MXPA06009304A - Methods of modulating il-23 activity;related reagents - Google Patents
Methods of modulating il-23 activity;related reagentsInfo
- Publication number
- MXPA06009304A MXPA06009304A MXPA/A/2006/009304A MXPA06009304A MXPA06009304A MX PA06009304 A MXPA06009304 A MX PA06009304A MX PA06009304 A MXPA06009304 A MX PA06009304A MX PA06009304 A MXPA06009304 A MX PA06009304A
- Authority
- MX
- Mexico
- Prior art keywords
- cells
- virus
- antigen
- influenza
- viral
- Prior art date
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Abstract
Provided are methods of modulating cytokine activity, namely of IL-23, e.g., for the purpose of treating viral infections. Also provided is a method of diagnosing a viral infection based of the detection of p19, IL-23 or IL-23R;or of a nucleic acid encoding p19 or IL-23R as well as a kit for performing the said method of diagnosing.
Description
METHODS TO MODULATE THE ACTIVITY OF IL-23; RELATED REAGENTS
FIELD OF THE INVENTION
The present invention relates generally to the uses of mammalian cytokines. More specifically, the invention describes the function of cytokine in the treatment of influenza viruses.
BACKGROUND OF THE INVENTION
The immune system protects individuals from infectious agents, for example, viruses, bacteria, multi-cellular organisms, and cancers. This system includes several types of lymphoid and myeloid cells such as monocytes, 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 systemically or at a particular place in the body. In response to an ineffective agent or foreign substance, immune cells secrete cytokines which, in turn, modulate the proliferation, development, differentiation, or migration of the cell. Cytokines have been implicated in immune responses of a number of viral infections (see, for example, Abbas, et al.
(eds.) (2000) Cellular and Molecular Immunology, W. B. 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 influenza virus is a dominant viral cause of mortality, contributing 20,000 deaths in the United States per year. The virus destroys the epithelium of the airways and can spread to the extrapulmonary tissues. High-risk individuals include those over 65, and those with disorders such as chronic obstructive pulmonary disease (COPD), asthma, chronic heart disease, diabetes, chronic kidney or liver disease, cancer, or chronic connective tissue disease . The influenza virus is classified into three types A, B, and C, of which A is clinically the most important. The genome of influenza A virus encodes 10 proteins. Due to the antigenic variability of surface proteins, hemagglutinin and neuramanidase, it has not been possible to produce a vaccine that provides long-term protection for, for example, the strain of influenza A (IV) virus (see, for example , Treanor (2004) New Engl., J. Med. 350: 218-220, Steinhauer and Skehel (2002) Annu., Rev. Genet, 36: 305-332, Mozdzanowska, et al., (2000) J. Immunol., 164: 2635-2643;
Nicholson, et al. (2003) The Lancet 362: 1733-1745). With influenza infection, the virus-specific CD8 + T cells exist at high concentrations in the respiratory tract, and rapidly express the effector functions upon re-exposure to a viral antigen. Although replication of the influenza virus is essentially limited to the respiratory tract, the infection results in the inactivation of immune cells in the respiratory tract, but also elsewhere in the body, for example, kidney. CD8 + T cells fight infection by virus through direct lysis of infected cells or through the secretion of antiviral cytokines, such as interferon-gamma (IFNgamma) and tumor necrosis factor alpha (TNFalpha). IFNgamma induces proteins that inhibit viral replication, for example, through the deterioration of metabolism in viral mRNA and double-stranded structure RNA. In addition, IFNgamma activates antigen presenting cells (APCs), for example, through up-regulation of the major histocompatibility complex (MHC) in APCs. The immune response to primary and secondary infection with influenza has different properties, since IFNgamma does not sto be necessary for the response to a primary infection, but it is used for the recovery of a secondary infection. Another difference is that the CD8 + T cell responds to acute infections, for example, the early stages of acute viral infection, it is relatively independent of CD4 + cells, while it responds by means of memory CD8 + T cells in secondary infections, it is improved Through CD40 cells After a primary infection with influenza, large groups of memory CD8 + T cells persist in secondary lymph organs, as well as non-lymphoid tissues, such as lungs and liver (see, for example, Kaech and Ahmed (2003). ) Science 300: 263-265; Sun and Bevan (2003) Science 300: 339-342; Turner, et al. (2003) Immunity 18: 549-559; Ely, et al. (2003) J Immunol. 170: 1423-1429; Topham, et al. (2001) J. Immunol. 167: 6983-6990). Other differences between the response to primary and secondary viral infections are as follows. Viral peptides bind to class I MHC molecules that stimulate CD8 + T cells, where the characteristics of the CD8 + T cell response, eg, cytokine production, may differ, depending on the identity of the peptide presented and if the infection is primary or secondary. For example, the primary infection may involve the immune response through influenza-specific nucleoprotein T cells and influenza acid polymerase, but during secondary infection, most T cells recognize the nucleoprotein but not the acid polymerase. After primary exposure, approximately 12% of the CD8 + T cells taken from the lungs are specific for the epitope NP366-374 while after secondary exposure this number increases, for example to 60-70%. Changes in the immune response during primary or secondary infection may reflect changes in the identity of APCs that present the antigen, for example, a dendritic cell (DC) against a macrophage, and in differences in the ability of DC against the ability of macrophage to activate a memory T cell during secondary infection (see, for example Yewell and Garcia-Sastre (2002) Curr. Opin. Microbiol. 5: 414-418; Canadian Medical Assoc. J. 168: 49-57; Nguyen , et al. (2000) R Virol. 74: 5495-5501; Graham, et al. (1993) J. Exp. Med. 178: 1725-1732; Wong and Pamer (2003) Annu. Rev. Immunol. 29-70; Crowe, et al. (2003) J. Exp. Med. 198: 399-410; Julkunen, et al. (2001) Vaccine 19: S32-S37; Webby, et al. (2003) Proc. Nati. Acad Sci. USA 100: 7235-7240; Turner, et al. (2001) J. Immunol., 167: 2753-2758; Wiley, et al (2001) J. Immunol., 167: 3293-3299; Belz, et al. (2000) J. Virol. 74: 3486-3493; Belz, et al. (1998) Proc. Nati, Acad. Sci. USA 95: 13812-13817). Long-term and broad immunity against influenza may depend on the ability to generate CD8 + T cell responses, but the generation of this response is usually not effective with current vaccines. There is an unmet need to provide protection against viruses during primary and secondary immune responses, for example, for the influenza virus. The present invention satisfies this need by providing methods for using agonists and antagonists of the IL-23 and IL-23 receptor.
