MX2008004815A

MX2008004815A - Methods and compositions for use in treatment of patients with autoantibody positive diseases

Info

Publication number: MX2008004815A
Application number: MXMX/A/2008/004815A
Authority: MX
Inventors: Marc Chevrier; William Friemuth; Zhenshao Zhong; Daniel Odenheimer; Melissa D Perkins
Original assignee: Human Genome Sciences Inc
Priority date: 2005-10-13
Filing date: 2008-04-11
Publication date: 2008-09-02

Abstract

The present invention relates to methods and compositions for use in treatment of patients with autoantibody positive disease. In a specific embodiment, the present invention relates to a method of treating a patient that has an ANA titer of 1:80 or greater and/or greater than or equal to 30 IU/ml of anti-dsDNA antibodies in his/her blood plasma or serum comprising administering a therapeutically effective amount of an immunomodulatory agent, such as an antagonist of Neutrokine-alpha. Additionally provided is a method of reducing the frequency and/or quantity of corticosteroid administration to patients. In preferred embodiments, the patient has systemic lupus erythematosus. Methods for determining if a lupus patient is responding to medical treatment are also provided.

Description

METHODS AND COMPOSITIONS FOR USE IN THE TREATMENT OF PATIENTS WITH POSITIVE AUTOANTIBODY DISEASES BACKGROUND OF THE INVENTION The neutrokine-alpha protein (SEQ ID NO: 2) is a member of the TNF ligand family that shares amino acid sequence identity with APRIL (28.7%, SEQ ID NO: 4), TNFa (16.2%) and lymphotoxin a ( LTa) (14.1%) (Moore et al. (1999), Science 285: 260-263). Neutrocin-alpha is known in the scientific and patent literature with many names, including B lymphocyte stimulator (BLyS), B cell activating factor (BAFF), ligand 1 expressed in leukocyte related to TNF, and ApoL (TALL- 1) (Moore et al. (1999), Science 285: 260-263; Shneider et al. (1999), J. Exp. Med 189: 1747-1756; and Khare et al. (2000), Proc. Nati. Acad. Sci. 97: 3370-3375). The official nomenclature for neutrocin-alpha is member 13B of the tumor necrosis factor (ligand) superfamily (TNFSF13b). The full-length neutrokine-alpha gene encodes a 285 amino acid polypeptide having a transmembrane domain between amino acids 47 and 73, preceded by a non-hydrophobic sequence characteristic of type II membrane-bound proteins. Like other members of the TNF family, neutrocin-alpha functions as a trimeric protein. Upon expression of neutrocin-alpha on the surface of the cell, the extracellular domain is cut at amino acid 134 to release a biologically active trimer. It is known that neutrocin-alpha binds to 3 different receptors of the tumor necrosis factor receptor superfamily. These are the transmembrane activator and the CAML interactor (TACI, GenBank registration number AAC51790, SEQ ID NO: 6), B cell activating factor receptor, B cell maturation antigen (BCMA, Registration No. from GenBank NP_001183 SEQ ID NO: 8) and (BAFF-R, GenBank Registration No. NP_443177 SEQ ID NO: 10) (Gross et al. (2000), Nature 404: 995-999; Thompson et al. (2001), Science 293: 2108-2111; and Yan et al. (2000), Nature Immunol., 1: 252-256). Expression of receptors is mainly restricted to B lymphocytes (Moore et al. (1999), Science 285: 260-263). It is believed that most of the effects of neutrocin-alpha are mediated by BAFF-R due to marked defects in the B cell compartments of the mice deficient in the expression of neutrocine-alpha or the expression of BAFF-R, which they are not evident in mice deficient in TACI or BCMA (Schieman et al. (2001), Science 292: 2111.2114; Gross et al. (2001) Immunity 15: 289-302; and Yan et al. (2000), Nature Immunol 1: 252- 256). When neutral-alpha protein was analyzed in vitro and in vivo, it was shown that neutrocin-alpha promotes the proliferation, differentiation and survival of B cells. Additionally, it was shown that neutrocin-alpha also has some effect on cells T (MacKay et al. (1999), J. Exp. Med. 190: 1697-1710; Huard et al. (2001), J. Immunol., 167: 6225-6231; Huard et al. (2004), Int. Immunol. 16: 467-475; Ng et al. (2004), J. Immunol. 173: 807-817). Mice that were genetically modified to genetically overexpress the neutroclin-alpha had an increase in the number of peripheral B cells and an increase in the concentration of immunoglobulin in the serum. Additionally, the transgenic mice in neutrocin-alpha presented an autoimmune phenotype similar to that observed in human systemic lupus erythematosus, including the development of autoantibodies and symptoms associated with glomerulonephritis (Moore et al. (1999), Science 285: 260-263; MacKay et al. others (1999), J. Exp Med. 192: 129-135). Subsequent studies showed that concentrations of neutrocine-alpha in the serum or synovial fluid were also positively regulated in patients with autoimmune diseases such as lupus erythematosus sistémico, rheumatoid arthritis and Sjögren's syndrome (Cheema et al. (2001), Arthritis Rheum. 1313-1319; Groom et al. (2002), J. Clin. Invest. 109: 59-68; Mariette et al. (2003), Ann. Rheum. Dis 62: 168-171). Accordingly, there is a widespread belief in the scientific community that neutrokine-alpha antagonists have a therapeutic potential in the treatment of autoimmune diseases. Systemic lupus erythematosus (SLE or "lupus") is an autoimmune disease whose symptoms are very heterogeneous. The current standard for diagnosing SLE in a patient contains 11 criteria: 1) "butterfly" malar rash, 2) discoid rash, 3) photosensitivity, 4) oral ulcers, 5) arthritis, 6) serositis, 7) kidney disorder, 8 ) neurological disorder, 9) hematological disorder, 10) immune disorder, and 11) presence of anti-nuclear antibody. These criteria are explained in more detail in Tan et al. (1982), Arthritis Rheum. 25: 1271-1277; and Hochberg et al., Arthritis Rheum. (1997) 40: 1725, which are incorporated herein by reference in their entirety. A person who has any 4 of these eleven criteria can be diagnosed with SLE. Therefore, people who have a clinical diagnosis of SLE may have non-overlapping symptoms. In addition, many of the symptoms of lupus overlap with symptoms of other diseases. For example, rheumatoid arthritis, polymyositis-dermatomyositis, systemic sclerosis (or scleroderma), Sjogren's syndrome, and various forms of vasculitis share symptoms with lupus, including one or more of the following characteristics: the presence of autoantibodies , which include anti-nuclear antibodies and anti-dsDNA antibodies, pain and swelling of joints and skin rash, and organ involvement. Thus, in practice, it is often difficult to correctly diagnose patients with lupus and patients with another similar disease. Additional factors that hinder the diagnosis of lupus disease include the fact that the disease does not develop rapidly; rather, patients gradually accumulate symptoms over time. Additionally, SLE is a disease with variable activity in a patient. Sometimes the disease is inactive, while other times patients experience an increase in the number or severity of their symptoms, in an episode of "attack". Finally, there is no laboratory test that definitively diagnoses lupus. Therefore, there is a need to be able to define subgroups of lupus patients with particular symptoms and to make correlations between the subgroups of patients and the treatments most likely to benefit the patients of those subgroups. The present application identifies particular subgroups of patients with autoimmune disease who are more likely to benefit from treatment with immunomodulatory agents.

BRIEF DESCRIPTION OF THE INVENTION In a phase 2 clinical trial, it was found that the treatment of lupus patients with an antibody neutralizing the neutrocyan-alpha protein, administered as an iv infusion on days 0, 14 and 28, and then every 4 weeks up to week 52 , significantly relieved the symptoms associated with lupus in the subgroup of patients having an ANA titre of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies in their plasma or blood serum (see example 1 ). Surprisingly, only statistically significant improvements were obtained in clinical endpoints that measure the activity of the disease (such as the reduction of the SELENA SLEDAI score, which is explained below in greater detail), in a subgroup of patients, unlike any other the population of patients enrolled in the clinical trial. In this way, the present invention relates to the identification of subgroups of patients most likely to respond to treatment with an immunomodulatory agent, such as a neutrokine-alpha antagonist. Accordingly, in one embodiment, the present invention provides a method of treating a patient having an ANA titer of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies in his / her plasma or blood serum, which comprises administering a therapeutically effective amount of an immunomodulatory agent. The immunomodulatory agents are described in more detail below. In a specific embodiment, the immunomodulatory agent is a neutrocin-alpha antagonist, which includes without limitation an anti-neutrocin-alpha antibody or antigen-binding fragment thereof, a neutrocin-alpha receptor protein or a fragment or variant of the same, an antibody that binds to the neutrokine-alpha receptor, or an antigen-binding fragment thereof, a neutrokine-alpha binding peptide or polypeptide, a neutrokine-alpha or APRIL polypeptide variant (e.g. dominant negative of neutrocin-alpha or APRIL). Additional neutrokine-alpha antagonists include neutrokine-alpha small molecule antagonists, neutrokine-alpha peptidomimetics, antisense RNAs and short interfering RNAs (RNAci's) directed to neutrocine-alpha, antisense RNAs and short interfering RNAs (RNAi's) directed to APRIL, antisense RNAs and short interfering RNAs (RNAci's) directed to receptors for neutrocine-alpha or receptors for APRIL. Neutrocin-alpha receptors include, for example, transmembrane activator and CAML interactor (TACI, No.

GenBank registry record AAC51790, SEQ ID NO: 6), T cell activating factor receptor, B cell maturation antigen (BCMA, GenBank registration No. NP_001183 SEQ ID NO: 8) and BAFF-R (No. of GenBank registration NP_443177 SEQ ID NO: 10). In another embodiment, the present invention provides a method of treating a patient with an autoimmune disease having an ANA titer of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies in his plasma or blood serum , which comprises administering a therapeutically effective amount of an immunomodulatory agent. Examples of autoimmune disease in which patients with an ANA titre of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies in their serum or blood plasma can be identified, include, without limitation, lupus erythematosus systemic (SLE), rheumatoid arthritis, Sjögren's syndrome, scleroderma, poliomisitis-dermatomyositis, Felty's syndrome, mixed connective tissue disease, Raynaud's syndrome, juvenile chronic arthritis, glomerulonephritis, idiopathic thrombocytopenic purpura, and IgA nephropathy. In a specific embodiment, the invention provides a method of treating a patient with Sjögren's syndrome who has an ANA titer of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies in his plasma or blood serum , which comprises administering a therapeutically effective amount of an immunomodulatory agent. In another specific modality, the invention provides a method of treating a patient with Sjogren's syndrome, having an ANA titer of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies in his plasma or blood serum, comprising administering a therapeutically effective amount of a neutral-alpha antagonist. In a specific embodiment, the invention provides a method of treating a patient with rheumatoid arthritis having an ANA titer of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies in his plasma or blood serum, which comprises administering a therapeutically effective amount of an immunomodulatory agent. In another specific embodiment, the invention provides a method of treating a patient with rheumatoid arthritis having an ANA titer of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies in his plasma or blood serum, which comprises administering a therapeutically effective amount of a neutral-alpha antagonist. In a specific embodiment, the invention provides a method of treating a patient with systemic lupus erythematosus (SLE) that has an ANA titer of 1: 80 or greater, or 30 UI / mL or more of anti-dsDNA antibodies in its plasma or blood serum, which comprises administering a therapeutically effective amount of an immunomodulatory agent. In another specific embodiment, the invention provides a method of treating a patient with systemic lupus erythematosus (SLE) who has an ANA titer of 1: 80 or greater, or 30 UI / mL or more of anti-dsDNA antibodies in his plasma or blood serum, which comprises administering a therapeutically effective amount of a neutral-alpha antagonist. In a specific modality, the lupus patient has a clinical diagnosis of SLE according to the criteria of the American College of Rheumatology (ACR) (see, for example, Tan et al., Arthritis Rheum 25: 1271-7, (1982)).; and Hochberg et al., Arthritis Rheum. 40: 1725, (1997), which are incorporated herein by reference in their entirety. The present invention also provides a method of treating a patient, comprising making a determination, prior to the administration of an immunomodulatory agent, to see if that patient has an ANA titre of 1: 80 or greater, or 30 IU / mL. or more anti-dsDNA antibodies in your plasma or blood serum. The present invention also provides a method of treating a patient, comprising making a determination, prior to the administration of a neutral-alpha antagonist, to see if the patient has an ANA titre of 1: 80 or greater, or IU / mL or more of anti-dsDNA antibodies in your plasma or blood serum. In other embodiments, the invention provides a method of treating a lupus patient, comprising making a determination, prior to the administration of an immunomodulatory agent, to see if the lupus patient has one or more of the following characteristics: a diagnosis clinical trial of SLE according to the criteria of the American College of Rheumatology (ACR) (see, for example, Tan et al., Arthritis Rheum, 25: 1271-7, (1982); and Hochberg et al., Arthritis Rheum. 40: 1725 (1997)); a SELENA SLEDAI score > 6; low values of complement C4 in its plasma or blood serum; low values of complement C3 in its plasma or blood serum; an ANA title of 1: 80 or higher; 30 IU / ml or more of anti-dsDNA antibodies in your plasma or blood serum; is receiving = 7.5 milligrams / day of prednisone or another corticosteroid for the treatment of symptoms related to lupus; or you are receiving or have previously received immunosuppressive therapy for the treatment of symptoms related to lupus. In a specific modality, the determination is made by a doctor based on an evaluation of the patient's medical history. In another specific modality, the determination is made by a doctor based on the results of laboratory tests obtained since the patient's last medical treatment (including medical treatment with immunomodulatory agents) for lupus, if any, and before beginning medical treatment, which comprises administering a therapeutically effective amount of an immunomodulatory agent (including a neutrokine-alpha antagonist) as described herein. In another embodiment, the present invention provides a method for reducing the frequency or amount of corticosteroid administered to a patient having an ANA titre of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies in its plasma or blood serum, which comprises administering a therapeutically effective amount of an immunomodulatory agent. In a specific embodiment, the invention provides a method for reducing the frequency or amount of corticosteroid administered to a patient with Sjögren's syndrome who has an ANA titre of 1: 80 or greater, or 30 IU / mL or more of anti-anti-HIV antibody. CDNA in its plasma or blood serum, which comprises administering a therapeutically effective amount of an immunomodulatory agent. In another specific embodiment, the invention provides a method for reducing the frequency or amount of corticosteroid administered to a patient with Sjögren's syndrome who has an ANA titre of 1: 80 or greater, or 30 IU / mL or more of anti-inflammatory antibodies. CDNA in its plasma or blood serum, which comprises administering a therapeutically effective amount of a neutral-alpha antagonist. In a specific embodiment, the invention provides a method for reducing the frequency or amount of corticosteroid administered to a patient with rheumatoid arthritis having an ANA titre of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies. in its plasma or blood serum, which comprises administering a therapeutically effective amount of an immunomodulatory agent. In another specific embodiment, the invention provides a method for reducing the frequency or amount of corticosteroid administered to a patient with rheumatoid arthritis who has an ANA titer of 1: 80 or greater., or 30 IU / mL or more of anti-dsDNA antibodies in your plasma or blood serum, which comprises administering a therapeutically effective amount of a neutral-alpha antagonist. In a specific embodiment, the invention provides a method for reducing the frequency or amount of corticosteroid administered to a patient with systemic lupus erythematosus (SLE) having an ANA titre of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies in their plasma or blood serum, which comprises administering a therapeutically effective amount of an immunomodulatory agent. In another specific embodiment, the invention provides a method for reducing the frequency or amount of corticosteroid administered to a patient with systemic lupus erythematosus (SLE) having an ANA titre of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies in its plasma or blood serum, which comprises administering a therapeutically effective amount of a neutral-alpha antagonist. In a specific modality, the lupus patient will have a clinical diagnosis of SLE according to the criteria of the American College of Rheumatology (ACR) (see, for example, Tan and others, Arthritis Rheum, 25: 1271-7, (1982)).; and Hochberg et al., Arthritis Rheum. 40: 1725, (1997), which are hereby incorporated by reference in their entirety. In a further embodiment, the invention provides a method for reducing the amount of corticosteroid administered to a patient having an ANA titre of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies in his plasma or serum blood, in at least 25% a = 7.5 milligrams / day. In a specific embodiment, the corticosteroid is selected from the group consisting of prednisone, prednisolone, hydrocortisone, methylprednisolone and dexamethasone. In a specific additional modality, the corticosteroid is prednisone. In another embodiment, a method is provided for reducing the frequency or amount of corticosteroid administered to a patient with an autoimmune disease, which comprises administering a therapeutically effective amount of an anti-neutrocin-alpha antibody.

In another phase 2 clinical trial (example 3) in which rheumatoid arthritis patients were treated with an antibody that neutralizes the neutrophil-alpha protein, administered as an iv infusion on days 0, 14, 28 and then every 4 weeks until week 24, treatment was more likely to improve symptoms associated with rheumatoid arthritis in patients who had a DAS28 score greater than 5.1, patients who had previously received no TNF therapy, or patients who had rheumatoid factor in their plasma or blood serum before starting treatment with the neutralizing antibody to the neutrocyan-alpha protein. Additional subgroups of rheumatoid arthritis patients that appeared to respond more to treatment with the antibody neutralizing the neutrophil-alpha protein, included male patients, patients who had anti-CCP antibodies (citric cyclic peptide) in their plasma or blood serum, patients who received methotrexate concomitantly with the antibody neutralizing the neutrophil-alpha protein, patients who had previously not responded to treatment with methotrexate, or patients who previously had not responded to methotrexate therapy and at least one other DMARD therapy. In another embodiment, the invention provides a method for determining whether a lupus patient is responding to medical treatment, which comprises determining the patient's SELENA SLEDAI, BILAG and PGA score before administering medical treatment; administer medical treatment; and determine the score of SELENA SLEDAI, BILAG and PGA of the patient after the administration of the medical treatment. In this method, the patient will be considered to respond to treatment if: the SELENA SLEDAI score of the patient determined after the administration of the medical treatment is 4 points or more lower than the SELENA SLEDAI score before the administration of the medical treatment; the patient's BILAG index score determined after the medical treatment administration does not include a new BILAG A organ domain score, nor does it include 2 new BILAG B organ domain scores, compared to the BILAG score determined before the administration of the medical treatment, and the PGA score determined after the administration of the medical treatment is < 0.3 points higher than the PGA score determined before the administration of medical treatment. Accordingly, in one embodiment, the invention provides a method of treating a rheumatoid arthritis patient, comprising making a determination, prior to the administration of an immunomodulatory agent, to see the rheumatoid arthritis patient having one or more of the following characteristics: the patient has not previously received anti-TNF therapy, for example Infliximab (also known as Remicade ™ Centocor, Inc.), adalimumab (Humira® from Abbott Laboratories) or etanercept (Enbrel®); the patient has the rheumatoid factor in their plasma or blood serum; the patient has measurable anti-CCP (cyclic peptide) antibodies in their plasma or blood serum; the patient has a high concentration of CRP (reactive protein C) in his plasma or blood serum; the patient has not previously responded to treatment with one or more disease-modifying antirheumatic drugs; the patient has a high score of modified disease activity (DAS28); the patient has swollen and painful joints; the patient suffers from morning stiffness; the patient has an increase in the rate of erythrocyte sedimentation (ESR), or the patient is male. In another embodiment, the invention provides an aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody, a buffer in an amount of about 5 mM to about 50 mM, NaCl in an amount of about 150 nM to about 500 nM., a surfactant in an amount of about 0.003% to about 0.05%, with a pH of about 5.5 to about 6.5. In a specific embodiment, the antibody in the formulation described above is an antibody having an IgG1 / lambda isotype. In a further embodiment, the antibody in the above-described formulation is a human antibody having a lgG1 / lambda isotype, the buffer of the formulation described above is histidine or 10 mM sodium citrate, the surfactant in the above-described formulation is polysorbate 80 in an amount of 0.01% w / v, the NaCl in the above-described formulation is present at a concentration of approximately 150 mM, and the formulation has a pH of 6.0. In other specific embodiments, the formulations described above are stable at a temperature of about 2 to 8 ° C for at least one year. In another embodiment, the antibody of the above-described formulation is present in an amount of 100 mg / ml. In a specific embodiment, the invention provides an aqueous pharmaceutical formulation comprising 10 mg / ml of IgG1 /? Antibody, 0.74 mg / ml of L-histidine, 1.1 mg / ml of L-histidine monohydrochloride, 8.8 mg / ml of NaCl and 0.1 mg / ml polysorbate 80, and wherein the formulation has a pH of 6.0.

BRIEF DESCRIPTION OF THE FIGURES The following figures are illustrative of the embodiments of the invention and do not limit the scope of the invention encompassed by the claims. Figure 1 shows the decrease in average percentage of SELENA SLEDAI week 52 in patients who have an ANA titre of 1: 80 or higher, or 30 IU / mL or more of anti-dsDNA antibodies as a reference value. The P values were determined using a t test.

Definitions In one aspect, the present invention is broadly directed to methods of treating a patient with a positive autoantibody disease by administering a therapeutically effective amount of an immunomodulatory agent. A patient with positive autoantibody disease is a patient who has detectable autoantibody titers in one or more samples of biological fluid, such as plasma or blood serum, or synovial fluid. Herein, reference to "an immunomodulatory agent" refers to the general class of pharmaceutical compounds that can stimulate or inhibit the immune system. The working examples herein describe the successful use of an anti-neutrocin-alpha antagonist antibody in the treatment of a subset of lupus patients. Thus, the term "immunomodulatory agent" is specifically intended to cover pharmaceutical compounds or molecules that can act as an antagonist of neutrocin-alpha. Antagonists of neutrocin-alpha include, without limitation, compositions comprising an anti-neutrocin-alpha antibody or antigen-binding fragments thereof, neutrocin-alpha receptor proteins or fragments or variants thereof, an antibody that is binds to a neutrokine-alpha receptor, or an antigen-binding fragment thereof, and neutrokine-alpha binding peptide or polypeptides. Neutrocin-alpha receptors include, for example, transmembrane activator and CAML-operator (TACI, GenBank registration number AAC51790), BAFF-R (GenBank registration number NP_443177), and B-cell maturation antigen. (BCMA, GenBank Registration No. NP_001183). Particularly useful forms of the neutrokine-alpha receptors include soluble forms of the extracellular domains. The neutrokine-alpha receptors or fragments or variants thereof, and the neutrokine-alpha binding polypeptides, can be used as fusion proteins, for example, Fe fusion proteins or human serum albumin (HSA). Other neutrokine-alpha antagonists include the neutrokine-alpha small molecule antagonists, neutrokine-alpha peptidomimetics, neutrokine-alpha polypeptide variants or APRIL (e.g., neutral dominant forms of neutrokine-alpha or APRIL). Such neutrokine-alpha or APRIL polypeptide variants can antagonize the function of neutrokine-alpha, for example by intervening in the homo- or hetero-multimerization of neutrokine-alpha or APRIL. Alternatively, the neutrokine-alpha or APRIL polypeptide variants will prevent the polypeptides comprising them from binding or signaling through the neutrokine alpha receptors, such as TACI, BCMA and BAFF-R. Additional neutrokine-alpha antagonists include neutrokine-alpha small molecule antagonists, neutrokine-alpha peptidomimetics, antisense RNAs and short interfering RNAs (RNAci's) targeting neutrocin-alpha, antisense RNAs and short interfering RNAs (RNAi's) directed to APRIL, antisense RNAs and short interfering RNAs (RNAci's) directed to receptors for neutrocin-alpha or to receptors for APRIL. The neutrokine-alpha antagonists are described below in greater detail. It is believed that the anti-neutrocin-alpha antibody works by reducing the number of B cells or the activity of B cells, such as the secretion of immunoglobulin. In this way, the term "immunomodulatory agent" is also specifically intended to cover B cell modulating agents., and in particular molecules and pharmaceutical compounds that directly or indirectly inhibit or reduce the activity of B cells (for example the proliferation, differentiation, survival or secretion of immunoglobulin from B cells), or the number of B cells. specifically, the B-cell modulating agent that can be used in conjunction with the methods of the present invention is an agent that reduces the activity or the total number of B cells, activated B cells, intact B cells, memory B cells, cells B plasma, and plasmacytoid B cells, CD19 + B cells, or CD20 + B cells. The immune system is a complex network of interacting cells and cytokines. For example, antigen-presenting cells (APC's, such as macrophages and dendritic cells) and T cells, specifically T (CD4 +) helper cells, have a role in the activation of B cells to proliferate and secrete antibodies ( which include autoantibodies in some pathological situations). In this way, it is possible to inhibit the activity of B cells by reducing or inhibiting the amount or activity of APCs or Th cells. Similarly, it is known that there are different types of immune responses such as Th1 and Th2 responses. The immunomodulatory agents that can be used in the methods of the invention can promote a type of immune response over another type, and thus have beneficial effects in the treatment of patients with positive autoantibody disease. Accordingly, in its broadest sense, the term "immunomodulatory agent" specifically covers molecules or pharmaceutical compounds that stimulate or inhibit the activity or amount of one or more cells, cell surface molecules (e.g., cell surface signaling molecules) or cytokines of the immune system, which includes cells, cell surface molecules (for example cell surface signaling molecules) and cytokines that are part of the innate or adaptive immune system. Cells of the immune system include, without limitation, B cells, T cells, dendritic cells, monocytes, macrophages, neutrophils, eosinophils, basophils, mast cells and natural killer cells (NK). Cell surface molecules on the surface of cells of the immune system that can be stimulated or inhibited by an immunomodulatory agent include, without limitation, CD antigens such as CD20. Important cytokines in the immune system include, without limitation, members of the TNF superfamily of ligands, including without limitation neutrocin alfa, APRIL and CD40L.

DETAILED DESCRIPTION OF THE INVENTION In a phase II clinical trial in patients with systemic lupus erythematosus, the applicants found that the treatment of lupus patients with an antibody neutralizing the neutrocyan-alpha protein, administered as an iv infusion on days 0, 14 and 28, and then every 4 weeks through week 52, significantly relieved the symptoms associated with lupus in patients who had an ANA titre of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies in their plasma or blood serum (see example 1). Accordingly, a specific embodiment of the present invention provides a method of treating a patient with systemic lupus erythematosus who has an ANA > 1: 80, or 30 IU / mL or more of anti-dsDNA antibodies in its plasma or blood serum, with a neutralizing antibody to neutrokine-alpha. However, one skilled in the art will readily understand that the antibody molecules are only a variety of molecules that can act as neutrokine-alpha antagonists. Thus, another specific embodiment of the present invention provides a method of treating a patient with systemic lupus erythematosus having an ANA > 1: 80, or 30 IU / mL or more of anti-dsDNA antibodies in your plasma or blood serum, with a neutral-alpha antagonist. Neutrocin-alpha antagonists include, without limitation, compositions comprising an anti-neutrocin alfa antibody or antigen-binding fragments thereof, neutrocin-alpha receptor proteins or fragments or variants thereof, an antibody that binds to a Neutroclin-alpha receptor or an antigen-binding fragment thereof, or Neutrocin-alpha binding peptide or polypeptides. Neutrokine-alpha receptors include, for example, transmembrane activator and CAML-operator (TACI, GenBank Registration No. AAC51790), BAFF-R (GenBank Registration No. NP 443177) and B-cell maturation antigen. (BCMA, GenBank Registration No. NP_001183). Particularly useful forms of the neutrokine-alpha receptors include the soluble forms of the extracellular domains capable of binding to neutrocine-alpha. The neutrokine-alpha receptors or fragments or variants thereof, and the neutrokine-alpha binding polypeptides, can be used as fusion proteins, for example, Fe fusion proteins or human serum albumin (HSA). In a specific embodiment, a neutrophil-alpha antagonist is a TACI-Fc protein. An example of a TACI-Fc protein comprises amino acids 1-154 of SEQ ID NO: 6 fused with the Fe region of a lgG1 immunoglobulin molecule. . In a specific embodiment, a neutrokine-alpha antagonist is a BAFF-R-Fc protein. An example of a BAFF-R-Fc protein comprises amino acids 1-70 of SEQ ID NO: 10 fused to the Fe region of an IgG1 immunoglobulin molecule. Optionally, amino acid 20 (valine) of BAFF-R is substituted with asparagine, and amino acid 27 (leucine) of BAFF-R is substituted with proline. SEQ ID NO: 26 shows amino acids 1-70 of BAFF-R with these two amino acid changes. Additional neutrokine-alpha antagonists include the small-molecule neutrokine-alpha antagonists, neutrokine-alpha peptidomimetics, neutrokine-alpha polypeptide variants or APRIL (e.g., neutral dominant forms of neutrokine-alpha or APRIL). Such neutrokine-alpha or APRIL polypeptide variants can antagonize the function of neutrokine-alpha, for example by intervening in the homo- or hetero-multimerization of neutrokine-alpha or APRIL. In a specific embodiment, a neutrokine-alpha antagonist is a fragment or vahant of neutral-alpha protein that functions as a negative dominant. Alternatively, the neutrokine-alpha or APRIL polypeptide variants will prevent the polypeptides comprising them from binding or signaling through the neutrokine alpha receptors., such as TACI, BCMA and BAFF-R. Additional neutrokine-alpha antagonists include neutrokine-alpha small molecule antagonists, neutrokine-alpha peptidomimetics, antisense RNAs and short interfering RNAs (RNAci's) targeting neutrocin-alpha, antisense RNAs and short interfering RNAs (RNAi's) directed to APRIL, antisense RNAs and short interfering RNAs (RNAci's) directed to neutrokine-alpha receptors or to APRIL receptors. The neutrokine-alpha antagonists are described below in greater detail. Similarly, one skilled in the art will appreciate that other immunomodulatory agents may be useful in the present invention, including in particular molecules that can modulate the activity or amount of B cells. In specific embodiments, a B-cell modulator agent that can be used in conjunction with the methods of the present invention, is an agent that directly or indirectly inhibits or reduces the activity of B cells (for example the proliferation, differentiation, survival or secretion of immunoglobulin from B cells), or the amount of B cells. In another embodiment, the B cell modulating agents that can be used in conjunction with the methods of the present invention are the agents that reduce the activity or the total number of B cells, activated B cells, intact B cells, cells Memory B, plasma B cells, and plasmacytoid B cells, CD19 + B cells, or CD20 + B cells. Immunomodulators and B-cell modulator molecules that can be used in the present invention are known and described below in greater detail. In another embodiment, the invention provides a method of treating a patient that is within the subset of patients with systemic lupus erythematosus who have systemic lupus erythematosus disease (SLE or "lupus") "active", which comprises administering a therapeutically amount effective of a neutral-alpha antagonist antibody. In specific embodiments, the invention provides a method of treating a patient who has previously been diagnosed with lupus and has active lupus, which comprises administering a therapeutically effective amount of a neutralizing antibody to neutrokine-alpha. The invention provides a method of treating a patient who is within the subgroup of patients with systemic lupus erythematosus who have systemic lupus erythematosus disease (SLE or "lupus") active, which comprises making a determination to see if the patient has " active lupus "before administering a therapeutically effective amount of a neutralizing antibody to neutrokine-alpha. In specific embodiments, the invention provides a method of treating a patient who has previously been diagnosed with lupus and has active lupus, which comprises making a determination to see if the patient was previously diagnosed with lupus and has active lupus, before administering it. a therapeutically effective amount of a neutral-alpha antagonist antibody. In another embodiment, the invention provides a method of treating a patient that is within the subset of patients with systemic lupus erythematosus who have systemic lupus erythematosus disease (SLE or "lupus") "active", which comprises administering a therapeutically amount effective of a neutrokine-alpha antagonist or other immunomodulatory agent known in the art or described herein. In specific embodiments, the invention provides a method of treating a patient who has previously been diagnosed with lupus and has active lupus, which comprises administering a therapeutically effective amount of a neutrokine-alpha antagonist or other immunomodulatory agent known in the art. or described herein. The invention provides a method of treating a patient that is within the subset of patients with systemic lupus erythematosus who have active systemic lupus erythematosus disease., which comprises determining whether the patient had "active lupus" before administering a therapeutically effective amount of a neutrokine-alpha antagonist or other immunomodulatory agent known in the art or described herein. In specific embodiments, the invention provides a method of treating a patient who has previously been diagnosed with lupus and has active lupus, which comprises determining whether the patient was previously diagnosed with lupus and has active lupus before administering a therapeutically effective amount of lupus. a neutrokine-alpha antagonist or other immunomodulatory agent known in the art or described herein. In specific embodiments, a patient with active lupus is defined as a patient who has a clinical diagnosis of SLE according to the criteria of the American College of Rheumatology (ACR) (see, for example, Tan et al., Arthritis Rheum 25: 1271 -7, (1982); and Hochberg et al., Arthritis Rheum. 40: 1725, (1997), which are incorporated herein by reference in their entirety). In specific modalities, a patient with active lupus is defined as a patient who has a SELENA SLEDAI > 4. SELENA SLEDAI represents the Activity Index of Systemic Lupus Erythematosus Disease, modified by the National Estrogen Safety Assessment test in Lupus Erythematosus. SELENA SLEDAI scores are routinely determined by clinicians or physicians using known techniques and methods; see, for example, Bombardier et al., Arthritis Rheum. Jun; 35 (6): 630-40, 1992; and Strand and others, J Rheumatol. Feb; 26 (2): 490-7, 1999, which are hereby incorporated by reference in their entirety. Briefly, a SELENA SLEDAI score is determined by considering the activity of the SLE disease in 24 extended categories through 9 organ systems. The disease in some organ systems is weighted more than the disease in other organ systems. In particular, if measurements of SLE disease activity in the central nervous system and vascular system are present, 8 points are assigned; if renal and musculoskeletal SLE disease activity measurements are present, 4 points are assigned; if serum, dermal and immunological SLE disease activity measurements are present, 2 points are assigned; and if constitutional and hematologic SLE disease activity measurements are present, 1 point is assigned. The theoretical maximum score of SELENA SLEDAI is 105, but in practice few patients have scores higher than 45. In the standard scoring system of SELENA SLEDAI 4 points are assigned if a subject has a new onset of proteinuria or a recent increase in proteinuria greater than 0.5 grams / 24 hours. In other words, if the proteinuria value obtained in a 24-hour urine sample is more than 0.5 g greater than the value determined in a patient's urine sample 24 hours immediately before, they will be assigned 4 points for proteinuria in the scale of SELENA SLEDAI. This is commonly described as an increase in proteinuria or new onset of proteinuria "> 0.5 g / 24 hours". Thus, under the standard SELENA SLEDAI scoring system, a subject assigned 4 points of proteinuria reference value will have an improvement in his SELENA SLEDAI on a subsequent visit, provided that his proteinuria value in the urine sample of Current 24 hours is not greater than 0.5 g higher than the proteinuria value determined in the patient's urine sample 24 hours immediately before. In other words, the patient will have 4 points deducted from their total score even in case of stable proteinuria or proteinuria increases < 0.5 g / 24 hours. In example 2, a modification of the proteinuria scoring rules for SELENA SLEDAI is described. In example 2, the proteinuria score is modified in such a way that 4 points are still assigned, unless the proteinuria determined in the current 24-hour urine sample is more than 0.5 grams lower than the proteinuria value determined in the patient's urine sample 24 hours immediately before. Also, there is a new onset of proteinuria or an increase in proteinuria that is > 0.5 g / 24 hours, 4 points will be assigned. Here, when reference is made to the scale of SELENA SLEDAI, the score for proteinuria can be made according to the standard scale of SELENA SLEDAI. Preferably, the score for proteinuria in the determination of the SELENA SLEDAI score of a patient is performed according to the proteinuria scoring system described in example 2. In specific modalities, a patient with active lupus is defined as a patient who has a SELENA SLEDAI score > 5. In additional specific modalities, a patient with active lupus is defined as a patient who has a SELENA SLEDAI score.; 6. In additional specific modalities, a patient with active lupus is defined as a patient who has a SELENA SLEDAI > 7. In additional specific modalities, a patient with active lupus is defined as a patient who has a SELENA SLEDAI > 8. In other specific embodiments, a patient with active lupus is defined as a patient who has a SELENA SLEDAI > 9. In other specific modalities, a patient with active lupus is defined as a patient who has a SELENA SLEDAI > 10. In additional specific modalities, a patient with active lupus is defined as a patient who has a SELENA SLEDAI > 11. In additional specific modalities, a patient with active lupus is defined as a patient who has a SELENA SLEDAI > 12. In other embodiments, a patient with active lupus is defined as a patient having anti-dsDNA antibodies in their plasma or blood serum. The titers or concentrations of anti-dsDNA antibody can be determined routinely by clinicians or clinicians using known techniques and methods. An exemplary test for determining the titers or concentrations of anti-dsDNA antibody is an enzyme-linked immunosorbent assay (ELISA) based on the specific binding of anti-dsDNA antibodies to immobilized dsDNA; see for example Halbert et al., J Lab Clin Med. 97: 97-111 (1981). Another exemplary test for determining the titers or concentrations of anti-dsDNA antibody is an indirect immunofluorescence test based on the specific binding of anti-dsDNA antibodies to the dsDNA of a Crithidia luciliae cell; see for example Whiteside et al., Am J Clin Pathol. 72: 829-35 (1979). Another exemplary test for determining the titers or concentrations of anti-dsDNA antibody is the Farr test based on the specific binding of anti-dsDNA antibodies to radiolabelled dsDNA, followed by the precipitation of radiolabelled anti-dsDNA-dsDNA antibody complexes; see for example Davis et al., Am J Clin Pathol., 67: 374-8, (1977). In specific embodiments, a patient with active lupus is defined as a patient having 30 International Units / mL, or more, of anti-dsDNA antibodies in their plasma or blood serum, wherein an International Unit is based on the preparation of anti-DNA antibody. -DNA of reference of the World Health Organization; see, for example, Feltkamp and others, Ann. Rheum. Dis., 47: 740-746 (1988). All references cited in this paragraph are incorporated herein by reference in their entirety. In a further specific embodiment, a patient with active lupus is defined as a patient having 40 IU / mL or more of anti-dsDNA antibodies in their plasma or blood serum. In a further specific embodiment, a patient with active lupus is defined as a patient having 50 IU / mL or more of anti-dsDNA antibodies in their plasma or blood serum. In a further specific embodiment, a patient with active lupus is defined as a patient having 60 IU / mL or more of anti-dsDNA antibodies in their plasma or blood serum. In a further specific embodiment, a patient with active lupus is defined as a patient having 75 IU / mL or more of anti-dsDNA antibodies in their plasma or blood serum. In a further specific embodiment, a patient with active lupus is defined as a patient having 100 IU / mL or more of anti-dsDNA antibodies in their plasma or blood serum. In a further specific embodiment, a patient with active lupus is defined as a patient having 125 IU / mL or more of anti-dsDNA antibodies in their plasma or blood serum. In a further specific embodiment, a patient with active lupus is defined as a patient having 150 IU / mL or more of anti-dsDNA antibodies in his plasma or blood serum. In a further specific embodiment, a patient with active lupus is defined as a patient who has 200 IU / mL or more of anti-dsDNA antibodies in his plasma or blood serum. In an additional specific modality, a patient with active lupus is defined as a patient who has 300 IU / mL or more of anti-dsDNA antibodies in his plasma or blood serum. In other embodiments, a patient with active lupus is defined as a patient having antinuclear antibodies (ANA +) in their plasma or blood serum. The antinuclear antibody titer can be determined routinely by clinicians or clinicians using known techniques and methods. An exemplary test to determine the antinuclear antibody titer is an indirect immunofluorescence test based on the specific binding of antinuclear antibodies to human epithelial cells HEp-2; see for example Osborn et al., Arthritis Rheum., 27: 1286-9, (1984). In another exemplary test, concentrations or titers of antinuclear antibodies can be determined using an ELISA test based on the specific binding of ANA to immobilized ANA antigens, eg, cDNA, Ro / SS-A, La / SS-B, Sm, RNP; see, for example, Fenger et al., Clin Chem., 50: 2141-7, (2004). The ANA tests are described more in Kavanaugh et al., Archives of Pathology & Laboratory Medicine (2000) 124: 71-81, and Greidinger, EL and Hoffman, RW, Laboratory Medicine (2003) 34: 113-117. All references cited in this paragraph are incorporated herein by reference in their entirety. In preferred specific embodiments, a patient with active lupus is defined as a patient having an ANA titre of 1: 80 or greater (i.e., a positive ANA test is obtained when the dilution factor of the patient's plasma or blood serum). is 80 or higher). For example, titles of 1: 160, 1: 320 and 1: 640, are greater than a title of 1: 80. In other preferred embodiments, a patient with active lupus is defined as a patient having an ANA titre of 1: 160 or greater. In a further preferred embodiment, a patient with active lupus is defined as a patient having an ANA titer of 1: 320 or greater. In a further preferred embodiment, a patient with active lupus is defined as a patient having an ANA titre of 1: 640 or greater. In a further preferred embodiment, the ANA titer is measured using indirect immunofluorescence on HEp-2 cells. In another specific embodiment, the ANA titer is measured using an anti-dsDNA ELISA test. In other embodiments, a patient with active lupus is defined as a patient having detectable autoantibodies, including without limitation anti-Ro / SS-A antibodies, anti-La / SS-B antibodies, anti-RNP antibodies, anti-cardiolipin ( anti-phospholipid), anti-dsDNA antibodies, anti-Sm antibodies. The titers or concentrations of autoantibodies can be determined routinely by clinicians or clinicians using known techniques and methods. In other embodiments, a patient with active lupus is defined as a patient having decreased C3 or C4 complement concentrations or both in their plasma or blood serum. The person skilled in the art will understand that the normal concentration of C3 or C4 may vary depending on the test used to measure C3 or C4. Accordingly, a normal concentration of C3 complement in plasma or serum can be from about 90 milligrams / deciliter to about 180 milligrams / deciliter. In other specific embodiments, a normal concentration of C3 complement in the plasma or serum can also range from about 88 milligrams / deciliter to about 206 milligrams / deciliter, or from about 88 milligrams / deciliter to about 252 milligrams / deciliter. A normal concentration of C4 complement in the plasma or serum can be from about 16 milligrams / deciliter to about 47 milligrams / deciliter. In other specific embodiments, a normal concentration of C4 complement in the plasma or serum can range from about 12 milligrams / deciliter to about 72 milligrams / deciliter, or from about 13 milligrams / deciliter to about 75 milligrams / deciliter. In specific embodiments, a decreased concentration of C3 complement in plasma or serum is defined as less than 90 milligrams / deciliter. In specific embodiments, a decreased concentration of C3 complement in the plasma or serum is defined as less than 88 milligrams / deciliter. In specific embodiments, a decreased concentration of C3 complement in plasma or serum is defined as less than 85 milligrams / deciliter. In specific embodiments, a decreased concentration of C3 complement in plasma or serum is defined as less than 80 milligrams / deciliter. In specific embodiments, a decreased concentration of C3 complement in plasma or serum is defined as less than 75 milligrams / deciliter. In specific modalities, a decreased concentration of C4 complement in plasma or serum is defined as less than 16 milligrams / deciliter. In specific embodiments, a decreased concentration of C4 complement in plasma or serum is defined as less than 15 milligrams / deciliter. In specific embodiments, a decreased concentration of C4 complement in plasma or serum is defined as less than 14 milligrams / deciliter. In specific embodiments, a decreased concentration of C4 complement in plasma or serum is defined as less than 13 milligrams / deciliter. In specific embodiments, a decreased concentration of C4 complement in plasma or serum is defined as less than 12 milligrams / deciliter. In specific embodiments, a decreased concentration of C4 complement in plasma or serum is defined as less than 11 milligrams / deciliter. In specific embodiments, a decreased concentration of C4 complement in plasma or serum is defined as less than 10 milligrams / deciliter. In specific embodiments, a decreased concentration of C4 complement in plasma or serum is defined as less than 9 milligrams / deciliter. Complement concentrations can be determined routinely by clinicians or clinicians using known techniques and methods, for example, using a radial immunodiffusion test. In other embodiments, a patient with active lupus is defined as a patient having any of one or more of the following characteristics: a clinical diagnosis of SLE according to the criteria of the American College of Rheumatology (ACR) (see, for example, Tan and others, Arthritis Rheum, 25: 1271-7, (1982); and Hochberg et al., Arthritis Rheum. 40: 1725 (1997)); a SELENA SLEDAI score > 6; decreased concentrations of C4 complement in your blood plasma or serum; decreased concentrations of C3 complement in your blood plasma or serum; an ANA title of 1: 80 or higher; 30 IU / ml or more of anti-dsDNA antibodies in your plasma or blood serum; is receiving > 7.5 milligrams / day of prednisone or another corticosteroid for the treatment of symptoms related to lupus; or you are receiving or have previously received immunosuppressive therapy for the treatment of symptoms related to lupus. In other embodiments, a patient with active lupus is defined as a patient who has any of one or more of the following characteristics: a clinical diagnosis of SLE according to the criteria of the American College of Rheumatology (ACR); a SELENA SLEDAI score > 8; decreased concentrations of C4 complement in your blood plasma or serum; decreased concentrations of C3 complement in your blood plasma or serum; an ANA title of 1: 80 or higher; 30 IU / ml or more of anti-dsDNA antibodies in your plasma or blood serum; is receiving up to 40 milligrams / day of prednisone or another corticosteroid for the treatment of symptoms related to lupus; or you are receiving or have previously received immunosuppressive therapy for the treatment of symptoms related to lupus. Multiple rates of disease activity are well known to clinicians or clinicians and can be used to measure the magnitude of rheumatic disease activity, such as the activity of the SLE disease (see, for example, Strand et al., J. Rheumatol., 26: 490-7, (1999)). In one embodiment, SELENA SLEDAI is used as an index of disease activity (DAI, for its acronym in English) (see, for example, Bombardier et al, Arthritis Rheum, 35: 630-40, (1992)). In another embodiment, the SLE attack index is used as an ICD (see, for example, Petri et al., Lupus, 8: 685-91, (1999)). In a further embodiment, the Systemic Lupus International Collaborative Clinics / American College of Rheumatology (SLICC / ACR) Damage Index is used as an ICD (see, for example, Gladman et al., Arthritis Rheum., 39: 363-9, (nineteen ninety six)). In another modality, the Global Physician Determination (PGA) is used as an ICD. PGA is a visual analog scale with a scale of 0 to 3, where 0 is without disease activity, 1 is mild disease activity, 2 is moderate disease activity, and 3 is severe disease activity. In another modality, the Medical Results Review Brief Form (SF-36) is used as an ICD. The SF-36 is a quality of life instrument related to general health (HRQOL), which has been shown to reflect the impact of SLE on all HRQOL domains in observational cohort studies, as well as randomized trials (Cook et al. , J. Rheumatol., 27: 1892-1895 (2000), Thumboo et al., J Rheumatol., 26: 97-102 (1999), Thumboo et al., J Rheumatol., 27: 1414-1420 (2000); JE et al., Med Care, 30: 473-483 (1992), Smolen JS et al., J Rheumatol., 26: 504-507, (1999), Gladman et al., Lupus, 5: 190-195, (1996). Alonso J. et al., Qual Life Res., 13: 283-298, 2004; and Gladman et al., J Rheumatol., 27: 377-9 (1995), each of which is incorporated herein by reference. In its whole). In a further embodiment, the EQ-5D (also known as the EuroQol instrument) is used as an ICD. The EQ-5D is a measure of quality of life related to general health. It is considered to be a simple self-administered questionnaire that contains not only a descriptive classification system of health status, but is also capable of generating a mixed index or score that reflects the preference value associated with a given health status. The descriptive EQ-5D system consists of 5 dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension has 3 levels that reflect "without health problems", "moderate health problems" and "extreme health problems" (see for example Health Policy, 1990 Dec; 16 (3): 199-208, which is incorporated herein by reference). In an additional modality, the Functional Assessment subscale for Chronic Disease-Fatigue Therapy (FACIT-F) of the Functional Assessment of Chronic Disease Therapy (FACIT) assessment system is used as a DAI. The FACIT-F subscale is a compilation of 27 questions of general questions divided into 4 main QOL domains: physical well-being, social / family welfare, emotional well-being and functional well-being. This measurement tool groups the patient's feedback on the degree of energy, indifference and ability to initiate or terminate activities (see, for example, Yellen, SB et al., Journal of Pain and Symptom Management, 13: 63-74, (1997); D. et al., 94 (2): 528-538, (2002), and Celia, D. et al., Journal of Pain &Symptom Management, 24 (6): 547-561, (2002), each of which is here incorporated as a reference in its entirety). In a further modality, the Disease Activity Score (DAS28) is used as an ICD. DAS28 is a standard tool used by rheumatologists to determine the activity of rheumatic disease. This measurement tool calculates an index score based on the determination of: the number of tender joints (TEN), the number of swollen joints (SW), the erythrocyte sedimentation rate (ESR), and the patient's determination of disease activity (VAS; mm) (see for example Van de Heijde DMFM et al., J. Rheumatol, 20: 579-8 (1993); Prevoo MLL et al., Arthritis Rheum, 38: 44-8, (1995) , each of which is incorporated here as a reference in its entirety). In a further embodiment, the Lupus Evaluation Group of the British Isles (BILAG) is used as an ICD (see for example Isenberg et al., Rheumatology, 44: 902-6, (2005); and others, Rheumatology, 42 (11): 1372-9, (2003), Isenberg, and others, Lupus, 9 (9): 651-4 (2002); Hay and others, QJ Med., 86: 447-58 , (1993), and the software user guide BLIPS ™ version 3.0, published on April 4, 2004, ADS-Limathon Ltd, each of which is incorporated herein by reference in its entirety). The BILAG index comprises 8 organs / body systems known to be affected by lupus, and the scores depend on whether the clinical features are new, worse, equal, or improve compared to the previous measurement. For each of the 8 body organs / systems, the severity of the manifestation of the SLE disease is a score of A, B, C, D or E, with A being the most severe (see for example Hay, ib.). The BILAG index provides a composite score to determine the severity of the disease and the efficiency of the treatment. This composite score adds contributions from each of the 8 body organs / systems affected by lupus. Using BILAG or other known measurements, treatment can be directed to lupus patients with disease manifestations in specific subgroups of organs / systems.

