claim 1, wherein the disorder or condition comprises: a) an innate response; b) asthma or allergy; c) multiple sclerosis; d) an inflammatory bowel disorder; e) arthritis; f) infection; g) a cancer or tumor.
3. The use claimed in claim 2, wherein the infection comprises: a) an intracellular pathogen; b) a bacterium; c) a parasite; or d) a virus.
4. The use claimed in claim 3, wherein the intracellular pathogen is: a) Leishmania sp .; b) Mycobacterium sp .; c) Listeria sp; d) Toxoplasma sp .; e) Schistosoma; or f) a respiratory virus.
5. The use claimed in claim 1, wherein the disorder or condition comprises: a) a TH1 type response; or b) a TH2 type response.
6. The use claimed in claim 5, wherein the TH2 type response comprises an early response event of type TH2.
7. The use claimed in claim 1, wherein the arthritis comprises: a) rheumatoid arthritis; b) osteoarthritis; or c) psoriatic arthritis.
8. The use claimed in claim 1, wherein the agonist comprises: a) IL-33 or; b) a nucleic acid.
9. The use claimed in claim 8, wherein the nucleic acid encodes IL-33.
10. The use claimed in claim 1, wherein the agonist comprises a binding composition of an antibody that specifically binds: a) IL-33; b) an IL-33R complex; or c) a complex of IL-33 and IL-33R.
11. The use claimed in claim 10, wherein the binding composition of an antibody comprises: a) a polyclonal antibody; b) a monoclonal antibody; c) a humanized fragment, or a fragment thereof; d) a Fab, Fv, or F (ab ') 2 fragment; e) a peptide mimetic of an antibody; or f) a detectable label.
12. The use claimed in claim 1, wherein the antagonist comprises: a) a soluble IL-33R; b) a small molecule; or c) a nucleic acid.
13. The use claimed in claim 12, wherein the nucleic acid specifically hybridizes with a polynucleotide encoding IL-33.
14. The use claimed in claim 13, wherein the nucleic acid comprises: a) an anti-sense nucleic acid; or b) a small interfering RNA (siRNA).
15. - The use of an IL-33 agonist or antagonist for the preparation of a medicine to modulate the white blood cell counts.
16. The use claimed in claim 15, wherein the IL-33 agonist increases the counts of: a) the total white blood cells; b) neutrophils; c) lymphocytes; or d) eosinophils.
17. The use claimed in claim 15, wherein the IL-33 antagonist increases the platelet count.
18. The use claimed in claim 16, wherein the IL-33 antagonist decreases the counts of: a) total white blood cells; b) neutrophils; c) lymphocytes; or d) eosinophils.
19. A method for diagnosing the immune condition or disorder according to claim 1 comprising contacting a binding composition with a biological sample, wherein the binding composition specifically binds to IL-33 and measures or determines the specific binding of the binding composition with the biological sample.
20. A kit for the diagnosis of the immune condition or disorder according to claim 1, comprising a compartment and a binding composition that specifically binds to: a) IL-33; b) an IL-33R complex; c) a complex of IL-33 and IL-33R; or d) a nucleic acid encoding IL-33.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60/545,730 | 2004-02-17 |
Publications (1)
Publication Number | Publication Date |
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MXPA06009362A true MXPA06009362A (en) | 2006-12-13 |
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