BRIEF DESCRIPTION OF THE INVENTION
The present invention is based, in part, on the discovery that an IL-23 antagonist or agonist modulates the immune response of the influenza virus. The present invention provides a method for modulating the response of the CD8 + T cell to a virus, viral antigen, or viral infection, comprising administering an effective amount of an agonist of p19, IL-23, or IL-23R or antagonist of p19, IL-23, or IL-23R. The above method is also provided wherein the antagonist comprises: a) a binding composition of an antibody that specifically binds p19, IL-23, or IL-23R; b) a soluble receptor derived from IL-23R that specifically binds to IL-23; c) a small molecule; or d) a nucleic acid that specifically hybridizes to a nucleic acid encoding p19 or IL-23R. In addition, the present invention provides the above method wherein the binding composition derived from the 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, as well as the above method wherein the nucleic acid comprises the antisense nucleic acid or a low interfering RNA (RNAsi). In another aspect, the present invention provides a method for modulating the response of the CD8 + T cell to a virus, viral antigen, or viral infection, comprising the administration of an effective amount of an agonist p19, IL-23, or IL- 23R, or antagonist p19, IL-23, or IL-23R, further comprises co-administration of an effective amount of a: a) agonist of p35, IL-12, p40, IL-12Rβ1, or IL-12Rβ2; or b) antagonist of p35, IL-12, p40, IL-12Rβ1, or IL-12β2, as well as the previous method where the p19, IL-23, or IL-23R agonist is decreased: a) the percentage of CD8 + T cells that are CD8 + T cells specific for viral antigen; b) the percentage of CD8 + T cells that are CD8 + T cells specific for viral antigens that produce IFNα; or c) cytotoxicity of CD8 + T cells specific for viral antigen. The invention contemplates the above method wherein the increase comprises an immune response to secondary viral infection, further comprising the administration of an effective amount of an antagonist p35, IL-12, p40, IL-12Rbeta1, or IL-12Rbeta2; also the above method wherein the atagonist of p19, IL-23, or IL-23R increases the total number of CD8 + T cells during the immune response to a secondary viral infection. In another embodiment, the present invention provides the above method, wherein the total number of CD8 + T cells are from one lung; a bronchoalveolar lavage (BAL); a spleen; or a lymph node, as well as the above method further comprises administering an effective amount of an antagonist of p35, IL-12, IL-12Rbeta2, or p40. Yet another aspect of the present invention is a method for modulating the response of the CD8 + T cell to a virus, viral antigen or viral infection comprising the administration of an effective amount of an agonist p19, IL-23, or IL-23R. , or antagonist p19, IL-23, or IL-23R; wherein the virus is a respiratory virus; a mucosal virus; an influenza virus; or where the influenza virus is influenza A, influenza B, or influenza C; or the above method wherein the viral antigen comprises an influenza virus antigen; as well as the above method wherein the influenza virus antigen is from the nucleoprotein of influenza A virus or acid polymerase of influenza A virus; or wherein the viral infection comprises a respiratory syndrome or pneumonia; In yet another embodiment, the present invention provides the above method further comprising administering a vaccine or an adjuvant, as well as a method for diagnosing a viral infection comprising contacting a binding composition with a biological sample, wherein the composition of binding specifically binds to p19, IL-23, or IL-23R; or a nucleic acid encoding p19 or IL-23R and measuring or determining the specific binding of the binding composition to the biological sample; the binding composition may be, for example, an antibody, a nucleic acid probe, a PCR primer, or a molecular model. A method for treating an influenza A virus infection comprising treating with an effective amount of an agonist or antagonist of p19, IL-23, or IL-23R is provided. A further embodiment of the present invention provides a kit for the diagnosis of a viral infection comprising a compartment and a binding composition that specifically binds to: a) p19, IL-23, or 1L-23R; or b) a nucleic acid encoding p19 or IL-23R.
DETAILED DESCRIPTION OF THE PREFERRED MODALITIES
As used herein, including the appended claims, the singular forms of words such as "a," "an," and "he or she" include their corresponding plural references unless the context clearly dictates otherwise. All references cited herein are incorporated by reference in the same degree as if each publication or individual patent application was specifically and individually indicated as being incorporated by reference.
I. Definitions "Activation", "stimulation", and "treatment", since it is applied to cells or receptors, may have the same meaning, for example, activation, stimulation, or treatment of a cell or receptor with a ligand, a unless indicated otherwise by the context or explicitly. "Ligands" encompasses natural or synthetic ligands, for example, cytokines, cytokine variants, analogs, muteins, and binding compositions derived from the antibodies. "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 through 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 expression 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 to a ligand or to a receptor, to a catalytic activity; to the ability to stimulate the expression of the gene or signaling, differentiation or maturation of the cell; to antigenic activity, to the modulation of 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, eg, cell membranes or cytoskeletons . "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, which is necessary for, or which is specifically associated with, for example, normal cell division, as well as cancer, tumors, dysplasia, transformation, metastasis, and cell angiogenesis. An "adjuvant" is a molecule, compound, or composition that improves the immune response to a vaccine. The present invention provides methods for administering an IL-23 or p19 agonist or antagonist, in conjunction with an adjuvant, for example, an interferon or a Freund's adjuvant. Adjuvants are described (Proietti, et al (2002) J. Immunol., 169: 375-383; Billiau and Matthys (2001) J. Leukoc.Biol., 70: 849-860; Klinman (2003), Expert Rev. Vaccines ( 2003) 2: 305-315; Hamilton (2003) J. Leukocyte Biol. 73: 702-712; Holmgren, et al. (2003) Vaccine 21 (Suppl 2): S89-S95; Lemieux (2002) Expert Rev. Vaccines 1: 85-93; Villinger (2003) Expert Rev. Vaccines 2: 317-326). "Administration" and "treatment", as applied to an animal, human being, experimental subject, cell, tissue, organ, or biological fluid, refers to the contact of an exogenous, therapeutic, diagnostic agent, compound, or composition with the animal, human being, experimental subject, cell, tissue, organ, or biological fluid. "Administration" and "treatment" may refer, for example, to a therapeutic, placebo, pharmacokinetic, diagnostic, research, and experimental method. "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, by means of a reagent, diagnosis, binding composition, or through another cell. "Treatment", as applied to a human being, veterinarian, or research subject, refers to the 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-23 agonist or IL-23 antagonist with a human or animal subject, a cell, a tissue, a physiological compartment or a physiological fluid. "Treatment of a cell" also encompasses situations in which the agonist 1L-23 or antagonist L-23 is contacted with the IL-23 receptor (heterodimer of IL-23R and IL-12Rbeta1), for example, in the fluid or colloidal phase, as well as in situations where the agonist or antagonist contacts a fluid, for example, when the fluid is in contact with a cell or receptor, but where it has not been demonstrated that the agonist or antagonist contacts the cell or the receiver. "Link composition" refers to a molecule, a small molecule, macromolecule, antibody, a fragment or analogue thereof, or soluble receptor, capable of binding to a target. "Binding composition" can also refer to a complex of molecules, for example, a non-covalent complex, or an ionized molecule, and still a covalently or non-covalently modified molecule, for example, modified through phosphorylation, acylation, entanglement , 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 linkage composition with a target where the association results in the reduction in normal Brownian movement of the linkage composition in cases where the linkage composition can be dissolved or suspended in 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. An example of a polypeptide (derivative) is a soluble receptor that comprises most or all of the extracellular amino acids of an integral membrane-bound receptor, but not any of the transmembrane segments and not any of the cytosolic segments of the membrane-bound receptor. . "Effective amount" or "therapeutically effective amount" means an amount sufficient to ameliorate a symptom or sign of a physiological condition or disorder or an amount sufficient to allow or facilitate a diagnosis of the disorder or physiological condition. An effective amount for a particular patient or veterinary subject may vary depending on factors such as 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, 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 in the measurement of the diagnosis, parameter, or detectable signal through at least 5% usually through 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 more ideally at least 90%, wherein 100% is defined as the parameter of diagnosis shown by a normal subject (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 body of a human being, depending on the context. "Endogenous" refers to substances that are produced within a cell, organism, body of a human being, 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, bacterium, parasite, virus, and the like, as well as to an inappropriate, 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-23 agonist, an IL-23 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-23 agonist, antagonist, or binding composition or composition, sufficient to allow or facilitate 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 . Control samples, ie, 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. 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%, more generally at least 160%, usually at least 180%, generally at less 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 a cytokine, toxic oxygen, or a protease. The end point can include, 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 endpoint of inhibitions is generally 75% control or less, preferably 50% control or less, more preferably 25% control or less, and more preferably 10% control or less. Generally, an activation endpoint is at least 150% control, preferably at least 2 times control, more preferably at least 4 times control, and more preferably at least 10 times control. "Expression" refers to a measure of mRNA or polypeptide encoded by a specific gene. Expression units can be measured, 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% 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 of sodium citrate / 0.1% sodium dodecyl sulfate at 50 ° C; (2) using during the hybridization a denaturing agent, such as formamide, for example 50% (vol / vol) of formamide with 0.1% bovine serum albumin / 0.1% Ficolle (Sigma-Aldrich, St. Louis, MO) /0.1% polyvinylpyrrolidone / 50 mM sodium phosphate pH regulator at a pH of 6.5 with 750 mM sodium chloride, 75 mM sodium citrate at 42 ° C; (3) use 50% 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 (US Patent 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" encompasses, 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, monocytes 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 eg, endothelial or epithelial cells that produce cytokine. "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 , monocytes or macrophages, alveolar macrophages, dendritic cells, NK cells, NKT cells, neutrophils, eosinophils, or mast cells.