Accordingly, in a specific embodiment, it is considered that a lupus patient who is being treated or has been treated with an immunomodulatory agent known or described herein, responds or has responded to treatment if he or she achieves a reduction in their SELENA SLEDAI score. In a specific embodiment, it is considered that a lupus patient that is being treated or has been treated with an immunomodulatory agent known or described herein, is responding or has responded to treatment if he has obtained a reduction of his SELENA SLEDAI score, in comparison with the SELENA SLEDAI reference of the patient, the SELENA SLEDAI score determined before the patient begins the treatment with the immunomodulatory agent. In a specific embodiment, it is considered that a lupus patient who is being or has been treated with an immunomodulatory agent known or described herein, is responding or has responded to treatment if he has obtained a reduction of at least 4 points in his or her SELENA SLEDAI score. In a specific embodiment, it is considered that a lupus patient who is being or has been treated with an immunomodulatory agent known or described herein, is responding or has responded to treatment if he has obtained a reduction of at least 4 points in his or her SELENA SLEDAI score, compared to the SELENA SLEDAI patient reference score, the SELENA SLEDAI score determined just before the patient begins treatment with the immunomodulatory agent. In another specific embodiment, it is considered that a lupus patient who is being treated or has been treated with an immunomodulatory agent known or described herein is responding or has responded to treatment if he has not experienced a worsening of the activity of the disease determined through the Global Physician Determination (PGA). In a specific modality, the patient has not experienced a worsening of the activity of the disease if his PGA score has decreased, remained stable, or increased less than 0.3 points. In a specific modality, the patient has not experienced a worsening of the activity of the disease if the PGA score has decreased, has remained stable or has increased less than 0.3 points of the same PGA reference score of the patient, the PGA score determined just before the patient begins the treatment with the immunomodulatory agent. In another specific embodiment, it is considered that a lupus patient who is being or has been treated with an immunomodulatory agent known or described herein is responding or has responded to treatment if he has not experienced a worsening of the disease activity determined by means of the disease activity index of the Lupus Evaluation Group of the British Isles (BILAG). In a specific modality, the patient has not experienced a worsening of disease activity if he has not gained a new BILAG A organ domain score, or has not gained two new BILAG B organ domain scores. In a specific modality, the patient has not experienced a worsening of disease activity if he has not gained a new BILAG A organ domain score or has not gained two new BILAG B organ domain scores, since the BILAG determination of the patient's reference, the determination of BILAG performed just before the patient begins the treatment with the immunomodulatory agent. In another specific embodiment, it is considered that a lupus patient who is being or has been treated with an immunomodulatory agent known or described herein, is responding or has responded to treatment if he has obtained a reduction in his SELENA SLEDAI score, has not had a substantial worsening of its PGA score, and has not experienced a worsening of disease activity determined by means of the disease activity index of the British Isles Lupus Evaluation Group (BILAG), compared to your SELENA SLEDAI, PGA and BILAG benchmark, respectively. In a specific modality, it is considered that a patient that is being treated or has been treated with an immunomodulatory agent, is responding or has responded to the treatment if he has obtained a reduction of at least 4 points in his SELENA SLEDAI score, he has not had an increase of 0.30 points higher in your PGA score, and you have not earned a new BILAG A organ domain score or you have not gained two new BILAG B organ domain scores, compared to your SELENA SLEDAI, PGA and BILAG scores reference, respectively.

In another specific embodiment, it is considered that a lupus patient who is being or has been treated with an immunomodulatory agent known or described herein is responding or has responded to treatment if the dose of prednisone in the patient has been reduced. In another specific embodiment, it is considered that a lupus patient who is being or has been treated with an immunomodulatory agent known or described herein is responding or has responded to treatment if the dose of prednisone in the patient has been reduced by comparison with the dose of reference prednisone of the patient, the prednisone dose of the patient taken just before the patient begins the treatment with the immunomodulatory agent. In another specific embodiment, it is considered that a lupus patient who is being or has been treated with an immunomodulatory agent known or described herein, is responding or has responded to treatment if the prednisone dose of the patient has been reduced at least 25% In another specific embodiment, it is considered that a lupus patient who is being or has been treated with a known or described immunomodulatory agent is responding or has responded to treatment if the dose of prednisone in the patient has been reduced by at least 25%, at 7.5 mg / day or less. In another specific embodiment, it is considered that a lupus patient who is being or has been treated with an immunomodulatory agent known or described herein, is responding or has responded to treatment if the prednisone dose of the patient has been reduced at least 25% of the patient's reference dose of prednisone, at 7.5 mg / day or less. In another specific embodiment, it is considered that a lupus patient who is being or has been treated with an immunomodulatory agent known or described herein is responding or has responded to treatment if the patient's dose of prednisone has been reduced by minus 50% In another specific embodiment, it is considered that a lupus patient who is being treated or has been treated with an immunomodulatory agent known or described herein, is responding or has responded to treatment if the dose of prednisone in the patient has been reduced by less 50% at 7.5 mg / day or less. In another specific embodiment, it is considered that a lupus patient who is being treated or has been treated with an immunomodulatory agent known or described herein, is responding or has responded to treatment if the dose of prednisone in the patient has been reduced by less 50% of the patient's reference dose of prednisone at 7.5 mg / day or less. Other measurements can be used to measure the quality of response of a lupus patient to treatment. In a specific embodiment, it is considered that a lupus patient who is being treated or has been treated with an immunomodulatory agent known or described herein is responding or has responded to treatment if he has an improved SF-36 health examination score. . In another specific embodiment, it is considered that a lupus patient who is being treated or has been treated with a known immunomodulatory agent or described herein, is responding or has responded to treatment if he has a health examination score of SF-36. improvement with respect to the patient's SF-36 health exam score. In a specific embodiment, it is considered that a lupus patient who is being treated or has been treated with an immunomodulatory agent known or described herein is responding or has responded to treatment if he has an improved EQ-5D score. In another specific embodiment, it is considered that a lupus patient who is being treated or has been treated with an immunomodulatory agent known or described herein, is responding or has responded to treatment if he has an improved EQ-5D score with respect to the EQ-5D patient reference score. In a specific modality, it is considered that a patient who has been treated or is being treated with a known or described immunomodulatory agent is responding or has responded to treatment if he shows less fatigue as shown by the patient's FACIT-F score. In another specific embodiment, it is considered that a lupus patient that is being treated or has been treated with an immunomodulatory agent known or described herein is responding or has responded to treatment if it shows less fatigue according to the patient's FACIT-F score. compared to the patient reference FACIT-F score. In a specific embodiment, it is considered that a lupus patient who is being or has been treated with an immunomodulatory agent known or described herein, is responding or has responded to treatment if he has an improved DAS28 score. In another specific embodiment, it is considered that a lupus patient who is being or has been treated with an immunomodulatory agent known or described herein is responding or has responded to treatment if he has an improved DAS28 score compared to the DAS28 score of Patient reference. In another specific embodiment, it is considered that a lupus patient who is being or has been treated with an immunomodulatory agent known or described herein is responding or has responded to treatment if he or she has a lower frequency or duration of attacks. In another specific embodiment, it is considered that a lupus patient who is being or has been treated with an immunomodulatory agent known or described herein is responding or has responded to treatment if he or she has a lower frequency or duration of attacks compared to the frequency or duration of attacks before treatment with the immunomodulatory agent. In another specific embodiment, it is considered that a lupus patient who is being treated or has been treated with an immunomodulatory agent known or described herein, is responding or has responded to treatment if it has a lower severity of attacks. In another specific embodiment, it is considered that a lupus patient who is being or has been treated with an immunomodulatory agent known or described herein, is responding or has responded to treatment if he has a decrease in the severity of attacks compared to the Severity of attacks before treatment with the immunomodulatory agent. The rate of attacks of SLE determines the frequency and severity of exacerbations of lupus symptoms (attacks). Attacks are classified as "mild" or "moderate" or "severe". Mild or moderate attacks include one or more of the following: changing the SELENA SLEDAI score of 3 points or more; discoid new / worse, photosensitivity, profundus, cutaneous vasculitis or bullous lupus; nasopharyngeal ulcers; pleuritis; pericarditis; arthritis; fever (SLE); increase in prednisone but not greater than 0.5 mg / kg / day; addition of NSAID or plaquenil for the activity of the disease; and increase greater than 1.0 in the PGA score, but not greater than 2.5. Severe attacks include one or more of the following: changing the SELENA SLEDAI score to more than 12; SLE-SNC new / worse; vasculitis; nephritis; myositis; Plt < 60,000; iron anemia (< 7% or decrease in Hb> 3%); doubling the dose of prednisone; increase in prednisone to more than 0.5 mg / kg / day; Cytoxan prescription; prescription of azathioprine; Prescription of methotrexate; hospitalization (SLE) and increase of the PGA score to more than 2.5. In another specific embodiment, it is considered that a lupus patient who is being or has been treated with an immunomodulatory agent known or described herein is responding or has responded to treatment if he or she has a lower frequency or severity of attacks measured by the index of SLE attacks. In another specific embodiment, it is considered that a lupus patient who is being or has been treated with a known or described immunomodulatory agent is responding or has responded to treatment if he has a lower frequency or severity of attacks measured according to SLE attack rate compared to the frequency or severity of previous patient attacks. In another specific embodiment, it is considered that a lupus patient who is being or has been treated with an immunomodulatory agent known or described herein, is responding or has responded to the treatment if he / she has a decrease in the frequency or severity of the attacks, measures through a modified version of the SLE attack index. In another specific embodiment, it is considered that a lupus patient who is being or has been treated with an immunomodulatory agent known or described herein, is responding or has responded to the treatment without limitation has a decrease in the frequency or severity of the attacks , measured by a modified version of the SLE attack rate, compared to the frequency or severity of previous patient attacks. The modified version of the SLE attack index excludes severe attacks triggered only by changing the SELENA SLEDAI score. Accordingly, in a specific embodiment, a lupus patient who is being treated or has been treated with a neutrocyan-alpha antagonist, including without limitation an anti-neutrocin-alpha antibody or antigen-binding fragment thereof, is considered. , a neutrokine-alpha receptor protein (eg TACI, BCMA or BAFF-R) or a fragment or variant thereof, an anti-neutrocine-alpha receptor antibody (eg, TACI, BCMA or BAFF-R) or a antigen binding fragment thereof, neutrophil-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or RNAci's directed to neutrocine-alpha, APRIL, TACI, BCMA or BAFF-R or other receptor for neutrocin-alfa or APRIL, you are responding or have responded to treatment if you have obtained a reduction of your SELENA SLEDAI score. In a specific modality, it is considered that a lupus patient who is being treated or has been treated with a neutral-alpha antagonist, is responding or has responded to treatment if he has achieved a reduction of his SELENA SLEDAI score in comparison with the score SELENA SLEDAI patient reference, the SELENA SLEDAI score determined just before starting the patient's treatment with the neutroclin-alpha antagonist. In a specific modality, it is considered that a lupus patient who is being or has been treated with a neutral-alpha antagonist, is responding or has responded to treatment if he has obtained a reduction of at least 4 points in his SELENA SLEDAI score. . In a specific modality, it is considered that a lupus patient who is being or has been treated with a neutrocin-alpha antagonist is responding or has responded to treatment if he has obtained a reduction of at least 4 points in his SELENA SLEDAI score compared to the SELENA SLEDAI patient reference score, the SELENA SLEDAI score determined just before the patient begins treatment with the neutrokine-alpha antagonist. In a specific embodiment, a neutrokine-alpha antagonist is an anti-neutrocine-alpha antibody. In a specific embodiment, a neutrophil-alpha antagonist is a TACI-Fc protein. In a specific embodiment, a neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, a neutrokine-alpha antagonist is an anti-neutrocine-alpha peptide antibody. In a specific embodiment, a neutrokine-alpha antagonist is a protein fragment of neutrokine-alpha or a variant that functions as a dominant negative. In another specific embodiment, a lupus patient who is being treated or has been treated with a neutrocyan-alpha antagonist, including without limitation an anti-neutrocyan-alpha antibody or binding fragment thereof, a neutrocytic receptor protein, is considered. -alpha (eg, TACI, BCMA or BAFF-R) or fragment or variant thereof, an anti-neutrocin-alpha receptor antibody (eg, TACI, BCMA or BAFF-R) or binding fragment thereof, neutral-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or RNAci's targeting neutrokine-alpha, APRIL, TACI, BCMA, BAFF-R or another receptor for neutrokine-alpha or APRIL, is responding or has responded to treatment if you have not experienced a worsening of the disease determined according to the Global Physician Determination (PGA). In a specific modality, the patient has not experienced a worsening of disease activity if the PGA score has decreased, remained stable or increased less than 0.3 points. In a specific modality, the patient has not experienced a worsening of the activity of the disease if the PGA score has decreased, has remained stable or has increased less than 0.3 points of the same PGA score of the reference patient, the PGA score determined just before the patient begins treatment with the neutrokine-alpha antagonist. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrophil-alpha antagonist is an anti-neutrocin-alpha antibody peptide. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutral-alpha protein that functions as a negative dominant. In another specific embodiment, a lupus patient who is being treated or has been treated with a neutrocyan-alpha antagonist, including without limitation an anti-neutrocyan-alpha antibody or binding fragment thereof, a neutrocytic receptor protein, is considered. -alpha (eg, TACI, BCMA or BAFF-R) or fragment or variant thereof, an anti-neutrocin-alpha receptor antibody (eg, TACI, BCMA or BAFF-R) or binding fragment thereof, neutral-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or RNAci's targeting neutrokine-alpha, APRIL, TACI, BCMA, BAFF-R or another receptor for neutrokine-alpha or APRIL, is responding or has responded to treatment if you have not experienced a worsening of the disease, determined according to the disease activity index of the British Islands Lupus Determination Group (BILAG). In a specific modality, the patient has not experienced a worsening of the activity of the disease if he has not gained a new BILAG A organ domain score or has not gained two new BILAG B organ domain scores. specific, the patient has not experienced a worsening of the activity of the disease if he has not gained a new BILAG A organ domain score or has not gained two new BILAG B organ domain scores since the reference BILAG determination, the determination of BILAG performed just before the patient begins treatment with the neutrokine-alpha antagonist. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrophil-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocin-alpha antibody peptide. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutral-alpha protein that functions as a negative dominant. In another specific embodiment, a lupus patient who is being treated or has been treated with a neutrocyan-alpha antagonist, including without limitation an anti-neutrocyan-alpha antibody or binding fragment thereof, a neutrocytic receptor protein, is considered. -alpha (eg, TACI, BCMA or BAFF-R) or fragment or variant thereof, an anti-neutrocin-alpha receptor antibody (eg, TACI, BCMA or BAFF-R) or binding fragment thereof, neutrocin-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or RNAci's targeting neutrokine-alpha, APRIL, TACI, BCMA, BAFF-R or another receptor for neutrokine-alpha or APRIL, is responding or has responded to treatment if you have achieved a reduction in your SELENA SLEDAI score, you have not had a substantial worsening in your PGA score, and you have not experienced a worsening of disease activity, as determined by activity index d and disease of the Lupus Determination Group of the British Isles (BILAG), compared to their SELENA SLEDAI, PGA and BILAG reference scores, respectively. In a specific modality, it is considered that a lupus patient that is being treated or has been treated with a neutral-alpha antagonist, is responding or has responded to treatment if he has achieved a reduction of at least 4 points in his SELENA score. SLEDAI, has an increase of no more than 0.30 points in its PGA score, and has not gained a new BILAG A organ domain score or has not gained two new BILAG B organ domain scores, as compared to their SELENA scores SLEDAI, PGA and BILAG reference, respectively. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocin-alpha antibody peptide. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutral-alpha protein that functions as a negative dominant. In another specific embodiment, a lupus patient who is being treated or has been treated with a neutrocyan-alpha antagonist, including without limitation an anti-neutrocyan-alpha antibody or binding fragment thereof, a neutrocytic receptor protein, is considered. -alpha (eg, TACI, BCMA or BAFF-R) or fragment or variant thereof, an anti-neutrocin-alpha receptor antibody (eg, TACI, BCMA or BAFF-R) or binding fragment thereof, neutral-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or RNAci's targeting neutrokine-alpha, APRIL, TACI, BCMA, BAFF-R or another receptor for neutrokine-alpha or APRIL, is responding or has responded to treatment if the dose of prednisone in the patient has been reduced. In another specific modality, it is considered that a lupus patient who is being treated or has been treated with a neutral-alpha antagonist is responding or has responded to treatment if the patient's prednisone dose has been reduced compared to the reference prednisone dose of the patient, the dose of prednisone from the patient taken just before the patient begins treatment with the neutrokine-alpha antagonist. In another specific embodiment, it is considered that a lupus patient who is being treated or has been treated with a neutral-alpha antagonist is responding or has responded to the treatment if the prednisone dose of the patient has been reduced by at least 25% . In another specific embodiment, it is considered that a lupus patient who is being treated or has been treated with a neutral-alpha antagonist is responding or has responded to the treatment if the prednisone dose of the patient has been reduced by at least 25% at 7.5 mg / day or less. In another specific embodiment, it is considered that a lupus patient who is being treated or has been treated with a neutral-alpha antagonist is responding or has responded to the treatment if the prednisone dose of the patient has been reduced by at least 25% of the dose of reference prednisone of the patient, to 7.5 mg / day or less. In another specific embodiment, it is considered that a lupus patient who is being treated or has been treated with a neutral-alpha antagonist is responding or has responded to treatment if the prednisone dose of the patient has been reduced by at least 50% . In another specific embodiment, it is considered that a lupus patient who is being treated or has been treated with a neutral-alpha antagonist is responding or has responded to treatment if the patient's dose of prednisone has been reduced by at least 50% , at 7.5 mg / day or less. In another specific embodiment, it is considered that a lupus patient who is being treated or has been treated with a neutral-alpha antagonist is responding or has responded to treatment if the prednisone dose of the patient has been reduced by at least 50% of the patient's reference prednisone dose at 7.5 mg / day or less. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine-alpha antibody peptide. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutral-alpha protein that functions as a negative dominant. Other measures of the quality of response of a lupus patient to treatment can be used. In a specific embodiment, a lupus patient who is being treated or has been treated with a neutrophil-alpha antagonist, including without limitation an anti-neutrocyan-alpha antibody or binding fragment thereof, a neutrocytic receptor protein, is considered. -alpha (eg, TACI, BCMA or BAFF-R) or fragment or variant thereof, an anti-neutrocin-alpha receptor antibody (eg, TACI, BCMA or BAFF-R) or binding fragment thereof, neutrocin-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or RNAci's directed to neutrocine-alpha, APRIL, TACI, BCMA, BAFF-R or another receptor for neutrokine-alpha or APRIL, are responding or has responded to treatment if you have an improved SF-36 score. In another specific embodiment, a lupus patient who is being treated or has been treated with a neutrocyan-alpha antagonist, including without limitation an anti-neutrocyan-alpha antibody or binding fragment thereof, a neutrocytic receptor protein, is considered. -alfa (for example, TACI, BCMA or BAFF-R) or fragment or variant thereof, an anti-neutrocine-alpha receptor antibody (eg, TACI, BCMA or BAFF-R) or binding fragment thereof, neutrokine-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and RNAs of antisense or RNAci's directed to neutrocin-alpha, APRIL, TACI, BCMA, BAFF-R or another receptor for neutrokine-alpha or APRIL, is responding or has responded to treatment if it has an improved SF-36 score compared to the SF score 36 reference of the patient. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine-alpha antibody peptide. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutral-alpha protein that functions as a negative dominant. In a specific embodiment, a lupus patient who is being treated or has been treated with a neutral-alpha antagonist, including without limitation an anti-neutrocyan-alpha antibody or binding fragment thereof, a neutrocytic receptor protein, is considered. -alpha (eg, TACI, BCMA or BAFF-R) or fragment or variant thereof, an anti-neutrocin-alpha receptor antibody (eg, TACI, BCMA or BAFF-R) or binding fragment thereof, neutrocin-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or RNAci's directed to neutrocine-alpha, APRIL, TACI, BCMA, BAFF-R or another receptor for neutrokine-alpha or APRIL, are responding or has responded to treatment if you have an improved EQ-5D score. In another specific embodiment, a lupus patient who is being treated or has been treated with a neutrocyan-alpha antagonist, including without limitation an anti-neutrocyan-alpha antibody or binding fragment thereof, a neutrocytic receptor protein, is considered. -alpha (eg, TACI, BCMA or BAFF-R) or fragment or variant thereof, an anti-neutrocin-alpha receptor antibody (eg, TACI, BCMA or BAFF-R) or binding fragment thereof, neutrocin-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or RNAci's directed to neutrocine-alpha, APRIL, TACI, BCMA, BAFF-R or another receptor for neutrokine-alpha or APRIL, are responding or has responded to treatment does have an improved EQ-5D score compared to the patient's EQ-5D score. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine-alpha antibody peptide. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutral-alpha protein that functions as a negative dominant. In a specific embodiment, a lupus patient who is being treated or has been treated with a neutrocyan-alpha antagonist, including without limitation an anti-neutrocyan-alpha antibody or binding fragment thereof, a neutrocytic receptor protein, is considered. -alpha (eg, TACI, BCMA or BAFF-R) or fragment or variant thereof, an anti-neutrocin-alpha receptor antibody (eg, TACI, BCMA or BAFF-R) or binding fragment thereof, neutrocin-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or RNAci's directed to neutrocine-alpha, APRIL, TACI, BCMA, BAFF-R or another receptor for neutrokine-alpha or APRIL, are responding or has responded to treatment if it shows a reduction in fatigue according to the patient's FACIT-F score. In another specific modality, a lupus patient who is being treated or has been treated with a neutral-alpha antagonist, including without limitation an anti-neutrocyan-alpha antibody or binding fragment thereof, a neutrokine-alpha receptor protein (for example, TACI, BCMA or BAFF-R) or fragment or variant thereof, an anti-neutrocine-alpha receptor antibody (eg, TACI, BCMA or BAFF-R) or binding fragment thereof, binding polypeptides of neutrocin-alpha, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or RNAci's targeting neutrocin-alpha, APRIL, TACI, BCMA, BAFF-R or another receptor for neutrokine-alpha or APRIL, is responding or has responded The treatment does show a reduction in fatigue according to the patient's FACIT-F score, compared to the patient's FACIT-F reference score. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine-alpha antibody peptide. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutral-alpha protein that functions as a negative dominant. In a specific embodiment, a lupus patient who is being treated or has been treated with a neutrocyan-alpha antagonist, including without limitation an anti-neutrocyan-alpha antibody or binding fragment thereof, a neutrocytic receptor protein, is considered. -alpha (eg, TACI, BCMA or BAFF-R) or fragment or variant thereof, an anti-neutrocin-alpha receptor antibody (eg, TACI, BCMA or BAFF-R) or binding fragment thereof, neutral-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or RNAci's targeting neutrokine-alpha, APRIL, TACI, BCMA, BAFF-R or another receptor for neutrokine-alpha or APRIL, is responding or has responded to treatment if it has an improved DAS28 score. In another specific embodiment, a lupus patient who is being treated or has been treated with a neutrophil-alpha antagonist, including without limitation an anti-neutrocyan-alpha antibody or binding fragment thereof, a neutrocytic receptor protein, is considered. -alpha (eg, TACI, BCMA or BAFF-R) or fragment or variant thereof, an anti-neutrocin-alpha receptor antibody (eg, TACI, BCMA or BAFF-R) or binding fragment thereof, neutral-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or RNAci's targeting neutrokine-alpha, APRIL, TACI, BCMA, BAFF-R or another receptor for neutrokine-alpha or APRIL, is responding or has responded to treatment if it has an improved DAS28 score compared to the patient's DAS28 reference score. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine-alpha antibody peptide. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutral-alpha protein that functions as a negative dominant. In another specific embodiment, a lupus patient who is being treated or has been treated with a neutrophil-alpha antagonist, including without limitation an anti-neutrocyan-alpha antibody or binding fragment thereof, a neutrocytic receptor protein, is considered. -alpha (for example, TACI, BCMA or BAFF-R) or fragment or variant thereof, an anti-neutrocin-alpha receptor antibody (e.g., TACI, BCMA or BAFF-R) or binding fragment thereof, neutrokine-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or RNAci's directed to neutrocine-alpha, APRIL, TACI, BCMA, BAFF-R or another receptor for neutrokine-alpha or APRIL, is responding or has responded to treatment if it presents a decrease in the frequency or duration of attacks. In another specific modality, it is considered that a patient of lupus who is being treated or who has been treated with an antagonist of neutrocine-alpha, is responding or has responded to the treatment if it presents a decrease in the frequency or duration of the attacks, in comparison with the frequency or duration of attacks before treatment with the neutrokine-alpha antagonist. In another specific modality, it is considered that a patient of lupus who is being treated or has been treated with an antagonist of neutrocína-alfa, is responding or has responded to the treatment if it presents a decrease in the severity of the attacks. In another specific modality, it is considered that a patient of lupus who is being treated or who has been treated with a neutral-alpha antagonist, is responding or has responded to the treatment if it presents a decrease in the severity of the attacks in comparison with the severity of the attacks before treatment with the neutrokine-alpha antagonist. The rate of attacks of SLE determines the frequency and severity of exacerbations of lupus symptoms (attacks). Attacks are classified as "mild or moderate" or "severe." Mild or moderate attacks include one or more of the following: changing the SELENA SLEDAI score of 3 points or more; discoid new / worse, photosensitivity, profundus, cutaneous vasculitis or bullous lupus; nasopharyngeal ulcers; pleuritis; pericarditis; arthritis; fever (SLE); increase in prednisone but not greater than 0.5 mg / kg / day; addition of NSAID or plaquenil for the activity of the disease; and increase greater than 1.0 in the PGA score, but not greater than 2.5. Severe attacks include one or more of the following: changing the SELENA SLEDAI score to more than 12; SLE-SNC new / worse; vasculitis; nephritis; myositis; Plt < 60,000; iron anemia (< 7% or decrease in Hb> 3%); doubling the dose of prednisone; increase in prednisone to more than 0.5 mg / kg / day; Cytoxan prescription; prescription of azathioprine; Prescription of methotrexate; hospitalization (SLE) and increase of the PGA score to more than 2.5. In another specific modality, it is considered that a patient of lupus who is being or has been treated with an antagonist of neutrocina-alfa, is responding or has responded to the treatment if it presents a decrease in the frequency or severity of the attacks measured according to the index of SLE attacks. In another specific modality, it is considered that a patient of lupus who is being or has been treated with an antagonist of neutrocína-alfa, is responding or has responded to the treatment if it presents a decrease in the frequency or severity of the attacks according to the index of SLE attacks compared to the frequency or severity of attacks prior to treatment with the neutrokine-alpha antagonist. In another specific modality, it is considered that a lupus patient who is being or has been treated with a neutral-alpha antagonist is responding or has responded to the treatment if it presents a decrease in the frequency or severity of the attacks, measured according to a modified version of the SLE attack index. In another specific modality, it is considered that a lupus patient who is being or has been treated with a neutral-alpha antagonist, is responding or has responded to the treatment without limitation has a decrease in the frequency or severity of the attacks, measured according to a modified version of the SLE attack rate, compared to the frequency or severity of attacks prior to treatment with the neutrokine-alpha antagonist. The modified version of the SLE attack index excludes severe attacks triggered only by changing the SELENA SLEDAI score. In a specific embodiment, the neutrophil-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a peptide of anti-neutrocine-alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutral-alpha protein that functions as a negative dominant. The above-described disease activity indices (eg, SELENA SLEDAI, PGA, BILAG, SLE attack index, health examination score SF-36, EQ-5D, FACIT-F, DAS28) can be used to assess the status of a lupus patient individually or in combination. Improvements in a patient's health measured by means of these rates of disease activity can also be determined at a time after the start of treatment with a neutrophil-alpha antagonist or other immunomodulatory agent known or described herein, which includes without limitation an anti-neutrocin alfa antibody or binding fragment thereof, a neutrocin-alpha receptor protein (eg, TACI, BCMA or BAFF-R) or fragment or variant thereof, an anti-neutrocyte receptor antibody alpha (eg, TACI, BCMA or BAFF-R) or binding fragment thereof, neutrokine-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or RNAci's directed to neutrocine-alpha, APRIL, TACI, BCMA, BAFF-R or another receptor for neutrokine-alpha or APRIL, with respect to one or more of the previous measurements of the patient's disease activity index score. Additionally, in a specific embodiment, it is considered that a lupus patient who is being treated or has been treated with a neutrocin-alpha antagonist or other immunomodulatory agent is responding or has responded to treatment if the patient maintains an activity score of Improved disease with respect to a previous measurement. In a specific embodiment, one or more disease index scores are determined before starting treatment with a neutrokine-alpha antagonist or other immunomodulatory agent in 1, 2, 3, 4, 5, 6 7, 8, 9, 10 , 11, or 12 weeks, months or years after beginning treatment with the neutrokine-alpha antagonist or other immunomodulatory agent. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine-alpha antibody peptide. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutral-alpha protein that functions as a negative dominant. In a specific embodiment, a lupus patient with manifestation of the disease in one or more organs / systems is treated with a neutrokine-alpha antagonist or other immunomodulatory agent known in the art or described herein, including without limitation an antibody anti-neutrocin alfa or binding fragment thereof, a neutrokine-alpha receptor protein (e.g., TACI, BCMA or BAFF-R) or a fragment or variant thereof, an anti-neutrocin-alpha receptor antibody (by example, TACI, BCMA or BAFF-R) or a binding fragment thereof, neutrophil-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or RNAci's directed to neutrocine-alpha, APRIL, TACI, BCMA, BAFF-R or another receptor for neutrocine-alpha or APRIL. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrophil-alpha antagonist is an anti-neutrocin-alpha antibody peptide. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutral-alpha protein that functions as a negative dominant. In specific embodiments, a lupus patient with manifestation of the disease in one or more internal organ systems, with or without involvement of the mucocutaneous or musculoskeletal systems, is treated with a neutrokine-alpha antagonist or other immunomodulatory agent known in the art or described in the present. In specific embodiments, a lupus patient with manifestation of the disease in one or more internal organ systems, without involvement of the mucocutaneous or musculoskeletal systems, is treated with a neutrokine-alpha antagonist or other immunomodulatory agent known in the art or described in the present. In lupus, disease manifestations involving the mucocutaneous or musculoskeletal systems include, without limitation, discoid rash, malar rash or other skin rash, mucosal ulceration, panniculitis, cutaneous vasculitis, digital infarcts, digital thrombosis, alopecia, periungual erythema, pernio, splinter hemorrhages, myositis, polyarthritis, arthritis, tendonitis, arthralgia and myalgia. In lupus, the systems of internal organs that can be affected by lupus include, without limitation, the nervous system, the circulatory system, the respiratory system, the urinary / excretory system, the digestive system, and the eyes. The manifestation of lupus in the nervous system includes, without limitation, aseptic meningitis, cerebral vasculitis, demyelinating syndrome, myelopathy, acute state of confusion, psychosis, acute inflammatory demyelinating polyradiculoneuropathy, mononeuropathy, cranial neuropathy, plexopathy, polyneuropathy, convulsion disorder, state epileptic, cerebrovascular disease not due to vasculitis, cognitive dysfunction, movement disorder, autonomic disorder, cerebellar ataxia, headache, migraine, mood disorder and anxiety disorder. The manifestations of lupus disease in the circulatory system include, without limitation, myocarditis, heart failure, arrhythmia, new valvular dysfunction, serositis, cardiac tamponade, pleural effusion with dyspnea, pulmonary hemorrhage, pulmonary vasculitis, interstitial alveolitis, interstitial pneumonitis, syndrome of shrinkage of the lung, aortitis and coronary vasculitism. The manifestations of lupus disease in the digestive system include, without limitation, peritonitis, abdominal serositis, ascites, lupus enteritis, lupus colitis, malabsorption, protein-losing enteropathy, hepatitis, intestinal pseudo-obstruction, acute cholecystitis, and pancreatitis. acute The manifestations of lupus disease associated with the eye include, without limitation, orbital inflammation, keratitis, anterior uveitis, posterior uveitis, retinal vasculitis, episcleritis, scleritis, retinal / choroidal vaso-occlusive disease, cutoid bodies, optic neuritis, and anterior ischemic optic neuropathy . The response of a patient to treatment with a neutrokine-alpha antagonist or other immunomodulatory agent known in the art or described herein, including without limitation an anti-neutrocin alfa antibody or binding fragment thereof, a neutrocytic receptor protein -alpha (eg, TACI, BCMA or BAFF-R) or fragment or variant thereof, an anti-neutrocin-alpha receptor antibody (eg, TACI, BCMA or BAFF-R) or binding fragment thereof, neutrokine-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or RNAci's directed to neutrocine-alpha, APRIL, TACI, BCMA, BAFF-R or another receptor for neutrokine-alpha or APRIL, also it can be monitored by determining biomarkers at one or more intervals after starting treatment and comparing the biomarker determination of the patient with the patient's reference values or a previous measurement of the same biomarkers. Biomarkers that can be used include, without limitation, immunoglobulin concentrations (e.g., total serum immunoglobulin and IgM, IgG, IgA or IgE in serum), autoantibody concentrations (e.g., anti-dsDNA antibody, anti-CCP antibody). , anti-Ro / SS-A antibody, anti-La / SS-B antibody, anti-RNP antibody, anti-cardiolipin antibody (anti-phospholipid) and anti-Sm antibody, and also the ANA titer), number of cells B (e.g., total number of B cells, number of activated B cells, number of intact B cells, number of memory B cells, number of B plasma cells, and number of plasma B cells, total number of B cells CD19 + or CD20 +), C4 complement concentration, C3 complement concentration. In a specific modality, biomarker measurements are taken before starting treatment with a neutrokine-alpha antagonist or other immunomodulatory agent, and 1, 2, 3, 4, 5, 6 7, 8, 9, 10, 11, or 12 weeks, months or years after starting treatment with the neutrokine-alpha antagonist or other immunomodulatory agent. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific modality, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine-alpha antibody peptide. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutral-alpha protein that functions as a negative dominant. In a specific embodiment, it is considered that a lupus patient who is being treated or has been treated with a neutrokine-alpha antagonist or other immunomodulatory agent known in the art or described herein, including without limitation an anti-neutrocyte antibody alpha or binding fragment thereof, a neutrocin-alpha receptor protein (eg, TACI, BCMA or BAFF-R) or fragment or variant thereof, an anti-neutrocin-alpha receptor antibody (eg, TACI, BCMA or BAFF-R) or binding fragment thereof, neutrokine-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or RNAi's directed to neutrocine-alpha, APRIL, TACI, BCMA, BAFF -R or another receptor for neutrocin-alpha or APRIL, is responding or has responded to treatment if it presents a decrease in the immunoglobulin concentration (for example, the total immunoglobulin concentration in the serum, and also the concentration IgM, IgG, IgA, or IgE in serum), compared to the patient's immunoglobulin reference measurement. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine-alpha antibody peptide. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutral-alpha protein that functions as a negative dominant. In a specific embodiment, it is considered that a lupus patient who is being treated or who has been treated with a neutrocin-alpha antagonist or other immunomodulatory agent is responding or has responded to treatment if he or she exhibits a decrease in the immunoglobulin concentration ( example, the total concentration of immunoglobulin in the serum, and also the concentration of IgM, IgG, IgA, or IgE in the serum), compared to one or more of the patient's previous immunoglobulin measurements. In a specific embodiment, it is considered that a lupus patient who is being treated or has been treated with a neutrocin-alpha antagonist or other immunomodulatory agent is responding or has responded to treatment if he maintains a decreased immunoglobulin concentration (e.g. the total immunoglobulin concentration in the serum, and the concentration of IgM, IgG, IgA, or IgE in the serum), compared with one or more of the patient's previous immunoglobulin measurements. In a specific embodiment, it is considered that a lupus patient who is being treated or has been treated with a neutral-alpha antagonist or other immunomodulatory agent is responding or has responded to the treatment if the patient manages to have a normal immunoglobulin concentration ( for example, the total concentration of immunoglobulin in the serum, and the concentration of IgM, IgG, IgA, or IgE in the serum). In a specific embodiment, a lupus patient who is being treated or has been treated with a neutrocyan-alpha antagonist, including without limitation an anti-neutrocyan-alpha antibody or binding fragment thereof, a neutrocytic receptor protein, is considered. -alpha (eg, TACI, BCMA or BAFF-R) or fragment or variant thereof, an anti-neutrocin-alpha receptor antibody (eg, TACI, BCMA or BAFF-R) or binding fragment thereof, neutrocin-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or RNAci directed to neutrocine-alpha, APRIL, TACI, BCMA, BAFF-R or another receptor for neutrokine-alpha or APRIL, is responding or has responded to treatment if it presents a decrease in autoantibody levels (eg, anti-dsDNA antibody, anti-CCP antibody, anti-Ro / SS-A antibody, anti-La / SS-B antibody, anti-RNP antibody, anti-cardiolipin antibody (anti-phospholipid) and anti-Sm antibody, and also the ANA titer), compared to autoantibody measurements of patient reference. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine-alpha antibody peptide. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutral-alpha protein that functions as a negative dominant. In a specific embodiment, it is considered that a lupus patient who is being treated or has been treated with a neutrokine-alpha antagonist or other immunomodulatory agent is responding or has responded to treatment if he or she exhibits a decrease in autoantibody levels ( example, anti-dsDNA antibody, anti-CCP antibody, anti-Ro / SS-A antibody, anti-La / SS-B antibody, anti-RNP antibody, anti-cardiolipin antibody (anti-phospholipid) and anti-Sm antibody, and also the ANA title), compared to one or more of the patient's previous autoantibody measurements. In a specific embodiment, it is considered that a lupus patient who is being treated or has been treated with a neutrocin-alpha antagonist or other immunomodulatory agent is responding or has responded to treatment if the patient maintains a decreased autoantibody concentration ( example, anti-dsDNA antibody, anti-CCP antibody, anti-Ro / SS-A antibody, anti-La / SS-B antibody, anti-RNP antibody, anti-cardiolipin antibody (anti-phospholipid) and anti-Sm antibody, and also the ANA title), compared to one or more previous autoantibody measurements of the patient. In a specific embodiment, it is considered that a lupus patient who is being treated or has been treated with a neutrocin-alpha antagonist or another immunomodulatory agent is responding or has responded to treatment if the patient is able to obtain a normal autoantibody concentration ( for example, anti-dsDNA antibody, anti-CCP antibody, anti-Ro / SS-A antibody, anti-La / SS-B antibody, anti-RNP antibody, anti-cardiolipin antibody (anti-phospholipid) and anti-Sm antibody , and also the title of ANA). In a specific embodiment, the autoantibodies of the IgG isotype are measured. In a specific embodiment, a lupus patient who is being treated or has been treated with a neutrokine-alpha antagonist or other immunomodulatory agent, including without limitation an anti-neutrocin alfa antibody or binding fragment thereof, is considered a Neutrokine-alpha receptor protein (eg, TACI, BCMA or BAFF-R) or fragment or variant thereof, an anti-neutrocine-alpha receptor antibody (eg, TACI, BCMA or BAFF-R) or fragment of binding thereof, neutrokine-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or RNAci's directed to neutrocine-alpha, APRIL, TACI, BCMA, BAFF-R or another receptor for neutrokine-alpha or APRIL, is responding to or has responded to treatment if it shows a decrease in the number of B cells (eg, total number of B cells, number of activated B cells, number of intact B cells, number of B plasma cells, and number from cé plasmacytoid B cells, total number of CD19 + or CD20 + B cells), compared with the measurement of the number of B reference cells of the patient. In a specific modality, the neutrokine-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine-alpha antibody peptide. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutral-alpha protein that functions as a negative dominant. In a specific embodiment, it is considered that a lupus patient who is being treated or has been treated with a neutrocin-alpha antagonist or other immunomodulatory agent is responding or has responded to treatment if he or she shows a decrease in the number of B cells (eg, example, total number of B cells, number of activated B cells, number of intact B cells, number of plasma B cells, and number of plasmacytoid B cells, total number of CD19 + or CD20 + B cells), compared to one or more of the previous measurements of the B cell number of the patient. In a specific embodiment, it is considered that a lupus patient who is being treated or has been treated with an antagonist of neutrocína-alfa or another immunomodulatory agent, is responding or has responded to the treatment if he maintains a decrease in the number of B cells (for example, total number of B cells, number of activated B cells, number of intact B cells, number of plasma B cells, and number of plasmacytoid B cells, total number of CD19 + or CD20 + B cells), compared to one or more previous measurements of the B-cell number of the patient. In a specific embodiment, it is considered that a lupus patient who is being treated or has been treated with a neutrocin-alpha antagonist or other immunomodulatory agent is responding or has responded to treatment if he manages to have a normal B cell number (for example, total number of B cells, number of activated B cells, number of intact B cells, number of plasma B cells, and number of plasmacytoid B cells, total number of CD19 + or CD20 + B cells). In a specific embodiment, it is considered that a lupus patient who is being treated or has been treated with a neutrokine-alpha antagonist or other immunomodulatory agent known in the art or described herein, including without limitation an anti-neutrocyte antibody alpha or binding fragment thereof, a neutrocin-alpha receptor protein (eg, TACI, BCMA or BAFF-R) or fragment or variant thereof, an anti-neutrocin-alpha receptor antibody (eg, TACI, BCMA or BAFF-R) or binding fragment thereof, neutrokine-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or RNAi's directed to neutrocine-alpha, APRIL, TACI, BCMA, BAFF -R or another receptor for neutrocin-alpha or APRIL, is responding or has responded to treatment if it presents an increase in the concentration of complement factor C4 in the serum compared to the measurement of C4 reference of the patient. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine-alpha antibody peptide. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutral-alpha protein that functions as a negative dominant. In a specific embodiment, it is considered that a lupus patient who is being treated or has been treated with a neutrokine-alpha antagonist or other immunomodulatory agent, is responding or has responded to treatment if he presents an increase in the concentration of C4 compared to with one or more of the patient's previous C4 measurements. In a specific modality, it is considered that a lupus patient who is being treated or has been treated with a neutrocin-alpha antagonist or another immunomodulatory agent is responding or has responded to treatment if he maintains an increase in the concentration of C4 compared to one or more of the patient's previous C4 measurements. In a specific embodiment, it is considered that a lupus patient who is being treated or has been treated with a neutrocin-alpha antagonist or other immunomodulatory agent is responding or has responded to treatment if he manages to obtain a normal concentration of C4.

In a specific embodiment, it is considered that a lupus patient who is being treated or has been treated with a neutrokine-alpha antagonist or other immunomodulatory agent known in the art or described herein, including without limitation an anti-neutrocyte antibody alpha or binding fragment thereof, a neutrocin-alpha receptor protein (e.g., TACI, BCMA or BAFF-R) or fragment or variant thereof, an anti-neutrocine-alpha receptor antibody (e.g., TACI, BCMA or BAFF-R) or binding fragment thereof, neutrokine-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or RNAi's directed to neutrocine-alpha, APRIL, TACI, BCMA, BAFF -R or another receptor for neutrocin-alpha or APRIL, is responding or has responded to treatment if it has an increase in the concentration of factor C3 in the serum compared to the C3 measurement of the patient's reference. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine-alpha antibody peptide. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutrophil-alpha protein that functions as a negative dominant. In a specific embodiment, it is considered that a lupus patient who is being treated or has been treated with a neutrocin-alpha antagonist or other immunomodulatory agent is responding or has responded to treatment if he has an increase in C3 concentration in comparison with one or more of the patient's previous C3 measurements. In a specific embodiment, it is considered that a lupus patient who is being treated or has been treated with a neutrokine-alpha antagonist or another immunomodulatory agent is responding or has responded to treatment if he maintains an increase in C3 concentration in comparison with one or more previous C3 measurements of the patient. In a specific embodiment, it is considered that a lupus patient who is being treated or has been treated with a neutrocin-alpha antagonist or other immunomodulatory agent is responding or has responded to treatment if he manages to obtain a normal concentration of C3. In specific embodiments, the invention provides a method of treating a patient who has previously been treated with one or more immunosuppressants, which comprises administering a therapeutically effective amount of a neutrocyan-alpha antagonist or other immunomodulatory agent known in the art or described in present, which includes without limitation an anti-neutrocin alfa antibody or binding fragment thereof, a neutrocin-alpha receptor protein (eg, TACI, BCMA or BAFF-R) or fragment or variant thereof, an anti-antibody -neutrocin-alpha receptor (eg, TACI, BCMA or BAFF-R) or binding fragment thereof, neutrokine-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or targeted RNAi to neutrocine-alpha, APRIL, TACI, BCMA, BAFF-R or another receptor for neutrocine-alpha or APRIL. In specific embodiments, the invention provides a method of treating a patient who has previously been diagnosed with systemic lupus erythematosus (lupus) and has previously been treated with one or more immunosuppressants, which comprises administering a therapeutically effective amount of an anti-inflammatory agent. Neutrocin-alpha or another immunomodulatory agent. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific modality, the neutrokine-alpha antagonist is an anti-neutrocine-alpha antibody peptide. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutral-alpha protein that functions as a negative dominant. In specific embodiments, the immunosuppressant previously administered to the patient is azathioprine (e.g., IMURAN ™), cyclophosphamide (e.g., Cytoxan®, Neosar®, CTX), a calcineurin inhibitor, e.g., FK506, tacrolimus or cyclosporin (e.g. , PROGRAF®) or CELLCEPT® (mycophenolate mofetil, whose active metabolite is mycophenolic acid). The most current therapies for lupus and other autoimmune diseases use drugs that nonspecifically block several inflammatory pathways. Perhaps the most dangerous medications used in this therapy are corticosteroids. Although corticosteroids such as prednisone are essential for controlling the manifestations of the disease, they also have many adverse effects on the patient's health, such as global immunosuppression, which produces infection, osteoporosis that produces fractures, and atherosclerosis that produces an early onset of attacks. cardiac and cerebral attacks. In a clinical trial, the applicants found that treatment with an antibody that neutralizes the neutrocyan-alpha protein, administered as an iv infusion on days 0, 14, 28 and then every four weeks up to week 52, was effective in reducing the dose of the corticosteroid prednisone that was necessary to alleviate the manifestations of the disease in lupus patients. Specifically, treatment with anti-neutrocin-alpha antibody appears to be associated with reduced use of prednisone during the last three months of the treatment period. In patients who had an ANA titre of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA at baseline, a higher percentage of subjects who received the anti-neutrocin-alpha antibody reduced their dose of prednisone, whereas, on the contrary, a larger number of subjects who received placebo treatment had increases at a dose of prednisone greater than 7.5 mg / day. Accordingly, in one embodiment, the invention provides a method for reducing the frequency of corticosteroid treatment or the amount of corticosteroid administered to a patient, which comprises administering a therapeutically effective amount of an antagonist of neutrokine-alpha or another known immunomodulating agent. in the art or described herein, including without limitation an anti-neutrocin alfa antibody or binding fragment thereof, a neutrocin-alpha receptor protein (eg, TACI, BCMA or BAFF-R) or fragment or variant of the same, an anti-neutrocin-alpha receptor antibody (e.g., TACI, BCMA or BAFF-R) or binding fragment thereof, neutrokine-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and Antisense RNAs or RNAci's directed to neutrocin-alpha, APRIL, TACI, BCMA, BAFF-R or another receptor for neutrocine-alpha or APRIL. In specific modalities, the corticosteroid is prednisone, prednisolone, hydrocortisone, methylprednisolone or dexamethasone. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine-alpha antibody peptide. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutral-alpha protein that functions as a negative dominant. In a specific embodiment, the patient whose corticosteroid therapy is reduced is a patient suffering from inflammation. In another specific embodiment, the patient whose corticosteroid therapy is reduced is a patient suffering from an autoimmune disease, which includes without limitation rheumatoid arthritis, Sjogren's syndrome or other autoimmune disease such as those noted here. Accordingly, in a specific embodiment, the invention provides a method for reducing the frequency of corticosteroid treatment or the amount of corticosteroid administered to a patient with systemic lupus erythematosus (lupus), which comprises administering a therapeutically effective amount of a neutrokinetic antagonist. α-alpha or other immunomodulatory agent known in the art or described herein, including without limitation an anti-neutrocin alfa antibody or binding fragment thereof, a neutrocin-alpha receptor protein (eg, TACI, BCMA or BAFF- R) or fragment or variant thereof, a neutrokine-alpha antireceptor antibody (eg, TACI, BCMA or BAFF-R) or binding fragment thereof, neutrokine-alpha binding polypeptides, neutrocytic polypeptide variants- alpha or APRIL, and antisense RNAs or RNAci's directed to neutrocine-alpha, APRIL, TACI, BCMA, BAFF-R or another receptor for neutrokine-alpha or APRIL. In another specific embodiment, the invention provides a method for reducing the frequency of prednisone treatments or the amount of prednisone administered to a patient with systemic lupus erythematosus (lupus), which comprises administering a therapeutically effective amount of a neutrokine-alpha antagonist or another immunomodulatory agent, including without limitation an anti-neutrocin alfa antibody or binding fragment thereof, a neutrocin-alpha receptor protein (eg, TACI, BCMA or BAFF-R) or fragment or variant thereof, a anti-neutrocine-alpha receptor antibody (eg, TACI, BCMA or BAFF-R) or binding fragment thereof, neutrokine-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense or RNAci directed to neutrocin-alpha, APRIL, TACI, BCMA, BAFF-R or another receptor for neutrocine-alpha or APRIL. In this context, the "therapeutically effective amount" refers to an amount that reduces the corticosteroid necessary to alleviate the manifestations of the disease for which corticosteroids are normally prescribed. These manifestations are well known by clinicians and doctors, since they are the methods to determine the amount of antibody / effective composition to reduce the severity of these manifestations. In preferred embodiments, the dose of the antibody of the invention administered to a patient is 0.1 mg / kg to 100 mg / kg of patient's body weight. Preferably, the dose administered to a patient is between 0.1 mg / kg and 20 mg / kg of the patient's body weight. In highly preferred embodiments, the dose administered to a patient is 1, 4, 10, or 20 mg / kg. In a specific embodiment, the amount of corticosteroid administered to a patient (for example prednisone) is reduced from a previously higher dose to <80 milligrams / day, while the same patient is concomitantly in a treatment regimen comprising the administration of a neutrokine-alpha antagonist or other immunomodulatory agent known or described herein, including without limitation an anti-neutrocyte antibody alpha or binding fragment thereof, a neutrocin-alpha receptor protein (eg, TACI, BCMA or BAFF-R) or fragment or variant thereof, an anti-neutrocin-alpha receptor antibody (eg, TACI, BCMA or BAFF-R) or binding fragment thereof, neutrokine-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or RNAi's directed to neutrocine-alpha, APRIL, TACI, BCMA, BAFF -R or another receptor for neutrocin-alpha or APRIL. In a specific embodiment, the amount of corticosteroid administered to a patient (e.g., prednisone) is reduced from a previously higher dose to < 40 milligrams / day, while the same patient is concomitantly in a treatment regimen comprising the administration of a neutrokine-alpha antagonist or another immunomodulatory agent. In a specific embodiment, the amount of corticosteroid administered to a patient (eg prednisone) is reduced from a previously higher dose to less than 20 milligrams / day, while the same patient is concomitantly in a treatment regimen comprising the administration of a neutral-alpha antagonist or other immunomodulatory agent. In a specific embodiment, the amount of corticosteroid administered to a patient (for example prednisone) is reduced from a previously higher dose to = 10 milligrams / day, while the same patient is concomitantly in a treatment regimen comprising administration of a neutrokine-alpha antagonist or other immunomodulatory agent. In a specific embodiment, the amount of corticosteroid administered to a patient (e.g., prednisone) is reduced from a previously higher dose to < 8 milligrams / day, while the same patient is concomitantly in a treatment regimen comprising the administration of a neutrokine-alpha antagonist or other immunomodulatory agent. In a specific embodiment, the amount of corticosteroid administered to a patient (e.g., prednisone) is reduced from a previously higher dose to < 6 milligrams / day while, that same patient is concomitantly in a treatment regimen comprising the administration of a neutrokine-alpha antagonist or other immunomodulatory agent. In a specific embodiment, the amount of corticosteroid administered to a patient (e.g., prednisone) is reduced from a previously higher dose to < 4 milligrams / day, while the same patient is concomitantly in a treatment regimen comprising the administration of a neutrophil-alpha antagonist or other immunomodulatory agent. In a specific embodiment, the amount of corticosteroid administered to a patient (e.g., prednisone) is reduced from a previously higher dose to < 2 milligrams / day, while the same patient is concomitantly in a treatment regimen comprising the administration of a neutrophil-alpha antagonist or other immunomodulatory agent. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrophil-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine-alpha antibody peptide. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutrocyan-alpha protein that functions as a negative dominant. In a specific embodiment, the amount of corticosteroid administered to a patient (for example prednisone) is reduced from a previously higher dose to <7.5 milligrams / day, while the same patient is concomitantly in a treatment regimen comprising the administration of a neutrokine-alpha antagonist or other immunomodulatory agent known in the art or described herein. In a specific embodiment, the amount of corticosteroid administered to a patient (e.g. prednisone) is ultimately reduced by at least 25%, while the patient is concomitantly in a treatment regimen comprising administration of a neutral-alpha antagonist. or another immunomodulatory agent, compared to the dose of prednisone the patient was taking before beginning the treatment regimen comprising the administration of a neutrokine-alpha antagonist or other immunomodulatory agent. In a specific embodiment, the amount of corticosteroid administered to a patient (e.g. prednisone) is ultimately reduced by at least 50%, while the patient is concomitantly in a treatment regimen comprising the administration of a neutral-alpha antagonist. or another immunomodulatory agent, compared to the dose of prednisone the patient was taking before beginning the treatment regimen, which comprises the administration of a neutrokine-alpha antagonist or other immunomodulatory agent. In a specific embodiment, the amount of corticosteroid administered to a patient (for example prednisone) is finally reduced by at least 25% at = 7.5 milligrams / day, while the patient is concomitantly in a treatment regimen comprising administration of a neutrokine-alpha antagonist or other immunomodulatory agent, as compared to the dose of prednisone the patient was taking before beginning the treatment regimen comprising the administration of a neutrokine-alpha antagonist or other immunomodulatory agent. In a specific embodiment, the amount of corticosteroid administered to a patient (e.g., prednisone) is ultimately reduced by at least 50% to < 7.5 milligrams / day, while the patient is concomitantly in a treatment regimen comprising the administration of a neutrokine-alpha antagonist or other immunomodulatory agent, as compared to the dose of prednisone the patient was taking before beginning the regimen. treatment comprising the administration of a neutrokine-alpha antagonist or other immunomodulatory agent. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine-alpha antibody peptide. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutral-alpha protein that functions as a negative dominant.

In a specific embodiment, a patient suspends, temporarily or permanently, corticosteroid therapy (e.g., prednisone), while the same patient is concomitantly in a treatment regimen comprising the administration of a neutrokine-alpha antagonist or other agent immunomodulator. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine-alpha antibody peptide. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutral-alpha protein that functions as a negative dominant. In specific embodiments, the neutrokine-alpha antagonists or other immunomodulatory agents known in the art or described herein are used to treat patients with a clinical diagnosis of rheumatoid arthritis (RA). In specific embodiments, the treated rheumatoid arthritis patient will not have a B-cell malignancy. In addition, the rheumatoid arthritis patient is optionally treated with any one or more agents used to treat RA, such as salicylate; non-steroidal antiinflammatory drugs such as indomethacin, phenylbutazone, phenylacetic acid derivatives (eg, ibuprofen and fenoprofen), naphthaleneacetic acids (naproxen), pyrrolalkanoic acid (tometin), indoleacetic acids (sulindac), halogenated anthranilic acid (sodium meclofenamate), piroxicam , zomepirac and diflunisal; antimalarials such as chloroquine; gold salts; penicillamine; or immunosuppressive agents such as methotrexate or corticosteroids, at known doses for such drugs, or at reduced doses. However, preferably, the rheumatoid arthritis patient is only treated with the neutrokine-alpha antagonist or other immunomodulatory agent known in the art or described herein. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrophil-alpha antagonist is an anti-neutrocin-alpha antibody peptide. In a specific embodiment, the neutrophil-alpha antagonist is a fragment or variant of neutrocyan-alpha protein that functions as a negative dominant. Such immunomodulatory agents are administered to the RA patient according to a dosage regimen that can be readily determined by the skilled person. The primary response is determined by the Paulus index (Paulus et al., Arthritis Rheum 33: 477-484 (1990)), ie, improvement in morning stiffness, the number of painful and swollen joints, erythrocyte sedimentation (ESR) ), and at least an improvement of 2 points on a scale of disease severity of 5 points determined by the patient and by the physician. Administration of the neutrokine-alpha antagonist or other immunomodulatory agent known in the art or described herein will alleviate one or more of the symptoms of RA in the patient treated as described above. In a phase 2 clinical trial (example 3), in which rheumatoid arthritis patients received an antibody treatment that neutralizes the neutrocyan-alpha protein, administered as an iv infusion on days 0, 14, 28 and then every 4 weeks Up to week 24, the likelihood of alleviating the symptoms associated with rheumatoid arthritis increased in patients who had a DAS28 score greater than 5.1, in patients who had not previously received anti-TNF therapy, or in patients who had a rheumatoid factor in their plasma or blood serum before starting the treatment with the antibody that neutralizes the protein neutrocin-alpha. Additional subgroups where the likelihood of responding to treatment with the antibody neutralizing the neutrocyan-alpha protein seemed to increase, included male patients, patients who had anti-CCP antibodies (citric cyclic peptide) in their plasma or blood serum, patients who received methotrexate concomitantly with the antibody that neutralizes the protein neutrocin-alpha, patients who had previously not responded to treatment with methotrexate , or patients who previously had not responded to methotrexate therapy and at least one other DMARD therapy. Accordingly, the invention provides a method of treating a rheumatoid arthritis patient with a neutrokine-alpha antagonist or other immunomodulatory agent known in the art or described herein, wherein said rheumatoid arthritis patient has one or more of the following characteristics: the patient has not previously received anti-TNF therapy, for example Infliximab (also known as Remicade ™, Centocor, Inc.), adalimumab (Humira® from Abbott Laboratories) or etanercept (Enbrel®); the patient has the rheumatoid factor in their plasma or blood serum; the patient has measurable anti-CCP (cyclic peptide) antibodies in their plasma or blood serum; the patient has a high concentration of CRP (reactive protein C) in his plasma or blood serum; the patient has not previously responded to treatment with one or more disease-modifying antirheumatic drugs; the patient has a high score of modified disease activity (DAS28); the patient has swollen and painful joints; the patient suffers from morning stiffness; the patient has an increase in the rate of erythrocyte sedimentation (ESR), or the patient is male. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine-alpha antibody peptide. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutrophil-alpha protein that functions as a negative dominant. In specific modalities, the rheumatoid arthritis patient has 12 IU / ml or more of rheumatoid factor in his plasma or blood serum. In specific embodiments, a high CRP concentration is defined as at least 1.5 milligrams per liter. In specific embodiments, a high concentration of CRP is defined as at least 5 milligrams per liter. In specific embodiments, a high concentration of CRP is defined as at least 6 milligrams per liter. In specific embodiments, a high concentration of CRP is defined as at least 9 milligrams per liter. In specific embodiments, a high concentration of CRP is defined as at least 10 milligrams per liter. In specific embodiments, a high concentration of CRP is defined as at least 20 milligrams per liter. In specific embodiments, the rheumatoid arthritis patient has 10 or more anti-CCP antibody units in his plasma or blood serum. In specific embodiments, the rheumatoid arthritis patient has 20 or more anti-CCP antibody units in his plasma or blood serum. In specific modalities, the patient had previously not responded to treatment with one or more DMARDs, which include without limitation methotrexate, aminoquinolone, sulfasalazine, and leflunomide. In specific modalities, the patient had previously not responded to treatment with methotrexate. In specific modalities, the patient has a DAS28 score greater than 5.1. In specific modalities, the patient has at least 6 swollen joints and at least 8 aching joints. In specific modalities, the patient has an ESR greater than 28 mm / h. In specific modalities, the patient suffers from morning stiffness for at least 45 minutes. In specific modalities, the patient suffers from morning stiffness for at least 1 hour. In specific modalities, the patient suffers from morning stiffness for at least one and a half hours. In specific modalities, the patient suffers from morning stiffness for at least 2 hours. In a specific embodiment, the neutrophil-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrophil-alpha antagonist is an anti-neutrocin-alpha antibody peptide. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutral-alpha protein that functions as a negative dominant. Accordingly, the invention provides a method of treating a patient with rheumatoid arthritis with a neutrokine-alpha antagonist or other immunomodulatory agent known in the art or described herein., which includes without limitation an anti-neutrocin alfa antibody or binding fragment thereof, a neutrophil-alpha receptor protein (eg, TACI, BCMA or BAFF-R) or fragment or variant thereof, an anti-receptor antibody of neutrocine-alpha (eg, TACI, BCMA or BAFF-R) or binding fragment thereof, neutrokine-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or RNAci's directed to neutrocine -alpha, APRIL, TACI, BCMA, BAFF-R or another receptor for neutrocin-alpha or APRIL, wherein said rheumatoid arthritis patient has one or more of the following characteristics: the patient has not previously received an anti-TNF therapy, for example Infliximab (also known as Remicade ™, Centocor, Inc.), adalimumab (Humira® from Abbott Laboratories) or etanercept (Enbrel®); the patient has the rheumatoid factor in their plasma or blood serum; the patient has measurable anti-CCP (cyclic peptide) antibodies in their plasma or blood serum; the patient has a high concentration of CRP (reactive protein C) in his plasma or blood serum; the patient has not previously responded to treatment with one or more disease-modifying antirheumatic drugs; the patient has a high score of modified disease activity (DAS28); the patient has swollen and painful joints; the patient suffers from morning stiffness; the patient has an increase in the rate of erythrocyte sedimentation (ESR), or the patient is male. In specific modalities, the rheumatoid arthritis patient has 12 IU / ml or more of rheumatoid factor in his plasma or blood serum. In specific embodiments, a high concentration of CRP is defined as at least 1.5 milligrams per liter. In specific embodiments, a high concentration of CRP is defined as at least 5 milligrams per liter. In specific embodiments, a high concentration of CRP is defined as at least 6 milligrams per liter. In specific embodiments, a high concentration of CRP is defined as at least 9 milligrams per liter. In specific embodiments, a high concentration of CRP is defined as at least 10 milligrams per liter. In specific embodiments, a high concentration of CRP is defined as at least 20 milligrams per liter. In specific embodiments, the rheumatoid arthritis patient has 10 or more anti-CCP antibody units in his plasma or blood serum. In specific embodiments, the rheumatoid arthritis patient has 20 or more anti-CCP antibody units in his plasma or blood serum. In specific modalities, the patient had previously not responded to one or more DMARDs, which include without limitation methotrexate, aminoquinolone, sulfasalazine and leflunomide. In specific modalities, the patient had previously not responded to treatment with methotrexate. In specific modalities, the patient has a DAS28 score greater than 5.1. In specific modalities, the patient has at least 6 swollen joints and at least 8 aching joints. In specific modalities, the patient has an ESR greater than 28 mm / h. In specific modalities, the patient suffers from morning stiffness for at least 45 minutes. In specific modalities, the patient suffers from morning stiffness for at least one hour. In specific modalities, the patient suffers from morning stiffness for at least one and a half hours. In specific modalities, the patient suffers from morning stiffness for at least 2 hours. In another specific embodiment, a rheumatoid arthritis patient who is being treated or has been treated with a neutrokine-alpha antagonist or other immunomodulatory agent known in the art or described herein, including without limitation an anti-HIV antibody, is considered. -neutrocin alfa or binding fragment thereof, a neutrocin-alpha receptor protein (eg, TACI, BCMA or BAFF-R) or fragment or variant thereof, an anti-neutrocin-alpha receptor antibody (eg, TACI, BCMA or BAFF-R) or binding fragment thereof, neutrokine-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or RNAci's directed to neutrocine-alpha, APRIL, TACI, BCMA , BAFF-R or another receptor for neutrocine-alpha or APRIL, is responding or has responded to treatment if it has managed to obtain an ACR20 response. The ACR20 is an index developed by the American College of Rheumatology (ACR) to determine the patient's response to the treatment of rheumatoid arthritis. An ACR20 response is defined as a reduction of at least 20% in the account of painful joints and the swollen joint count, in addition to an improvement of at least 20% in another three of five determinations of symptoms or manifestations of disease ( this is, determination of patient's pain, global determination of the patient, overall determination of the doctor, self-determined disability by the patient, acute phase reagent [ESR or CRP]). In a specific embodiment, the neutrophil-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocin-alpha antibody peptide. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutral-alpha protein that functions as a negative dominant. In another specific embodiment, a rheumatoid arthritis patient is considered to be being treated or treated with a neutrokine-alpha antagonist or other immunomodulatory agent known in the art or described herein, including without limitation an anti-cancer antibody. alpha-neutrocin or binding fragment thereof, a neutrokine-alpha receptor protein or fragment or variant thereof, neutrokine-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or RNAi's directed to neutrocin-alfa, APRIL, TACI, BCMA, BAFF-R or another receptor for neutrocin-alpha or APRIL, is responding or has responded to treatment if it has managed to obtain an ACR50 response. The ACR50 is an index developed by the American College of Rheumatology (ACR) to determine the patient's response to the treatment of rheumatoid arthritis. An ACR50 response is defined as a reduction of at least 50% in the account of painful joints and the swollen joint count, in addition to an improvement of at least 50% in another three out of five determinations of symptoms or manifestations of disease ( that is, determination of patient's pain, overall determination of the patient, overall determination of the doctor, self-determined disability by the patient, acute phase reagent [ESR or CRP]). In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine-alpha antibody peptide. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutral-alpha protein that functions as a negative dominant. In another specific embodiment, a rheumatoid arthritis patient is considered to be being treated or treated with a neutrokine-alpha antagonist or other immunomodulatory agent known in the art or described herein, including without limitation an anti-cancer antibody. alpha neutrocin or binding fragment thereof, a neutrocin-alpha receptor protein (eg, TACI, BCMA or BAFF-R) or fragment or variant thereof, an anti-neutrocin-alpha receptor antibody (eg, TACI , BCMA or BAFF-R) or binding fragment thereof, neutrokine-alpha binding polypeptides, neutrokine-alpha or APRIL polypeptide variants, and antisense RNAs or RNAci's directed to neutrocine-alpha, APRIL, TACI, BCMA, BAFF-R or another receptor for neutrophil-alpha or APRIL, is responding or has responded to treatment if it has been successful in obtaining an ACR70 response. The ACR70 is an index developed by the American College of Rheumatology (ACR) to determine the patient's response to the treatment of rheumatoid arthritis. An ACR70 response is defined as a reduction of at least 70% in the account of painful joints and the swollen joint count, in addition to an improvement of at least 70% in another three out of five determinations of symptoms or manifestations of disease ( this is, determination of patient's pain, global determination of the patient, overall determination of the doctor, self-determined disability by the patient, acute phase reagent [ESR or CRP]). In a specific embodiment, the neutrokine-alpha antagonist is an anti-neutrocine alpha antibody. In a specific embodiment, the neutrokine-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the neutrokine-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the neutrophil-alpha antagonist is an anti-neutrocin-alpha antibody peptide. In a specific embodiment, the neutrokine-alpha antagonist is a fragment or variant of neutrocyan-alpha protein that functions as a negative dominant.

Immunomodulatory agents The present invention provides a method for treating a patient having an ANA titer of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies in his or her blood serum or plasma with an immunomodulatory agent. The meaning of "immunomodulatory agent", when used herein, was discussed above. In a specific embodiment, the immunomodulatory agent is an antagonist of neutrocine-alpha. By "antagonist" is meant agents capable of inhibiting or counteracting the biological or functional actions in vitro or in vivo of neutrokine-alpha (eg, stimulation of differentiation, proliferation or survival of B cells, stimulation of Ig production by B cells, and binding to a neutrokine-alpha receptor This inhibition can occur with or without direct physical contact between the antagonist and the neutrokine-alpha polypeptide (eg, the antagonist can modulate an initial effector of neutrocine activity- alpha to reduce such activity.) Tests are herein described to determine the ability of neutrokine-alpha antagonists to inhibit B-cell activity. Neutrocin-alpha antagonists include, without limitation, an anti-neutrocine-alpha antibody , or antigen-binding fragment thereof, a neutrocin-alpha receptor protein or fragment or variant thereof, an antibody that binds to a rec Neutrokine-alpha eptor or antigen-binding fragment thereof, a neutrokine-alpha-binding peptide or polypeptide, or a variant of neutrokine-alpha or APRIL polypeptide (eg, a dominant negative form of neutrokine-alpha or APRIL) ). Additional neutrokine-alpha antagonists include neutrokine-alpha small molecule antagonists, neutrokine-alpha peptidomimetics, antisense RNAs and short interfering RNAs (RNAci's) targeted to neutrocine-alpha, antisense RNAs and short interfering RNAs (RNAi's) targeted to APRIL, and antisense RNAs and short interfering RNAs (RNAi's) directed to receptors for neutrokine-alpha or receptors for APRIL. Each of these are described in more detail below.