"Annihilate" (KO) refers to the partial or complete reduction of the expression of at least a portion of a polypeptide encoded by a gene, for example, the p19 subunit of IL23, wherein the gene is endogenous to a single cell, selected cells, or for all cells of a mammal. KO also encompasses embodiments wherein the biological function is reduced, but where the expression is not necessarily reduced, for example, a p19KO polypeptide comprising a expressed p19 polypeptide containing an inserted peptide, oligopeptide, or inactivated polypeptide. Interruptions in a coding sequence or regulatory sequence are encompassed by the annihilation technique. The cell or mammal may be an "annihilation of heterozygous", wherein an allele of the endogenous gene has been interrupted. Alternatively, the cell or mammal may be a "homozygous annihilation" wherein both alleles of the endogenous gene have been disrupted. "Homozygous annihilation" is not intended to limit the interruption of both alleles to identical techniques or to identical results in the genome. Included within the scope of this invention is a mammal in which one or both p19 alleles have been killed. "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 side 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. "Memory response" encompasses a method to modulate the activation of the immune system. Activation can be achieved through the administration of an antigen from a pathogen or cancer cell, while modulation of activation can be achieved with an IL-23 agonist or an IL-23 antagonist. Improvement of activation can be achieved through the administration, for example, of an IL-23 agonist. The increased memory response, that is, activation increases, encompasses two responses found with or without the secondary administration of the antigen. The memory response increases, that is, the increased activation, can be measured with or without the secondary administration of an antigen. "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. Commun. 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; Domingues, 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. "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 modulating the immune response for a virus or viral infection using polypeptides, nucleic acids, variants, muteins, and mimetics of the IL-23 heterodimer, the p19 subunit of IL-23, the p40 subunit of IL-23. 23 and IL-12, the heterodimer of the IL-23 receptor, the IL-23R subunit, or the IL-12Rbeta 1 subunit. Methods for using a hypercin, i.e., a fusion protein comprising, for example, the p19 subunit linked to the p40 subunit, as well as nucleic acids encoding the hypercin (Oppmann, et al., supra; Fischer, et al. (1997) Nature Biotechnol., 15: 142-145; Rakemann, et al. (1999) ) J. Biol. Chem. 274: 1257-1266; and Peters, et al. (1998) J. Imol. 161: 3575-3581). Interleukin-23 (IL-23; a.k.a.-IL-B30) is a heterodimeric cytokine composed of a novel p19 subunit and the p40 subunit of IL-12 (Oppmann, et al, supra). Like p35, p19 requires the coexpression of p40 for biological activity (Wiekowski, et al., Supra). The IL-23 receptor comprises a novel receptor subunit (IL-23R) that binds p19 and IL-12Rbeta that binds p40. These two subunits of the receptor form the functional signaling complex and are expressed in CD4 + CD45Rb 'memory T cells as well as spinal cord macrophages activated with IFNgamma (see, for example Parham, et al (2002) J. Immunol. 168: 5699-5708). Antibodies can be raised for several cytokine proteins, including individual, polymorphic, allelic, strain, or variant variants, and fragments thereof, both in their natural (full length) forms or in their recombinant forms. Additionally, the antibodies can be raised to the receptor proteins in both their native (or active) or inactive forms, for example, denatured forms. Anti-idiotypic antibodies can also be used. The administration of a 1L-23 agonist, i.e., IL-23 or the hypercin IL-23, can induce, for example, the proliferation of memory T cells, PHA blasts, CD45RO T cells, CD45RO T cells, or enhance the production of interferon-gamma (IFNgamma) through PHA blasts or CD45RO T cells. In contrast to IL-12, IL-23 preferentially stimulates memory as opposed to inexperienced T cell populations in both ns and mice. IL-23 activates a number of intracellular cell signaling molecules, for example, Jak2, Tyk2, Statl, Stat2, Stat3, and Stat4. IL-12 activates this same group of molecules, but the response of Stat4 for IL-23 is relatively weak, while the response of Stat4, for IL-12 is strong (Oppmann, et al., Supra).; Parham, et al., Supra).