Neutrokine-alpha Antagonists A. Neutrokine-alpha and APRIL Polypeptides In a specific embodiment, the neutrokine-alpha antagonist for use in the methods of the present invention, is a polypeptide, fragment or variant of neutrocine-alpha or APRIL. Neutrocin-alpha polypeptides, APRIL polypeptides and fragments and variants thereof are described in more detail below. The neutrophil-alpha protein (SEQ ID NO: 2) is a member of the TNF ligand family that shares amino acid sequence identity with APRIL (SEQ ID NO: 4, GenBank registration No. AF046888; PCT number WO97 / 33902; Hahne, M., et al., J Exp Med. (1998) 188 (6): 1185-90), TNFa and lymphotoxin-a (LTa) (Moore et al., 1999). The full-length neutrokine-alpha gene codes for a polypeptide of 285 amino acids that has an intracellular domain between residues 1 and 46, a domain that covers the transmembrane between residues 47 and 73 preceded by a non-hydrophobic sequence characteristic of type proteins. II bound to the membrane, and an extracellular domain between residues 74 and 285. Like other members of the TNF family, neutrocin-alpha functions as a trimeric protein. Upon expression of the neutrokine-alpha on the surface of the cell, the extracellular domain is digested at amino acid 134 to release a biologically active trimer. The structural characterization reveals that while the ligands of the TNF family demonstrate sequence diversity, they show high structural homology. The neutrokine-alpha protein, like other members of the TNF ligand family, is a two-layer sandwich that forms a structure in the form of a gypsy arm type FNT. The neutrophil-alpha protein is similar to the other ligands of the TNF family in structure and overall dimensions. Nevertheless, the receptor binding region of neutrocin-alpha is a more pronounced groove than that observed for other cytokines (Oren et al., (2002) Nature Structural Biology 9: 288-292). Neutrokine-alpha polypeptides are described in more detail, for example, in the international publication numbers W098 / 18921, WO00 / 50597, WO02 / 1820 and WO03 / 033658, each of which is hereby incorporated herein by reference in its entirety. . As described above, the neutrokine-alpha polypeptides function to stimulate B cell proliferation, differentiation and survival, and Ig secretion. Thus, one would not expect to use the native form of neutrocine-alpha in the methods of the present invention. However, the native form of neutrokine-alpha can be used as a targeting agent to bring in proximity other agents that can inhibit the activity of B cells (e.g., portions or cytotoxic proteins) with a B cell (see, for example. , examples 12 and 13 of WO00 / 033658, wherein radiolabelled neutrocin alfa is used to reach and destroy cells expressing neutrocin-alpha receptors that originate predominantly from B cells). Alternatively, fragments or variants of neutrokine-alpha that bind to one or more neutrokine-alpha receptors but do not induce signaling, can be used as a neutral-alpha antagonist. Fragments or variants of neutrocin-alpha that affect the ability of neutrokine-alpha to form or maintain stable homotrimers or heterotrimers can also be used as an antagonist of neutrocine-alpha in the methods of the invention. In this manner, the neutrokine-alpha polypeptides that can be used in the methods of the present invention include fragments or polypeptide variants of the neutrokine-alpha protein of SEQ ID NO: 2. Fragments or variants of polypeptide can be "autonomous ", or may be comprised within a larger polypeptide of which the fragment forms a part or region, more preferably as an individual continuous region. In specific embodiments, the neutrokine-alpha polypeptides that can be used in the methods of the invention encompass polypeptide fragments comprising, or consisting alternatively of, the predicted extracellular domain of neutrokine-alpha (amino acid residues 73-285 of SEQ ID NO: 2) and the soluble neutrokine-alpha fragment (amino acid residues 134-285 of SEQ ID NO: 2). In another embodiment, fragments or polypeptide variants that can be used in the methods of the invention comprise, or alternatively consist of, a fragment or variant of polypeptide at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to the native neutrocine-alpha polypeptide fragments described above. In another embodiment, the neutrokine-alpha polypeptide variants that can be used in the methods of the present invention include peptidomimetics. Mimetics are molecules that contain peptides that mimic elements of secondary protein structure. See, for example, Johnson et al., "Peptide Turn Mimetics," in "BIOTECHNOLOGY AND PHARMACY," Pezzuto et al., Eds., Chapman and Hall, New York (1993), citation incorporated herein by reference. The fundamental reason supporting the use of peptidomimetics is that the base structure of the peptide of the proteins exists mainly to orient the side chains of amino acids in a way that facilitates molecular interactions, such as those of antibody and antigen. It is expected that a peptidomimetic allows molecular interactions similar to the natural molecule. These principles can be used to design second generation molecules that have many of the natural properties of the target determination peptides described herein, but with altered and even improved characteristics. APRIL (SEQ ID NO: 4) is a member of the TNF ligand family that shares amino acid sequence identity with neutrocine-alpha (SEQ ID NO: 2; GenBank registration number NM_006573; Moore, et al., (1999) Science 285: 260-263; Schneider et al., (1999) J. Exp. Med. 189: 1747-1756; and Khare et al. (2000) Proc. Nati Acad Sci. 97: 3370-3375), TNF-a and lymphotoxin-a (LTa) (Moore, et al., 1999)). The full-length APRIL gene encodes a 250 amino acid polypeptide having an intracellular domain between residues 1 and 28, a transmembrane domain between residues 29 and 49, and an extracellular domain between residues 50 and 250. Like Other members of the FNT family, APRIL works as a trimeric protein. Upon expression of APRIL on the surface of the cell, the extracellular domain is digested at amino acid 105 to release a biologically active trimer. In a specific embodiment, an APRIL polypeptide that can be used in the methods of the present invention includes fragments or polypeptide variants of the APRIL protein of SEQ ID NO: 4. The polypeptide fragments can be "autonomous", or they can be comprised within a larger polypeptide of which the fragment forms a part or region, more preferably as an individual continuous region. In specific embodiments, the APRIL polypeptides that can be used in the methods of the invention encompass polypeptide fragments comprising, or alternatively consisting of, the predicted extracellular domain of APRIL (amino acid residues 50-250 of SEQ ID NO: 4) and the soluble fragment of APRIL (amino acid residues 105-250 of SEQ ID NO: 4). In another embodiment, fragments or polypeptide variants that can be used in the methods of the invention comprise, or alternatively consist of, a fragment or variant of polypeptide at least 80%, 85% ,. 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to the native APRIL polypeptide fragments described above. In another embodiment, the APRIL polypeptide variants that can be used in the methods of the present invention include peptidomimetics. Mimetics are molecules that contain peptides that mimic elements of secondary protein structure. See, for example, Johnson et al., "Peptide Turn Mímetics," in "BIOTECHNOLOGY AND PHARMACY," Pezzuto et al., Eds., Chapman and Hall, New York (1993), citation incorporated herein by reference. The fundamental reason supporting the use of peptidomimetics is that the base structure of the peptide of the proteins exists mainly to orient the side chains of amino acids in a way that facilitates molecular interactions, such as those of antibody and antigen. It is expected that a peptidomimetic allows molecular interactions similar to the natural molecule. These principles can be used to design second generation molecules that have many of the natural properties of the target determination peptides described herein, but with altered and even improved characteristics. The neutrokine-alpha and APRIL polypeptides that can be used in the methods of the invention can be expressed or synthesized in a modified form, such as a fusion protein comprising the polypeptide linked via a peptide bond to a heterologous protein sequence. of a different protein)), and may include not only secretion ligands, but also additional heterologous functional regions. Said fusion protein can be obtained by ligating neutrokine-alpha or APRIL polynucleotides, and the desired nucleic acid sequence coding for the desired amino acid sequence from each other, by methods known in the art, in the proper reading frame, and expressing the fusion protein product by methods known in the art. Alternatively, said fusion protein can be obtained by protein synthesis techniques, for example, by the use of a peptide synthesizer. In this way, for example, a region of additional amino acids, in particular charged amino acids, can be added to the N-terminus of the polypeptide to improve stability and persistence in the host cell, during purification, or during subsequent handling and storage. Also, portions of peptides may be added to the polypeptide to facilitate purification. Said regions can be removed before the final preparation of the polypeptide. The addition of portions of peptides to polypeptides to cause secretion or excretion, to improve stability and to facilitate purification, among other things, are familiar and routine techniques in the art. A preferred neutrokine-alpha or APRIL fusion protein that can be used in the methods of the invention comprises a heterologous immunoglobulin region that is useful for stabilizing and purifying proteins. For example, EP-A-0 464 533 (Canadian counterpart of document 2045869) and WO00 / 024782 disclose fusion proteins comprising several portions of the constant region of immunoglobulin molecules together with another human protein or part Of the same. Neutrokine-alpha-immunoglobulin fusion proteins have been described, for example, in Yu, et al., (2000) Nat Immunol 1: 252-256, citation incorporated herein by reference in its entirety. APRIL-immunoglobulin fusion proteins have been described, for example, in PCT publication WO01 / 087977, incorporated herein by reference in its entirety. In many cases, the Fe part in a fusion protein is completely advantageous for use in therapy and diagnosis, and thus results, for example, in improved pharmacokinetic properties (see EP-A-0232 262). On the other hand, for some uses, it would be desirable to be able to suppress the Fe part after the fusion protein has been expressed, detected and purified in the advantageous manner described. This is the case when the Fe portion proves to be an impediment to its use in therapy and diagnosis, for example, when the fusion protein is used as an antigen for immunizations. In drug discovery, for example, human proteins such as hIL-5 have been fused with Fe portions for the purpose of high throughput identification tests to identify hIL-5 antagonists. See, D. Bennett et al., J. Molecular Recognition 8: 52-58 (1995) and K. Johanson et al., J. Biol. Chem. 270: 9459-9471 (1995). As the skilled artisan will appreciate, and as discussed above, the neutrokine-alpha and APRIL polypeptides can be fused with other polypeptide sequences. For example, the neutrokine-alpha polypeptides that can be used in the methods of the present invention can be fused to the constant domain of immunoglobulins (IgA, IgE, IgG, IgM), or portions thereof (CH1, CH2, CH3, or any combination thereof, and portions thereof), or albumin (including, but not limited to, recombinant human albumin, or fragments or variants thereof (see, e.g., U.S. Patent No. 5,876,969 , issued March 2, 1999, EP 0 413 622, and U.S. Patent No. 5,766,883, issued June 16, 1998, incorporated herein by reference in their entirety), resulting in polypeptides chimeric Such fusion proteins can facilitate purification, can extend shelf life and can increase the half-life in vivo. This has been shown for chimeric proteins consisting of the first two domains of the human CD4 polypeptide and several domains of the constant regions of the heavy or light chains of mammalian immunoglobulins. See, for example, EP 394,827; Traunecker et al., Nature, 331: 84-86 (1988). Intensified delivery of an antigen through the epithelial barrier to the immune system has been demonstrated for antigens (eg, insulin) conjugated to an FcRn binding member, such as fragments of IgG or Fe (see, for example, PCT publications WO 96/22024 and WO 99/04813). It has also been found that IgG fusion proteins having a disulfide linked dimeric structure due to the disulfide bonds of the IgG portion are more efficient in the binding and neutralization of other molecules than monomeric polypeptides or fragments thereof. alone See, for example, Fountoulakis et al., J. Biochem., 270: 3958-3964 (1995).

Human serum albumin (HSA or HA), a protein of 585 amino acids in its mature form (SEQ ID NO: 11), is responsible for a significant proportion of the serum osmotic pressure, and also functions as a vehicle for endogenous ligands and exogenous. At present, HA for clinical use is produced by the extraction of human blood. The production of recombinant HA (rHA) in microorganisms has been described in EP 330 451 and EP 361 991. The function of albumin as a carrier molecule (vehicle) and its inert nature, are desirable properties for use as a carrier and polypeptide transporter in vivo. The use of albumin as a component of an albumin fusion protein as a carrier for various proteins has been suggested in WO 93/15199, WO 93/15200 and EP 413 622. The use of N-fragments has also been proposed. - HA terminals for fusions with polypeptides (see EP 399 666). Fusion of the albumin with a therapeutic protein can be achieved by genetic manipulation such that the DNA encoding HA, or a fragment thereof, is linked to the DNA encoding the therapeutic protein. A suitable host is then transformed or transfected with the fused nucleotide sequences, thus arranged in a suitable plasmid to express a fusion polypeptide. The expression can be carried out in vitro, for example, from prokaryotic or eukaryotic cells, or in vivo, for example, from a transgenic organism.

An albumin fusion protein that can be used in the methods of the present invention comprises at least one fragment or variant of a neutrocin-alpha polypeptide, and at least one fragment or variant of human serum albumin, which are associated with some other, preferably by genetic fusion (i.e., the albumin fusion protein is generated by the translation of a nucleic acid in which a polynucleotide encoding a complete neutrocyan-alpha or a portion thereof, is linked in the frame of reading with a polynucleotide that encodes the whole albumin or a portion thereof), or chemical conjugation with some other. The neutrokine-alpha polypeptide and the albumin protein, once part of the albumin fusion protein, can be referred to as a "portion" or "region" of the albumin fusion protein (e.g. neutrocin-alpha "or a" protein portion of albumin "). In one embodiment, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a neutrocine-alpha polypeptide and a serum albumin protein. In other embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a neutrocine-alpha fragment and a serum albumin protein. In other embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a variant of neutrocine-alpha and a serum albumin protein. In preferred embodiments, the protein component of serum albumin of the albumin fusion protein is the mature portion of serum albumin. In other embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a neutrocine-alpha polypeptide and a biologically active or therapeutically active fragment of serum albumin. In other embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a neutrocine-alpha polypeptide and a biologically active or therapeutically active variant of serum albumin. In preferred embodiments, the neutrokine-alpha portion of the albumin fusion protein is the full-length neutrokine-alpha polypeptide. In another preferred modality, the neutrokine-alpha protein portion of the albumin fusion protein is the mature soluble domain of the neutrokine-alpha polypeptide. In other embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a fragment or variant of neutrocin-alpha and a fragment or biologically active or therapeutically active variant of serum albumin. In preferred embodiments, the invention provides an albumin fusion protein comprising, or alternatively consisting of, the mature portion of the neutrokine-alpha polypeptide and the mature portion of serum albumin (including, but not limited to, human serum albumin). recombinant or fragments or variants thereof (see, for example, U.S. Patent No. 5,876,969, issued March 2, 1999, EP 0 413 622 and U.S. Patent No. 5,766,883, issued on June 16, 1998, incorporated herein by reference in its entirety)). In a preferred embodiment, the neutrokine-alpha polypeptides (including fragments or variants thereof) are fused to the mature form of human serum albumin (ie, amino acids 1 to 585 of human serum albumin as shown in FIG. Figures 1 and 2 of EP 0 322 094, which is incorporated herein by reference in its entirety). In another preferred embodiment, the antibodies of the present invention (including fragments or variants thereof) are fused to polypeptide fragments comprising, or alternatively consist of, the amino acid residues 1-x of human serum albumin, wherein x is an integer from 1 to 565, and the albumin fragment has human serum albumin activity. In another preferred embodiment, the neutrokine-alpha polypeptides (including fragments or variants thereof) are fused to polypeptide fragments comprising, or alternatively consist of, the amino acid residues 1-z of human serum albumin, wherein z is an integer from 369 to 419, as described in US Pat. UU 5,766,883, incorporated herein by reference in its entirety. The neutrokine-alpha polypeptides (including fragments or variants thereof) can be fused to the N-terminus or the C-terminus of the heterologous protein (e.g., immunoglobulin Fe polypeptide or human serum albumin polypeptide) . In preferred embodiments, the human serum albumin protein used in the albumin fusion proteins that can be used in the methods of the invention contains the following series of point mutations, or one of them, with respect to SEQ ID NO. : 11: Leu-407 to Ala, Leu-408 to Val, Val-409 to Ala and Arg-410 to Ala; or Arg-410 to A, Lys-413 to Gln and Lys-414 to Gln (see, for example, International Publication No. W095 / 23857, hereby incorporated herein by reference in its entirety). In even more preferred embodiments, the albumin fusion proteins that can be used in the methods of the invention containing the dot mutations series, or one thereof, described above, have improved stability / resistance to proteolytic digestion by the yeast Yap3p, which allows the increased production of recombinant albumin fusion proteins expressed in yeast host cells. Preferably, the albumin fusion protein that can be used in the methods of the invention comprises HA as the N-terminal portion, and the neutrophil-alpha polypeptide as the C-terminal portion. Alternatively, an albumin fusion protein comprising HA as the C-terminal portion, and the neutrokine-alpha polypeptide as the N-terminal portion can also be used. In other embodiments, the albumin fusion protein that can be used in the methods of the invention has an alpha-neutrocine polypeptide fused to the N-terminus and the C-terminal end of albumin. In a specific embodiment, the neutrokine-alpha polypeptides fused at the N-terminus and C-terminus are the same. In another embodiment, the neutrokine-alpha polypeptides fused at the N-terminus and C-terminus are different neutrokine-alpha polypeptides. In another embodiment, a neutral-alpha polypeptide is fused at the N-terminus or the C-terminal end of albumin, and a heterologous polypeptide is fused at the remaining end. In addition, albumin fusion proteins that can be used in the methods of the invention can include a linker peptide between the fused portions to provide greater physical separation between the portions. The linker peptide can consist of amino acids, so that it is flexible or more rigid. In general, albumin fusion proteins that can be used in the methods of the invention can have a region derived from HA and a region from neutrocine-alpha. However, multiple regions of each protein can be used to obtain an albumin fusion protein that can be used in the methods of the invention. Also, more than one protein can be used to obtain an albumin fusion protein that can be used in the methods of the invention. For example, a protein can be fused to the N-terminal and C-terminal ends of HA. In such a configuration, the protein portions may be the same protein molecules or different protein molecules. The structure of bifunctional albumin fusion proteins can be represented as: X-HA-Y or Y-HA-X. In a specific embodiment, the neutrokine-alpha protein or fragment or variant thereof that can be used in the methods of the invention can be conjugated to a cytotoxin (eg, a cytostatic or cytocidal agent). A cytotoxin or cytotoxic agent includes any agent that is detrimental to the cells. Examples include paclitaxel, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, teniposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthrazynanone, mitoxantrone, mitramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine , lidocaine, propranolol and puromycin, and analogs or homologs thereof. In another embodiment, a neutrokine-alpha protein or fragment or variant thereof that can be used in the methods of the invention, can be conjugated to a toxin. By "toxin" is meant one or more compounds that bind to and activate endogenous cytotoxic effector systems, radioisotopes, holotoxins, modified toxins, catalytic subunits of toxins, or any molecule or enzyme not normally present on or on the surface of a cell that under defined conditions, causes the death of the cell. Toxins that can be used include, without limitation, radioisotopes known in the art, compounds such as, for example, antibodies (or portions thereof that contain complement fixation) that bind an inherent or induced endogenous cytotoxic effector system, thymidine kinase, endonuclease. , ribonuclease, alpha toxin, ricin, abrin, Pseudomonas exotoxin A, diphtheria toxin, saponin, momordin, gelonin, carmine herb antiviral protein, alpha sarcina and cholera toxin. The term "toxin" also includes a cytostatic or cytocidal agent, a therapeutic agent or a radioactive metal ion, for example, alpha emitters such as, for example, 213Bi, or other radioisotopes such as, for example, 103Pd, 133Xe, 131l , 68Ge, 57Co, 65Zn, 85Sr, 32P, 35S, 90Y, 153Sm, 153Gd, 169Yb, 51Cr, 54Mn, 75Se, 113Sn, 90ytrio, 1 7estaño, 186renio, 166holmio and 188renío. In a further example, the APRIL polypeptides that can be used in the methods of the present invention can be fused to the constant domain of immunoglobulins (IgA, IgE, IgG, IgM), or portions thereof (CH1, CH2, CH3, or any combination thereof, and portions thereof), or albumin (including, but not limited to, recombinant human albumin, or fragments or variants thereof (see, e.g., U.S. Patent No. 5,876,969 , issued March 2, 1999, EP 0 413 622, and U.S. Patent No. 5,766,883, issued June 16, 1998, incorporated herein by reference in their entirety), resulting in chimeric polypeptides. Such fusion proteins can facilitate purification, can extend shelf life and can increase the half-life in vivo. This has been shown for chimeric proteins consisting of the first two domains of the human CD4 polypeptide and several domains of the constant regions of the heavy or light chains of mammalian immunoglobulins. See, for example, EP 394,827; Traunecker et al., Nature, 331: 84-86 (1988). The enhanced delivery of an antigen through the epithelial barrier to the immune system has been demonstrated for antigens (eg, insulin) conjugated to an FcRn binding member such as fragments of IgG or Fe (see, for example, publications of PCT WO 96/22024 and WO 99/04813). It has also been found that IgG fusion proteins having a disulfide linked dimeric structure due to the disulfide bonds of the IgG portion are more efficient in the binding and neutralization of other molecules than monomeric polypeptides or fragments thereof. alone See, for example, Fountoulakis et al., J. Biochem., 270: 3958-3964 (1995). An albumin fusion protein that can be used in the methods of the present invention comprises at least one fragment or variant of an APRIL polypeptide, and at least one fragment or variant of human serum albumin, which are associated with some another, preferably by genetic fusion (i.e., the albumin fusion protein is generated by the translation of a nucleic acid in which a polynucleotide encoding a complete APRIL or a portion thereof, is linked in the framework of reading with a polynucleotide that encodes the whole albumin or a portion thereof), or chemical conjugation with some other. The APRIL polypeptide and the albumin protein, once part of the albumin fusion protein, can be referred to as a "portion" or "region" of the albumin fusion protein (eg, a "portion of APRIL"). or a "protein portion of albumin"). In one embodiment, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, an APRIL polypeptide and a serum albumin protein. In other embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, an APRIL fragment and a serum albumin protein. In other embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a variant of APRIL and a serum albumin protein. In preferred embodiments, the protein component of serum albumin of the albumin fusion protein is the mature portion of serum albumin. In other embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, an APRIL polypeptide and a biologically active or therapeutically active fragment of serum albumin. In other embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, an APRIL polypeptide and a biologically active or therapeutically active variant of serum albumin. In preferred embodiments, the APRIL portion of the albumin fusion protein is the full-length APRIL polypeptide. In another preferred embodiment, the APRIL portion of the albumin fusion protein is the mature soluble domain of the APRIL polypeptide. In other embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a fragment or variant of APRIL and a biologically active or therapeutically active fragment or variant of serum albumin. In preferred embodiments, the invention provides an albumin fusion protein comprising, or alternatively consisting of, the mature portion of the APRIL polypeptide and the mature portion of serum albumin. In additional embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a fragment or variant of APRIL and a biologically active or therapeutically active fragment or variant of serum albumin. In preferred modalities, the invention provides an albumin fusion protein comprising, or alternatively consisting of, the mature portion of the APRIL polypeptide and the mature portion of serum albumin (including, but not limited to, recombinant human serum albumin or fragments or variants). of the same (see, for example, U.S. Patent No. 5,876,969, issued March 2, 1999, EP 0 413 622 and U.S. Patent No. 5,766,883, issued June 16, 1998. , incorporated herein by reference in its entirety)). In a preferred embodiment, the APRIL polypeptides (including fragments or variants thereof) are fused to the mature form of human serum albumin (i.e., amino acids 1 to 585 of human serum albumin as shown in the figures) 1 and 2 of EP 0 322 094, which is incorporated herein by reference in its entirety). In another preferred embodiment, the antibodies of the present invention (including fragments or variants thereof) are fused to polypeptide fragments comprising, or alternatively consist of, the amino acid residues 1-x of human serum albumin, wherein x is an integer from 1 to 585, and the albumin fragment has human serum albumin activity. In another preferred embodiment, the APRIL polypeptides (including fragments or variants thereof) are fused to polypeptide fragments comprising, or alternatively consist of, the amino acid residues 1-z of human serum albumin, wherein z is a whole from 369 to 419, as described in U.S. Pat. UU 5,766,883, incorporated herein by reference in its entirety. The APRIL polypeptides (including fragments or variants thereof) can be fused to the N-terminus or the C-terminus of the heterologous protein (e.g., Immunoglobulin Fe polypeptide or human serum albumin polypeptide). In preferred embodiments, the human serum albumin protein used in the albumin fusion proteins that can be used in the methods of the invention contains the following series of point mutations, or one of them, with respect to SEQ ID NO. : 11: Leu-407 to Ala, Leu-408 to Val, Val-409 to Ala and Arg-410 to Ala; or Arg-410 to A, Lys-413 to Gln and Lys-414 to Gln (see, for example, International Publication No. W095 / 23857, hereby incorporated herein by reference in its entirety). In even more preferred embodiments, the albumin fusion proteins that can be used in the methods of the invention containing the dot mutations series, or one thereof, described above, have improved stability / resistance to proteolytic digestion by the yeast Yap3p, which allows higher production of recombinant albumin fusion proteins expressed in yeast host cells. Preferably, the albumin fusion protein that can be used in the methods of the invention comprises HA as the N-terminal portion, and the APRIL polypeptide as the C-terminal portion. Alternatively, an albumin fusion protein comprising HA as the C-terminal portion, and the APRIL polypeptide as the N-terminal portion may also be used. In other embodiments, the albumin fusion protein that can be used in the methods of the invention has an APRIL polypeptide fused to the N-terminus and the C-terminal end of albumin. In a specific embodiment, the APRIL polypeptides fused at the N-terminal and C-terminal ends are the same. In another embodiment, the APRIL polypeptides fused at the N-terminus and C-terminal ends are different APRIL polypeptides. In another embodiment, an APRIL polypeptide is fused at the N-terminus or the C-terminal end of albumin, and a heterologous polypeptide is fused at the remaining end. In addition, albumin fusion proteins that can be used in the methods of the invention can include a linker peptide between the fused portions to provide greater physical separation between the portions. The linker peptide can consist of amino acids, so that it is flexible or more rigid. In general, albumin fusion proteins that can be used in the methods of the invention can have a region derived from HA and an APRIL region. However, multiple regions of each protein can be used to obtain an albumin fusion protein that can be used in the methods of the invention. Also, more than one protein can be used to obtain an albumin fusion protein that can be used in the methods of the invention. For example, a protein can be fused to the N-terminal and C-terminal ends of HA. In such a configuration, the protein portions may be the same protein molecules or different protein molecules. The structure of bifunctional albumin fusion proteins can be represented as: X-HA-Y or Y-HA-X. In a specific embodiment, an APRIL protein or fragment or variant thereof that can be used in the methods of the invention can be conjugated to a cytotoxin (eg, a cytostatic agent or cytocide). A cytotoxin or cytotoxic agent includes any agent that is detrimental to the cells. Examples include paclitaxel, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, teniposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracendione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine , lidocaine, propranolol and puromycin, and analogs or homologs thereof. In another embodiment, an APRIL protein or fragment or variant thereof that can be used in the methods of the invention can be conjugated to a toxin. By "toxin" is meant one or more compounds that bind to and activate endogenous cytotoxic effector systems, radioisotopes, holotoxins, modified toxins, catalytic subunits of toxins, or any molecule or enzyme not normally present on or on the surface of a cell that under definite conditions, it causes the death of the cell. Toxins that can be used include, without limitation, radioisotopes known in the art, compounds such as, for example, antibodies (or portions thereof that contain complement fixation) that bind an endogenous or induced endogenous cytotoxic effector system, thymidine kinase, endonuclease, ribonuclease, alpha toxin , ricin, abrin, Pseudomonas exotoxin A, diphtheria toxin, saporin, momordin, gelonin, carmint antiviral protein, alpha sarcina and cholera toxin. The term "toxin" also includes a cytostatic or cytocidal agent, a therapeutic agent or a radioactive metal ion, for example, alpha emitters such as, for example, 213Bi, or other radioisotopes such as, for example, 103Pd, 33Xe, 131l , 68Ge, 57Co, 65Zn, 85Sr, 32P, 35S, 90Y, 153Sm, 153Gd, 169Yb, 51Cr, 54Mn, 75Se, 113Sn, 90ytrio, 117th, 186renio, 166holmio and 188renio. Protein engineering can be used to alter the characteristics of the neutrokine-alpha and APRIL polypeptides to generate polypeptides that can be used in the methods of the invention. Recombinant DNA technology known to those skilled in the art can be used to create novel mutant proteins or "muteins," including single or multiple amino acid substitutions, deletions or additions, or fusion proteins. Such modified polypeptides can show, for example, improved activity, decreased activity or increased stability. In addition, they can be purified in higher yields, and may show better solubility than the corresponding natural polypeptide, at least under certain purification and storage conditions. For example, for many proteins, including the extracellular domain or the mature forms of a secreted protein, it is known in the art that one or more amino acids can be deleted from the N-terminal or C-terminus without substantial loss of biological function. For example, Ron et al., J. Biol. Chem., 268: 2984-2988 (1993), reported modified KGF proteins that had heparin-binding activity even if 3, 8 or 27 amino-terminal amino acid residues were missing. The neutrokine-alpha and APRIL polypeptides that can be used in the methods of the present invention can be monomers or multimers (ie, dimers, trimers, tetramers and higher multimers). In specific embodiments, the neutrokine-alpha and APRIL polypeptides that can be used in the methods of the invention can be homomers or heteromers. A neutrocin-alpha homomer refers to a multimer containing only neutrocin-alpha polypeptides (including fragments, variants and neutrocin-alpha fusion proteins, as described herein). These homomers may contain neutrokine-alpha polypeptides having identical or different amino acid sequences. In specific embodiments, the neutrokine-alpha polypeptide that can be used in the methods of the present invention are neutrokine-alpha homodimers (e.g., containing two neutrokine-alpha polypeptides having identical or different amino acid sequences), or are homotrimers of neutrocin-alpha (for example, containing three neutrokine-alpha polypeptides having identical or different amino acid sequences). In a preferred embodiment, the neutrokine-alpha polypeptides that can be used in the methods of the invention are neutrokine-alpha homotrimers. In further embodiments, the neutrocin-alpha polypeptide that can be used in the methods of the invention is at least one homodimer, at least one homotrimer, or at least one homotetramer. An "APRIL homomer" refers to a multimer containing only APRIL polypeptides (including fragments, variants, and APRIL fusion proteins, as described herein). These homomers may contain APRIL polypeptides having identical or different amino acid sequences. In specific embodiments, the APRIL polypeptide that can be used in the methods of the present invention are APRIL homodimers (e.g., containing two APRIL polypeptides having identical or different amino acid sequences), or are homotrimers of APRIL (eg, containing three APRIL polypeptides having identical or different amino acid sequences). In a preferred embodiment, the APRIL polypeptides that can be used in the methods of the invention are homotrimers of APRIL. In further embodiments, the APRIL polypeptide that can be used in the methods of the invention is at least one homodimer, at least one homotrimer, or at least one homotetramer. Heteromeric neutrocin-alpha refers to a multimer containing heterologous polypeptides (ie, polypeptides of a different protein) in addition to neutrokine-alpha polypeptides. In a specific embodiment, the neutrokine-alpha polypeptide that can be used in the methods of the invention is a heterodimer, a heterotrimer or a heterotetramer. In further embodiments, the neutrokine-alpha polypeptide that can be used in the methods of the invention is a multimer that is at least one heterodimer, at least one heterotrimer, or at least one heterotetramer. Heteromeric APRIL refers to a multimer containing heterologous polypeptides (ie, polypeptides of a different protein) in addition to APRIL polypeptides. In a specific embodiment, the APRIL polypeptide that can be used in the methods of the invention is a heterodimer, a heterotrimer or a heterotetramer. In further embodiments, the APRIL polypeptide that can be used in the methods of the invention is a multimer that is at least one heterodimer, at least one heterotrimer, or at least one heterotetramer. In additional embodiments, the neutrocine-alpha polypeptide that can be used in the methods of the invention is a heterotrimer comprising neutrokine-alpha polypeptides and APRIL polypeptides or fragments or variants thereof. In further embodiments, the neutrokine-alpha polypeptide that can be used in the methods of the invention is a heterotrimer comprising a neutrocine-alpha polypeptide (including fragments or variants) and two APRIL polypeptides (including fragments or variants). In additional embodiments, the neutrocine-alpha polypeptide that can be used in the methods of the invention is a heterotrimer comprising two polypeptides of neutrocin-alpha (including fragments or variants) and an APRIL polypeptide (including fragments or variants). In further embodiments, the neutrokine-alpha polypeptides that can be used in the methods of the invention are homomeric, especially homotrimeric neutrokine-alpha polypeptides, wherein the individual protein components of the multimers comprise, or alternatively consist of, the mature form of neutrocin-alpha (e.g., amino acid residues 134-285 of SEQ ID NO: 2), or fragments or variants thereof. In other specific embodiments, the neutrokine-alpha polypeptides that can be used in the methods of the invention are heteromeric, especially heterotrimeric neutrokine-alpha polypeptides, such as a heterotrimer containing two neutrokine-alpha polypeptides and an APRIL polypeptide or a heterotrimer containing a neutrokine-alpha polypeptide and two APRIL polypeptides, and wherein the individual protein components of the neutrokine-alpha heteromer comprise, or alternatively consist of, the mature extracellular soluble portion of neutrokine-alpha (e.g. amino acid residues 134-285 of SEQ ID NO: 2), or fragments or variants thereof, or the mature extracellular soluble portion of APRIL (eg, amino acid residues 105-250 of SEQ ID NO: 4), or fragments or variants of it. In further embodiments, the APRIL polypeptides that can be used in the methods of the invention are homomeric, especially homotrimeric APRIL polypeptides, wherein the individual protein components of the multimers comprise, or alternatively consist of, the mature form of APRIL (eg, amino acid residues 105-250 of SEQ ID NO: 4), or fragments or variants thereof. In other specific embodiments, the APRIL polypeptides that can be used in the methods of the invention are heteromeric, especially heterotrimeric, APRIL polypeptides, such as a heterotrimer containing two APRIL polypeptides and a neutrokine-alpha polypeptide or a heterotrimer containing a APRIL polypeptide and two neutrokine-alpha polypeptides, and wherein the individual protein components of the APRIL heteromer comprise, or alternatively consist of, the mature extracellular soluble portion of APRIL (e.g., amino acid residues 105-250 of SEQ ID NO: 4), or fragments or variants thereof, or the mature extracellular soluble portion of neutrocine-alpha (e.g., amino acid residues 134-285 of SEQ ID NO: 2), or fragments or variants thereof . The multimers that can be used in the methods of the invention can be the result of hydrophobic, hydrophilic, ionic or covalent associations, or they can be linked indirectly, for example, by liposome formation. Thus, in one embodiment, multimers such as, for example, homodimers or homotrimers are formed when the polypeptides come into contact with some other in solution. In another embodiment, heteromultimers such as, for example, heterotrimers or heterotetramers, are formed when the polypeptides come into contact with some other in solution. In other embodiments, multimers are formed by covalent associations with or between the neutrokine-alpha polypeptides. In other embodiments, multimers are formed by covalent associations with or between the APRIL polypeptides. Said covalent associations can include one or more amino acid residues contained in the polypeptide sequence (for example, that cited in SEQ ID NO: 2 for neutrocine-alpha, or that cited in SEQ ID NO: 4 for APRIL). In one example, covalent associations are entanglement between cysteine residues located within polypeptide sequences that interact in the native polypeptide (i.e., of natural occurrence). In another example, covalent associations are the consequence of chemical or recombinant manipulation. Alternatively, said covalent associations may involve one or more amino acid residues contained in the heterologous polypeptide sequence in a neutrocin-alpha or APRIL fusion protein (see, e.g., U.S. Patent No. 5,478,925) . In a specific example, the covalent associations are between the heterologous sequence contained in a neutrokine-alpha-Fe fusion protein (as described herein). In a specific example, the covalent associations are between the heterologous sequence contained in an APRIL-Fc fusion protein (as described herein). In another specific example, the covalent associations in fusion proteins that can be used in the methods of the invention are between heterologous polypeptide sequences of another receptor / ligand member of the TNF family that is capable of forming covalently associated multimers such as, for example, osteoprotegerin (see, for example, international publication No. WO 98/49305, the contents of which are hereby incorporated by reference in their entirety). In another embodiment, two or more neutrokine-alpha polypeptides or APRIL polypeptides are linked through synthetic linkers (e.g., peptide linkers, carbohydrates or soluble polymers). Examples include those peptide linkers described in U.S. Pat. UU No. 5,073,627 (incorporated herein by reference). Proteins comprising neutrokine-alpha polypeptides or multiple APRIL polypeptides separated by peptide linkers can be produced using conventional recombinant DNA technology. In a specific modality, a neutrocin-alpha antagonist that can be used in the methods of the invention is a dominant negative form of neutrocine-alpha or APRIL. In particular, neutrokine-alpha or APRIL variants, including dominant negative forms have been described, for example, in international patent publication numbers WO06 / 034106, WO05 / 113598, WO04 / 089982, WO04 / 081043 and WO03 / 057856, and in the US patent publications. UU Nos. US20060014248, US20050221443, US20050130892, US20050048626, US2005003480 and US20030166559. Each of the references mentioned above is incorporated herein by reference in its entirety. Said neutrokine-alpha or APRIL polypeptide variants can antagonize the neutrokine-alpha function, for example, by interfering with the homo-multimerization or hetero-multimerization of neutrocine-alpha or APRIL. Alternatively, neutrophil-alpha or APRIL polypeptide variants can prevent polypeptides comprising them from binding to, or signaling through, neutrokine-alpha receptors, such as TACI, BCMA and BAFF-R. In another embodiment, the neutrokine-alpha antagonist is the mutant alpha-neutrophil protein described in Gao et al. (2006) Biotechnol. Lett. 28: 1649-54, which is incorporated herein by reference in its entirety. In another embodiment, the neutrocin-alpha antagonist that can be used in the methods of the invention is? BAFF (SEQ ID NO: 12).

B. Anti-Neutrocin-alpha Antibodies In a specific embodiment, the neutrocin-alpha antagonist is an anti-neutrocin alfa antibody or a binding fragment tof. Anti-neutrocin-alpha antibodies and fragments tof have been described for example in PCT publications WO01 / 087977, WO03 / 016468, WO01 / 60397, WO02 / 02641 and WO03 / 55979; The publications of EE. UU Nos. 2005/0070694 and 2005/0255532; and Cao et al. (2005), Immunol Lett 101: 87-94; Ch'en et al. (2005), Cell Immunol 236: 78-85; Liu et al. (2005) Acta Biochim Biophys Sin (Shanghai) 37: 415-420; Schneider et al. (1999) J Exp Med 189: 1747-1756; Sun et al. (2006) Hybridoma 25: 80-85; Sun et al. (2006) Hybridoma 25: 238-242; and are described below in more detail. Each of these citations is incorporated as a reference in its entirety. The term "antibody", as used in, refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, ie, molecules that contain an antigen-binding site that immunospecifically bind to an antigen. As such, the term "antibody" encompasses not only complete antibody molecules, but also antibody fragments as well as antibody variants (including derivatives), and antibody fragments. Examples of molecules described with the term "antibody" in this application include, without limitation: single chain Fvs (scFvs), Fab fragments, Fab 'fragments, F (ab') 2, Fvs linked with disulfide (sdFvs), Fvs and fragments comprising, or alternatively consisting of, a VL domain or a VH domain. The term "single chain Fv" or "scFv", as used in, refers to a polypeptide comprising a VL domain of antibody bound to a VH domain of an antibody. Antibodies that bind nonspecifically to a particular antigen (eg, neutrocine-alpha) may have cross-reactivity with otantigens. Preferably, antibodies that bind immunospecifically to a particular antigen do not cross-react with otantigens. Antibodies that bind immunospecifically to a particular antigen can be identified for example by means of immunoassays or ottechniques known to the person skilled in the art, for example the immunoassays described in the US patent application. UU No. 60 / 834,152, filed July 31, 2006, which is incorporated in by reference. Antibodies that can be used in the methods of the present invention include, without limitation, monoclonal, multispecific, human or chimeric antibodies, single chain antibodies, Fab fragments, F (ab ') fragments, anti-idiotypic antibodies (anti-ld) ), and epitope binding fragments of any of the foregoing. The immunoglobulin molecules of the invention can be of any type (for example IgG, IgE, IgM, IgD, IgA and IgY), class (for example IgGi, IgG2, IgGβ, IgG4, IgAi and IgA2) or subclass. Antibodies that can be used in the methods of the present invention may also include multimeric forms of antibodies. For example, antibodies that can be used in the methods of the present invention can take the form of higorder dimers, trimers, or multimers of monomeric immunoglobulin monomer molecules. The dimers of complete immunoglobulin molecules or F (ab ') 2 fragments are tetravalent, was the dimers of Fab fragments or scFv molecules are bivalent. The individual monomers in a multimeric antibody can be identical or different, that is, they can be heteromeric or homomeric antibody multimers. For example, individual antibodies within a multimer may have the same or different binding specificities. The multimerization of antibodies can be carried out by means of natural antibody aggregation or by means of known chemical or recombinant binding techniques. For example, a certain percentage in purified antibody preparations (e.g., purified IgG1 molecules) spontaneously forms protein aggregates containing antibody homodimers and other higher order antibody multimers. Alternatively, antibody homodimers can be formed by known chemical bonding techniques. For example, heterobifunctional crosslinking agents can be used including, without limitation, SMCC [4- (maleimidomethyl) cyclohexane-1-carboxylate] of succinimidyl and SATA [S-acetylthio-acetate / succinimidyl] (available for example from Pierce Biotechnology, Inc. (Rockford, Illinois)), to form multimeric antibodies. An exemplary protocol for the formation of homodimeric antibodies is given in Ghetie et al., Proceedings of the National Academy of Sciences USA (1997) 94: 7509-7514, which is incorporated herein by reference in its entirety. Homodimer antibodies can be converted to Fab'2 homodimers by digestion with pepsin. Another way to form homodimeric antibodies is by using the T15 autophilic peptide described by Zhao and Kohler, The Journal of Immunology (2002) 25: 396-404, which is incorporated herein by reference in its entirety. Alternatively, the antibodies can be made to multimerize by means of recombinant DNA techniques. IgM and IgA naturally form multimeric antibodies by interaction with the J-chain polypeptide. Non-IgA or non-IgM molecules, such as IgG molecules, can be engineered to contain the IgA J-chain interaction domain or IgM, thereby conferring the ability to form higher order multimers on non-IgA or non-IgM molecules (see for example, Chintalacharuvu et al. (2001) Clinical Immunology 101: 21-31, and Frigerio et al. (2000) Plant Physiology 123 : 1483-94, both incorporated herein by reference in their entirety). The scFv dimers can also be formed by known recombinant techniques; an example of the construction of scFv dimers is given in Goel et al. (2000) Cancer Research 60: 6964-6971, which is incorporated herein by reference in its entirety. Multimeric antibodies can be purified using any suitable method known in the art, including without limitation size exclusion chromatography. Unless defined otherwise in the specification, the specific binding or immunospecific binding by an antibody means that the antibody binds to the target antigen but does not bind (i.e., does not cross-react) significantly with proteins other than the target antigen, such as other proteins of the same protein family (for example another family of TNF ligands). An antibody that binds to a target antigen and does not cross-react with other proteins is not necessarily an antibody that does not bind to these other proteins under all conditions; rather, the antibody specific for the target antigen binds preferentially to the target antigen as compared to its ability to bind to said other proteins, such that it will be suitable for use in at least one type of assay or treatment, i.e. low basal values, or does not produce immoderate adverse effects during treatment. It is well known that the portion of a protein that binds to an antibody is referred to as the epitope. An epitope can be linear (i.e., sequentially comprised of amino acid residues in a protein sequence) or conformational (i.e., comprised of one or more amino acid residues that are not contiguous in the primary structure of the protein, but which is put in contact by the secondary, tertiary or quaternary structure of a protein). Since the target antigen-specific antibodies bind to the epitopes of the target antigen, an antibody that specifically binds to the target antigen may or may not bind to target antigen fragments or target antigen variants (e.g., proteins that are at least 90% identical to the target antigen), depending on the presence or absence of the epitope bound by a given antibody specific for the target antigen of the target antigen fragment or variant. Similary, the target antigen-specific antibodies can be linked with orthologous species of the target antigen (including fragments thereof) depending on the presence or absence of the epitope recognized by the antibody in the orthologous. Additionally, the target antigen-specific antibodies can be linked with modified forms of the target antigen, for example target antigen fusion proteins. In such a case, when the antibodies bind to target antigen fusion proteins, the antibody must make binding contact with the target antigen portion of the fusion protein so that the binding is specific. Antibodies that bind specifically to any particular target antigen can be identified, for example, by means of immunoassays or other techniques known to the person skilled in the art, for example the immunoassays described in the US patent application. UU No. 60 / 834,152, filed July 31, 2006, which is incorporated herein by reference in its entirety. The antibodies that can be used in the methods of the present invention can be "specific" for neutrocin-alpha but this is not a requirement. The anti-neutrocin-alpha antibodies that can be used in the methods of the invention can be described or specified based on their cross-reactivity. Antibodies that do not bind to any other analog, ortholog, or homolog of a neutrophil-alpha polypeptide can be used in the methods of the invention. In a specific embodiment, antibodies that can be used in the methods of the invention cross-react with APRIL. In specific embodiments, antibodies that can be used in the methods of the invention cross-react with murine homologs, of rat or rabbit, of human proteins and their corresponding epitopes. In a specific embodiment, the antibodies that bind to a neutrokine-alpha polypeptide, fragment or polypeptide variant of SEQ ID NO: 2, or to an epitope of neutrocine-alpha (determined by well-known immunoassays to test specific antibody binding- antigen), can be used in the methods of the invention. In a specific embodiment, antibodies that can be used in the methods of the invention can be linked to neutrokine-alpha polypeptides fused to other polypeptide sequences. For example, neutrokine-alpha polypeptides can be fused to the constant domain of immunoglobulins (IgA, IgE, IgG, IgM), or portions thereof (CH1, CH2, CH3, or any combination thereof, and portions thereof). the same), or albumin (including, without limitation, recombinant human albumin, or fragments or variants thereof (see, for example, U.S. Patent No. 5,876,969, issued March 2, 1999, EP patent) 0 413 622, and U.S. Patent No. 5,766,883, issued June 16, 1998, incorporated herein by reference in its entirety), resulting in chimeric polypeptides. Such fusion proteins can facilitate purification and can increase the half-life in vivo.