IL12 and IL-23 activate similar signal transduction mechanisms. IL-23 activates its receptor complex, activates Jak2, Tyk2, and Stat-1, -3, -4, and -5, as IL-12. However, the activation of Stat4 is significantly weaker in response to IL-23, than IL-12. Also, in contrast to IL-12, the most prominent Stat induced by IL-23 is Stat-3 (see, for example, Parham, et al., Supra). Administration of the p19 subunit of IL-23 may result in, for example, stunted growth, infertility, and death of animals, as well as inflammatory infiltrates, for example, in the gastrointestinal tract, lungs, skin, and blood. liver, and epithelial cell hyperplasia, microcytic anemia, increased neutrophil count, increased serum TNFalpha; and the increased expression of acute phase genes in the liver. Enhanced IL-23 expression occurred in untransformed immortalized epithelial cell lines (Wiekowski, et al., Supra). Other studies have shown that IL-23 modulates the immune response for infection (see, for example, Pirhonen, et al (2002) J. Immunol., 169: 5673-5678; Broberg, et al. (2002) J. Interferon Cytokine. Res. 22: 641-651; Elkins, et al. (2002) Infection Immunity 70: 1936-1948; Cooper, et al. (2002) J. Immunol. 168: 1322-1327). The present invention provides methods for modulating the immune response for a virus, including modulation of the response of CD4 + T cells, CD8 + T cells, antigen presenting cells (APCs) such as macrophages and dendritic cells (DCs), B cells, and the antibody response. Methods to modulate the response to primary and secondary infections are also provided. Both CD4 + T and CD8 + T cells have a role in the response to influenza virus infection. CD4 + T cells can respond using infected cells expressing MHC class II, while CD8 + T cells can respond using infected cells expressing MCH class 1 (see, for example, Epstein, et al (1998) J. Immunol., 160: 322-327; Jameson, et al (1999) J. Immunol., 162: 7578-7583). In the situation where several different viral subtypes invade during primary and secondary infections, the immune response may be more dependent on CD8 + T cells (see, for example, Walzl, et al. (2000) J. Exp. Med. 192 : 1317-1326; Epstein, et al. (1998) J. Immunol., 160: 322-327; Murali-Krishna, et al. (1998) Immunity 8: 177-187). In addition, the present invention contemplates methods to protect against the pathological immune response to a virus. Pathological conditions that may result with the immune response to viral infections include, for example, lung eosinophilia, asthma, and allergies (see, for example, Walzl, et al. (2000) J. Exp. Med. 192: 1317- 1326; van Benten, et al. (2001) Allergy 56: 949-956; Wohlleben, et al. (2003) J. Immunol., 170: 4601-4611). In addition, the present invention contemplates methods for recruiting immune cells for the lung, for example, during infection, with a respiratory virus. Note that the primary response to viral respiratory tract infections may include virus-specific CD8 + T cells and non-specific CD8 + T cells. Although the influenza virus usually only infects the lung, the immune response includes the activation of T cells in non-pulmonary tissues, for example, the spleen, and the draining medians lymph nodes (MLNs), and the recruitment of these immune cells for the lungs (see, for example, Topham, et al (2001) J. Immunol., 167: 6983-6990; Román, et al. (2002) J. Exp. Med. 196: 957-968; Doherty; , et al (1997) Immunol Rev. 159: 105-117; Woodland, et al. (2001) Immunol Res.24: 53-67). The present invention provides methods for using an IL-23 agonist, or antagonist, to modulate the immune response that is specific and that is not specific for the viral antigen. The immune reaction to the viruses, for example, the influenza virus, includes specific and non-specific responses, as documented by a number of IL-12 studies. IL-12 has been identified as promoting the antigen-specific response, for example, to bacteria and viruses while consistently, the anti-IL-12 antibody has been identified as an inhibitor of antigen-specific response (see, for example, Cooper , et al. (2002) J. Immunol. 168: 1322-1327; Miller, et al. (1995) J. Immunol. 155: 4817-4828; Jong, et al. (1997) J. Immunol. 159: 786-793; Knutson and Disis (2004) Clin. Exp. Immunol. 135: 322-329; Clerici, et al. (1993) Science 262: 1721-1724; Lohr, et al. (2002) Clin. Exp. Immunol. 130: 107-114; Foss, et al. (2002) Viral Immunol. 15: 557-566; Seaman, et al. (2004) J. Virol. 78: 206-215; van der Meide, et al. (2002) Vaccine 20: 2296-2302).
Investigations into the antigen-specific response to a virus may include response measurements in terms of, for example, IFNgamma production, as well as CD80 T cell proliferation. For example, in the case of lymphocytic co-meningitis virus, the specific response of antigen supported by IL-12 manifested by the specific increase of antigen in the production of IFNgamma, although IL-12 was not necessary for and did not contribute to the proliferation of antigen-specific CD8 + T cell (Cousens, et al. (1999) J Exp. Med. 189: 1315-1327). The present invention also contemplates methods for increasing the B cell response. For example, CD4 + T cells and CD8 + T cells can drive the B cell response to influenza by several mechanisms. Immune responses comprise B cells and antibodies that may exist in both primary and secondary viral infections (see, for example, Sangster, et al (2003) J. Exp. Med. 198: 1011-1021; Graham and Braciale (1997) J. Exp. Med. 186: 2063-2068). The present invention contemplates methods for modulating the response of an antigen-presenting cell (APC) to a virus, such as influenza virus. The APCs include dendritic cells (DCs), macrophages, and Langerhans cells. The relative importance of DCs against macrophages can differ in immune responses to primary and secondary infections (see, for example, Bender, et al (1995) J. Exp. Med. 182: 1663-1671; Crowe, et al. (2003) J. Exp. Med. 198: 399-410). The cytokine responses have been documented as part of the immune response for influenza. Influenza infections result in the production of a number of cytokines, for example, IL-12, IFNgamma, IL-4, IL-5, IL-1 alpha, IL-1 beta, IL-6, IL-10, TNF, granulocyte macrophage colony stimulation factor (GM-CSF), and macrophage colony stimulation factor. A number of details about IL-12 are as follows. IL-12, a strong IFNgamma inducer, induces cytotoxicity and activated CD8 + T cells. IFNgamma induced, for example, by IL-12 causes the expression of MHC class I antigens, by means of infected target cells, thereby enabling CD8 + T cells to recognize infected cells and kill them. Different antigens can be expressed in different MHC species. For example, class I MHC H-2Db is used to present the nucleoprotein and acid polymerase peptides of influenza viruses, while class I MHC H-2Kb is used to present a number of other influenza virus peptides. The dependence of IL-12 may change during the course of the influenza infection. Studies on the anterior and posterior stages of primary infection revealed that early primary infection, there is a dependence on IL-12, but then apparently, there is no dependence on IL-12 (see, for example, Tsurita, et al. 2001) J. Pharmacol. Exp. Therapeutics 298: 362-368; Pirhonen, et al. (2002) J Immunol., 169: 5673-5678; Monteiro, et al. (1998) J. Virol. 72: 4825-4831; Julkunen, et al. (2001) Vaccine 19: S32-S37; Julkunen, et al. (2001) Cytokine Growth Factor Rev. 12: 171-180; Mbawuike, et al. (1999) J. Infect. Dis. 180: 1477-1486; Turner, et al (2001) J. Immunol., 167: 2753-2758). Arulandandam, et al. (1999) J. Infect. Dis. 180: 940-949; Monteiro, et al. (1998) J Yirol. 72: 4825-4831). Different viruses can elicit different responses in terms of IL-23 expression. For example, IL-23 plays a part in the immune response for simple type I herpesvirus (HSV-1) and Sendai virus infection, as measured by the expression of the p19 subunit (from IL-23). ) while, in contrast, p19 is not induced in the response to influenza A virus (Broberg, et al. (2002) J. Interferon Cytokine Res. 22: 641-651; Pirhonen, et al. (2002) J. Immunol 169: 5673-5678). Since IL-12 and IL-23 each have been correlated with the immune response for viral infection, therapy with an IL-23 agonist has an advantage over IL-12 therapy, due to the lower induction of IFNgamma to through IL-23, and the lower IFNgamma-induced toxicity (see, for example, Lo, et al., (2003) J. Immunol., 171: 600-607).; Leonard, et al. (1997) Blood 90: 2541-2548; Trinchieri (2003) Nature Revs. Immunol. 3: 133-146; Cousens, et al. (1999) J. Exp. Med. 189: 1315-1328; Naylor and Hadden (2003) Int. Immunopharmacol. 70: 1205-1215; Fernandez, et al. (1999) J. Immunol. 162: 609-617; Orange, et al. (1995) J. Exp. Med. 181: 901-914). In the studies of the present invention, a model for human influenza using Influenza A virus infection in C57BL / 6J mice was used to characterize the antigen-specific CD8 + T cell responses. The primary infections were carried out intranasally (in) using the recombinant strain X31 of influenza A virus. Secondary infections of mice were activated with an intraperitoneal (ip) injection of the PR8 strain of influenza A virus, and then became to attack on day 30 intranasally with strain X.31. The nodes of the lungs, spleen, and lymph of the infected mice were harvested and analyzed. Complete lung digestions, instead of bronchoalveolar lavage (BAL), were used to allow the isolation and detection of all cell types in the lungs of mice infected with influenza. The influence of IL-23 agonists and antagonists on the immune response to infection by primary and secondary influenza A was studied. The influence of IL-23 agonists and antagonists on the memory response was also characterized, where the memory response was defined as, for example, a change in the immune response that is caused by an IL-23 agonist or antagonist. administered during activation. The IL-23 agonists take the form of 1L-23 polypeptide administrations. The IL-23 antagonists take the form of p35KO, resulting in deficiency in IL-12, and p40KO, resulting in deficiencies in both IL-23 and IL-12. The annihilation studies, the physiological responses specific for IL-23, instead of for IL-12, can be determined by comparing the physiological responses with p35KO and p40KO. The tetramer technology was used to quantify and phenotype the CD8 + T cells that are specific for the peptide NP366-374 of the nuclear protein type A of the immunodominant influenza virus (NP). The tetramer complexes are comprised of the peptide NP366-374 of influenza loaded with monomers of class I MHC (H-2Db). Kinetic studies were carried out on both type A infection of the primary and secondary influenza viruses.
lll. Agonists, Antagonists, and Binding Compositions The present invention provides methods for using IL-23 agonists and antagonists. An IL-23 agonist encompasses for example, 1L-23, a variant of IL-23, mutein, hypercin, or a peptide mimetic thereof, agonistic antibodies to IL-23R, and nucleic acids encoding these agonists. Antagonists of IL-23 include, for example, antibodies to IL-23, blocking antibodies to IL-23R, a soluble receptor based on the extracellular region of a subunit of IL-23R, peptide mimics thereof, and nucleic acids. which encode these antagonists. The present invention provides methods for using p19 agonists and antagonists, the p19 and p40 complex, IL-23R, and the IL-23R and IL-12Rbeta1 complex, including binding compositions that specifically bind to proteins and complexes of p19 protein, the p19 and p40 complex, IL-23R, and the IL-23R and IL-12Rbeta1 complex. An IL-23 hypernucleus, encompasses, for example, a fusion protein comprising the polypeptide sequence of p19 and p40, wherein p19 and p40 exist in a continuous polypeptide chain. The sequences of p19 and p40 may be in any order in the continuous polypeptide chain. The fusion protein may contain a linker sequence, resident between the p19 and p40 sequences, in a continuous polypeptide chain. The increased antigenicity regions can be used for the generation of the antibody. The regions of increased antigenicity of p19 exist, for example, in amino acids 16-28; 57-87; 110-114; 136-154; and 182-186 of GenBank AAQ89442 (gi: 37183284). The regions of increased antigenicity of human IL-23R exist, for example at amino acids 22-33; 57-63; 68-74; 101-112; 117-133; 164-177; 244-264; 294-302; 315-326; 347-354; 444-473; 510-530; and 554-558 of GenBank AAM44229 (gi: 21239252). The analyzes were through a Parker plot using Vector NTISuite (Informax, Inc., Bethesda, MD). Antibodies have been prepared for the IL-23, IL-12 subunits, and for the subunits of the IL-23 and IL-12 receptors. The present invention provides antibodies, and fragments thereof, for p19, p40, p35, IL-23R, IL-12Rbetal, and IL-12Rbeta2 (see, e.g., Lee, et al. (2004) J. Exp. Med. 199: 125-130; Parham, et al. (2002) J. Immunol., 168: 5699-5708; Rogge, et al. (1999) J. Immunol., 162: 3926-3932; Hoeve, et al. (2003). ) Eur. J. Immunol 33: 3393-3397; Oppmann, et al. (2000) Immunity 13: 715-725; Presky, et al. (1998) J. Immunol. 160: 2174-2179). Antibodies that bind epitopes of both p19 and p40, epitopes of both p35 and p40, epitopes of both IL-23R and IL-12Rbeta1, and epitopes of both IL-12Rbetal and IL-12Rbeta2 are also contemplated. Soluble receptors corresponding to an extracellular domain of IL-23R, IL-12Rbetal, or IL-12Rbeta2 are also provided. The present invention also provides an IL-23 antagonist comprising an extracellular region of human IL-23R, for example, amino acids 1-353 of GenBank AAM44229, or a fragment thereof, wherein the extracellular region or fragment thereof specifically it links to IL-23. The mouse IL-23R is GenBank NP_653131 (gi: 21362353) is also available to be a soluble receptor. The sequence of IL-12Rbetal and IL-12Rbeta2 is available. Extracellular reactions of these receptor subunits comprise amino acids 24-545 of IL-12Rbetal (GenBank P42701; Gl: 1170462) and amino acids 22-624 of IL-12Rbeta2 (GenBank Q99665; Gl: 12229836). Soluble receptors based on these extracellular regions are not limited by these exact N-terminal and C-terminal amino acids, but may be longer or shorter, for example, through 1, 2, 3, or more amino acids, so long as the ligand properties are substantially maintained. Fusion proteins based on soluble receptors are also contemplated, for example, to facilitate purification or stability. Monoclonal, polyclonal, and humanized antibodies 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; U.A. Patent No. 6,329, 511 issued to Vasquez, et al.). Luteins and variants of antibodies and 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, 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 assays. functional or biological assays, that is, assays not dependent on the possession of purified antigen Immunization with cells may prove to be superior for the generation of the antibody than immunization with purified antigen (Kaithamana, et al (1999) J. Immunol. 163: 5157-5164.) Antibodies u sually they will bond with at least one KD of about 10"3 M, more usually at least 10" 6 typically at least 10"7 M, more typically at least 10 ~ 8 M, preferably at least about 10" 9 M, and more preferably at least 10"10 M, and more preferably at least 10" 11 (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). Soluble receptors are provided that buy the extracellular domains of the IL-23R or IL-12Rbeta1 receptor polypeptides the soluble receptors can be prepared and used according to standard methods (see, for example, Jones, et al. (2002) Biochim, Biophys, Acta 1592: 251-263, Prudhomme, et al. (2001) Expert Opinion Biol. 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 for treating or preventing viral infections. These methods can be used in conjunction with a vaccine, for example, inactivated influenza, live attenuated influenza vaccines, and mucosal vaccines, or a small molecule, for example, an ion channel blocker, such as amantadite, and rimantadine. , and a neuraminidase inhibitor, such as zanamivir and oseltamivir. Methods are provided for the treatment and diagnosis of respiratory viruses, including influenza virus, for use in agriculture, such as domestic pigs, livestock, or poultry (see, for example, van Ginkel, et al., 2000). Emerging Infectious Diseases 6: 123-132; Sidwell and Smee (2000) Antiviral Res. 48: 1-16; Couch
(2000) New Engl. J. Med. 343: 1178-1787; Yewdell and Garcia-Sastre (2002) Curr. Opinion Microbiol. 5: 414-418; Prober (2002) Semin. Pediatr. Infect. Dis. 13: 31-39; Ellis and Zambón (2002) Rev. Med. Virol. 12: 375-389; Zambón
(2001) Rev. Med. Virol. 11: 227-241; Ulmer (2002) Vaccine 20 (Suppl 2): S74-S76; Tollis and Di Trani (2002) The Veterinary J. 164: 202-215). To prepare pharmaceutical or sterile compositions that include an agonist or antagonist of p19 or IL-23, the reagent is mixed with a pharmaceutically acceptable carrier or excipient. Formulations of therapeutic and diagnostic agents can be prepared through mixing with physiologically acceptable carriers, excipients or stabilizers, in the form of, for example, lyophilized powders, slurries, aqueous solutions, lotions, or suspensions (see, for 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 performance of the entity's jurisdiction or tissue, the level of symptoms, the immunogenicity of the entity, and the accessibility of the target cells in the matrix. biological Preferably, an administrator regimen maximizes the amount of therapeutic delivered to the patient consistent with an acceptable level of side effects. Therefore, the amount of biological distributed depends in part on the particular entity and the severity of the conditions being treated. Guidance and selection of the appropriate dose of antibodies, cytokines, and small molecules are 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) New Engl. 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) Immunol. 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, a cytokine, 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, Lippincott , 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%; 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, intraocular, infraocular, intra-arterial, intracerebroespinal, intra-lesional, or pulmonary routes. , 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, U.S. Patent Nos. 6,350,466 and 6,316,024).