This has been shown for chimeric proteins consisting of the first two domains of the human CD4 polypeptide and several domains of the constant regions of the heavy or light chains of mammalian immunoglobulins. See, for example, EP 394,827; Traunecker et al., Nature, 331: 84-86 (1988). Intensified delivery of an antigen through the epithelial barrier to the immune system has been demonstrated for antigens (eg, insulin) conjugated to an FcRn binding member, such as fragments of IgG or Fe (see, for example, PCT publications WO 96/22024 and WO 99/04813). It has also been found that IgG fusion proteins having a disulfide linked dimeric structure due to the disulfide bonds of the IgG portion are more efficient in the binding and neutralization of other molecules than monomeric polypeptides or fragments thereof. alone See, for example, Fountoulakis et al., J. Biochem., 270: 3958-3964 (1995). In another embodiment, antibodies that can be used in the methods of the invention bind to neutrokine-alpha polypeptides that have been generated by random mutagenesis of a polynucleotide encoding the neutrokine-alpha polypeptide, by means of test PCR and error, random insertion of nucleotides or other methods, before recombination. In another embodiment, antibodies that can be used in the methods of the invention bind to one or more components, motifs, sections, parts, domains, fragments, etc., of neutrocyan-alpha recombined with one or more components, motifs, sections , parts, domains, fragments etc. of one or more other heterologous molecules. In preferred embodiments, the heterologous molecules are for example TNF-alpha, lymphotoxin alpha (LT-alpha, also known as TNF-beta), LT-beta (found in the heterotrimer complex LT-alpha2-beta), OPGL, FasL, CD27L , CD30L, CD40L, 4-1 BBL, DcR3, OX40L, TNF-gamma (international publication No. WO 96/14328), AIM-I (international publication No. WO 97/33899), AIM-II (international publication No. WO 97/34911), APRIL (J. Exp. Med. 188 (6): 1185-1190), endocin alfa (International Publication No. WO 98/07880), OPG, OX40, and nerve growth factor (NGF). , and soluble forms of Fas, CD30, CD27, CD40 and 4 IBB, TR2 (international publication No. WO 96/34095), DR3 (international publication No. WO 97/33904), DR4 (international publication No. WO 98/32856 ), TR5 (international publication No. WO 98/30693), TR6 (international publication No. WO 98/30694), TR7 (international publication No. WO 98/41629), TRANK, TR9 (international publication No. WO 98/56892 ), TR10 (publication International No. WO 98/54202), 312C2 (International Publication No. WO 98/06842), TR12, CAD, and v-FLIP. In additional embodiments, the heterologous molecules are any member of the TNF family. In specific embodiments, the antibodies that can be used in the methods of the invention bind homomeric, especially homotrimeric, neutrokine-alpha polypeptides. In other specific embodiments, the antibodies that can be used in the methods of the invention bind to heteromeric, especially heterotrimeric neutrokine-alpha polypeptides, such as a heterotrimer containing two neutrokine-alpha polypeptides and an APRIL polypeptide, or a heterotrimer containing a neutrocine-alpha polypeptide and two APRIL polypeptides. In a specific embodiment, antibodies that can be used in the methods of the invention bind to homomeric, especially homotrimeric, neutrokine-alpha polypeptides, wherein the individual protein components of the multimers consist of the mature form of neutrokine-alpha ( for example amino acid residues 134-285 of SEQ ID NO: 2). In other specific embodiments, antibodies that can be used in the methods of the invention bind to heteromeric, especially heterotrimeric, neutrokine-alpha polypeptides, such as a heterotrimer containing two neutrocin-alpha polypeptides and an APRIL polypeptide., or a heterotrimer containing a neutrokine-alpha polypeptide and two APRIL polypeptides, and wherein the individual protein components of the neutrokine-alpha heteromer consist of the mature extracellular soluble portion of neutrokine-alpha (e.g. amino acid 134-285 of SEQ ID NO: 2) or the mature extracellular soluble portion of APRIL (eg, amino acid residues 105-250 of SEQ ID NO: 4). In specific embodiments, the antibodies that can be used in the methods of the invention bind to conformational epitopes of a neutrocytic-alpha monomeric protein. In specific embodiments, antibodies that can be used in the methods of the invention bind to conformational epitopes of a multimeric neutrocyan-alpha protein, especially trimeric. In other embodiments, the antibodies that can be used in the methods of the invention bind to conformational epitopes that arise from the juxtaposition of neutrocine-alpha with a heterologous polypeptide, such as could be present when the neutrokine-alpha forms heterotrimers (by example with APRIL polypeptides), or in fusion proteins between neutrokine-alpha and a heterologous polypeptide. Antibodies that can be used in the methods of the invention include, without limitation, polyclonal, monoclonal, multispecific, human, humanized or chimeric antibodies, single chain antibodies, Fab fragments, F (ab ') fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-ld) antibodies (including, for example, anti-id antibodies for anti-neutrocin-alpha antibodies), and epitope binding fragments of any of the foregoing. In preferred embodiments, the immunoglobulin is an isotype IgG1 or IgG4. The immunoglobulins can have both a heavy chain and a light chain. An array of heavy chains of IgG, IgE, IgM, IgD, IgA, and IgY can be paired with a light chain of the kappa or lambda forms. In a specific embodiment, the antibodies that can be used in the methods of the invention are neutrocin-alpha binding fragments and include, without limitation, Fab, Fab 'and F (ab') 2, Fd, Fvs of a single chain (scFv), single-chain antibody, disulfide-linked Fvs (sdFv) and fragments comprising a VL or VH domain. Neutrocin-alpha binding antibody fragments, including single chain antibodies, may comprise the variable region alone or in combination with all or a portion of the following: hinge region, CH1, CH2, and CH3 domains. In a specific embodiment, the neutrocin-alpha binding fragments that can be used in the methods of the invention comprise any combination of the variable regions with a hinge region, or the CH1, CH2, and CH3 domains. The antibodies that can be used in the methods of the invention can be of any animal origin, including birds and mammals. Preferably, the antibodies are human, murine (e.g., mouse and rat), donkey, sheep, rabbit, goat, guinea pig, camel, horse, or chicken. As used herein, "human" antibodies include antibodies that have the amino acid sequence of a human immunoglobulin and include antibodies isolated from collections of human immunoglobulin or from animals transgenic for one or more human immunoglobulins, and that do not express endogenous immunoglobulins, such as it is described, for example, in U.S. Pat. UU No. 5,939,598 to Kucherlapati et al., The content of which is incorporated herein by reference. The antibodies that can be used in the methods of the invention can be monospecific, bispecific, trispecific or of greater specificity. Multispecific antibodies may be specific for different epitopes of a neutrokine-alpha polypeptide, or may be specific for either a neutrokine-alpha polypeptide or a heterologous epitope, such as a heterologous polypeptide or solid support material. See, for example, PCT publications WO 93/17715; WO 92/08802; WO91 / 00360; WO 92/05793; Tutt et al., J. Immunol. 147: 60-69 (1991); US patents UU Nos. 4,474,893; 4,714,681; 4,925,648; 5,573,920; 5,601, 819; Kostelny et al., J. Immunol. 148: 1547-1553 (1992). Antibodies that can be used in the methods of the invention can be described or specified based on their binding affinity to a neutrokine-alpha polypeptide. In specific embodiments, the antibodies that can be used in the methods of the invention bind to the neutrokine-alpha polypeptides, or fragments or variants thereof, with a dissociation constant, or KD, < 5 X I0"9 M, I0" 9 M, 5 X 10"10 M, 10'10 M, 5 X 10" 11 M, 10"11 M, 5 X 10 ~ 12 M, or 10" 12 M. In In a specific embodiment, the antibodies that can be used in the methods of the invention bind to the neutrokine-alpha polypeptides with a dissociation constant or KD that is within any of the scales that fall between each individual cited value. Neutrokine-alpha antibodies that disrupt receptor / ligand interactions with the neutrokine-alpha polypeptides, either partially or totally, can be used in the methods of the invention. Also included are neutrokine-alpha-specific antibodies that do not prevent ligand binding but that prevent receptor activation. Activation of the receptor (i.e., signaling) can be determined by the techniques described herein or otherwise known. For example, receptor activation can be determined by detecting the activation of transcription factors NF-AT, AP-1, MAPK8 / JNK or NF-kappaB (including the non-canonical NF-kappaB signaling pathway), using techniques known, or phosphorylation (for example, thirosin or serine / threonine) of the receptor or its substrate by immunoprecipitation, followed by western blot analysis. The neutrophil-alpha antibodies described above can be made using known methods. See, for example, PCT publication WO 96/40281; the US patent UU No. 5,811, 097; Deng et al., Blood 92 (6): 1981 -1988 (1998); Chen et al., Cancer Res. 58 (16): 3668-3678 (1998); Harrop et al., J. Immunol. 161 (4): 1786-1794 (1998); Zhu et al., Cancer Res. 58 (15): 3209-3214 (1998); Yoon et al., J. Immunol. 160 (7): 3170-3179 (1998); Prat et al., J. Cell. Sci. 111 (Pt2): 237-247 (1998); Pitard et al., J. Immunol. Methods 205 (2): 177-190 (1997); Liautard et al., Cytokine 9 (4): 233-241 (1997); Carlson et al., J. Biol. Chem. 272 (17): 11295-11301 (1997); Taryman et al., Neuron 14 (4): 755-762 (1995); Muller et al., Structure 6 (9): 1153-1167 (1998); Bartunek et al., Cytokine 8 (1): 14-20 (1996) (all of which are incorporated herein by reference in their entirety). In a specific embodiment, the neutrophil-alpha antibodies (which include molecules comprising, or alternatively consisting of, fragments or antibody variants thereof) that can be used in the methods of the invention, specifically bind to neutrocyanin. alpha or a fragment or variant of neutrocine-alpha. In particular, antibodies such as for example single-chain Fvs (scFvs), having an amino acid sequence of any of SEQ ID NOs: 13-18, can be used in the methods of the invention, as referred to in the table 1.

TABLE 1 scFvs that binds immunospecifically to neutrocine-alpha Clone ID scFv AAs of VL AAs of AAs of AAs of AAs of AAs of AAs AAs of SEQ ID VLCDR1 VL CDR2 VL CDR3 VH VH of VH VH NO • CDR1 CDR2 CDR3 I006D08 13 141 -249 163-173 189-195 228-238 1 -123 26-35 50-66 99-112 I050B11 14 143-251 166-177 193-199 232-240 1 -125 26-35 50-66 99-114 I050A12 15 142- • 250 164-174 190-196 229-239 1 -124 26-35 50-66 99-113 I050B11- 16 143- -251 166-177 193-199 232-240 1 -125 26-35 50-66 99-114 I116A01 17 141 - -249 163-173 189-195 228-238 1 -123 26-35 50-66 99-112 I026C04-K 18 142 -250 164-176 192-198 231 -239 1 -125 26-35 50-66 99-114 In one embodiment of the present invention, the antibodies that can be used in the methods of the invention bind to neutrocin-alpha and comprise a polypeptide having the amino acid sequence of any of the VH domains referred to in Table 1, or any of the VL domains referred to in Table 1. In preferred embodiments, the antibodies that can be used in the methods of the invention comprise the amino acid sequence of a VH domain and a VL domain of the same scFv referred to in Table 1. In embodiments Alternatively, the antibodies that can be used in the methods of the invention comprise the amino acid sequence of a VH domain and a VL domain of different scFv referred to in Table 1. In another embodiment, the antibodies that can be used in the methods of The invention specifically binds to neutrokine-alpha and comprises a polypeptide having the amino acid sequence of any one, two or more of the VR refs. in Table 1 or any one, two, three or more of the VL CDRs referred to in Table 1. In preferred embodiments, antibodies that can be used in the methods of the invention comprise the amino acid sequence of a CDR of VH and VL CDRs of the same scFv referred to in Table 1. In alternative embodiments, the antibodies that can be used in the methods of the invention comprise the amino acid sequence of a VH CDR and VL CDRs of different scFv's referred to in Table 1. Molecules comprising, or alternatively consisting of, fragments or antibody variants of the scFvs referred to in Table 1 which bind immunospecifically to neutrocyan-alpha can also be used in the methods of the invention. In a specific embodiment, an anti-neutrocin alfa antibody that can be used in the methods of the invention comprises the VH and VL domains of SEQ ID NO: 13, which are described in Table 1. In another specific embodiment, an antibody which can be used in the methods of the present invention comprises the VHCDR1, VHCDR2, VHCDR3 and VL CDR1, VLCDR2 and VLCDR3 regions of SEQ ID NO: 13, which are described in Table 1. In a specific embodiment, an anti-antibody -neutrocin alfa that can be used in the methods of the invention comprises the VH and VL domains of SEQ ID NO: 14, which are described in Table 1. In another specific embodiment, an antibody that can be used in the methods of The present invention comprises the VHCDR1, VHCDR2, VHCDR3, and VLCDR1, VLCDR2 and VLCDR3 regions of SEQ ID NO: 13, which are described in Table 1. In a specific embodiment, an anti-neutrocyanin alfa antibody that can be used in the methods of the invention comprises the VH and VL domains of SEQ ID NO: 13, which are described in Table 1. In another specific embodiment, an antibody that can be used in the methods of the present invention comprises the VHCDR1, VHCDR2, VHCDR3, and VLCDR1 regions, VLCDR2 and VLCDR3 of SEQ ID NO: 14, which are described in Table 1. In a specific embodiment, an anti-neutrocin alfa antibody that can be used in the methods of the invention comprises the VH and VL domains of SEQ ID NO: 15, which are described in Table 1. In another specific embodiment, an antibody that can be used in the methods of the present invention comprises the VHCDR1 regions., VHCDR2, VHCDR3, and VLCDR1, VLCDR2 and VLCDR3 of SEQ ID NO: 15, which are described in Table 1. In a specific embodiment, an anti-neutrocin alfa antibody that can be used in the methods of the invention comprises the VH and VL domains of SEQ ID NO: 16, which are described in Table 1. In another specific embodiment, an antibody that can be used in the methods of the present invention comprises the VHCDR1, VHCDR2, VHCDR3, and VLCDR1 regions, VLCDR2 and VLCDR3 of SEQ ID NO: 16, which are described in Table 1. In a specific embodiment, an anti-neutrocin alfa antibody that can be used in the methods of the invention comprises the VH and VL domains of SEQ ID NO: 17, which are described in Table 1. In another specific embodiment, an antibody that can be used in the methods of the present invention comprises the VHCDR1, VHCDR2, VHCDR3, and VLCDR1, VLCDR2 and VLCDR3 regions of SEQ ID NO. : 17, which are described in table 1. In a specific modality, u An anti-neutrophilic alpha antibody that can be used in the methods of the invention comprises the VH and VL domains of SEQ ID NO: 18, which are described in Table 1. In another specific embodiment, an antibody that can be used in The methods of the present invention comprise the VHCDR1, VHCDR2, VHCDR3, and VLCDR1, VLCDR2 and VLCDR3 regions of SEQ ID NO: 18, which are described in Table 1. In a specific embodiment, an anti-neutrocin-alpha antibody that can be used in the methods of the invention comprises the VH and VL domains of 15C10, an anti-neutrocin-alpha neutralizing antibody which is described for example in the US patent publication. UU No. 20050186637. The amino acid sequence of the VH domain of 15C10 is given in SEQ ID NO: 19. The amino acid sequence of the VL domain is given in the VH domain of 15C10 is given in SEQ ID NO: 20. In a specific embodiment, an anti-neutrocin-alpha antibody that can be used in the methods of the invention is an antigen binding fragment or variant of 15C10. In a specific embodiment, an antibody that can be used in the methods of the present invention is a humanized version of 15C10. In another specific embodiment, an antibody that can be used in the methods of the present invention comprises the VHCDR1, VHCDR2, VHCDR3, and VLCDR1, VLCDR2 and VLCD3 regions of 15C10. In another specific embodiment, an anti-neutrocin-alpha antibody that can be used in the methods of the invention comprises the VH and VL domains of the anti-neutrocine-alpha antibody 4A5-3.11-B4 which is described in International Patent Publication No. WO03 / 0164468, which is incorporated herein by reference in its entirety. Neutrocin-alpha is referred to as hTNFS13b in WO03 / 0164468. The amino acid sequence of the VH domain of 4A5.3.1.1-B4 is given in SEQ ID NO: 21. The amino acid sequence of the VL domain is given in the VH domain of 4A5-3.1.1-B4 given in SEQ ID NO: 22. In a specific embodiment, an anti-neutrocin-alpha antibody that can be used in the methods of the invention is an antigen-binding fragment or variant of 4A5-3.1.1-B4. In another specific embodiment, an antibody that can be used in the methods of the present invention comprises the VHCDR1, VHCDR2, VHCDR3 and VLCDR1, VLCDR2 and VLCDR3 regions of 4A5-3.1.1-B4. In a specific embodiment, the neutrokine-alpha antibodies that can be used in the methods of the invention bind specifically to the expressed native neutrokine-alpha polypeptide of a cell.

C. Neutrokine-alpha binding polypeptides In a specific embodiment, the neutrokine-alpha antagonist is a neutrokine-alpha binding peptide or polypeptide. Neutrocin-alpha binding peptides or polypeptides have been described, for example, in international patent publications Nos. WO05 / 005462, WO05 / 000351, WO02 / 092620, WO02 / 16412, WO02 / 02641 and WO02 / 16411, and in the publications of US patent UU Nos. US2006135430, US2006084608, US2003194743, US20030195156 and US2003091565, each of which is incorporated herein by reference in its entirety. Neutrokine-alpha peptides or polypeptides have been described, for example, in Sun et al. (2006), Biochem. Biophys. Res. Common 346: 1158-1162, which is hereby incorporated by reference in its entirety. The neutrokine-alpha binding peptides that can be used in the methods of the present invention include short polypeptides identified in random peptide sequences deployed by fusion with filamentous phage coat proteins. For an exposition of phage display peptide collection technology see, for example, Scott et al. (1990), Science 249: 386; Devlin et al. (1990), Science 249: 404; US patent UU No. 5,223,409, issued June 29, 1993; US patent UU No. 5,733,731, issued March 31, 1998; US patent UU No. 5,498,530, issued March 12, 1996; US patent UU No. 5,432,018, issued July 11, 1995; US patent UU No. 5,338,664, issued August 16, 1994, US patent. UU No. 5, 922,545, issued July 13, 1999; WO 96/40987, published December 19, 1996; and W098 / 15833, published April 16, 1998 (each of which is incorporated herein by reference in its entirety). The phages expressing the peptides are isolated by successive rounds of affinity purification against an immobilized neutrokine-alpha target peptide, followed by repropagation. The candidates with the highest binding to neutrocin-alpha can be sequenced to determine the identity of each binding peptide. Each identified neutrokine-alpha binding peptide can then be linked to a "carrier" to generate an additional neutrocin-alpha binding peptide, for use in the methods of the present experiment. The term "vehicle" refers to a molecule that prevents degradation or increases half-life, reduces toxicity, reduces immunogenicity, or increases the biological activity of a neutrokine-alpha binding peptide. Exemplary carriers include an Fe domain and variants thereof (a "peptide antibody" thereof is preferred); a linear polymer (for example polyethylene glycol (PEG) including PEG of 5 kD, 20 kD, and kD, polylysine, dextran, etc.); a branched chain polymer (see for example U.S. Patent No. 4,289,872 to Denkenwaiter et al., issued September 15, 1981; 5,229,490 to Tam, issued July 20, 1993; WO 93/21259 to Frechet et al. others, published on October 28, 1993); a lipid; a cholesterol group (such as a steroid); a carbohydrate or oligosaccharide (e.g. dextran); a natural or synthetic protein, polypeptide or peptide that binds to a salvage receptor; albumin, including without limitation recombinant human albumin or fragments or variants thereof (see for example U.S. Patent No. 5,876,969, issued March 2, 1999, EP 0 413 622, and U.S. Pat. No. 5,766,883, issued June 16, 1998, which is incorporated herein by reference in its entirety), and a leucine closure domain, and other such proteins and protein fragments. The neutrokine-alpha binding polypeptides that can be used in the methods of the invention require the presence of at least one vehicle attached to the peptide via the N-terminus, the C-terminus, or a side chain of one of the residues of amino acid You can also use multiple vehicles, for example Fc's at each end, or a Faith at one end and a PEG group at the other end or a side chain. For neutrokine-alpha binding peptides, a Fe domain is preferred as vehicle. The Fe domain can be fused with the N or C termini of the peptides, or both at the N and C termini. Fusion at the N terminus is preferred. As indicated above, the Fe variants are suitable vehicles for the peptides Neutrocin-alpha binding agents that can be used in the methods of the invention. A native Fe can be modified extensively to form a Fe variant, as long as the union with the salvage receptor is maintained.; see for example WO 97/34631 and WO 96/32478. In such Fe variants, one or more native Fe sites that provide structural features or functional activity not required by the neutrokine-alpha binding peptides that can be used in the methods of the invention can be removed. These sites can be removed, for example, by substituting or deleting waste, inserting waste into the site, or truncating portions that contain the site. The inserted or substituted residues may also be altered amino acids, such as peptidomimetics or D-amino acids. Fe variants may be desirable for several reasons, several of which are described below. Exemplary Fe variants include molecules and sequences in which: 1. The sites involved in disulfide bond formation are removed. Said removal can avoid the reaction with other cysteine-containing proteins present in the host cell used to produce the molecules of the invention. For this purpose, the segment containing cysteine at the N-terminus can be truncated, or the cysteine residues can be deleted or substituted with other amino acids (eg, alanyl, seryl). Even when the cysteine residues are removed, the single chain Fe domains can still form a chimeric Fe domain that remains non-covalently bound. 2. A native Fe is modified to make it more compatible with the selected host cell. For example, the PA sequence can be removed near the N-terminus of a typical native Fe, which can be recognized by a digestive enzyme in E. coli, such as proline iminopeptidase. An N-terminal methionine residue can also be added, especially when the molecule is recombinantly expressed in a bacterial cell such as E. coli. 3. A portion of the N-terminus of a native Fe is removed to prevent N-terminal heterogeneity when expressed in a selected host cell. For this purpose, any of the first 20 amino acid residues at the N-terminus can be deleted. 4. One or more glycosylation sites are removed. Residues that are normally glycosylated (eg asparagine) can confer a cytolytic response. Said residues can be deleted or substituted with non-glycosylated residues (for example alanine). 5. The sites involved in the interaction with the complement, such as the C1q binding site, are removed. For example, the EKK sequence of human IgG1 can be deleted or substituted. Complement recruitment may not be advantageous for molecules that can be used in the methods of the invention, and thus can be avoided with said Fe variant. 6. Sites that affect binding to different Fe receptors are removed. of a salvage receiver. A native Fe may have sites for interaction with certain leukocytes that are not required in the neutrokine-alpha binding peptide fusion molecules that can be used in the methods of the invention, and therefore can be removed. 7. The ADCC site is removed. ADCC sites are known in the art; see for example Molec. Immunol. 29 (5): 633-9 (1992) with respect to the ADCC sites in IgG1. These sites are also not required in the fusion molecules that can be used in the methods of the invention, and therefore can be removed. 8. When the native Fe is derived from a non-human antibody, the native Fe can be humanized. Normally, to humanize a native Fe, selected residues in native non-human Fe will be substituted with residues normally found in native Fe. The techniques for antibody humanization are well known. An alternative vehicle for the neutrokine-alpha binding peptides that can be used in the methods of the invention would be a protein, polypeptide, peptide, antibody, antibody fragment, or small molecule (e.g., a peptidomimetic compound), able to join a rescue receiver. For example, a polypeptide such as that described in US Pat. UU No. 5,739,277. Also, the peptides could be selected by phage display or screening and selection of RNA-peptide for binding to the salvage receptor. Said salvage receptor binding compounds are also included within the meaning "carrier" and can be used in neutrokine-alpha binding peptides that can be used in the methods of the invention. Said vehicles would be selected according to their increase in half-life (for example avoiding sequences recognized by proteases) and decrease in immunogenicity (for example by favoring non-immunogenic sequences, as was discovered in the humanization of the antibody). As indicated above, polymer carriers can also be used in the neutrokine-alpha binding peptides that can be used in the methods of the invention. Several means are now available to link useful chemical moieties as vehicles, see for example the international publication of the Patent Cooperation Treaty ("PTC") No. WO 96/11953, which is incorporated herein by reference in its entirety. This PCT publication describes among other things the selective binding of water-soluble polymers to the N-terminus of the proteins. In a specific embodiment, a preferred polymer carrier is polyethylene glycol (PEG). The PEG group may be of any convenient molecular weight and may be linear or branched. The average molecular weight of the PEG will preferably be in the range of about 2 kiloDalton ("kD"), to about 100 kD, preferably from 5 kD to about 50 kD, preferably from 5 KD to about 10 kD. PEG groups generally bind to the neutrokine alpha binding peptides that can be used in the methods of the invention, by means of acylation or reductive alkylation, through a reactive group in the PEG portion (eg, a group an aldehyde, amino, thiol or ester) with a reactive group of the compound of the invention (for example an aldehyde, amino, or ester group). A useful strategy for the pegylation of synthetic peptides is to combine in solution, by forming a conjugated bond, a peptide and a portion of PEG, each carrying a special functional group that is mutually reactive towards the other. The peptides can be easily prepared by conventional solid phase synthesis. The peptides are "preactivated" with a suitable functional group at a specific site. The precursors are completely purified and characterized before being reacted with the PEG portion. Ligation of the peptide with PEG usually occurs in the aqueous phase and can be easily monitored by analytical reverse phase HPLC. The pegylated peptides can be easily purified by preparative HPLC and can be characterized by analytical HPLC, amino acid analysis and laser desorption mass spectrometry. Polysaccharide polymers are another type of water-soluble polymer that can be used for neutrokine-alpha binding peptides that can be used in the methods of the invention. Dextrans are polysaccharide polymers comprised of individual glucose subunits linked predominantly by alpha 1-6 bonds. Dextran itself is available in many molecular weight scales, and is readily available in molecular weights of about 1 kD to about 70 kD. Dextran is a water soluble polymer suitable for use as a carrier for the neutrokine alpha binding peptides which can be used in the methods of the invention, either alone or in combination with another vehicle (for example Fe). See for example WO 96/11953 and WO 96/05309. The use of dextran conjugated with therapeutic or diagnostic immunoglobulins has been reported; see, for example, European Patent Publication No. 0 315 456, which is incorporated herein by reference in its entirety. Dextran of about 1 kD to about 20 kD is preferred when used as a carrier according to the present invention. In a specific embodiment, the neutrokine-alpha binding peptides that can be used in the methods of the invention optionally include a "linker". When present, its chemical structure is not critical since it serves mainly as a spacer. The linker is preferably formed of amino acids linked together by peptide bonds. Thus, in preferred embodiments, the linker is formed from 1 to 30 amino acids joined by peptide bonds, wherein the amino acids are selected from the 20 natural amino acids. Some of these amino acids may be glycosylated, as is well understood by those skilled in the art. In a preferred embodiment, amino acids 1 to 20 are selected from glycine, alanine, proline, asparagine, glutamine and lysine. Preferably, a linker will consist mostly of amino acids that are not sterically hindered, such as glycine and alanine. In this manner, the preferred linkers are polyglycines (particularly (Gly) 4, (Gly) 5), poly (Gly-Ala), and polyamines. Preferred linkers are amino acid linkers comprising more than 5 amino acids, suitable linkers having up to about 500 amino acids, selected from glycine, alanine, proline, asparagine, glutamine, lysine, threonine, serine or aspartate. Linkers of about 20 to 50 amino acids are preferred. Non-peptidic linkers are also useful for neutrokine-alpha binding peptides that can be used in the methods of the invention. For example, alkyl linkers such as NH- (CH2) n-C (0) -, where n = 2-20 can be used. These alkyl linkers can be substituted with any non-sterically hindered group, such as lower alkyl (for example C? -C6), lower acyl, halogen (for example Cl, Br), CN, NH2, phenyl, etc. In preferred embodiments, the neutrokine-alpha binding peptides that can be used in the methods of the invention include the amino acid sequence of SEQ ID NO: 23, the amino acid sequence of SEQ ID NO: 24, or the amino acid sequence of SEQ ID NO: 25. In a particularly preferred embodiment, the neutrocin-alpha binding peptide that can be used in the methods of the invention is the amino acid sequence SEQ ID NO: 23 (AMG 623; AGP3 peptide antibody).

Neutrokine-alpha Receptors In a specific embodiment, the neutrokine-alpha antagonist is a neutrokine-alpha receptor protein, or fragment or variant thereof. Neutrokine-alpha receptors include, for example, the transmembrane activator and CAML interactor (TACI, GenBank registration No. AAC51790, SEQ ID NO: 6), B cell activating factor receptor (BAFF-R, No GenBank registry NP_443177, SEQ ID NO: 10) and B cell maturation antigen (BCMA, GenBank Registration No. NP_001183, SEQ ID NO: 8). Neutrokine-alpha receptor proteins, fragments and variants thereof, as well as antibodies thereto, have been described for example in PCT publications WO03 / 014294, WO02 / 066516, WO02 / 024909, WO03 / 014294, WO03 / 024991, WO02 / 094852 and WO04 / 011611 and U.S. Patent Publications. UU Nos. US20030148445, US20030099990, US2005070689, US2005043516 and US2003012783, and are described below in greater detail. Each of the aforementioned references is incorporated herein by reference in its entirety. D. Neutrokine-alpha Receptors, TACI TACI polypeptides, such as those described below, act as neutrokine-alpha or APRIL antagonists, and may also be used in the methods of the present invention. TACI, also known as TR17, is a protein of 293 amino acid residues (SEQ ID NO: 6), with a deduced molecular weight of approximately 31.8 kDa. A nucleotide sequence of a cDNA encoding TACI is given in SEQ ID NO: 5. Predicted amino acids from about 1 to about 165 constitute the extracellular domain (SEQ ID NO: 6); the amino acids from about 166 to about 186 constitute the transmembrane domain (SEQ ID NO: 6); and amino acids from about 187 to about 293 constitute the intracellular domain (SEQ ID NO: 6). Accordingly, in one embodiment, a TACI protein that can be used in the methods of the present invention is an isolated polypeptide comprising, or alternatively consisting of, the amino acid sequence of SEQ ID NO: 6, or a polypeptide that comprises, or alternatively consisting of, a portion of SEQ ID NO: 6, such as for example the extracellular domain of TACI (comprising amino acids 1 to 165 of SEQ ID NO: 6), or the domain rich in cysteine of TACI (comprising amino acids 33 to 104 of SEQ ID NO: 6); as well as polypeptides that are at least 80% identical, preferably at least 90% or 95% identical, preferably at least 96%, 97%, 98%, 99%, or 100% identical to the polypeptides described above . In another embodiment a TACI protein that can be used in the methods of the present invention is an isolated polypeptide comprising amino acids 1 to 154 of SEQ ID NO: 6, as well as polypeptides that are at least 80% identical, preferably at least 90% or 95% identical, preferably 96%, 97%, 98%, 99%, or 100% identical to the polypeptides described above. By expressing a polypeptide having at least one amino acid sequence, for example, 95% "identical" to a reference amino acid sequence of a TACI polypeptide, it is understood that it is the amino acid sequence of the identical polypeptide with respect to the reference sequence, except that the polypeptide sequence may include up to 5 amino acid alterations per 100 amino acids of the reference amino acid of the TACI receptor. In other words, to obtain a polypeptide having an amino acid sequence at least 95% identical to a reference amino acid sequence, up to 5% of the amino acid residues of the reference sequence can be deleted or substituted with another amino acid, or a number of amino acids of up to 5% of the total amino acid residues in the reference sequence can be inserted into the reference sequence. These alterations of the reference sequences can occur at the amino or carboxy terminal positions of the reference amino acid sequence or anywhere between those terminal positions, interleaved individually between residues in the reference sequence, or in one or more contiguous groups within the reference sequence. TACI polypeptide fragments include polypeptides comprising, or alternatively consisting of, an amino acid sequence contained in SEQ ID NO: 6. The polypeptide fragments may be "autonomous" or may be comprised within a larger polypeptide of which the fragment forms a part or region, preferably as a single continuous region. In additional embodiments, the polypeptide fragments comprise, or alternatively consist of, one or more TACI domains. Preferred polypeptide fragments include a member selected from the group: a) a polypeptide comprising, or alternatively consisting of, the extracellular domain of TACI (which is predicted to constitute amino acid residues from about 1 to about 165 of SEQ ID. NO 6); b) a polypeptide comprising, or alternatively consisting of, a TACI cysteine-rich domain (which is predicted to constitute amino acid residues from about 33 to about 104 of SEQ ID NO: 6); c) a polypeptide comprising, or alternatively consisting of, the transmembrane domain of TACI (which is predicted to constitute the amino acid residues from about 166 to about 186 of SEQ ID NO: 6); d) a polypeptide comprising, or alternatively consisting of, the intracellular domain of TACI (which is predicted to constitute the amino acid residues from about 187 to about 295 of SEQ ID NO: 6); or e) any combination of the polypeptides (a) - (d). It is believed that the extracellular cysteine-rich motifs of TACI are important for the interactions between TACI and its ligands, neutrocin-alpha and APRIL. Accordingly, in preferred embodiments, the TACI polypeptide fragments that can be used in the methods of the present invention comprise, or alternatively consist of, the amino acid residues of about 33 to 66, or 70 to 104, of SEQ ID NO 6. In a specific embodiment, the TACI polypeptides that can be used in the methods of the present invention comprise, or alternatively consist of, one or both of the extracellular cysteine-rich motifs (residues 33 to 66 and residues 70 to 104 of SEQ ID NO. : 6). Also preferred are proteins comprising, or alternatively consisting of, a polypeptide sequence that is at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the polypeptide sequences of one or both of the cysteine-rich motifs. Other fragments of the TACI protein that can be used in the methods of the invention are the fragments characterized by structural or functional attributes of TACI. Such fragments include amino acid residues comprising alpha-helix and alpha-helix forming regions ("alpha regions"), beta-sheet regions and beta-sheet forming regions ("beta regions"), regions of turn and spin-forming regions. ("spin regions"), spiral regions and spiral-forming regions ("spiral regions"), hydrophilic regions, hydrophobic regions, alpha amphipathic regions, beta amphipathic regions, surface forming regions and regions of high antigenic index (ie say, that contains four or more contiguous amino acids that have an antigenic index greater than or equal to 1.5, identified using the default parameters of the Jameson-Wolf program), of the full TACI (ie, full-length) (SEQ ID NO: 6), as set forth in US Pat. UU No. 6,969,159. Some preferred regions include, without limitation, predicted alpha regions according to Garnier-Robson, beta regions, turn regions and spiral regions; alpha regions predicted according to Chou-Fasman, beta regions and regions of return; predicted hydrophilic regions according to Kyte-Doolittle; Hydrophobic regions predicted by Hopp-Woods; alpha and beta amphipathic regions of Eisenberg; surface forming regions of Emini; and regions of high antigenic index of Jameson-Wolf, as predicted using the default parameters of these computer programs.