V. Kits and Diagnostic Reagents Diagnostic methods for influenza, based on antibodies, nucleic acid hybridization and PCR method are described. Methods for testing and diagnosis related to viruses, including respiratory viruses and mucosal viruses such as influenza, include enzyme-based assays, such as influenza virus neuraminidase inhibitors, cell-based assays, for example, using kidney cells. of canine Madin Darby, and animal models, for example, animal models of ferret, mouse, and chicken, for influenza infection. This invention provides IL-23 polypeptides, fragments thereof, IL-23 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. Bonding compassions, including antibodies or antibody fragments, are also provided for the detection of IL-23, and metabolites and disruption products thereof. Typically, the kit will have a compartment containing either an IL-23 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) Trends 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-23 or IL-23 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 may 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-23 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 polypeptide of p19, p40, IL-23R, IL-12Rbetal, or a nucleic acid encoding pl9, p40, IL-23R, IL-12Rbetal. The segment may comprise 0, 1, 2, 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).
SAW. Uses The present invention provides methods using IL-23 agonists and antagonists, and the IL-23 receptor for the diagnosis, prevention, and treatment of mucosal viruses, respiratory viruses, viruses of the Orthomyxoviridae family, influenza viruses, viruses. of measles, rhinovirus, coronavirus, enterovirus, adenovirus, parainfluenza virus (PIV), respiratory syncytial virus (RSV), and herpes virus (see, for example, Mackie (2003) Paediatr. Respir. Rev. 4: 84-90 Wilson and von Itzstein (2003) Curr. Drug Targets 4: 389-408; Cox, et al. (2004) Scand., J. Immunol., 59: 1-15; Wiley, et al. (2001) J. Immunol 167 : 3293-3299; Ninomiya, et al. (2002) Vaccine 20: 3123-3129; Crowe and Williams (2003) Pediatric Respiratory Revs. 4: 112-119; O'Hagan (1998) J. Pharm. Pharmacol 50: 1-10). The mucosal regions of the body include, for example, the pulmonary, nasal, gastrointestinal, and urogenital mucosa. Viruses that result in mucosal infections include influenza virus, herpes, and immunodeficiency. Methods are provided for increasing the non-antigen-specific immunity and the specific immunity of the antigen to viruses, as well as methods for increasing the immune response to primary infections, secondary infections, and for the memory response, paraviruses such as influenza viruses. Methods for modulating the CD8 + T cell response, including CD8 + T cell mediated cytotoxicity, activation or proliferation of the CD8 + T cell, in response to a virus or a vital antigen, are also provided. 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 techniques are available for virus characterization, virus modification through genetic engineering, and treatment and diagnosis of viral infections (see, for example, Mahy and Kango (1996) Virology Methods Manual, Academic Press, San Diego, CA; Flint, et al. (2003) Principles of Virology: Molecular Biology, Pathogenesis, and Control of Animal Viruses, Am. Soc. Microbiol., Wash. D. C; Fields, et al. (Eds.) (2001) Virology, Lippincott, Williams, and Wiikins, NY, NY, Cann (2001) Principles of Molecular Virology, Academic Press, San Diego, CA, White and Fenner (1994) Medical Virology, 4th ed., Academic Press, San Diego, CA; Murphy, et al. (1999) Veterinary Virology, 3rd ed., Academic Press, San Diego, CA; Richman, et al. (Eds.) (2002) Clinical Virology, 2nd ed., Am. Soc. Microbiol., Wash. D. C). 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). Suitable fluorescent reagents are available for modifying nucleic acids, including nucleic acid primers and 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 immune 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 agents 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). Standard methods in 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; Wu (1993) Recombinant DNA, Vol. 217, Academic Press, San Diego, CA). Standard methods also appear in Ausbel, et al. (2001) Current Protocols in Molecular Biology, Vols. 1-4, John Wiley and Sons, Inc. New York, NY, which describe cloning in bacterial cells and DNA mutagenesis (volume 1), cloning in mammalian and yeast cells (volume 2), and the expression of glycoconjugates and protein (volume 3), and bioinformatics (volume 4). Methods for protein purification are described including immunoprecipitation, chromatography, electrophoresis, centrifugation and crystallization (Coligan, et al., (2000) Current Protocols in Protein Science, Vol. 1, John Wiley and Sons, Inc., New York). Clinical analysis, chemical modification, post-translational modification, production of fusion proteins, protein glycosylation are described (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 Protcols Immunology, Vol. 1, John Wiley and Sons, 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 the characterization of ligand / receptor interactions are available (see, for example, Coligan, et al (2001) Current Protcols in Immunology, Vol. 4, John Wiley, Inc., New York). Software packages and databases are available to determine, for example, antigenic fragments, leader sequences, protein folds, functional domains, glycosylation sites, and sequence alignments, (see, for example, GenBank, Vector NTI Suite (Informax, Inc., Bethesda, MD), GCG Wisconsin Package (Accelrys, Inc., San Diego, CA); DeCyphert) (TimeLogic Corp., Crystal 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. Primary Infection of p35KO Mice of Silvester Type and Mice p40KO Protocols are provided for cytotoxicity assays, intracellular IFNgamma assays, the treatment method to identify antigen-specific CD8 + T cells and for infected mice (see, for example, Leander, et al., (2002) Mechanisms Ageing Devel., 123: 1167-1181;
Halstead, et ai. (2002) Nature Immunol. 3: 536-541). The CD8 + T cells mediate the death of the virus-infected cell through the perfumer / granzyme mechanism or through Fas-mediated cytotoxicity. The 51Cr release assay (5 h) is sensitive only to the perfuran / granzyme mechanism (Belz, et al (2000) J. Virol. 74: 3486-3493). Studies with infection of mice with influenza viruses include the use of HKx31 (aka H3N2), which is a relatively light strain, and strain PR8, which is more virulent (Flynn, et al. (1998) Immunity 8: 683 -691; Belz, et al. (2000) J. Virol. 74: 3486-3493). The primary infection was induced through the intranasal administration of recombinant influenza virus X31. The infection was induced in wild type mice, p35KO mice (aka p35"/ _ mice), which are specifically deficient in IL-12, and p40KO mice (aka p40_ /" mice), which are both IL-12 deficient as of IL-23. Lungs were harvested at t = 10 days after inoculation. Total CD8 + T cells harvested from lungs, during primary infection, were increased in p35KO. No increase occurred in the p40KO mice (Table 1). Although an increase in p40KO mice was expected, due to lack of IL-12, this increase was prevented by p40KO, indicating that the additional lack of IL-23 prevents the expected increase in CD80 T cells. The present invention provides a 1L-12 antagonist to stimulate an increase in total CD8 + T cells (Table 1). An IL-23 antagonist is also provided to stimulate total CD8 + T cells (Table 1). In addition to the modulation of the total number of CD8 T cells, p35KO and p40KO had influence on the percentage or proportion of CD8 + T cells that were specific for the viral antigen. The proportion or percentage of antigen-specific CD8 + T cells was increased from about 7.0% in the wild type to approximately 11.5% with p35KO. The present invention provides an IL-12 antagonist, to stimulate an increase in the antigen-specific CD8 + T cell response (Table 1). No increase in antigen-specific CD8 + cell response occurred in p40KO, indicating that deficiency in IL-23 prevents the increase in antigen-specific CD8 + T cells, that is, it avoids the same kind of detected increment found with p35KO (Table 1). In this way, the invention provides an IL-23 agonist to increase the antigen-specific CD8 + T cell response (Table 1). Studies of IFNgamma expression provide the following results. The proportion of the antigen-specific CD8 + T cells producing IFNgamma was increased from about 9.0% in the wild type, to about 13.0% in p35KO. Thus, the present invention provides an IL-12 antagonist to increase the percentage of CD8 + T cells which is an antigen-specific CD8 + T cell. This increase did not occur with p40KO (Table 1). In this way, the present invention provides an IL-23 antagonist to increase the response of the antigen-specific CD8 + T cell that produces IFNgamma (Table 1).