The TACI polypeptide for use in the methods of the invention can be expressed in a modified form, such as a fusion protein (comprising the polypeptide linked via a peptide bond to a heterologous protein sequence (of a different protein)), and it can include not only secretory signals but also additional heterologous functional regions. Alternatively, said fusion protein can be prepared by synthetic protein techniques, for example using a peptide synthesizer. In this manner, a region of additional amino acids, particularly charged amino acids, can be added to the N-terminus of the polypeptide for better stability and persistence in the host cell, during purification or during subsequent handling and storage. Portions of peptide can be added to the polypeptide to facilitate its purification. Said regions can be removed before the final preparation of the polypeptide. The addition of portions of peptide to the polypeptides to engender secretion or excretion, to improve stability and to facilitate purification, among other things, are familiar and routine techniques. A TACI fusion protein that can be used in the methods of the invention comprises a heterologous region of an immunoglobulin that is useful for solubilizing proteins. For example, EP-AO-464533 (Canadian counterpart 2045869) and WO00 / 024782, describe fusion proteins comprising several portions of the constant region of immunoglobulin molecules together with another human protein or part thereof. TACI immunoglobulin fusion proteins have been described for example in PCT publications WO01 / 60397, WO01 / 81417, WO01 / 087977, and WO02 / 94852; US publications UU US2003103986 and US2006034852 and Gross, et al. (2000) Nature 404: 995-999, and Yu et al. (2000) Nat Immunol 1: 252-256, which are incorporated herein by reference in their entirety. In many cases, the Fe part of a fusion protein is very advantageous for use in therapy and diagnosis, and thus results in, for example, improved pharmacokinetic properties (EP-A 0232 262). On the other hand, for some uses it would be desirable to be able to suppress the Fe part after the fusion protein has been expressed, detected and purified in the advantageous manner described. This is the case when the Fe portion proves to be an impediment for use in therapy and diagnosis, for example when the fusion protein is to be used as an antigen for immunizations. In drug discovery, for example, human proteins such as the hIL-5 receptor have been fused with Fe portions for the purpose of performing high throughput screening tests to identify hIL-5 antagonists. See, D. Bennett et al., Journal of Molecular Recognition 8: 52-58 (1995) and K. Johanson et al., The Journal of Biological! Chemistry 270: 16: 9459-9471 (1995). In a specific embodiment, the TACI-Fc fusion protein that can be used in the methods of the invention is Atacicept (TACI-Ig). As the skilled person will appreciate, and as discussed above, the TACI polypeptides can be fused with other polypeptide sequences. For example, TACI polypeptides can be fused to the constant domain of the immunoglobulins (IgA, IgE, IgG, IgM), or portions thereof (CH1, CH2, CH3, or any combination or portions thereof), or albumin (including without limitation recombinant human albumin or fragments or variants thereof (see for example U.S. Patent No. 5,876,969, issued March 2, 1999, EP 0 413 622, and the patent No. 5,766,883, issued June 16, 1998, incorporated herein by reference in its entirety), resulting in chimeric polypeptides. Such fusion proteins can facilitate purification, can extend shelf life and can increase the half-life in vivo. This has been shown for chimeric proteins consisting of the first two domains of the human CD4 polypeptide and several domains of the constant regions of the heavy or light chains of human immunoglobulins. See for example, EP 394,827; Traunecker et al., Nature, 331: 84-86 (1988). Improved delivery of an antigen through the epithelial barrier to the immune system has been demonstrated for antigens (eg insulin) conjugated to an FcRn binding partner, such as IgG or Fe fragments (see for example the PCT publications WO 96/22024 and WO 99/04813). It has also been found that IgG fusion proteins having a disulfide linked dimeric structure due to the disulfide bonds of the IgG portion are more efficient for binding and neutralizing other molecules than monomeric polypeptides or their fragments alone. See, for example, Fountoulakis et al., J. Biochem., 270: 3958-3964 (1995). An albumin fusion protein that can be used in the methods of the present invention comprises at least one fragment or variant of a TACI polypeptide and at least one fragment or variant of human serum albumin, which are associated with each other, preferably by genetic fusion (i.e., the albumin fusion protein is generated by translation of a nucleic acid in which a polynucleotide encoding all or part of the TACI is bound in frame with a polynucleotide that encodes a part or all of the albumin ), or by chemical conjugation with each other. The TACI polypeptide and the albumin protein, once part of the albumin fusion protein, can be referred to as a "portion" or "region" of the albumin fusion protein (e.g., a "TACI portion" or a "protein albumin portion"). In one embodiment, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a TACI polypeptide and a serum albumin protein. In other embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a fragment of TACI and a whey protein albumin. In other embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a variant TACI and a whey protein albumin. In preferred embodiments, the protein component of serum albumin of the albumin fusion protein is the mature portion of serum albumin. In additional embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a TACI polypeptide and a biologically active or therapeutically active fragment of serum albumin. In additional embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a TACI polypeptide and a biologically active or therapeutically active variant of serum albumin. In preferred embodiments, the TACI portion of the albumin fusion protein is the full-length TACI polypeptide. In a further embodiment, the TACI portion of the albumin fusion protein is the soluble mature domain of the TACI peptide. In additional embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a fragment or variant of TACI and a biologically active or therapeutically active fragment of serum albumin. In preferred embodiments, the invention provides an albumin fusion protein comprising, or alternatively consisting of, the mature portion of the TACI polypeptide and the mature portion of serum albumin. In additional embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a fragment or variant of TACI and a biologically active or therapeutically active fragment of serum albumin. In preferred embodiments, the invention provides an albumin fusion protein comprising, or alternatively consisting of, the mature portion of the TACI polypeptide and the mature portion of the serum albumin (including without limitation recombinant human serum albumin or fragments or variants thereof (see for example U.S. Patent No. 5,876,969, issued on March 2, 1999, EP 0 413 622, and U.S. Patent No. 5,766,883, issued June 16, 1998, which is incorporated herein by reference in its entirety)). In a preferred embodiment, the TACI polypeptides (which include fragments or variants thereof) are fused to the mature form of human serum albumin (i.e., amino acids 1-585 of human serum albumin, as shown in FIG. Figures 1 and 2 of EP 0 322 094), which are incorporated herein by reference in their entirety. In another preferred embodiment, the antibodies of the invention (including fragments or variants thereof), are fused to fragments of polypeptides comprising or alternatively consist of, the amino acid residues 1-x of human serum albumin, wherein x is an integer from 1 to 585, and the albumin fragment has human serum albumin activity. In another preferred embodiment, the TACI polypeptides (including fragments or variants thereof) are fused to polypeptide fragments comprising, or alternatively consist of, the amino acid residues 1-z of human serum albumin, wherein z is an integer from 369 to 419, as described in U.S. Pat.

UU 5,766,883, which is incorporated herein by reference in its entirety. The TACI polypeptides (which include fragments or variants thereof) can be fused at the N or C terminus of the heterologous protein (e.g., immunoglobulin Fe polypeptide or human serum albumin polypeptide). In preferred embodiments, the human serum albumin protein used in the albumin fusion proteins that can be used in the methods of the invention contains one or both of the following groups of dot mutations with respect to SEQ ID NO: 11: Leu -407 to Ala, Leu-408 to Val, Val-409 to Ala, and Arg-410 to Ala; or Arg-410 to A, Lys-413 to Gln, and Lys-414 to Gin (see for example the international publication No. W095 / 23857, which is incorporated herein in its entirety as a reference). In highly preferred embodiments, the albumin fusion proteins that can be used in the methods of the invention containing one or both of the above-described groups of dot mutations have improved stability or resistance to the proteolytic cleavage of yeast Yap3p, allowing an increase in the production of recombinant albumin fusion proteins expressed in yeast host cells. Preferably, the albumin fusion protein that can be used in the methods of the invention comprises HA as the N-terminal portion, and the TACI polypeptide as the C-terminal portion. Alternatively, an albumin fusion protein comprising HA as the C-terminal portion and the TACI polypeptide as the N-terminal portion may also be used. In other embodiments, the albumin fusion protein that can be used in the methods of the invention has a TACI polypeptide fused to both the N-terminus and the C-terminus of albumin. In a specific embodiment, the TACI polypeptides fused at the N and C ends are the same. In another embodiment, the TACI polypeptides fused at the N and C ends are different TACI polypeptides. In another embodiment, a TACI polypeptide is fused at the N-terminus or C-terminus of albumin, and a heterologous polypeptide is fused at the remaining end. Additionally, albumin fusion proteins that can be used in the methods of the invention can include a linker peptide between the fused portions to provide greater physical separation between the portions. The linker peptide can consist of amino acids so that it is flexible or more rigid. Generally, albumin fusion proteins that can be used in the methods of the invention can have a region derived from HA and a region from TAC1. However, multiple regions of each protein can be used to make an albumin fusion protein that can be used in the methods of the invention. Similarly, more than one protein can be used to make an albumin fusion protein that can be used in the methods of the invention. For example, a protein can be fused to both the N-terminus and the C-terminus of HA. In such a configuration, the protein portions may be the same or different protein molecules.

The structure of the bifunctional albumin fusion proteins can be represented as: X-HA-Y or Y-HA-X. In a specific embodiment, a TACI protein or fragment or variant thereof, which can be used in the methods of the invention, can be conjugated with a cytotoxin (for example a cytostatic or cytocidal agent). A cytotoxin or cytotoxic agent includes any agent that is harmful to the cells. Examples include paclitaxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracendione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol and puromycin, and analogs and homologs thereof. In another embodiment, a TACI protein or fragment or variant thereof that can be used in the methods of the invention can be conjugated to a toxin. By "toxin" is meant one or more compounds that bind and activate cytotoxic effector systems, endogenous, radioisotopes, holotoxins, modified toxins, catalytic subunits of toxins, or any molecule or enzyme not normally present on or on the surface of a cell, which under defined conditions cause the death of the cell. Toxins that can be used include, without limitation, known radioisotopes, compounds such as for example antibodies (or portions containing complement fixation thereof) that bind to an inherent or induced endogenous cytotoxic effector system, thymidine kinase, endonuclease, RNAse, alpha toxin, ricin, abrin, Pseudomonas exotoxin A, diphtheria toxin, saponin, mormodin, gelonin, phytolac antiviral protein, alpha sarcina and cholera toxin. "Toxin" also includes a cytostatic or cytocidal agent, a therapeutic agent or a radioactive metal ion, for example alpha emitters such as for example 213Bi, or other radioisotopes such as for example 103Pd, 133Xe, 131l, 68Ge, 57Co, 65Zn, 85Sr, 32P, 35S, 90Y, 153Sm, 153Gd, 169Yb, 51Cr, 54Mn, 75Se, 113Sn, 90Ytrium, 117Stand, 186Renium, 166Holm, and 188Renio. To improve or alter the characteristics of the TACI polypeptides that can be used in the methods of the invention, protein engineering can be used. The known recombinant DNA technology can be used to create novel mutant proteins or "muteins that include single or multiple substitutions of amino acids, deletions, additions or fusion proteins". Said modified polypeptides may for example show higher activity or greater stability. In addition, they can be purified in high yields and show a better solubility than the corresponding natural polypeptide, at least under certain purification and storage conditions. The TACI proteins that can be used in the methods of the invention can be monomers or multimers (ie, dimers, trimers, tetramers and higher multimers). In specific embodiments, the polypeptides of the invention are monomers, dimers, trimers, or tetramers. In further embodiments, the multimers of the invention are at least dimers, at least trimers, or at least tetramers. It is believed that some members of the TNF family of proteins exist in trimeric form (Beutler and Huffel, Science 264: 667, 1994).; Banner et al., Cell 73: 431, 1993). In this way, trimeric TACI can offer the advantage of greater biological activity. In specific embodiments, the multimers may be homomers or heteromers. As used herein, the term "homomer" refers to a multimer containing only TACI proteins (including fragments, variants, and TACI fusion proteins, as described herein). These homomers may contain TACI proteins that have identical or different polypeptide sequences. In a specific embodiment, a homomer is a multimer containing only TACI proteins that have an identical polypeptide sequence. In another specific embodiment, a homomer is a multimer containing TACI proteins having different polypeptide sequences. As used herein, the term "heteromer" refers to a multimer containing heterologous proteins (ie, proteins that contain only polypeptide sequences that do not correspond to a polypeptide sequence encoded by the TACI gene), in addition to the TACI proteins. The multimers can be the result of hydrophobic, hydrophilic, ionic or covalent associations, or they can be linked indirectly, for example, by liposome formation. Thus, in one embodiment, multimers such as, for example, homodimers, homotrimers, heterotrimers, or heterotetramers are formed when the proteins contact each other in solution. In other embodiments, the multimers are formed by covalent associations with or between the TAC1 proteins. Said covalent associations may involve one or more amino acid residues contained in the polypeptide sequence of the protein. In one case, the covalent associations are entanglement between cysteine residues located within the polypeptide sequences of the proteins that interact in the native polypeptide (i.e., occur naturally). In another case, covalent associations are a consequence of chemical or recombinant manipulation. Alternatively, said covalent associations may include one or more amino acid residues contained in the sequence of the heterologous polypeptide in a TAC1 fusion protein. In one example, the covalent associations are between the heterologous sequence contained in a fusion protein (see for example U.S. Patent No. 5,478,925, the content of which is incorporated herein by reference in its entirety). In a specific example, the covalent associations are between the heterologous sequence contained in a TACI-Fc fusion protein (as described herein). In another specific example, the covalent associations of fusion proteins are between heterologous polypeptide sequences of another ligand / receptor member of the TNF family, which is capable of forming covalently associated multimers, such as for example osteoprotegerin (see for example the publication WO 98/49305, the content of which is incorporated herein by reference in its entirety). In another embodiment, two or more TACI polypeptides are linked through synthetic linkers (e.g., peptide, carbohydrate or soluble polymer linkers). Examples include the peptide linkers described in US Pat. UU No. 5,073,627 (which is incorporated herein by reference). Proteins comprising multiple TACI polypeptides separated by peptide linkers can be produced using conventional recombinant DNA technology. In a specific embodiment, antibodies that bind to a TACI polypeptide, a polypeptide fragment, a variant of SEQ ID NO: 6, or an epitope of the TACI polypeptide (determined by very high immunoassays) can be used in the methods of the invention. known to determine antibody-specific antigen binding). Anti-TACI antibodies and fragments thereof have been described, for example in PCT publications WO04 / 011611, WO01 / 087977, WO01 / 60397, and WO02 / 66516; the US patent publication UU US2005043516 US2003012783; and Ch'en and others, (2005) Cell Immunol 236: 78-85 and Liu and others (2003) Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 19: 168-169. Each of the aforementioned references is incorporated herein by reference in its entirety. The antibodies include, without limitation, polyclonal, monoclonal, multispecific, human, humanized, or chimeric antibodies, single chain antibodies; Fab fragments, F (ab ') fragments, fragments produced by a collection of Fab expression, idiotypic antibodies (anti-id) (including for example anti-ld antibodies for anti-TACI antibodies), and epitope binding fragments of any of the above. The term "antibody", as used herein, refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, ie, molecules that contain an antigen-binding site that binds immunospecifically to an antigen. The immunoglobulin molecules can be of any type (for example IgG, IgE, IgM, IgD, IgA, and IgY), class (for example lgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass immunoglobulin molecule. . In specific modalities, the immunoglobulin molecules are IgG1. In other specific embodiments, the immunoglobulin molecules are IgG4. TACI binding antibody fragments that can be used in the methods of the invention include, without limitation, Fab, Fab 'and F (ab') 2, Fd, single-chain Fvs (scFv), single-chain antibodies. chain, Fvs linked by disulfide (sdFv) and fragments comprising a VL or VH domain. Antigen-binding antibody fragments, including single-chain antibodies, may comprise the variable region alone or in combination with all or a portion of the following: hinge region, CH1, CH2, and CH3 domains. They also include antigen binding fragments that comprise any combination of the variable regions with a hinge region, or the CH1, CH2, and CH3 domains. The antibodies can be of any animal origin, including birds and mammals. Preferably, the antibodies are human, murine (e.g., mouse and rat), donkey, sheep, rabbit, goat, guinea pig, camel, horse, or chicken. As used herein, "human" antibodies include antibodies that have the amino acid sequence of a human immunoglobulin and include antibodies isolated from collections of human immunoglobulin or from animals transgenic for one or more human immunoglobulins, and that do not express endogenous immunoglobulins, such as it is described, for example, in U.S. Pat. UU No. 5,939,598 to Kucherlapati et al., The contents of which are incorporated herein by reference in their entirety. The anti-TACI antibodies that can be used in the methods of the invention can be monospecific, bispecific, trispecific, or of greater specificity. Multispecific antibodies may be specific for different epitopes of a TACI polypeptide, or may be specific for both a TACI polypeptide and a heterologous epitope, such as a heterologous polypeptide or solid support material. See, for example, PTC publications WO 93/17715; WO 92/08802; WO 91/00360; WO 92/05793; Tutt et al., J. Immunol. 147: 60-69 (1991); US patent UU Nos. 4,474,893; 4,714,681; 4,925,648; 5,573,920; 5,601, 819; Kostelny et al., J. Immunol. 148: 1547-1553 (1992), the content of which is hereby incorporated by reference in its entirety. TACI antibodies can be described or specified based on their cross-reactivity. Antibodies that do not bind to any other analog, ortholog, or homologue of a TACI polypeptide can be used in the methods of the invention. In specific embodiments, TACI antibodies cross-react with murine, rat or rabbit homologs, human TACI proteins, and corresponding epitopes thereof. In a specific modality, an anti-TACI antibody that can be used in the methods of the invention binds not only to TACI but also binds to BCMA and BAFF-R. The TACI antibodies that can be used in the methods of the invention can also be described or specified based on their binding affinity to a TACI polypeptide. Preferred binding affinities include those with a dissociation constant or Kd less than 5 X 10"9 M, 10" 9 M, 5 X 10-10 M, 10 10 M, 5 X 10"11 M, 10" 11 M , 5 X 10"12 M, or 10" 12 M. The TACI antibodies that can be used in the methods of the invention can act as agonists or antagonists of the TAC1 polypeptides. For example, TACI antibodies that interrupt receptor / ligand interactions with TACI polypeptides are included partially or completely. Also included are receptor-specific antibodies that do not prevent ligand binding but that prevent receptor activation. The activation of the receptor (i.e., signaling) can be determined by techniques described herein or otherwise known. For example, activation of the receptor can be determined by detecting the activation of the transcription factors NF-AT, AP-1 or NF-kappaB using known techniques, or phosphorylation (for example tyrosine or serine / threonine) of the receptor or its substrate, by means of immunoprecipitation, followed by Western blot analysis.

In a specific embodiment, antibodies of receptor-specific TACI that prevent ligand binding and receptor activation, as well as TACI antibodies that recognize the receptor-ligand complex, and preferably do not recognize, can be used in the methods of the invention. specifically the unbound receptor or the unbound ligand. The above TACI antibodies can be made using the known methods. See, for example, PCT publication WO 96/40281; the US patent UU No. 5,811, 097; Deng et al., Blood 92 (6): 1981 -1988 (1998); Chen et al., Cancer Res. 58 (16): 3668-3678 (1998); Harrop et al., J. Immunol. 161 (4): 1786-1794 (1998); Zhu et al., Cancer Res. 58 (15): 3209-3214 (1998); Yoon et al., J. Immunol. 160 (7): 3170-3179 (1998); Prat et al., J. Cell. Sci. 111 (Pt2): 237-247 (1998); Pitard et al., J Immunol. Methods 205 (2): 177-190 (1997); Liautard et al., Cytokine 9 (4): 233-241 (1997); Carlson et al., J. Biol. Chem. 272 (17): 11295-11301 (1997); Taryman et al., Neuron 14 (4): 755-762 (1995); Muller et al., Structure 6 (9): 1153-1167 (1998); Bartunek et al., Cytokine 8 (1): 14-20 (1996) (which are hereby incorporated by reference in their entirety).

E. Neutrocin-alpha receptor, BCMA BCMA polypeptides, such as those described below, act as neutrocin-alpha or APRIL antagonists and can also be used in the methods of the present invention. BCMA, also known as TR18, is a protein of 184 amino acid residues (SEQ ID NO: 8), with a deduced molecular weight of 20.1 kDa. A nucleotide sequence of a cDNA encoding BCMA is given in SEQ ID NO: 7. Predicted amino acids from about 1 to 54 constitute the extracellular domain (SEQ ID NO: 8); the amino acids of about 55 to 80 constitute the transmembrane domain (SEQ ID NO: 8); and amino acids of about 81 to 184 constitute the intracellular domain (SEQ ID NO: 8). Accordingly, in one embodiment, a BCMA protein that can be used in the methods of the present invention is an isolated polypeptide comprising, or alternatively consisting of, the amino acid sequence of SEQ ID NO: 8, or a polypeptide that comprises, or alternatively consisting of, a portion of SEQ ID NO: 8, such as for example the extracellular domain of BCMA (comprising amino acids 1 to 54 of SEQ ID NO: 8), or the domain rich in cysteine of BCMA (comprising amino acids 8 to 41 of SEQ ID NO: 8); as well as polypeptides that are at least 80% identical, preferably at least 90% or 95% identical, preferably at least 96%, 97%, 98%, 99%, or 100% identical to the polypeptides described above . By expressing a polypeptide having at least one amino acid sequence, for example, 95% "identical" to a reference amino acid sequence of a BCMA polypeptide, it is understood that it is the amino acid sequence of the polypeptide identical to that of the reference sequence, except that the polypeptide sequence can include up to 5 amino acid alterations per 100 amino acids of the reference amino acid of the BCMA receptor. In other words, to obtain a polypeptide having an amino acid sequence at least 95% identical to a reference amino acid sequence, up to 5% of the amino acid residues of the reference sequence can be deleted or substituted with another amino acid, or a number of amino acids of up to 5% of the total amino acid residues in the reference sequence can be inserted into the reference sequence. These alterations of the reference sequences may occur at the amino or carboxy terminal positions of the reference amino acid sequence or anywhere between those terminal positions, interspersed individually between residues in the reference sequence, or in one or more contiguous groups within of the reference sequence. BCMA polypeptide fragments include polypeptides comprising, or alternatively consisting of, an amino acid sequence contained in SEQ ID NO: 8. The polypeptide fragments may be "autonomous" or may be comprised within a larger polypeptide of which the fragment forms a part or region, preferably as a single continuous region. In additional embodiments, the polypeptide fragments comprise, or alternatively consist of, one or more BCMA domains. Preferred polypeptide fragments include a member selected from the group: (a) a polypeptide comprising, or alternatively consisting of, the extracellular domain of BCMA (which is predicted to constitute the amino acid residues from about 1 to about 54 of the SEQ ID NO: 8); (b) a polypeptide comprising, or alternatively consisting of, a cysteine-rich domain of BCMA (which is predicted to constitute amino acid residues from about 8 to about 41 of SEQ ID NO: 8); (c) a polypeptide comprising, or alternatively consisting of, the transmembrane domain of BCMA (which is predicted to constitute the amino acid residues from about 55 to about 80 of SEQ ID NO: 8); (d) a polypeptide comprising, or alternatively consisting of, the intracellular domain of BCMA (which is predicted to constitute the amino acid residues from about 81 to about 184 of SEQ ID NO: 8); or (e) any combination of the polypeptides (a) - (d). It is believed that the extracellular cysteine-rich motifs of BCMA are important for the interactions between BCMA and its ligands, neutrocin-alpha and APRIL. Accordingly, in preferred embodiments, the BCMA polypeptide fragments that can be used in the methods of the present invention comprise, or alternatively consist of, the amino acid residues of about 8 to 41 of SEQ ID NO: 8. Also preferred are proteins comprising, or alternatively consisting of, a polypeptide sequence that is at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the polypeptide sequences of the motif rich in cysteine. Other fragments of the BCMA protein that can be used in the methods of the invention are the fragments characterized by structural or functional attributes of BCMA. Such fragments include amino acid residues comprising alpha-helix and alpha-helix forming regions ("alpha regions"), beta-sheet regions and beta-sheet forming regions ("beta regions"), regions of turn and spin-forming regions. ("spin regions"), spiral regions and spiral-forming regions ("spiral regions"), hydrophilic regions, hydrophobic regions, alpha amphipathic regions, beta amphipathic regions, surface forming regions and regions of high antigenic index (ie say, that contains four or more contiguous amino acids that have an antigenic index greater than or equal to 1.5, identified using the default parameters of the Jameson-Wolf program), of the complete BCMA (ie, full-length) (SEQ ID NO: 8), as set forth in the US patent application. UU No. 10 / 786,176. Some preferred regions include, without limitation, predicted alpha regions according to Gamier-Robson, beta regions, turn regions and spiral regions; alpha regions predicted according to Chou-Fasman, beta regions and regions of return; Hydrophilic regions predicted according to Kyte-Doolíttle; Hydrophobic regions predicted according to Hopp-Woods; alpha and beta amphipathic regions of Eisenberg; surface forming regions of Emini; and regions of high antigenic index of Jameson-Wolf, as predicted using the default parameters of these computer programs. The BCMA polypeptide for use in the methods of the invention can be expressed in a modified form, such as a fusion protein (comprising the polypeptide linked via a peptide bond to a heterologous protein sequence (of a different protein)), and it can include not only secretory signals but also additional heterologous functional regions. Alternatively, said fusion protein can be prepared by synthetic protein techniques, for example using a peptide synthesizer. In this manner, a region of additional amino acids, particularly charged amino acids, can be added to the N-terminus of the polypeptide for better stability and persistence in the host cell, during purification or during subsequent handling and storage. Portions of peptide can be added to the polypeptide to facilitate its purification. Said regions can be removed before the final preparation of the polypeptide. The addition of peptide portions to the polypeptides to generate secretion or excretion, to improve stability and to facilitate purification, among other things, are familiar and routine techniques. A preferred BCMA fusion protein that can be used in the methods of the invention comprises a heterologous region of an immunoglobulin that is useful for solubilizing proteins. For example, EP-AO-464533 (Canadian counterpart 2045869) and WO00 / 024782, describe fusion proteins comprising several portions of the constant region of immunoglobulin molecules together with another human protein or part thereof. BCMA immunoglobulin fusion proteins have been described, for example, in PCT publications WO 01/087977, WO 01/60397, and WO 01/24811 and Gross et al., (2000) Nature 404: 995-999, Thompson et al. (2000) J Exp Med 192: 129-135, and Yu et al., (2000) Nat Immunol 1: 252-256, which are incorporated herein by reference in their entirety. In many cases, the Fe part of a fusion protein is very advantageous for use in therapy and diagnosis, and thus results in, for example, improved pharmacokinetic properties (EP-A 0232 262). On the other hand, for some uses it would be desirable to be able to suppress the Fe part after the fusion protein has been expressed, detected and purified in the advantageous manner described. This is the case when the Fe portion proves to be an impediment for use in therapy and diagnosis, for example when the fusion protein is to be used as an antigen for immunizations. In drug discovery, for example, human proteins such as the hIL-5 receptor have been fused with Fe portions for the purpose of performing high throughput screening tests to identify hIL-5 antagonists. See, D. Bennett et al., Journal of Molecular Recognition 8: 52-58 (1995) and K. Johanson et al., The Journal of Biological! Chemistry 270: 16: 9459-9471 (1995). As will be appreciated by those skilled in the art, and as discussed above, BCMA polypeptides can be fused with other polypeptide sequences. For example, BCMA polypeptides can be fused to the constant domain of immunoglobulins (IgA, IgE, IgG, IgM), or portions thereof (CH1, CH2, CH3, or any combination or portions thereof), or albumin (which includes without limitation recombinant human albumin or fragments or variants thereof (see for example U.S. Patent No. 5,876,969, issued March 2, 1999, EP 0 413 622, and U.S. Pat. U.S. Patent No. 5,766,883, issued June 16, 1998, which are incorporated herein by reference in its entirety), resulting in chimeric polypeptides. Such fusion proteins can facilitate purification, can extend shelf life and can increase the life span in vivo. This has been shown for chimeric proteins consisting of the first two domains of the human CD4 polypeptide and several domains of the constant regions of the heavy or light chains of human immunoglobulins. See for example, EP 394,827; Traunecker et al., Nature, 331: 84-86 (1988). Improved delivery of an antigen through the epithelial barrier to the immune system has been demonstrated for antigens (eg insulin) conjugated to an FcRn binding partner, such as IgG or Fe fragments (see for example the PCT publications WO 96/22024 and WO 99/04813). It has also been found that IgG fusion proteins having a disulfide linked dimeric structure due to the disulfide bonds of the IgG portion are more efficient for binding and neutralizing other molecules than monomeric polypeptides or their fragments alone. See, for example, Fountoulakis et al., J. Biochem., 270: 3958-3964 (1995). An albumin fusion protein that can be used in the methods of the present invention comprises at least one fragment or variant of a BCMA polypeptide and at least one fragment or variant of human serum albumin, which are associated with each other, preferably by genetic fusion (i.e., the albumin fusion protein is generated by translation of a nucleic acid in which a polynucleotide that encodes all or part of the BCMA is bound in frame with a polynucleotide that encodes a part or all of the albumin ), or by chemical conjugation with each other. The BCMA polypeptide and the albumin protein, once part of the albumin fusion protein, can be referred to as a "portion" or "region" of the albumin fusion protein (e.g., a "portion of BCMA" or a "protein albumin portion"). In one embodiment, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a BCMA polypeptide and a serum albumin protein. In other embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a fragment of BCMA and a serum albumin protein. In other embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a variant of BCMA and a serum albumin protein. In preferred embodiments, the protein component of serum albumin of the albumin fusion protein is the mature portion of serum albumin. In additional embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a BCMA polypeptide and a biologically active or therapeutically active fragment of serum albumin. In additional embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a BCMA polypeptide and a biologically active or therapeutically active variant of serum albumin. In preferred embodiments, the BCMA portion of the albumin fusion protein is the full-length BCMA polypeptide. In a further embodiment, the BCMA portion of the albumin fusion protein is the soluble mature domain of the BCMA peptide. In additional embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a fragment or variant of BCMA and a biologically active or therapeutically active fragment of serum albumin. In preferred embodiments, the invention provides an albumin fusion protein comprising, or alternatively consisting of, the mature portion of the BCMA polypeptide and the mature portion of the serum albumin. In additional embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a fragment or variant of BCMA and a biologically active or therapeutically active fragment of serum albumin. In preferred embodiments, the invention provides an albumin fusion protein comprising, or alternatively consisting of, the mature portion of the BCMA polypeptide and the mature portion of the serum albumin (including without limitation recombinant human serum albumin or fragments or variants thereof (see for example U.S. Patent No. 5,876,969, issued on March 2, 1999, EP 0 413 622, and U.S. Patent No. 5,766,883, issued June 16, 1998, which is incorporated herein by reference in its entirety)). In a preferred embodiment, the BCMA polypeptides (which include fragments or variants thereof) are fused to the mature form of human serum albumin (i.e., amino acids 1-585 of human serum albumin, as shown in FIG. Figures 1 and 2 of EP 0 322 094), which are incorporated herein by reference in their entirety. In another preferred embodiment, the antibodies of the invention (including fragments or variants thereof), are fused to fragments of polypeptides comprising or alternatively consist of, the amino acid residues 1-x of human serum albumin, wherein x is an integer from 1 to 585, and the albumin fragment has human serum albumin activity. In another preferred embodiment, the BCMA polypeptides (including fragments or variants thereof) are fused to polypeptide fragments comprising, or alternatively consist of, the amino acid residues 1-z of human serum albumin, wherein z is an integer from 369 to 419, as described in U.S. Pat. UU 5,766,883, which is incorporated herein by reference in its entirety. BCMA polypeptides (including fragments or variants thereof) can be fused at the N or C terminus of the heterologous protein (e.g., immunoglobulin Fe polypeptide or human serum albumin polypeptide). In preferred embodiments, the human serum albumin protein used in the albumin fusion proteins that can be used in the methods of the invention contains one or both of the following groups of dot mutations with respect to SEQ ID NO: 11: Leu -407 to Ala, Leu-408 to Val, Val-409 to Ala, and Arg-410 to Ala; or Arg-410 to A, Lys-413 to Gln, and Lys-414 to Gin (see for example the international publication No. W095 / 23857, which is incorporated herein in its entirety as a reference). In highly preferred embodiments, the albumin fusion proteins that can be used in the methods of the invention that contain one or both of the above-described groups of dot mutations have improved stability or resistance to the proteolytic cleavage of yeast Yap3p, allowing an increase in the production of recombinant albumin fusion proteins expressed in yeast host cells. Preferably, the albumin fusion protein that can be used in the methods of the invention comprises HA as the N-terminal portion, and the BCMA polypeptide as the C-terminal portion. Alternatively, an albumin fusion protein comprising HA as the C-terminal portion and the BCMA polypeptide as the N-terminal portion may also be used. In other embodiments, the albumin fusion protein that can be used in the methods of the invention has a BCMA polypeptide fused to both the N-terminus and the C-terminus of albumin. In a specific embodiment, the BCMA polypeptides fused at the N and C ends are the same. In another embodiment, the BCMA polypeptides fused at the N and C ends are different BCMA polypeptides. In another embodiment, a BCMA polypeptide is fused at the N-terminus or C-terminus of albumin, and a heterologous polypeptide is fused at the remaining terminus. Additionally, albumin fusion proteins that can be used in the methods of the invention can include a linker peptide between the fused portions to provide greater physical sation between the portions. The linker peptide can consist of amino acids so that it is flexible or more rigid. Generally, albumin fusion proteins that can be used in the methods of the invention can have a region derived from HA and a region from BCMA. However, multiple regions of each protein can be used to make an albumin fusion protein that can be used in the methods of the invention. Similarly, more than one protein can be used to make an albumin fusion protein that can be used in the methods of the invention. For example, a protein can be fused to both the N-terminus and the C-terminus of HA. In such a configuration, the protein portions may be identical or different protein molecules. The structure of the bifunctional albumin fusion proteins can be represented as: X-HA-Y or Y-HA-X. In a specific embodiment, a BCMA protein or fragment or variant thereof, which can be used in the methods of the invention, can be conjugated with a cytotoxin (for example a cytostatic or cytocidal agent). A cytotoxin or cytotoxic agent includes any agent that is harmful to the cells. Examples include paclitaxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracendione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol and puromycin, and analogs and homologs thereof. In another embodiment, a BCMA protein or fragment or variant thereof that can be used in the methods of the invention can be conjugated to a toxin. By "toxin" is meant one or more compounds that bind and activate cytotoxic, endogenous effector systems, radioisotopes, holotoxins, modified toxins, catalytic subunits of toxins, or any molecule or enzyme not normally present on or on the surface of a cell, that under definite conditions cause the death of the cell. Toxins that can be used include, without limitation, known radioisotopes, compounds such as for example antibodies (or portions containing complement fixation thereof) that bind to an inherent or induced endogenous cytotoxic effector system., thymidine kinase, endonuclease, RNAse, alpha toxin, ricin, abrin, Pseudomonas exotoxin A, diphtheria toxin, saponin, mormodin, gelonin, phytolac antiviral protein, alpha sarcina and cholera toxin. "Toxin" also includes a cytostatic or cytocidal agent, a therapeutic agent or a radioactive metal ion, for example alpha emitters such as for example 213Bi, or other radioisotopes such as for example 103Pd, 133? E 131, 68G? ? 57Co_ 65 ^ 85 ^ 32p_ SSg 90 ^ 153Sm 153 ^ 169? B? 51 ^ 54 ^ 75Se, 113Sn, 90Ytrio, 117Stay, 186Renium, 166Holmio, and 188Renio. To improve or alter the characteristics of the polypeptides BCMA that can be used in the methods of the invention, protein engineering can be used. The known recombinant DNA technology can be used to create novel mutant proteins or "muteins that include single or multiple substitutions of amino acids, deletions, additions or fusion proteins". Said modified polypeptides may for example show higher activity or greater stability. In addition, they can be purified in high yields and show a better solubility than the corresponding natural polypeptide, at least under certain purification and storage conditions. In another embodiment of the invention, the mutant BCMA polypeptide can be a "dominant negative". For this purpose, defective BCMA polypeptides, such as for example mutants lacking a portion or the entire conserved domain of TNF, can be used to decrease the activity of BCMA. These non-functional BCMA polypeptides will be assembled to form a receptor (e.g., multimer) which may be capable of binding, but which is unable to induce signal transduction. The BCMA proteins that can be used in the methods of the invention can be monomers or multimers (ie, dimers, trimers, tetramers and higher multimers). In specific embodiments, the polypeptides of the invention are monomers, dimers, trimers, or tetramers. In further embodiments, the multimers of the invention are at least dimers, at least trimers, or at least tetramers. It is believed that some members of the TNF protein family exist in trimeric form (Beutler and Huffel, Science 264: 667, 1994; Banner et al., Cell 73: 431, 1993). In this way, trimeric BCMA can offer the advantage of greater biological activity. In specific embodiments, the multimers may be homomers or heteromers. As used herein, the term "homomer" refers to a multimer containing only BCMA proteins (including fragments, variants and fusion proteins of BCMA, as described herein). These homomers may contain BCMA proteins that have identical or different polypeptide sequences. In a specific embodiment, a homomer is a multimer containing only BCMA proteins that have an identical polypeptide sequence. In another specific embodiment, a homomer is a multimer containing BCMA proteins having different polypeptide sequences. As used herein, the term "heteromer" refers to a multimer containing heterologous proteins (ie, proteins that contain only polypeptide sequences that do not correspond to a polypeptide sequence encoded by the BCMA gene), in addition to the BCMA proteins. The multimers can be the result of hydrophobic, hydrophilic, ionic or covalent associations, or they can be linked indirectly, for example, by liposome formation. Thus, in one embodiment, multimers such as, for example, homodimers, homotrimers, heterotrimers, or heterotetramers are formed when the proteins contact each other in solution. In other embodiments, the multimers are formed by covalent associations with or between the BCMA proteins. Said covalent associations may involve one or more amino acid residues contained in the polypeptide sequence of the protein. In one case, the covalent associations are entanglement between cysteine residues located within the polypeptide sequences of the proteins that interact in the native polypeptide (i.e., occur naturally). In another case, covalent associations are a consequence of chemical or recombinant manipulation. Alternatively, said covalent associations may include one or more amino acid residues contained in the sequence of the heterologous polypeptide in a BCMA fusion protein. In an example, the covalent associations are between the heterologous sequence contained in a fusion protein (see for example U.S. Patent No. 5,478,925, the content of which is incorporated herein by reference in its entirety). In a specific example, the covalent associations are between the heterologous sequence contained in a BCMA-Fc fusion protein (as described herein). In another specific example, the covalent associations of fusion proteins are between heterologous polypeptide sequences of another ligand / receptor member of the TNF family, which is capable of forming covalently associated multimers, such as for example osteoprotegerin (see for example the publication WO 98/49305, the content of which is incorporated herein by reference in its entirety). In another embodiment, two or more BCMA polypeptides are linked through synthetic linkers (e.g., peptide, carbohydrate or soluble polymer linkers). Examples include the peptide linkers described in US Pat. UU No. 5,073,627 (which is incorporated herein by reference). Proteins comprising multiple BCMA polypeptides separated by peptide linkers can be produced using conventional recombinant DNA technology. In a specific embodiment, antibodies that bind to a BCMA polypeptide, a polypeptide fragment, a variant of SEQ ID NO: 8, or an epitope of the BCMA polypeptide (determined by very high immunoassays) can be used in the methods of the invention. known to determine antibody-specific antigen binding). Anti-BCMA antibodies and fragments thereof have been described, for example in PCT publications WO01 / 087977, WO01 / 60397, and WO02 / 66516 and Ch'en et al., (2005) Cell Immunol 236: 78-85. Each of the aforementioned references is incorporated herein by reference in its entirety. Antibodies include, without limitation, polyclonal, monoclonal, multispecific, human, humanized, or chimeric antibodies, single chain antibodies; Fab fragments, F (ab ') fragments, fragments produced by a collection of Fab expression, idiotypic (anti-id) antibodies (including for example anti-ld antibodies for anti-BCMA antibodies), and epitope binding fragments of any of the above. The term "antibody", as used herein, refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, ie, molecules that contain an antigen-binding site that immunospecifically binds to an antigen. Immunoglobulin molecules can be of any type (eg, IgG, IgE, IgM, IgD, IgA, and IgY), class (eg, IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass immunoglobulin molecule. In specific modalities, the immunoglobulin molecules are IgG1. In other specific embodiments, the immunoglobulin molecules are IgG4. BCMA binding antibody fragments that can be used in the methods of the invention include, without limitation, Fab, Fab 'and F (ab') 2, Fd, single-chain Fvs (scFv), single-chain antibodies. chain, Fvs linked by disulfide (sdFv) and fragments comprising a VL or VH domain. The antigen-binding antibody fragments, including the single-chain antibodies, may comprise the variable region alone or in combination with all or a portion of the following: hinge region, CH1, CH2, and CH3 domains. They also include antigen binding fragments that comprise any combination of the variable regions with a hinge region, or the CH1, CH2, and CH3 domains. The antibodies can be of any animal origin, including birds and mammals.

Preferably, the antibodies are human, murine (e.g., mouse and rat), donkey, sheep, rabbit, goat, guinea pig, camel, horse, or chicken. As used herein, "human" antibodies include antibodies that have the amino acid sequence of a human immunoglobulin and include antibodies isolated from collections of human immunoglobulin or from animals transgenic for one or more human immunoglobulins, and that do not express endogenous immunoglobulins, such as it is described, for example, in U.S. Pat. UU No. 5,939,598 to Kucherlapati et al., The contents of which are incorporated herein by reference in their entirety. Anti-BCMA antibodies that can be used in the methods of the invention may be monospecific, bispecific, trispecific, or of greater specificity. The multispecific antibodies may be specific for different epitopes of a BCMA polypeptide, or may be specific for both a BCMA polypeptide and a heterologous epitope, such as a heterologous polypeptide or solid support material. See, for example, PTC publications WO 93/17715; WO 92/08802; WO 91/00360; WO 92/05793; Tutt et al., J. Immunol. 147: 60-69 (1991); US patents UU Nos. 4,474,893; 4,714,681; 4,925,648; 5,573,920; 5,601, 819; Kostelny et al., J. Immunol. 148: 1547-1553 (1992), the content of which is hereby incorporated by reference in its entirety. BCMA antibodies can be described or specified based on their cross-reactivity. Antibodies that do not bind to any other analog, ortholog, or homologue of a BCMA polypeptide can be used in the methods of the invention. In specific embodiments, BCMA antibodies cross-react with murine, rat or rabbit homologs, human BCMA proteins, and corresponding epitopes thereof. In a specific embodiment, an anti-BCMA antibody that can be used in the methods of the invention binds not only to BCMA but also binds TACI and BAFF-R. The BCMA antibodies that can be used in the methods of the invention can also be described or specified based on their binding affinity to a BCMA polypeptide. Preferred binding affinities include those with a dissociation constant or Kd less than 5 X 10"9 M, 10" 9 M, 5 X 10"10 M, 10" 10 M, 5 X 10 11 M, 10"11 M , 5 X 1012 M, or 10"12 M. BCMA antibodies that can be used in the methods of the invention can act as agonists or antagonists of the BCMA polypeptides. For example, BCMA antibodies that interrupt receptor / ligand interactions with BCMA polypeptides are partially or completely included. Also included are receptor-specific antibodies that do not prevent ligand binding but that prevent receptor activation. The activation of the receptor (i.e., signaling) can be determined by techniques described herein or otherwise known. For example, activation of the receptor can be determined by detecting the activation of the transcription factors NF-AT, AP-1 or NF-kappaB using known techniques, or phosphorylation (for example tyrosine or serine / threonine) of the receptor or its substrate, by means of immunoprecipitation, followed by Western blot analysis. In a specific embodiment, receptor-specific BCMA antibodies that prevent ligand binding and receptor activation, as well as BCMA antibodies that recognize the receptor-ligand complex, and preferably do not recognize, can be used in the methods of the invention. specifically the unbound receptor or the unbound ligand. The above BCMA antibodies can be made using the known methods. See, for example, PCT publication WO 96/40281; the US patent UU No. 5,811, 097; Deng et al., Blood 92 (6): 1981 -1988 (1998); Chen et al., Cancer Res. 58 (16): 3668-3678 (1998); Harrop et al., J. Immunol. 161 (4): 1786-1794 (1998); Zhu et al., Cancer Res. 58 (15): 3209-3214 (1998); Yoon et al., J. Immunol. 160 (7): 3170-3179 (1998); Prat et al., J. Cell. Sci. 111 (Pt2): 237-247 (1998); Pitard et al., J Immunol. Methods 205 (2): 177-190 (1997); Liautard et al., Cytokine 9 (4): 233-241 (1997); Carlson et al., J. Biol. Chem. 272 (17): 11295-11301 (1997); Taryman et al., Neuron 14 (4): 755-762 (1995); Muller et al., Structure 6 (9): 1153-1167 (1998); Bartunek et al., Cytokine 8 (1): 14-20 (1996) (which are hereby incorporated by reference in their entirety).

F. Neutrocin-alpha receptor, BAFF-R BAFF-R polypeptides, such as those described below, act as neutrokine-alpha or APRIL antagonists and can also be used in the methods of the present invention. BAFF-R, also known as TR21, is a protein of 184 amino acid residues (SEQ ID NO: 10), with a deduced molecular weight of 18.9 kDa. A nucleotide sequence of a cDNA encoding BAFF-R is given in SEQ ID NO: 9. Predicted amino acids from about 1 to 81 constitute the extracellular domain (SEQ ID NO: 10); the amino acids of about 82 to 101 constitute the transmembrane domain (SEQ ID NO: 10); and amino acids of about 102 to 184 constitute the intracellular domain (SEQ ID NO: 10). Accordingly, in one embodiment, a BAFF-R protein that can be used in the methods of the present invention is an isolated polypeptide comprising, or alternatively consisting of, the amino acid sequence of SEQ ID NO: 10, or a polypeptide comprising, or alternatively consisting of, a portion of SEQ ID NO: 10, such as for example the extracellular domain of BAFF-R (comprising amino acids 1 to 81 of SEQ ID NO: 10), or the BAFF-R cysteine-rich domain (comprising amino acids 19 to 35 of SEQ ID NO: 10); as well as polypeptides that are at least 80% identical, preferably at least 90% or 95% identical, preferably at least 96%, 97%, 98%, 99%, or 100% identical to the polypeptides described above . In another embodiment, a BAFF-R protein that can be used in the methods of the present invention is an isolated polypeptide comprising amino acids 1 to 70 of SEQ ID NO: 10 or the amino acid sequence of SEQ ID NO: 26 . SEQ ID NO: 26 shows amino acids 1-70 of BAFF-R wherein amino acid 20 (valine) in BAFF-R is substituted with asparagine, and amino acid 27 (leucine) in BAFF-R is substituted with proline. In another embodiment, a BAFF-R protein that can be used in the methods of the present invention is an isolated polypeptide comprising amino acids 2 to 70 of SEQ ID NO: 26. Polypeptides that are at least 80% identical, preferably at least 90% or 95% identical, very preferably at least 96%, 97%, 98%, 99% or 100% identical to the polypeptides described above also they can be used in the methods of the present invention. By expressing a polypeptide having at least one amino acid sequence, for example, 95% "identical" to a reference amino acid sequence of a BAFF-R polypeptide, it is understood to be the amino acid sequence of the identical polypeptide with respect to to the reference sequence, except that the polypeptide sequence may include up to 5 amino acid alterations per 100 amino acids of the reference amino acid of the BAFF-R receptor. In other words, to obtain a polypeptide having an amino acid sequence at least 95% identical to a reference amino acid sequence, up to 5% of the amino acid residues of the reference sequence can be deleted or substituted with another amino acid, or a number of amino acids of up to 5% of the total amino acid residues in the reference sequence can be inserted into the reference sequence. These alterations of the reference sequences may occur at the amino or carboxy terminal positions of the reference amino acid sequence or anywhere between those terminal positions, interspersed individually between residues in the reference sequence, or in one or more contiguous groups within of the reference sequence. The BAFF-R polypeptide fragments include polypeptides comprising, or alternatively consisting of, an amino acid sequence contained in SEQ ID NO: 10. The polypeptide fragments may be "autonomous" or may be comprised within a further polypeptide. large of which the fragment forms a part or region, preferably as a single continuous region. In additional embodiments, the polypeptide fragments comprise, or alternatively consist of, one or more BAFF-R domains. Preferred polypeptide fragments include a member selected from the group: (a) a polypeptide comprising, or alternatively consisting of, the extracellular domain of BAFF-R (which is predicted to constitute the amino acid residues from about 1 to about 81 of SEQ ID NO: 10); (b) a polypeptide comprising, or alternatively consisting of, a cysteine-rich domain of BAFF-R (which is predicted to constitute amino acid residues from about 19 to about 35 of SEQ ID NO: 10); (c) a polypeptide comprising, or alternatively consisting of, the transmembrane domain of BAFF-R (which is predicted to constitute the amino acid residues from about 82 to about 101 of SEQ ID NO: 10); (d) a polypeptide comprising, or alternatively consisting of, the intracellular domain of BAFF-R (which is predicted to constitute amino acid residues from about 102 to about 184 of SEQ ID NO: 10); or (e) any combination of the polypeptides (a) - (d). It is believed that the extracellular cysteine-rich motifs of BAFF-R are important for the interactions between BAFF-R and its ligands, neutrocin-alpha and APRIL. Accordingly, in preferred embodiments, the BAFF-R polypeptide fragments that can be used in the methods of the present invention comprise, or alternatively consist of, the amino acid residues of about 19 to 35 of SEQ ID NO: 10. preferred are proteins comprising, or alternatively consisting of, a polypeptide sequence that is at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the polypeptide sequences of the motive rich in cysteine. Other fragments of the BAFF-R protein that can be used in the methods of the invention are the fragments characterized by structural or functional attributes of BAFF-R. Such fragments include amino acid residues comprising alpha-helix and alpha-helix forming regions ("alpha regions"), beta-sheet regions and beta-sheet forming regions ("beta regions"), regions of turn and spin-forming regions. ("spin regions"), spiral regions and spiral-forming regions ("spiral regions"), hydrophilic regions, hydrophobic regions, alpha amphipathic regions, beta amphipathic regions, surface forming regions and regions of high antigenic index (ie say, that contains four or more contiguous amino acids that have an antigenic index greater than or equal to 1.5, identified using the default parameters of the Jameson-Wolf program), of the full BAFF-R (ie, full-length) (SEQ ID NO: 10), as set forth in US Pat. UU No. 7,112,410. Some preferred regions include, without limitation, predicted alpha regions according to Garnier-Robson, beta regions, turn regions and spiral regions; alpha regions predicted according to Chou-Fasman, beta regions and regions of return; predicted hydrophilic regions according to Kyte-Doolittle; Hydrophobic regions predicted according to Hopp-Woods; alpha and beta amphipathic regions of Eisenberg; surface forming regions of Emini; and regions of high antigenic index of Jameson-Wolf, as predicted using the default parameters of these computer programs. The BAFF-R polypeptide for use in the methods of the invention can be expressed in a modified form, such as a fusion protein (comprising the polypeptide linked via a peptide bond to a heterologous protein sequence (of a different protein)) , and may include not only secretory signals but also additional heterologous functional regions. Alternatively, said fusion protein can be prepared by synthetic protein techniques, for example using a peptide synthesizer. In this manner, a region of additional amino acids, particularly charged amino acids, can be added to the N-terminus of the polypeptide for better stability and persistence in the host cell, during purification or during subsequent handling and storage. Portions of peptide can be added to the polypeptide to facilitate its purification. Said regions can be removed before the final preparation of the polypeptide. The addition of peptide portions to the polypeptides to generate secretion or excretion, to improve stability and to facilitate purification, among other things, are familiar and routine techniques. A preferred BAFF-R fusion protein that can be used in the methods of the invention comprises a heterologous region of an immunoglobulin that is useful for solubilizing proteins. For example, EP-A 0 464 533 (Canadian counterpart 2045869) and WO 00/024782, describe fusion proteins comprising several portions of the constant region of immunoglobulin molecules together with another human protein or part thereof. Immunoglobulin fusion proteins BAFF-R have been described for example in Pelletier et al. (2003) J Biol Chem 278: 33127-33133, and Carter et al. (2005) Arthritis Rheum 52: 3943-3954, which are incorporated herein by reference In its whole. In many cases, the Fe part of a fusion protein is very advantageous for use in therapy and diagnosis, and thus results in, for example, improved pharmacokinetic properties (EP-A 0232 262). On the other hand, for some uses it would be desirable to be able to suppress the Fe part after the fusion protein has been expressed, detected and purified in the advantageous manner described. This is the case when the Fe portion proves to be an impediment for use in therapy and diagnosis, for example when the fusion protein is to be used as an antigen for immunizations. In drug discovery, for example, human proteins such as the hIL-5 receptor have been fused with Fe portions for the purpose of performing high throughput screening tests to identify hIL-5 antagonists. See, D. Bennett et al., Journal of Molecular Recognition 8: 52-58 (1995) and K. Johanson et al., The Journal of Biological Chemistry 270: 16: 9459-9471 (1995). In a specific embodiment, the BAFF-R-Fc fusion protein that can be used in the methods of the invention is BR3-Fc. As the skilled person will appreciate, and as discussed above, the BAFF-R polypeptides can be fused with other polypeptide sequences. For example, BAFF-R polypeptides can be fused to the constant domain of immunoglobulins (IgA, IgE, IgG, IgM), or portions thereof (CH1, CH2, CH3, or any combination or portions thereof) , or albumin (including without limitation recombinant human albumin or fragments or variants thereof (see for example U.S. Patent No. 5,876,969, issued March 2, 1999, EP 0 413 622, and U.S. Patent No. 5,766,883, issued June 16, 1998, which are incorporated herein by reference in its entirety), resulting in chimeric polypeptides. Such fusion proteins can facilitate purification, can extend shelf life and can increase the half-life in vivo. This has been shown for chimeric proteins consisting of the first two domains of the human CD4 polypeptide and several domains of the constant regions of the heavy or light chains of human immunoglobulins. See for example, EP 394,827; Traunecker et al., Nature, 331: 84-86 (1988). Improved delivery of an antigen through the epithelial barrier to the immune system has been demonstrated for antigens (eg insulin) conjugated to an FcRn binding partner, such as IgG or Fe fragments (see for example the PCT publications WO 96/22024 and WO 99/04813). It has also been found that IgG fusion proteins having a disulfide linked dimeric structure due to the disulfide bonds of the IgG portion are more efficient for binding and neutralizing other molecules than monomeric polypeptides or their fragments alone. See, for example, Fountoulakis et al., J. Biochem., 270: 3958-3964 (1995). An example of a BAFF-R-Fc protein comprises amino acids 1-70 of SEQ ID NO: 10 fused to the Fe region of an IgG1 immunoglobulin molecule. Optionally, amino acid 20 (valine) of BAFF-R is replaced with asparagine, and amino acid 27 (leucine) of BAFF-R is substituted with proline. SEQ ID NO: 26 shows amino acids 1-70 of BAFF-R with these two amino acid changes. An albumin fusion protein that can be used in the methods of the present invention comprises at least one fragment or variant of a BAFF-R polypeptide and at least one fragment or variant of human serum albumin, which are associated with another, preferably by genetic fusion (i.e., the albumin fusion protein is generated by translation of a nucleic acid in which a polynucleotide encoding all or part of the BAFF-R is linked in frame with a polynucleotide that encodes a part or all albumin), or by chemical conjugation with each other. The BAFF-R polypeptide and the albumin protein, once part of the albumin fusion protein, can be referred to as a "portion" or "region" of the albumin fusion protein (eg, a "portion of BAFF"). -R "or a" protein albumin portion "). In one embodiment, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a BAFF-R polypeptide and a serum albumin protein. In other embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a BAFF-R fragment and a serum albumin protein. In other embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a variant of BAFF-R and a whey protein albumin. In preferred embodiments, the protein component of serum albumin of the albumin fusion protein is the mature portion of serum albumin. In additional embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a BAFF-R polypeptide and a biologically active or therapeutically active fragment of serum albumin. In additional embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a BAFF-R polypeptide and a biologically active or therapeutically active variant of serum albumin. In preferred embodiments, the BAFF-R portion of the albumin fusion protein is the full-length BAFF-R polypeptide. In a further embodiment, the BAFF-R portion of the albumin fusion protein is the soluble mature domain of the BAFF-R polypeptide. In additional embodiments, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a fragment or variant of BAFF-R and a biologically active or therapeutically active fragment of serum albumin. In preferred embodiments, the invention provides an albumin fusion protein comprising, or alternatively consisting of, the mature portion of the BAFF-R polypeptide and the mature portion of the serum albumin. In additional modalities, an albumin fusion protein that can be used in the methods of the invention comprises, or alternatively consists of, a fragment or variant of BAFF-R and a biologically active or therapeutically active fragment of serum albumin. In preferred embodiments, the invention provides an albumin fusion protein comprising, or alternatively consisting of, the mature portion of the BAFF-R polypeptide and the mature portion of the serum albumin (including without limitation recombinant human serum albumin or fragments). or variants thereof (see for example U.S. Patent No. 5,876,969, issued March 2, 1999, EP 0 413 622, and U.S. Patent No. 5,766,883, issued 16 June 1998, which is incorporated here as a reference in its entirety)). In a preferred embodiment, the BAFF-R polypeptides (which include fragments or variants thereof) are fused to the mature form of human serum albumin (i.e., amino acids 1-585 of human serum albumin, as shown in Figures 1 and 2 of EP 0 322 094), which are incorporated herein by reference in their entirety. In another preferred embodiment, the antibodies of the invention (including fragments or variants thereof), are fused with polypeptide fragments comprising or alternatively consisting of the amino acid residues 1-x of human serum albumin, wherein x is an integer from 1 to 585, and the albumin fragment has human serum albumin activity. In another preferred embodiment, the BAFF-R polypeptides (including fragments or variants thereof) are fused to polypeptide fragments comprising, or alternatively consisting of, the 1-z amino acid residues of human serum albumin, wherein z is an integer from 369 to 419, as described in US Pat. UU 5,766,883, which is incorporated herein by reference in its entirety. BAFF-R polypeptides (which include fragments or variants thereof) can be fused at the N or C terminus of the heterologous protein (e.g., immunoglobulin Fe polypeptide or human serum albumin polypeptide). In preferred embodiments, the human serum albumin protein used in the albumin fusion proteins that can be used in the methods of the invention contains one or both of the following groups of dot mutations with respect to SEQ ID NO: 11: Leu -407 to Ala, Leu-408 to Val, Val-409 to Ala, and Arg-410 to Ala; or Arg-410 to A, Lys-413 to Gln, and Lys-414 to Gin (see for example the international publication No. W095 / 23857, which is incorporated herein in its entirety as a reference). In highly preferred embodiments, the albumin fusion proteins that can be used in the methods of the invention that contain one or both of the above-described groups of dot mutations have improved stability or resistance to the proteolytic cleavage of yeast Yap3p, allowing an increase in the production of recombinant albumin fusion proteins expressed in yeast host cells. Preferably, the albumin fusion protein that can be used in the methods of the invention comprises HA as the N-terminal portion, and the BAFF-R polypeptide as the C-terminal portion. Alternatively, an albumin fusion protein comprising HA as the C-terminal portion and the BAFF-R polypeptide as the N-terminal portion may also be used. In other embodiments, the albumin fusion protein that can be used in the methods of the invention has a BAFF-R polypeptide fused to both the N-terminus and the C-terminus of albumin. In a specific embodiment, the BAFF-R polypeptides fused at the N and C ends are the same. In another embodiment, the BAFF-R polypeptides fused at the N and C ends are different BAFF-R polypeptides. In another embodiment, a BAFF-R polypeptide is fused at the N-terminus or C-terminus of albumin, and a heterologous polypeptide is fused at the remaining terminus. Additionally, albumin fusion proteins that can be used in the methods of the invention can include a linker peptide between the fused portions to provide greater physical separation between the portions. The linker peptide can consist of amino acids so that it is flexible or more rigid. Generally, albumin fusion proteins that can be used in the methods of the invention can have a region derived from HA and a region from BAFF-R. However, multiple regions of each protein can be used to make an albumin fusion protein that can be used in the methods of the invention. Similarly, more than one protein can be used to make an albumin fusion protein that can be used in the methods of the invention. For example, a protein can be fused to both the N-terminus and the C-terminus of HA. In such a configuration, the protein portions may be the same or different protein molecules. The structure of the bifunctional albumin fusion proteins can be represented as: X-HA-Y or Y-HA-X. In a specific embodiment, a BAFF-R protein or fragment or variant thereof, which can be used in the methods of the invention, can be conjugated with a cytotoxin (for example a cytostatic or cytocidal agent). A cytotoxin or cytotoxic agent includes any agent that is harmful to the cells. Examples include paclitaxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracendione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol and puromycin, and analogs and homologs thereof. In another embodiment, a BAFF-R protein or fragment or variant thereof that can be used in the methods of the invention can be conjugated to a toxin. By "toxin" is meant one or more compounds that bind and activate cytotoxic, endogenous effector systems, radioisotopes, holotoxins, modified toxins, catalytic subunits of toxins, or any molecule or enzyme not normally present on or on the surface of a cell, that under definite conditions cause the death of the cell. Toxins that may be used include, without limitation, known radioisotopes, compounds such as for example antibodies (or portions containing complement fixation thereof) that bind to an inherent or induced endogenous cytotoxic effector system., thymidine kinase, endonuclease, RNAse, alpha toxin, ricin, abrin, Pseudomonas exotoxin A, diphtheria toxin, saponin, mormodin, gelonin, phytolac antiviral protein, alpha sarcina and cholera toxin. "Toxin" also includes a cytostatic or cytocidal agent, a therapeutic agent or a radioactive metal ion, for example alpha emitters such as for example 213B1, or other radioisotopes such as for example 103Pd, 33? E_131, 68G? 57Co_ 75Se, 113Sn, 90Ytrio, 117Stay, 186Renium, 166Holmio, and 188Renio. To improve or alter the characteristics of the BAFF-R polypeptides that can be used in the methods of the invention, protein engineering can be used. The known recombinant DNA technology can be used to create novel mutant proteins or "muteins that include single or multiple substitutions of amino acids, deletions, additions or fusion proteins". Said modified polypeptides may for example show higher activity or greater stability. In addition, they can be purified in high yields and show a better solubility than the corresponding natural polypeptide, at least under certain purification and storage conditions. In another embodiment of the invention, the BAFF-R mutant polypeptide can be a "dominant negative". For this purpose, defective BAFF-R polypeptides, such as for example mutants lacking a portion or the entire conserved domain of TNF, can be used to decrease the activity of BAFF-R. These nonfunctional BAFF-R polypeptides will be assembled to form a receptor (e.g., multimer) that may be capable of binding, but which is unable to induce signal transduction. The BAFF-R proteins that can be used in the methods of the invention can be monomers or multimers (ie, dimers, trimers, tetramers and higher multimers). In specific embodiments, the polypeptides of the invention are monomers, dimers, trimers, or tetramers. In further embodiments, the multimers of the invention are at least dimers, at least trimers, or at least tetramers. It is believed that some members of the TNF family of proteins exist in trimeric form (Beutler and Huffel, Science 264: 667, 1994).; Banner et al., Cell 73: 431, 1993). In this way, the trimeric BAFF-R may offer the advantage of greater biological activity. In specific embodiments, the multimers may be homomers or heteromers. As used herein, the term "homomer" refers to a multimer containing only BAFF-R proteins (including fragments, variants and fusion proteins of BAFF-R, as described herein). These homomers may contain BAFF-R proteins having identical or different polypeptide sequences. In a specific embodiment, a homomer is a multimer containing only BAFF-R proteins having an identical polypeptide sequence. In another specific embodiment, a homomer is a multimer containing BAFF-R proteins having different polypeptide sequences. As used herein, the term "heteromer" refers to a multimer containing heterologous proteins (ie, proteins that contain only polypeptide sequences that do not correspond to a polypeptide sequence encoded by the BAFF-R gene), in addition to proteins BAFF-R. The multimers may be the result of hydrophobic, hydrophilic, ionic or covalent associations, or they may be linked indirectly, for example, by liposome formation. Thus, in one embodiment, multimers such as, for example, homodimers, homotrimers, heterotrimers, or heterotetramers are formed when the proteins contact each other in solution. In other embodiments, the multimers are formed by covalent associations with or between the BAFF-R proteins. Said covalent associations may involve one or more amino acid residues contained in the polypeptide sequence of the protein. In one case, the covalent associations are entanent between cysteine residues located within the polypeptide sequences of the proteins that interact with the native polypeptide (i.e., occur naturally). In another case, covalent associations are a consequence of chemical or recombinant manipulation. Alternatively, said covalent associations may include one or more amino acid residues contained in the heterologous polypeptide sequence in a BAFF-R fusion protein. In one example, the covalent associations are between the heterologous sequence contained in a fusion protein (see for example U.S. Patent No. 5,478,925, the content of which is incorporated herein by reference in its entirety). In a specific example, the covalent associations are between the heterologous sequence contained in a BAFF-R-Fc fusion protein (as described herein). In another specific example, the covalent associations of fusion proteins are between heterologous polypeptide sequences of another ligand / receptor member of the TNF family, which is capable of forming covalently associated multimers, such as for example osteoprotegerin (see for example the publication WO 98/49305, the content of which is incorporated herein by reference in its entirety). In another embodiment, two or more BAFF-R polypeptides are linked through synthetic linkers (e.g., peptide, carbohydrate or soluble polymer linkers). Examples include the peptide linkers described in US Pat. UU No. 5,073,627 (which is incorporated herein by reference). Proteins comprising multiple BAFF-R polypeptides separated by peptide linkers can be produced using conventional recombinant DNA technology. In a specific embodiment, antibodies that bind to a BAFF-R polypeptide, a polypeptide fragment, a variant of SEQ ID NO: 10, or an epitope of the BAFF-R polypeptide can be used in the methods of the invention. determined by well-known immunoassays to determine antibody-specific antigen binding). Anti-BAFF-R antibodies and fragments thereof have been described, for example in Lee et al. (2006) "Synthetic anti-BR3 antibodies that mimic BAFF binding and target both human and murine B cells" Blood (Blood First Edition Paper, prepublished online on July 13, 2006) Vol. 0, No. 2006, p. 200603011, Ch'en et al. (2005) Cell Immunol 236: 78-85, Nakamura et al. (2005), Virchows Arch 447: 53-60, and Carter et al. (2005) Arthritis Rheum 52: 3943-3954 .. Each one of the aforementioned references is incorporated herein by reference in its entirety. Antibodies include, without limitation, polyclonal, monoclonal, multispecific, human, humanized, or chimeric antibodies, single chain antibodies; Fab fragments, F (ab ') fragments, fragments produced by a collection of Fab expression, idiotypic (anti-id) antibodies (including, for example, anti-ld antibodies for anti-BAFF-R antibodies), and binding fragments of epitope of any of the above. The term "antibody", as used herein, refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, ie, molecules that contain an antigen-binding site that binds nonspecifically to an antigen. Immunoglobulin molecules can be of any type (eg, IgG, IgE, IgM, IgD, IgA, and IgY), class (eg, IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass immunoglobulin molecule. In specific modalities, the immunoglobulin molecules are IgG1. In other specific embodiments, the immunoglobulin molecules are IgG4. The BAFF-R binding antibody fragments that can be used in the methods of the invention include, without limitation, Fab, Fab 'and F (ab') 2, Fd, single-chain Fvs (scFv), a single chain, Fvs linked by disulfide (sdFv) and fragments comprising a VL or VH domain. Antigen-binding antibody fragments, including single-chain antibodies, may comprise the variable region alone or in combination with all or a portion of the following: hinge region, CH1, CH2, and CH3 domains. They also include antigen binding fragments that comprise any combination of the variable regions with a hinge region, or the CH1, CH2, and CH3 domains. The antibodies can be of any animal origin, including birds and mammals. Preferably, the antibodies are human, murine (e.g., mouse and rat), donkey, sheep, rabbit, goat, guinea pig, camel, horse, or chicken. As used herein, "human" antibodies include antibodies that have the amino acid sequence of a human immunoglobulin and include antibodies isolated from collections of human immunoglobulin or from animals transgenic for one or more human immunoglobulins, and that do not express endogenous immunoglobulins, such as it is described, for example, in U.S. Pat. UU No. 5,939,598 to Kucherlapati et al., The contents of which are incorporated herein by reference in their entirety. The anti-BAFF-R antibodies that can be used in the methods of the invention can be monospecific, bispecific, trispecific, or of greater specificity. Multispecific antibodies may be specific for different epitopes of a BAFF-R polypeptide, or may be specific for both a BAFF-R polypeptide and a heterologous epitope, such as a heterologous polypeptide or solid support material. See, for example, PTC publications WO 93/17715; WO 92/08802; WO 91/00360; WO 92/05793; Tutt et al., J. Immunol. 147: 60-69 (1991); US patents UU Nos. 4,474,893; 4,714,681; 4,925,648; 5,573,920; 5,601, 819; Kostelny et al., J. Immunol. 148: 1547-1553 (1992), the content of which is hereby incorporated by reference in its entirety. BAFF-R antibodies can be described or specified based on their cross-reactivity. Antibodies that do not bind to any other analog, ortholog, or homolog of a BAFF-R polypeptide can be used in the methods of the invention. In specific embodiments, the BAFF-R antibodies cross-react with murine, rat or rabbit homologs, human BAFF-R proteins, and corresponding epitopes thereof. In a specific embodiment, an anti-BAFF-R antibody that can be used in the methods of the invention binds not only to BAFF-R but also binds TACI and BCMA. The BAFF-R antibodies that can be used in the methods of the invention can also be described or specified based on their binding affinity to a BAFF-R polypeptide. Preferred binding affinities include those with a dissociation constant or Kd less than 5 X 10"9 M, 10"9 M, 5 X 10" 10 M, 10"10 M, 5 X 10" 11 M, 10"11 M, 5 X 10" 12 M, or 10"12 M. The BAFF-R antibodies that can be used in the methods of the invention can act as agonists or antagonists of the BAFF-R polypeptides, For example, BAFF-R antibodies that disrupt receptor / ligand interactions with the BAFF-R polypeptides are included partially or completely. Also included are receptor-specific antibodies which do not prevent ligand binding but which prevent receptor activation.Activation of the receptor (ie, signaling) can be determined by techniques described herein or otherwise known. , activation of the receptor can be determined by detecting the activation of the transcription factors NF-AT, AP-1 or NF-kappaB using known techniques, or phosphorylation (for example tyrosine or serine / threonine) of the receptor or its substrate, by means of immunoprecipitation, followed by analysis of Western blot In a specific embodiment, receptor-specific BAFF-R antibodies that prevent ligand binding and receptor activation can be used in the methods of the invention, as well as BAFF-R antibodies that recognize the receptor complex -linking, and preferably do not specifically recognize the unbound receptor or unbound ligand. The above BAFF-R antibodies can be made using the known methods. See, for example, PCT publication WO 96/40281; the US patent UU No. 5,811, 097; Deng et al., Blood 92 (6): 1981-1988 (1998); Chen et al., Cancer Res. 58 (16): 3668-3678 (1998); Harrop et al., J. Immunol. 161 (4): 1786-1794 (1998); Zhu et al., Cancer Res. 58 (15): 3209-3214 (1998); Yoon et al., J. Immunol. 160 (7): 3170-3179 (1998); Prat et al., J. Cell. Sci. 111 (Pt2): 237-247 (1998); Pitard et al., J Immunol. Methods 205 (2): 177-190 (1997); Liautard et al., Cytokine 9 (4): 233-241 (1997); Carlson et al., J. Biol. Chem. 272 (17): 11295-11301 (1997); Taryman et al., Neuron 14 (4): 755-762 (1995); Muller et al., Structure 6 (9): 1153-1167 (1998); Bartunek et al., Cytokine 8 (1): 14-20 (1996) (which are hereby incorporated by reference in their entirety).

G) Anti-APRIL Antibodies In a specific embodiment, the neutrophil-alpha antagonist is an anti-APRIL antibody or an antigen-binding fragment thereof. Anti-APRIL antibodies and fragments thereof have been described for example in PCT publications WO01 / 087977, W099 / 12965, WO01 / 60397, and WO02 / 094192; the US patent UU No. 6,506,882; the US patent publication UU No. 2003/0166864, filed on October 11, 2002; and Ch'en et al. (2005) Cell Immunol 236: 78-85; and are described below in more detail. Each of the aforementioned references is incorporated herein by reference in its entirety. In a specific embodiment, antibodies that bind to a polypeptide, polypeptide fragment or variant of APRIL of SEQ ID NO: 4, or an epitope of APRIL (determined by well-known immunoassays) can be used in the methods of the invention. to determine the specific antibody-antigen binding). In a specific embodiment, the antibodies that can be used in the methods of the invention can be attached to fused APRIL peptides to other polypeptide sequences. For example, the APRIL polypeptides can be fused to the constant domain of immunoglobulins (IgA, IgE, IgG, IgM), or portions thereof (CH1, CH2, CH3), or any combination thereof and portions thereof) , or albumin (including without limitation recombinant human albumin or fragments or variants thereof (see for example U.S. Patent No. 5,876,696, issued March 2, 1999, EP 0413 622 and the patent of US No. 5,766,883, issued June 16, 1988, which are incorporated herein by reference in its entirety), resulting in chimeric polypeptides. Such fusion proteins can facilitate purification and can increase the half-life in vivo. This has been shown for chimeric proteins consisting of the first two domains of the human CD4 polypeptide and several domains of the constant regions of the heavy or light chains of mammalian immunoglobulin. See for example EP 394,827; Traunecker et al., Nature, 331: 84-86 (1988). Improved delivery of an antigen through the epithelial barrier to the immune system has been demonstrated for antigens (eg, insulin) conjugated to an FcRn binding partner, such as IgG or Fe fragments (see for example PCT publications WO 96 / 22024 and WO 99/04813). It has also been found that fusion proteins having a disulfide linked dimeric structure due to the disulfide bonds of the IgG portion are more efficient for binding and neutralizing other molecules than the monomeric polypeptides or fragments thereof alone. See, for example, Fountoulakis et al., J. Biochem., 270: 3958-3964 (1995). In specific embodiments, antibodies that can be used in the methods of the invention bind to homomeric, especially homotrimeric, APRIL polypeptides. In other specific embodiments, the antibodies that can be used in the methods of the invention bind to heterodimeric, especially heterotrimeric APRIL polypeptides, such as a heterotrimer containing two APRIL polypeptides and a neutrokine-alpha polypeptide, or a heterotrimer containing a APRIL polypeptide and two neutrokine-alpha polypeptides. In a specific embodiment, the antibodies that can be used in the methods of the invention bind to homomeric, especially homotrimeric, APRIL polypeptides, wherein the individual protein components of the multimers consist of the mature form of APRIL (e.g. amino acid 102-250 of SEQ ID NO: 4). In other specific embodiments, the antibodies that can be used in the methods of the invention bind to heteromeric, especially heterotrimeric, APRIL polypeptides, such as a heterotrimer containing two APRIL polypeptides and a neutrocin-alpha polypeptide, or a heterotrimer containing a APRIL polypeptide and two neutrocine-alpha polypeptides, and wherein the individual protein components of the APRIL heteromer consist of the mature extracellular soluble portion of APRIL (eg, amino acid residues 102-250 of SEQ ID NO: 4) or soluble extracellular portion of neutrocine-alpha (by example amino acid residues 134-285 of SEQ ID NO: 2). In specific embodiments, antibodies that can be used in the methods of the invention bind to conformational epitopes of a monomeric APRIL protein. In specific embodiments, antibodies that can be used in the methods of the invention bind to conformational epitopes of a multimeric, especially trimeric, APRIL protein. In other embodiments, the antibodies that can be used in the methods of the invention bind to conformational epitopes that originate from the juxtaposition of APRIL with a heterologous polypeptide, such as could be present when APRIL forms heterotrimers (e.g. with neutrokine polypeptides). -alpha) or fusion proteins between APRIL and a heterologous polypeptide. Antibodies that can be used in the methods of the invention include, without limitation, polyclonal, monoclonal, multispecific, human, humanized or chimeric antibodies, single chain antibodies, Fab fragments, F (ab ') fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-ld) antibodies (including for example anti-ld antibodies for anti-APRIL antibodies) and epitope binding fragments of any of the foregoing. The term "antibody" as used herein, refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, ie, molecules that contain an antigen-binding site that immunospecifically binds to an antigen. The immunoglobulin molecules of the invention can be of any type (for example IgG, IgE, IgM, IgD, IgA and IgY), class (for example lgG1, IgG2, IgG3, IgG4, IgA1 and IgA2), or subclass of IgG molecule. Immunoglobulin. In preferred embodiments, the immunoglobulin is a IgG1 or an IgG4 isotype. The immunoglobulins can have both a heavy chain and a light chain. An array of heavy chains of IgG, IgE, IgM, IgD, IgA, and IgY can be paired with a light chain of the kappa or lambda forms. In a specific embodiment, the antibodies that can be used in the methods of the invention are the APRIL binding antibody fragments and include, without limitation, Fab, Fab 'and F (ab') 2, Fd, Fvs of a single chain (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv) and fragments comprising a VL or VH domain. The APRIL binding antibody fragments, which include single chain antibodies, may comprise the variable regions alone or in combination with all or a portion of the following: hinge region, CH1, CH2 and CH3 domains. In a specific embodiment, the APRIL binding fragments that can be used in the methods of the invention comprise any combination of variable regions with a hinge region, CH1, CH2 and CH3 domains. The antibodies that can be used in the methods of the invention can be of any animal origin, including birds and mammals. Preferably, the antibodies are human, murine (e.g., mouse and rat), donkey, sheep, rabbit, goat, guinea pig, camel, horse, or chicken. As used herein, "human" antibodies include antibodies that have the amino acid sequence of a human immunoglobulin and include antibodies isolated from collections of human immunoglobulin or from animals transgenic for one or more human immunoglobulins, and that do not express endogenous immunoglobulins, such as it is described, for example, in U.S. Pat. UU No. 5,939,598 to Kucherlapati et al., The contents of which are hereby incorporated by reference in their entirety. The antibodies that can be used in the methods of the invention can be monospecific, bispecific, trispecific or more specific. The multispecific antibodies may be specific for different epitopes of an APRIL polypeptide, or may be specific for both an APRIL polypeptide and a heterologous epitope, such as a heterologous polypeptide or solid support material. See, for example, PCT publications WO 93/17715; WO 92/08802; WO91 / 00360; WO 92/05793; Tutt et al., J. Immunol. 147: 60-69 (1991); US patents UU Nos. 4,474,893; 4,714,681; 4,925,648; 5,573,920; 5,601, 819; Kostelny et al., J. Immunol. 148: 1547-1553 (1992). The anti-APRIL antibodies that can be used in the methods of the invention can be described or specified based on their cross-reactivity. Antibodies that do not bind to any other analog, ortholog, or homolog of an APRIL polypeptide can be used in the methods of the invention. In a specific embodiment, antibodies that can be used in the methods of the invention cross-react with neutrocin-alpha. In specific embodiments, antibodies that can be used in the methods of the invention cross-react with murine, rat or rabbit homologs of human proteins and their corresponding epitopes. Antibodies that can be used in the methods of the invention can also be described or specified based on their binding affinity to an APRIL polypeptide. In specific embodiments, antibodies that can be used in the methods of the invention bind to APRIL polypeptides, or fragments or variants thereof, with a dissociation constant or KD less than 5 X 10"9 M, 10" 9 M, 5 X 10-10 M, 10"10 M, 5 X 10'11 M, 10" 11 M, 5 X 10 ~ 12 M, or 10 ~ 12 M. In a specific embodiment, the antibodies that can be used in the methods of the invention, APRIL polypeptides are linked with a dissociation constant KD within any of the scales that fall between each individual value quoted. For example, APRIL antibodies that disrupt receptor / ligand interactions with APRIL polypeptides are included partially or completely. Also included are APRIL-specific antibodies that do not prevent ligand binding but that prevent receptor activation. The activation of the receptor (i.e., signaling) can be determined by techniques described herein or otherwise known. For example, activation of the receptor can be determined by detecting the activation of the transcription factors NF-AT, AP-1 or NF-kappaB using known techniques, or phosphorylation (for example tyrosine or serine / threonine) of the receptor or its substrate, by means of immunoprecipitation, followed by Western blot analysis. In a specific embodiment, APRIL-specific antibodies that prevent ligand binding and receptor activation, as well as antibodies that recognize the receptor-ligand complex, and preferably do not specifically recognize the receptor can not be used in the methods of the invention. united nor the unbound ligand. In a specific embodiment, neutralizing antibodies which bind to the ligand and prevent ligand binding to the receptor can be used in the methods of the invention, as well as antibodies that bind to the ligand preventing activation of the receptor, but which do not prevent the ligand binds to the receptor. The above APRIL antibodies can be made using known methods. See, for example, PCT publication WO 96/40281; the US patent UU No. 5,811, 097; Deng et al., Blood 92 (6): 1981 -1988 (1998); Chen et al., Cancer Res. 58 (16): 3668-3678 (1998); Harrop et al., J. Immunol. 161 (4): 1786-1794 (1998); Zhu et al., Cancer Res. 58 (15): 3209-3214 (1998); Yoon et al., J. Immunol. 160 (7): 3170-3179 (1998); Prat et al., J. Cell. Sci. 111 (Pt2): 237-247 (1998); Pitard et al., J Immunol. Methods 205 (2): 177-190 (1997); Liautard et al., Cytokine 9 (4): 233-241 (1997); Carlson et al., J. Biol. Chem. 272 (17): 11295-11301 (1997); Taryman et al., Neuron 14 (4): 755-762 (1995); Muller et al., Structure 6 (9): 1153-1167 (1998); Bartunek et al., Cytokine 8 (1): 14-20 (1996) (which are hereby incorporated by reference in their entirety).