TABLE 1 Number of CD8 * T cells and proportion of CD8 + T cells specific for viral antigen in cells harvested from lungs in primary infection
The production of IFNgamma was measured through intracellular staining. The cytotoxicity assays (chromium release) were performed in the proportion of performer: 50: 1 objective; 25: 1; 12.5: 1; and 6.25: 1. Table 1 describes the results of cytotoxicity in the proportion of 50: 1.
The ex vivo cytotoxicity assays, at performer / target ratios of 50: 1, 25: 1, 12.5: 1, all demonstrated lower cytotoxicity using wild-type cells; intermediate cytotoxicity using cells from p35KO mice, and increased cytotoxicity using p40KO cells. The results of the tests are shown at a ratio of 50: 1 (Table 1). The present invention provides an IL-12 antagonist, an IL-23 antagonist to increase antigen-specific cytotoxicity, or the combination of an IL-12 antagonist and an IL-23 antagonist, to increase the cytotoxicity of the CD8 + T cell antigen-specific (Table 1).
lll. Secondary Infection of Wild-type Mice,
P35KO mice, v p40KO mice Secondary influenza A virus infection was studied in wild type p35KO mice and p40KO mice. The protocol for secondary infection involved activation with the intraperitoneal PR8 strain of influenza virus at t = day 0, with a re-attack at t = day 30 with strain X31 of the influenza virus. Tissues were harvested at t = day 35, ie, after 5 days of exposure to the X31 virus (Table 2). The total number of CD8 + T cells was increased in lungs of p35KO mice, relative to the numbers found in wild-type mice, while this relative increase does not appear to occur in p40KO mice. Some enrichment was found in antigen-specific CD8 + T cells in the lungs of both p35KO and p40KO mice (Table 2).
TABLE 2 Secondary infection of wild type mice. Mice p35KO, and Mice p40KO
IV. Administration of IL-23 during Primary Infection and
Secondary Infection IL-23 or IL-12 (i.p.) was administered at intervals to the mice, as described below. In the primary infection tests, the cytokine was administered starting at the time of intranasal inoculation (Table 3). In the secondary infection tests, the cytokine was administered at the start of the re-attack (Table 4). In the memory response tests, the cytokine was administered at the start at the time of initial activation, but here the cytokine was not administered at the time of re-attack (Table 5). The additional methodological details were as follows. For primary infection, mice were infected intransally (i.n.) with strain X31 of influenza A virus and treated with 20 mmole (i.p.) of either IL-23 every other day or with IL-12 every alternate day. The cytokine treatment was on days 0, 2, 4, 6, and 8. Lungs were harvested on day 10 for use in the analysis of the immune response, for example, tests of the amount and cytotoxicity of CD8 + T cells , (Table 3). For secondary infection, the mice were activated (i.p.) with the PR8 strain of influenza A virus (day 0). On day 30 the mice were attacked intranasally (i.n.) with strain X31 of the influenza virus and treated with either 20 mmol of either IL-23 (i.p.) or IL-12 (i.p.) each alternate day. The cytokine treatment was on days 30, 32 and 34. The lungs were harvested on day 35 for the analysis of the immune response (Table 4). For memory response tests, the mice were activated with the PR8 strain of influenza virus (ip) and treated with mmoles of either IL-23 (ip) or IL-12 (ip) every alternate day until the day 8. Treatment with cytokine was on days 9, 2, 4, 6 and 8. The mice were then again attacked with strain X31 of the influenza (in) virus. Lungs were harvested on day 35 for use in the analysis of the immune response (Table 5). The administration of the cytokine during the primary response to influenza infection provided the following results. In tests of total CD8 + T cell number, the total number of CD8 + T cells were approximately equal for untreated mice, and for mice treated with IL-23, while the total number of CD8 + T cells was increased in mice treated with IL-12 (Table 3). The proportion of CD8 + T cells that were specific for viral antigen was decreased in mice treated with IL-23 (Table 3). In the CD8 + T cell assays, which produce antigen-specific IFNgamma, the results also demonstrated that the administration of IL-23 decreased the proportion of antigen-specific CD8 + T cells (Table 3). The present invention provides an IL-23 agonist to decrease the proportion of antigen-specific CD8 + T cells, and an IL-23 antagonist to increase the proportion of antigen-specific CD8 + T cells, for example, during primary infection ( 3). The results of the cytotoxicity test were as follows. In studies of primary infection the administration of IL-23 decreased the viral antigen specific cytotoxicity mediated by CD80 T cells. The present invention provides an IL-23 agonist to decrease the specific cytotoxicity of viral antigen mediated by CD80 T cells. an IL-23 antagonist is provided to stimulate or increase the viral antigen-specific cytotoxicity mediated by CD8 + T cells (Table 3). The levels of IFNgamma in the serum were also measured.
During the course of primary infection, administration of IL-12, but not-of IL-23, increased the IFNgamma in serum from infected mice, as determined by ELISA assays. On days 1, 3, and 5 after infection, the IFNgamma in serum in mice treated with IL-12 was approximately 100, 570, and 130 pg / ml, respectively. The levels of IFNgamma in the serum of mice treated with no cytokine and with IL-23 were below 50 pg / ml within the time frame studied. Secondary infection response tests only led to total CD8 + T cells, the proportion of CD8 + T cells that were specific for viral antigen, and cytotoxicity assays (Table 4). In number of CD8 + T cells decreased with the IL-23 treatment, in relation to the number of mice not treated with cytokine, where a greater increase in the total number of CD8 + T cells, occurred with the treatment of IL-12. The present invention provides a method for using an IL-23 agonist, IL-12 agonist, or agonist of both IL-23 and IL-12, to decrease the total number of CD8 + cells, during secondary infection. A method is also provided for using an IL-23 antagonist, IL-12 antagonist, or antagonists of both IL-23 and IL-12, to increase the total number of CD8 + T cells, during secondary infection (Table 4 ). The administration of IL-23 or IL-12 has little influence on the proportion of the total number of CD8 + T cells that was specific for the viral antigen, while the administration of IL-23 or IL-12 tended to reduce the proportion of cells T CD8 + that were CD8 + T cells products of IFNgamma-specific antigen (Table 4). Cytokine treatment during secondary infection caused changes in cytotoxicity. The administration of IL-12 resulted in a decrease in cytotoxicity, relative to that found in the mice that received no cytokine, while administration of IL-12 resulted in a greater decrease in cytotoxicity (Table 4). The present invention provides methods for administering the IL-23 agonist, or the IL-23 agonist, with the IL-12 agonist, to decrease the cytotoxicity of the antigen-specific CD8 + T cells. Methods are also provided for administering an IL-23 antagonist, or an IL-23 antagonist, with an IL-12 antagonist, to decrease the cytotoxicity of antigen-specific CD8 + T cells. IFNgamma in serum was approximately 1000 pg / ml in serum, as determined on the day of harvest of mice treated with IL-12, during secondary infection. IFNgamma in serum was not detected in mice not treated with cytokine, or treated with IL-23, during secondary infection. The memory response study involved cytokine treatment for several days after initial activation, but with no cytokine treatment at the time of re-attack (Table 5). IL-23 caused an increase in the total number of CD8 + T cells, where this increase included an increase in the total number of antigen-specific CD8 + T cells and an increase in the total number of antigen-specific CD8 + T cells that produce IFN gamma. , while the treatment of IL-12 caused an even greater increase in the total number of CD80 T cells As measured in percentage of CD8 + T cells, which produce antigen-specific IFNgamma, there was a slight increase in this percentage with the treatment of IL- 23, and a greater increase with the treatment of IL-12 (Table 5). The present invention contemplates methods for modulating the memory response to viral infections, for example, through the administration of an IL-23 agonist or antagonist or antagonist. A method is provided for using an IL-23 agonist or the combination of an IL-23 agonist and an IL-12 agonist, to increase the memory response, for example, as determined through the proportion of specific CD8 + T cells of antigen or the proportion of antigen-specific CD8 + T cells that are positive IFNgamma.
TABLE 3 Primary response without treatment, treatment with IL-23, or treatment with IL-12
The data reflects measurements of lung T cells. The determination of INFgamma was with intracellular staining. The cytotoxicity assays (chromium release) were performed in the proportions of performer. 50: 1 objective; 25.1: 1, 12.5: 1; and 6.25: 1. Table 1 describes the results of cytotoxicity in the proportion of 50: 1
TABLE 4 Secondary response (memory response) without treatment, treatment with IL-23, or treatment with IL-12
The data reflects measurements of lung T cells. The determination of INFgamma was with intracellular staining. The cytotoxicity assays (chromium release) were performed in the proportions of executed target of 50: 1; 25.1: 1, 12.5: 1; and 6.25: 1. Table 1 describes the results of cytotoxicity in the proportion of 50: 1
TABLE 5 Memory response without treatment, treatment with IL-23, or treatment with IL-12
The data reflects measurements of lung T cells. The determination of INFgamma was with intracellular staining. The SD means were not determined. The cytotoxicity assays (chromium release) were performed in the proportions of executed target of 50: 1; 25.1: 1, 12.5: 1; Y
6. 25: 1. Table 1 describes the results of cytotoxicity in the proportion of 50: 1
All citations herein are incorporated herein by reference to the same extent as if each individual publication, patent application, or patent was specifically and individually indicated as being incorporated by reference. Many modifications and variations of this invention, as will be apparent to one skilled in the art can be made to adapt a particular situation, material, composition of matter, procedure, step or procedural steps, to preserve the purpose, spirit and scope of the invention. invention. All said modifications are intended to be within the scope of the appended claims therein 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 not be limited by the terms of the appended claims, together with the full scope of the equivalents to which the claims are entitled; and the invention will not be limited by the specific embodiments that have been presented here by way of example.
Claims (19)
1. - The use of a) an agonist of p19, IL-23, or IL-23R; or b) an antagonist of p19, IL-23, or IL-23R for the manufacture of a medicament for modulating the response of the CD8 + T cell to a virus, viral antigen, or viral infection in a mammal.
2. The use claimed in claim 1, wherein the antagonist comprises: a) a binding composition of an antibody that specifically binds p19, IL-23, or IL-23R; b) a soluble receptor derived from IL-23R that specifically binds to IL-23; c) a nucleic acid that specifically hybridizes a polypeptide encoding p19 or IL-23R; or d) a small molecule.
3. The use claimed in claim 2, wherein the binding composition derived from an antibody comprises: a) a polyclonal antibody; b) a monoclonal antibody; c) a humanized antibody, 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.
4. The use claimed in claim 2, wherein the nucleic acid comprises: a) an antisense nucleic acid; or b) a low interference RNA (siRNA).
5. The use claimed in claim 1, wherein a) an agonist of p35, IL-12, p40, IL-12Rβ1, or IL-12Rβ2; or b) an antagonist of p35, IL-12, p40, IL-12Rβ1, or IL-12β2 is co-administrable further to the mammal.
6. The use claimed in claim 1, wherein the p19, IL-23, or IL-23R agonist decreases: a) the percentage of T cells CD8 + which are CD8 + T cells specific for viral antigen; b) the percentage of CD8 + T cells that are CD8 + T cells specific for viral antigens that produce IFNα; or c) cytotoxicity of CD8 + T cells specific for viral antigen.
7. The use claimed in claim 1, wherein the antagonists of p19, IL-23, or IL-23R, increase: a) the percentage of cells CD8 + T which are antigen-specific CD8 + T cells; b) the percentage of CD8 + T cells that are CD8 + T cells specific for viral antigen that produce IFNgamma; or c) the cytotoxicity of vital antigen-specific CD8 + T cells.
8. The use claimed in claim 1, wherein the antagonist of p19, IL-23, or IL-23R increases the total number of CD8 + T cells during the immune response to a secondary viral infection.
9. The use claimed in claim 8, wherein the total number of CD8 + T cells is: a) a lung; b) a bronchoalveolar lavage (BAL); c) a spleen; or, d) a lymph node.
10. The use claimed in claim 8, wherein an antagonist of p35, IL-12, IL-12Rbeta2, or p40 is additionally co-administrable.
11. The use claimed in claim 1, wherein the virus is: a) a respiratory virus; b) a mucosal virus; or c) an influenza virus.
12. The use claimed in claim 11, wherein the influenza virus is: a) an influenza A virus; b) an influenza B virus; or c) an influenza C virus.
13. The use claimed in claim 1, wherein the viral antigen comprises an influenza virus antigen.
14. The use claimed in claim 13, wherein the influenza virus antigen is: a) a viral nucleoprotein; b) a viral acid polymerase.
15. The use claimed in claim 1, wherein the viral infection comprises: a) a respiratory syndrome; or b) pneumonia.
16. The use claimed in claim 1, further comprising the administration of: a) a vaccine; or b) an adjuvant.
17. The use of the agonist or antagonist of claim 1 for the manufacture of a medicament for treating an influenza A virus infection.
18. A method for diagnosing a viral infection comprising contacting a binding composition with a virus. biological sample wherein the binding composition specifically binds to: a) p19, IL-23, or IL-23R; or, b) a nucleic acid encoding p19 or IL-23R; and measuring or determining the specific binding of the binding composition to the biological sample
19. A kit for diagnosing a viral infection comprising a compartment and a binding composition that specifically binds to: a) p19, IL-23, or IL-23R; or, b) a nucleic acid encoding p19 or IL-23R.
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US60/545,708 | 2004-02-17 |
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