H. APRIL BINDING POLYPEPTIDES In a specific embodiment, the neutrokine-alpha antagonist is an APRIL binding peptide or polypeptide. APRIL binding peptides or polypeptides have been described, for example, in International Patent Publication Nos. WO 01/87977, WO 01/87979 and U.S. Patent Publications. UU Nos. US2002081296 and US2002086018, each of which is incorporated herein by reference in its entirety. The APRIL binding peptides that can be used in the methods of the present invention include short polypeptides identified in random peptide sequences deployed by fusion with filamentous phage coat proteins. For an exposition of phage display peptide collection technology see, for example, Scott et al. (1990), Science 249: 386; Devlin et al. (1990), Science 249: 404; US patent UU No. 5,223,409, issued June 29, 1993; US patent UU No. 5,733,731, issued March 31, 1998; US patent UU No. 5,498,530, issued March 12, 1996; US patent UU No. 5,432,018, issued July 11, 1995; US patent UU No. 5,338,664, issued August 16, 1994, US patent. UU No. 5, 922,545, issued July 13, 1999; WO 96/40987, published December 19, 1996; and WO 98/15833, published April 16, 1998 (each of which is incorporated herein by reference in its entirety). The phages expressing the peptides are isolated by successive rounds of affinity purification against an immobilized APRIL target peptide, followed by re-paging. The candidates with the highest binding to APRIL can be sequenced to determine the identity of each binding peptide. Each APRIL binding peptide identified can then be linked to a "vehicle" to generate an additional APRIL binding peptide, for use in the methods of the present experiment. The term "vehicle" refers to a molecule that prevents degradation or increases half-life, reduces toxicity, reduces immunogenicity, or increases the biological activity of an APRIL binding peptide. Exemplary carriers include an Fe domain and variants thereof (a "peptide antibody" thereof is preferred); a linear polymer (for example polyethylene glycol (PEG) including PEG of 5 kD, 20 kD, and kD, polylysine, dextran, etc.); a branched chain polymer (see for example U.S. Patent No. 4,289,872 to Denkenwaiter et al., issued September 15, 1981; 5,229,490 to Tam, issued July 20, 1993; WO 93/21259 to Frechet et al. others, published on October 28, 1993); a lipid; a cholesterol group (such as a steroid); a carbohydrate or oligosaccharide (e.g. dextran); a natural or synthetic protein, polypeptide or peptide that binds to a salvage receptor; albumin, including without limitation recombinant human albumin or fragments or variants thereof (see for example U.S. Patent No. 5,876,969, issued March 2, 1999, EP 0 413 622, and U.S. Pat. No. 5,766,883, issued June 16, 1998, which is incorporated herein by reference in its entirety), and a leucine closure domain, and other such proteins and protein fragments. The APRIL binding polypeptides that can be used in the methods of the invention require the presence of at least one vehicle attached to the peptide via the N-terminus, the C-terminus, or a side chain of one of the amino acid residues. Multiple vehicles can also be used, for example Fc's at each end, or a Fe at one end and a PEG group at the other end or a side chain. For APRIL binding peptides, a Fe domain is preferred as carrier. The Fe domain can be fused to the N or C termini of the peptides, or both at the N and C termini. Fusion to the N terminus is preferred. As indicated above, the Fe variants are suitable vehicles for the peptides of APRIL binding that can be used in the methods of the invention. A native Fe can be modified extensively to form a Fe variant, as long as the union with the salvage receptor is maintained.; see for example WO 97/34631 and WO 96/32478. In such Fe variants, one or more native Fe sites that provide structural features or functional activity not required by the APRIL binding peptides that can be used in the methods of the invention can be removed. These sites can be removed, for example, by substituting or deleting waste, inserting waste into the site, or truncating portions that contain the site. The inserted or substituted residues can also be altered amino acids, such as peptidomimetics or D-amino acids. Fe variants may be desirable for several reasons, several of which are described below. Exemplary Fe variants include molecules and sequences in which: 1. The sites involved in disulfide bond formation are removed. Said removal can avoid the reaction with other cysteine-containing proteins present in the host cell used to produce the molecules of the invention. For this purpose, the segment containing cysteine at the N-terminus can be truncated, or the cysteine residues can be deleted or substituted with other amino acids (eg, alanyl, seryl). Even when the cysteine residues are removed, the single-chain Fe domains can still form a chimeric Fe domain that remains non-covalently bound. 2. A native Fe is modified to make it more compatible with the selected host cell. For example, the PA sequence can be removed near the N-terminus of a typical native Fe, which can be recognized by a digestive enzyme in E. coli, such as proline iminopeptidase. A N-terminally methionine residue may also be added, especially when the molecule is recombinantly expressed in a bacterial cell such as E. coli. 3. A portion of the N-terminus of a native Fe is removed to prevent N-terminal heterogeneity when expressed in a selected host cell. For this purpose, any of the first 20 amino acid residues at the N-terminus can be deleted. 4. One or more glycosylation sites are removed. Residues that are normally glycosylated (eg asparagine) can confer a cytolytic response. Said residues can be deleted or substituted with non-glycosylated residues (for example alanine). 5. The sites involved in the interaction with the complement, such as the C1q binding site, are removed. For example, the EKK sequence of human IgG1 can be deleted or substituted. The complement recruitment may not be advantageous for the molecules that can be used in the methods of the invention, and thus can be avoided with said Fe variant. 6. Sites that affect the binding to different Fe receptors of a salvage receptor are removed. A native Fe may have sites for interaction with certain leukocytes that are not required in the APRIL binding peptide fusion molecules that can be used in the methods of the invention, and therefore can be removed. 7. The ADCC site is removed. ADCC sites are known in the art; see for example Molec. Immunol. 29 (5): 633-9 (1992) with respect to the ADCC sites in IgG1. These sites are also not required in the fusion molecules that can be used in the methods of the invention, and therefore can be removed. 8. When the native Fe is derived from a non-human antibody, the native Fe can be humanized. Normally, to humanize a native Fe, selected residues in native non-human Fe will be substituted with residues normally found in native Fe. The techniques for antibody humanization are well known. An alternative vehicle for the APRIL binding peptides that can be used in the methods of the invention would be a protein, polypeptide, peptide, antibody, antibody fragment, or small molecule (e.g., a peptidomimetic compound), capable of binding to a salvage receiver. For example, a polypeptide such as that described in US Pat. UU No. 5,739,277. Also, the peptides could be selected by phage display or screening and selection of RNA-peptide for binding to the salvage receptor. Said salvage receptor binding compounds are also included within the meaning "carrier" and can be used in APRIL binding peptides that can be used in the methods of the invention. Said vehicles would be selected according to their increase in half-life (for example avoiding sequences recognized by proteases) and decrease in immunogenicity (for example by favoring non-immunogenic sequences, as was discovered in the humanization of the antibody). As indicated above, polymer carriers can also be used in the APRIL binding peptides that can be used in the methods of the invention. Several means are now available to link useful chemical moieties as vehicles, see for example the international publication of the Patent Cooperation Treaty ("PTC") No. WO 96/11953, which is incorporated herein by reference in its entirety. This PCT publication describes among other things the selective binding of water-soluble polymers to the N-terminus of the proteins. In a specific embodiment, a preferred polymer carrier is polyethylene glycol (PEG). The PEG group may be of any convenient molecular weight and may be linear or branched. The average molecular weight of the PEG will preferably be in the range of about 2 kiloDalton ("kD"), to about 100 kD, preferably from 5 kD to about 50 kD, preferably from 5 KD to about 10 kD. PEG groups generally bind to neutrokine alpha binding peptides that can be used in the methods of the invention, by means of acylation or reductive alkylation, through a reactive group in the PEG portion (eg, a group an aldehyde, amino, thiol or ester) with a reactive group of the compound of the invention (for example an aldehyde, amino, or ester group). A useful strategy for the pegylation of synthetic peptides is to combine in solution, by forming a conjugated bond, a peptide and a portion of PEG, each carrying a special functional group that is mutually reactive towards the other. The peptides can be easily prepared by conventional solid phase synthesis. The peptides are "preactivated" with a suitable functional group at a specific site. The precursors are completely purified and characterized before being reacted with the PEG portion. Ligation of the peptide with PEG usually occurs in the aqueous phase and can be easily monitored by analytical reverse phase HPLC. Pegylated peptides can be easily purified by preparative HPLC and can be characterized by analytical HPLC, amino acid analysis and laser desorption mass spectrometry. Polysaccharide polymers are another type of water soluble polymer that can be used for APRIL binding peptides that can be used in the methods of the invention. Dextrans are polysaccharide polymers comprised of individual glucose subunits linked predominantly by alpha 1-6 bonds. Dextran itself is available in many molecular weight scales, and is readily available in molecular weights of about 1 kD to about 70 kD. Dextran is a water soluble polymer suitable for use as a carrier for the neutrokine alpha binding peptides which can be used in the methods of the invention, either alone or in combination with another vehicle (for example Fe). See for example WO 96/11953 and WO 96/05309. The use of dextran conjugated with therapeutic or diagnostic immunoglobulins has been reported; see, for example, European Patent Publication No. 0 315 456, which is incorporated herein by reference in its entirety. Dextran of about 1 kD to about 20 kD is preferred when used as a carrier according to the present invention. In a specific embodiment, the APRIL binding peptides that can be used in the methods of the invention optionally include a "linker". When present, its chemical structure is not critical since it serves mainly as a spacer. The linker is preferably formed of amino acids linked together by peptide bonds. Thus, in preferred embodiments, the linker is formed from 1 to 30 amino acids joined by peptide bonds, wherein the amino acids are selected from the 20 natural amino acids. Some of these amino acids may be glycosylated, as is well understood by those skilled in the art. In a preferred embodiment, amino acids 1 to 20 are selected from glycine, alanine, proline, asparagine, glutamine and lysine. Preferably, a linker will consist mostly of amino acids that are not sterically hindered, such as glycine and alanine. In this manner, the preferred linkers are polyglycines (particularly (Gly) 4, (Gly) 5), poly (Gly-Ala), and polyamines. Preferred linkers are amino acid linkers comprising more than 5 amino acids, suitable linkers having up to about 500 amino acids, selected from glycine, alanine, proline, asparagine, glutamine, lysine, threonine, serine or aspartate. Linkers of about 20 to 50 amino acids are preferred. Non-peptide linkers are also useful for the APRIL binding peptides that can be used in the methods of the invention. For example, alkyl linkers such as NH- (CH2) n-C (O) -, where n = 2-20 can be used. These alkyl linkers can be substituted with any non-sterically hindered group, such as lower alkyl (for example CrC6), lower acyl, halogen (for example Cl, Br), CN, NH2, phenyl, etc.

I. RNAi's and antisense In a specific embodiment, the neutrokine-alpha antagonist is an antisense RNA, catalytic RNA (ribozyme) or short interfering RNA (RNAi) directed at neutrokine-alpha, APRIL or neutrokine-alpha receptors ( for example, TACI, BCMA and BAFF-R). In a specific embodiment, antisense molecules directed against neutrocine-alpha, APRIL, TACI, BCMA or BAFF-R can be used in the methods of the invention. Antisense technology can be used to control gene expression by means of DNA or RNA or by triple helix formation. Antisense techniques are discussed, for example, in Okano, J. Neurochem. 56: 560 (1991); "Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression", CRC Press, Boca Raton, Florida (1988). The formation of the triple helix is discussed, for example, in Lee et al., Nucleic Acids Research 6: 3073 (1979); Cooney et al., Science 241: 456 (1988); and Dervan et al., Science 251: 1360 (1991). The methods are based on the binding of a polypeptide to a complementary DNA or RNA. For example, the 5 'coding portion of a polynucleotide encoding the extracellular domain of the polypeptide of the present invention can be used to design an antisense RNA oligonucleotide of a length of about 10 to 40 base pairs. A DNA oligonucleotide is designed to be complementary to a region of the gene involved in transcription, thus preventing the transcription and production of neutrocine-alpha, APRIL, TACI, BCMA or BAFF-R. The antisense RNA oligonucleotide hybridizes to the mRNA in vivo and blocks translation of the mRNA molecule to neutrokine-alpha polypeptide, APRIL, TACI, BCMA or BAFF-R. Oligonucleotides described above can also be delivered to cells so that the antisense RNA or DNA can be expressed in vivo to inhibit the production of neutrocine-alpha, APRIL, TACI, BCMA or BAFF-R. In one embodiment, the neutrophil-alpha antisense nucleic acid, APRIL, TACI, BCMA or BAFF-R that can be used in the methods of the invention is produced intracellularly by transcription of an exogenous sequence. For example, a vector or a portion thereof is transcribed, producing an antisense nucleic acid (RNA) that can be used in the methods of the invention. Such a vector would contain a sequence encoding the antisense nucleic acid of neutrocine-alpha, APRIL, TACI, BCMA or BAFF-R. Said vector can remain episomal or be chromosomally integrated, as long as it can be transcribed to produce the desired antisense RNA. Such vectors can be constructed by standard recombinant DNA technology. The vectors can be plasmidic, viral or other known vectors used for duplication and expression in vertebrate cells. The expression of the sequence encoding neutrocin-alpha, APRIL, TACI, BCMA or BAFF-R, or fragments thereof, can be by means of any promoter known to act on vertebrate cells, preferably human. Such promoters may be inducible or constitutive. Such promoters include, without limitation, the early promoter region of SV40 (Bernoist and Chambon, Nature 29: 304-310 (1981), the promoter contained in the 3 'long terminal repeat of the Rous sarcoma virus (Yamamoto et al., Cell 22: 787-797 (1980), the herpes thymidine promoter (Wagner et al., Proc. Nati, Acad. Sci. USA 78: 1441-1445 (1981), the regulatory sequences of the metallothionein gene (Brinster et al. Nature 296: 39-42 (1982)), etc. The antisense nucleic acids that can be used in the methods of the invention comprise a sequence complementary to at least a portion of an RNA transcript of a neutrocine-alpha gene , APRIL, TACI, BCMA or BAFF-R However, absolute complementarity is not required, although it is preferred A sequence "complementary to at least a portion of an RNA", referred to herein, means a sequence that has sufficient complementarity to can hybridize with the RNA, forming a stable duplex; thus, in the case of neutrophil-alpha double-stranded antisense nucleic acids, APRIL, TACI, BCMA or BAFF-R, a single strand of duplex DNA can be tested, or the formation of triplex can be tested. The ability to hybridize will depend on the degree of complementarity and the length of the antisense nucleic acid. Generally, the larger the hybridizing nucleic acid, it may contain more base mismatches with an RNA of neutrocine-alpha, APRIL, TACI, BCMA or BAFF-R, and still form a stable duplex (or triplex, as the case may be) . The person skilled in the art can determine a tolerable degree of discordance using standard procedures to determine the melting point of the hybridized complex. Oligonucleotides that are complementary to the 5 'end of the message, for example the 5' untranslated sequence up to and including the AUG start codon, must work more efficiently by inhibiting translation. However, it has been shown that sequences complementary to the 3 'untranslated sequences of mRNAs are also effective in inhibiting the translation of mRNAs. See, in general, Wagner, R., 1994, Nature 372: 333-335. In this manner, the oligonucleotides complementary to any of the 5 'or 3' non-translated non-coding regions of neutrocine-alpha (SEQ ID NO: 1), APRIL (SEQ ID NO: 3), TACI (SEQ ID NO: 5) , BCMA (SEQ ID NO: 7) or BAFF-R (SEQ ID NO: 9), can be used in an antisense approach to inhibit translation of endogenous mRNA from neutrokine-alpha, APRIL, TACI, BCMA or BAFF-R . Oligonucleotides complementary to the 5 'untranslated region of the mRNA must include the complement of the initiation codon AUG. Antisense oligonucleotides complementary to mRNA coding regions are less efficient inhibitors of translation, but could be used according to the methods of the invention. Designed to hybridize with the 5 ', 3' or non-coding region of neutrokine-alpha mRNA, APRIL, TACI, BCMA or BAFF-R, antisense nucleic acids must have a length of at least 6 nucleotides, and are Oligonucleotide preference whose length varies from 6 to about 50 nucleotides. In specific aspects, the oligonucleotide is at least 10 nucleotides, at least 17 nucleotides, at least 25 nucleotides, or at least 50 nucleotides. The polynucleotides that can be used in the methods of the invention can be DNA or RNA, or chimeric mixtures or derivatives or modified versions thereof, single chain or double chain. The oligonucleotide can be modified in the base portion, in the sugar portion or in the phosphate backbone, for example to improve the stability of the molecule, hybridization, etc. The oligonucleotide may include other linked groups such as peptides (for example to direct it to host cell receptors in vivo), or agents that facilitate transport across the cell membrane (see, for example, Letsinger et al., 1989, Proc. Nati, Acad. Sci. USA 86: 6553-6556; Lemaitre et al., Proc. Nati, Acad. Sci. 84: 648-652 (1987), PCT publication No. WO88 / 09810, published on December 15, 1988. ) or the blood-brain barrier (see, for example, PCT publication No. WO89 / 10134, published April 25, 1988), hybridization-activated cutting agents (see, for example, Krol et al., BioTechniques 6: 958). -976 (1988)) or intercalation agents (see, for example, Zon, Pharm. Res. 5: 539-549 (1988)). For this purpose, the oligonucleotide can be conjugated with another molecule, for example a peptide, hybridization-activated entanglement agent, transport agent, hybridization activated cutting agent, etc. The antisense oligonucleotide that can be used in the methods of the invention can comprise at least a portion of the modified base selected from the group including, without limitation, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodoouracil , hypoxanthine, xanthine, 4-acetylcytosine, 5- (carboxyhydroxymethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, nosine, N6-isopentenyladenine, 1-methylguanine, 1 -methylnosin, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyamomethyl-2-thiouracyl, beta-D - mannosylkeosine, 5-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wibutoxosine, pseudoouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil , 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methyl ester, uracil-5-oxyacetic acid (v), 5-methyl-2-thououcil, 3- (3-amino-3-N-2- carboxypropyl) uracil, (acp3) w, and 2,6-diamnopurine. The antisense oligonucleotide that can be used in the methods of the invention may also comprise at least a portion of modified sugar selected from the group including, without limitation, arabinose, 2-fluoroarabinose, xylulose, and hexose. In another embodiment, the antisense oligonucleotide that can be used in the methods of the invention comprises at least one modified phosphate backbone, selected from the group including, without limitation, a phosphorothioate, a phospho-rhodium thioate, a phosphoramidothioate, a phosphoroamidate , a phosphorodiamidate, a methylphosphonate, an alkyl phosphotriester, and a formatetal or analogue thereof. In another embodiment, the antisense oligonucleotide that can be used in the methods of the invention is an alpha-anomeric oligonucleotide. An alpha-anomeric oligonucleotide forms double-stranded specific hybrids with complementary RNA in which, contrary to the usual beta units, the strands run parallel to one another (Gautier et al., Nucí Acids Res. 15: 6625-6641 ( 1987. The oligonucleotide is a 2-O-methyl ribonucleotide (Inoue et al., Nucí Acids Res. 15: 6131-6148 (1987), or a chimeric RNA-DNA analogue (Inoue et al., FEBS Lett. : 327-330 (1997).

Polynucleotides that can be used in the methods of the invention can be synthesized by standard known methods, for example using an automated DNA synthesizer (such as that which is commercially available from Biosearch, Applied Biosystems, etc.). As examples, phosphorothioate oligonucleotides can be synthesized by the method of Stein et al. (Nucí Acids Res. 16: 3209 (1988); methylphosphonate oligonucleotides can be prepared using controlled pore glass polymer supports (Sarin et al., Proc. Nati, Acad. Sci. USA 85: 7448-7451 (1988)), etc. Although antisense nucleotides complementary to the sequence of the coding region of neutrocine-alpha, APRIL, TACI, BCMA or BAFF-R can be used, Preferred are those complementary to the untranslated transcribed region for use in the methods of the invention In a specific embodiment, the neutrokine-alpha antagonists that can be used in the methods of the invention also include a catalytic RNA or ribozyme (see example, PCT international publication WO90 / 11364, published October 4, 1990; Sarver et al., Science 247: 1222-1225 (1990)), directed against neutrocine-alpha, APRIL, TACI, BCMA or BAFF-R. You can in using ribozymes that cut mRNA in site-specific recognition sequences to destroy the neutrokine-alpha, APRIL, TACI, BCMA or BAFF-R mRNAs, for the methods of the invention, hammerhead ribozymes are preferred. Hammerhead ribozymes cut mRNAs at sites dictated by flanking regions that form base pairs complementary to the target mRNA. The only requirement is that the target mRNA has the following sequence of two bases: 5'-UG-3 '. The construction and production of hammerhead ribozymes is well known and is described more fully in Haseloff and Gerlach, Nature 334: 585-591 (1988). There are many potential hammerhead ribozyme cleavage sites within the nucleotide sequence of neutrokine-alpha APRIL, TACI, BCMA or BAFF-R. Preferably, the ribozyme is engineered so that the cut recognition site is located near the 5 'end of the neutrokine-alpha mRNA, APRIL, TACI, BCMA or BAFF-R; that is, to increase the efficiency and minimize the intracellular accumulation of non-functional mRNA transcripts. As in the antisense approach, the ribozymes that can be used in the methods of the invention can be composed of modified oligonucleotides (e.g., to improve stability, direction, etc.), and must be delivered to the cells expressing neutrocin. -alfa, APRIL, TACI, BCMA or BAFF-R. DNA constructs encoding the ribozyme can be introduced into the cell, in the same manner as described above for the introduction of antisense coding DNA. A preferred method of delivery includes the use of a DNA construct "encoding" the ribozyme under the control of a strong constitutive promoter, such as for example the pol II or pol II promoter, so that the transfected cells produce sufficient amounts of the promoter. ribozíma to destroy the endogenous messages of neutrocina-alfa, APRIL, TACI, BCMA or BAFF-R, and inhibit their translation. Since ribozymes, unlike antisense molecules, are catalytic, a lower intracellular concentration is required for efficiency. In a specific embodiment, short interfering RNA directed against neutrocine-alpha, APRIL, TACI, BCMA or BAFF-R can be used in the methods of the invention. RNAi technology can be used to control gene expression by inducing the RNA-induced silencing complex of cells (RISC). RNAi techniques are discussed, for example, in Hamilton AJ and Baulcombe DC. Science. 1999, Oct 29; 286 (5441): 950-2; Elbashir SM et al., Nature, 2001 May 24; 411 (6836): 494-8, and Hanon, Gregory J. and Rossi, John J., Nature 431, 371-378 (2004). The methods are based on the introduction of short double-stranded RNA (usually 20 to 25 nucleotides) into a cell. The double-stranded RNA is uncoiled and each chain is separated. A single strand of RNA is then incorporated into the RISC. The RISC then directs the cutting of the sequence specific RNA, resulting in a repression of the translation. For example, the coding portion of a polynucleotide encoding a neutrocin-alpha, APRIL, TACI, BCMA or BAFF-R polypeptide can be used to design an RNAi oligonucleotide of a length of about 20 to 25 nucleotides. A DNA oligonucleotide is designed with the appropriate fragment of 20 to 25 nucleotides, a spacer of approximately 9 nucleotides, and the reverse complement of the chosen nucleotide fragment. It would be expected that the RNA transcript produced from this construction will fold over itself to form a hairpin loop. The delivery of the hairpin RNA to the cell results in processing by the Rnasa, Dicer, to produce short double-stranded RNAi. Incorporation of a strand of this RNAi to the effector complex of RISC results in the cleavage of mRNA directed by the RNAi to inhibit the production of neutrocine-alpha, APRIL, TACI, BCMA or BAFF-R. In one embodiment, the nucleic acid RNAci of neutrokine-alpha, APRIL, TACI, BCMA or BAFF-R that can be used in the methods of the invention, is produced intracellularly by transcription of an exogenous sequence. For example, a vector or portion thereof is transcribed, producing a siRNA that can be used in the methods of the invention. Said vector would contain a sequence encoding the nucleic acid RNAi of neutrokine-alpha, APRIL, TACI, BCMA or BAFF-R. Such vectors can be constructed by standard methods of recombinant DNA technology. The vectors can be plasmids, viral or other known, used for duplication and expression of cells in vertebrates. Transcription of the sequence encoding the neutrokine-alpha, APRIL, TACI, BCMA or BAFF-R is normally performed using an RNA polymerase III promoter (eg, U6 or H1), which usually directs the transcription of nuclear RNAs small (ARNnp's).

B-cell modulators In addition to the receptors for neutrokine-alpha and APRIL, B-lymphocytes express a variety of cell surface molecules that function to inform B cells about the extracellular microenvironment and act as transmembrane signals to positively and negatively regulate the function and survival of B cells. CD19, CD20 and CD22 have been identified as potential targets for therapeutic intervention among these receptors. CD20 is an integral membrane protein that acts on a complex like a calcium channel. The calcium channel inhibitors of CD20 disrupts Ca2 + homeostasis and cell cycle progression. In a specific embodiment, an anti-CD20 antibody can be used in the methods of the present invention. In a preferred embodiment, the anti-CD20 antibody that can be used in the methods of the invention is Rituxan® (rituximab). In another preferred embodiment, the anti-CD20 antibody that can be used in the methods of the invention is TRU-015. In another preferred embodiment, the anti-CD20 antibody that can be used in the methods of the invention is ocrelizumab (PRO70769). In another embodiment, the anti-CD20 antibody that can be used in the methods of the invention is IMMU-106. In another preferred embodiment, the anti-CD20 antibody that can be used in the methods of the invention is HuMax-CD20. CD22 is a member of the siglec family of sialic acid binding proteins found in a variety of cells that include B lymphocytes. The interaction of CD22 with a variety of cis and trans carbohydrate ligands results in the regulation of several aspects of the development, proliferation and activation of B cells. In a specific embodiment, the anti-CD22 antibody can be used in the methods of the invention. In a preferred embodiment, the anti-CD22 antibody that can be used in the methods of the invention is epratuzumab.

Other immunomodulatory agents In a specific embodiment, the methods of the present invention can be practiced with one or more of the following drugs: Celicept (mycophenolate mofetil; MMF), Orencia® (abatacept; CTLA4-lg), Riquent ™ (abetimus sodium; LJP 394), Prestara ™ (praserone), Edratide (TV-4710), Actemra® (tocilizumab; atlizumab), VX-702, TRX 1, IPP-201101, ABR-215757, sphingosine-1-phosphate-1 agonist ( S1 P1), HuMax-Inflam ™ (MDX 018), MEDI-545 (MDX-1103/1333), RhuDex®, Deoxyspergualin, ENBREL ™ (Etanercept), anti-TNF antibody, anti-interferon alpha antibody.

Patient populations As described here, data from a clinical trial in which lupus patients were treated with an antibody that neutralizes the neutrocyan-alpha protein indicate a significant improvement in the symptoms associated with lupus in patients who had a titer. of ANA of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA (example 1). Surprisingly, only statistically significant improvements were obtained in clinical endpoints that measure the activity of the disease (such as a reduction of the SELENA SLEDAI score, which is explained below in greater detail), in a subgroup of patients, and not in the entire population of patients enrolled in the clinical trial. Thus, the present invention relates to the identification of subgroups of patients most likely to respond to treatment with an immunomodulatory agent such as a neutrokine-alpha antagonist. Additionally, as described herein, systemic lupus erythematosus (SLE) is a very heterogeneous disease that is difficult to diagnose correctly due to the wide nature of the symptoms that a patient may present, and the fact that many of the symptoms associated with Lupus are also observed in other autoimmune diseases. Thus, one embodiment of the present invention provides a method of treating a patient having an ANA titer of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies in his plasma or blood serum, which comprises administering a therapeutically effective amount of a neutrokine-alpha antagonist or other immunomodulatory agent known or described herein, without considering the diagnosis of the disease. Another embodiment of the present invention provides a method of treating a patient having an ANA titer of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies in his plasma or blood serum, which comprises administering a Therapeutically effective amount of a neutrokine-alpha antagonist or other immunomodulatory agent known or described herein, without considering the diagnosis of the disease, and further comprising making a determination to see if the patient has an ANA titre of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies in your plasma or blood serum, before administering the immunomodulatory agent. In additional embodiments, the patient who has an ANA titre of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies in his plasma or blood serum, has an autoimmune disease that is not SLE. In additional modalities, the patient having an ANA titre of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies in his plasma or blood serum, has rheumatoid arthritis. In additional modalities, the patient who has an ANA titre of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies in his plasma or blood serum, has Sjögren's syndrome. In additional embodiments, the patient who has an ANA titre of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies in his plasma or blood serum, has scleroderma. In additional modalities, the patient having an ANA titre of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies in his plasma or blood serum, has polymyositis-dermatomyositis. In additional embodiments, the patient having an ANA titre of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies in his plasma or blood serum, has Felty's syndrome. In additional embodiments, the patient having an ANA titre of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies in his plasma or blood serum, has mixed connective tissue disease. In additional embodiments, the patient who has an ANA titre of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies in his plasma or blood serum, has Raynaud's syndrome. In additional embodiments, the patient having an ANA titre of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies in his plasma or blood serum, has juvenile chronic arthritis. Furthermore, it should be noted that in phase 2 clinical trials using an antibody that neutralizes the neutrocyan-alpha protein to treat patients with systemic lupus erythematosus and rheumatoid arthritis (see examples 1 and 3), it was observed that patients with disease of positive antibody at the reference point were more likely to respond to treatment. As described here, SLE patients who obtained an ANA titre of 1: 80 or greater, or 30 IU / mL or more of anti-dsDNA antibodies at the reference point, showed a stronger response as a group than the patients of SLE whose ANA titre was less than 1: 80 and whose anti-dsDNA antibody value was less than 30 IU / mL. Similarly, in rheumatoid arthritis, patients who were positive for rheumatoid factor [RF] antibodies or citric anticyclic peptide [CCP] at the reference point were shown to have a stronger response as a group than rheumatoid arthritis patients they were not positive for rheumatoid factor [RF] antibodies or citric anticyclic peptide [CCP] at the reference point.

Thus, in another aspect of the invention, there is provided a method of treating a patient that is positive for rheumatoid factor [RF] antibodies or citric anticyclical peptide [CCP] at the reference point, which comprises administering a therapeutically amount effective of a neutrokine-alpha antagonist or other immunomodulatory agent known or described herein, without considering the diagnosis of the disease. Another embodiment of the present invention provides a method of treating a patient that is positive for rheumatoid factor [RF] antibodies or citric anticyclic peptide [CCP] at the reference point, which comprises administering a therapeutically effective amount of a neutralizing agent. α-alpha or other immunomodulatory agent known or described herein, without considering the diagnosis of the disease, and further comprising making a determination to see if the patient is positive for rheumatoid factor [RF] antibodies or citric anticyclical peptide [CCP] at the reference point, before administering the immunomodulatory agent. In specific modalities, a patient is considered positive for rheumatoid factor if he has > 12 IU / ml of rheumatoid factor in your plasma or blood serum. In specific modalities, a patient is considered to be positive for anti-CCP antibody if the patient has > 10 units of anti-CCP antibody in its plasma or blood serum. In a further aspect of the present invention, there is provided a method of treating a patient that is positive autoantibody at the reference point, which comprises administering a therapeutically effective amount of a neutrocyan-alpha antagonist or other immunomodulatory agent known or described in the present, without considering the diagnosis of the disease. Another embodiment of the present invention provides a method of treating a patient that is positive autoantibody at the reference point, which comprises administering a therapeutically effective amount of a neutrocyanalpha-alpha antagonist or other agent known or described herein, without considering the diagnosis of the disease, and which further comprises making a determination to see if the patient is a positive autoantibody at the reference point, before administering the immunomodulatory agent.

Preparation of immunomodulatory agents The methods for preparing or isolating immunomodulatory agents that can be used in the present invention are known to those skilled in the relevant arts. Below are briefly reviewed the methods available to prepare immunomodulatory agents that are protein-like (e.g., anti-neutrocine-alpha antibodies, neutrokine-alpha binding peptides and polypeptides, neutrokine-alpha receptor proteins and also fragments and variants of the aforementioned polypeptides). In one embodiment, a polynucleotide that encodes an immunomodulatory protein is inserted into a vector (e.g., a cloning or expression vector). The vector can be, for example, a phage, plasmid, viral or retroviral vector. Retroviral vectors may be replication competent or defective duplication. In the latter case, viral propagation will usually only occur in complementing host cells. The polynucleotides encoding a immunomodulatory protein can be attached to a vector containing a selectable marker for propagation in a host. The introduction of the vector construct into the host cell can be effected by known techniques including, without limitation, calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid mediated transfection, electroporation, transduction, infection, or other methods. Such methods are described in many standard laboratory manuals, such as for example Davis and others, "Basic Methods In Molecular Biology" (1986). Usually, the recombinant expression vectors will include duplication origins and selectable markers that allow the transformation of the host cell, for example the ampicillin resistance gene of E. coli and the TRP1 gene of S. cerevisiae, and. a promoter derived from a gene highly expressed to direct the transcription of a structural sequence downstream. Such promoters can be derived from operons encoding glycolytic enzymes such as 3-phosphoglycerate kinase (PGK), alpha factor, acid phosphatase, or heat shock proteins, among others. The heterologous structural sequence is assembled in the appropriate phase with translation initiation and termination sequences, and preferably a leader sequence capable of directing the secretion of the translated protein into the perplasmic space or extracellular media. Optionally, the heterologous sequence can encode a fusion protein that includes an N-terminal identification peptide that imparts the desired characteristics, for example stabilization or simplified purification of the expressed recombinant product. In one embodiment, the polynucleotide encoding an immunomodulatory protein is operatively associated with a suitable heterologous regulatory element (e.g., promoter or enhancer), such as the PL promoter of lambda phage, the lac, trp, phoA and tac promoters of E. coli. , the early and late promoters are SV40, and retroviral LTRs promoters, to name a few. Other suitable promoters will be known to the person skilled in the art. As indicated, the expression vectors will preferably include at least one selectable marker. Such markers include dihydrofolate reductase, G418 or neomycin resistance for a eukaryotic cell culture, and tetracycline, kanamycin, or ampicillin resistance genes for cultivation in E. coli and other bacteria. Representative examples of suitable hosts include, without limitation, bacterial cells such as E. coli, Streptomyces and Salmonella typhimurium cells.; mushroom cells, such as yeast cells (eg, Saccharomyces cerevisiae or Pichia pastoris (ATCC Registry No. 201178)), insect cells such as Drosophila S2 and Spodoptera Sf9 cells; animal cells such as CHO, COS, 293 and Bowes melanoma cells; and plant cells. Suitable culture media and conditions for the host cells described above are known. The host cell can be a higher eukaryotic cell, such as a mammalian cell (e.g., a human-derived cell), or a lower eukaryotic cell such as a yeast cell, or the host cell can be a prokaryotic cell, such as a bacterial cell. The host strain can be chosen to modulate the expression of the inserted gene sequences, or to modify and process the gene product in the specific manner desired. The expression of certain promoters can be raised in the presence of some inducers; in this way, the expression of the genetically engineered polypeptide can be controlled. In addition, different host cells have specific characteristics and mechanisms for translation processing and modification and subsequent translation of proteins (eg, phosphorylation, cleavage). Appropriate cell lines can be chosen to ensure that modifications and processing of the foreign protein are expressed. The selection of appropriate vectors and promoters for expression in a host cell is a well-known procedure, and the techniques required for the construction of the expression vector, introduction of the vector into the host and expression in the host, are routine techniques in the field. . Useful expression vectors for bacterial use are constructed by inserting a structural DNA sequence encoding a desired protein together with suitable translation initiation and termination signals in operable reading phase with a functional promoter. The vector will comprise one or more selectable phenotypic markers and a duplication origin, to ensure maintenance of the vector, and if desirable to provide amplification within the host. Prokaryotic hosts suitable for transformation include E. coli, Bacillus subtilis, Salmonella typhimurium, and several species of the genera Pseudomonas, Streptomyces and Staphylococcus, although others may also be used at choice. As a representative but non-limiting example, expression vectors useful for bacterial use may comprise a selectable marker and bacterial origin of duplication derived from commercially available plasmids, comprising genetic elements of the known cloning vector pBR322 (ATCC 37017). Such commercial vectors include, for example, pKK223-3 (Pharmacia Fine Chemicals, Uppsala, Sweden), GEM1 (Promega Biotec, Madison, Wisconsin, USA). These "skeleton" sections of pBR322 are combined with a suitable promoter and the structural sequence to be expressed. Among the preferred vectors for use in bacteria include pHE4-5 (ATCC Registration No. 209311, and variations thereof), pQE70, pQE60 and pQE-9, available from QIAGEN Inc., cited above; pBS vectors, Phagescript vectors; Bluescript vectors, pNH8A, pNH16a, pNH18A, pNH46A, available from Stratagene; and ptrc99a, pKK223-3, pKK233-3, pDR540, pRIT5, available from Pharmacia. Preferred expression vectors for use in yeast systems include, without limitation, pYES2, pYD1, pTEF1 / Zeo, pYES2 / GS, pPICZ, pGAPZ, pGAPZalpha, pPIC9, pPIC3.5, pHIL-D2, pHIL-S1, pPIC3. 5K, pPIC9K, and PA0815 (all available from Invitrogen, Carlsbad, California). Among the preferred eukaryotic vectors are pWLNEO, pSV2CAT, pOG44, pXT1 and pSG, available from Stratagene; and pSVK3, pBPV, pMSG and pSVL (available from Pharmacia). Other suitable vectors will be very apparent to the person skilled in the art. After transformation of a suitable host strain and growth of the host strain to a suitable cell density, the selected promoter is induced by the appropriate means (e.g., temperature change or chemical induction), and the cells are cultured for an additional period. Normally the cells are harvested by centrifugation, they are broken by physical or chemical means and the resulting crude extract is retained for further purification. The microbial cells used in the expression of proteins can be broken by any convenient method including freeze-thaw cycles, mechanical disruption, or the use of cell lysis agents, such methods are well known to those skilled in the art. In one embodiment, the yeast Pichia pastoris is used to express the neutrocyan-alpha protein in a eukaryotic system. Pichia pastoris is a methylotrophic yeast that can metabolize methanol as its sole carbon source. A major step in the route of methanol metabolism is the oxidation of methanol to formaldehyde using 02. This reaction is catalyzed by the enzyme alcohol oxidase. To metabolize methanol as the sole carbon source, Pichia pastoris must generate large amounts of alcohol oxidase due in part to the relatively low affinity of alcohol oxidase for 02. Consequently, in a growth medium that depends on methanol as the main source of carbon , the promoter region of one of the two alcohol oxidase genes (AOX1) is highly active. In the presence of methanol, the alcohol oxidase produced from the AOX1 gene comprises up to about 30% of the total soluble protein of Pichia pastoris. See Ellis, S.B. and others, Mol. Cell. Biol. 5: 1111-21 (1985); Koutz, P.J et al., Yeast 5: 167-77 (1989); Tschopp, J.F. and others, Nucí. Acids Res. 15: 3859-76 (1987). In this way, a heterologous coding sequence under the transcription regulation of part or all of the regulatory sequence of AOX1, is expressed in exceptionally high amounts in the Pichia yeast grown in the presence of methanol. In one example, the plasmid vector pPIC9k is used to express DNA encoding an immunomodulatory protein, or a portion thereof, as set forth herein, in a Pichia yeast system, essentially as described in "Pichia Protocols: Methods in Molecular Biology ", DR Higgins and J. Cregg, eds. The Humana Press, Totowa, New Jersey, 1998. This expression vector allows the expression and secretion of an immunomodulatory protein by virtue of the strong AOX1 promoter linked to the secretory (ie, leader) signal peptide of alkaline phosphatase (PHO) of Pichia. pastoris, located 3 'away from a multiple cloning site. Many other yeast vectors can be used in place of pPIC9K, such as pYES2, pYD1, pTEF1 / Zeo, pYES2 / GS, pPICZ, pGAPZ, pGAPZalpha, pPIC9, pPIC3.5, pHIL-D2, pHIL-S1, pPIC3.5K , and PA0815, as the skilled artisan will readily appreciate, provided that the proposed expression construct provides suitably localized signals for transcription, translation, secretion (if desired), etc., including an AUG in frame as required. In one embodiment high-level expression of a heterologous coding sequence can be obtained by cloning the heterologous polynucleotide of the invention in an expression vector, such as for example pGAPZ or pGAPZalpha, and developing the culture in the absence of methanol. The transcription of the DNA encoding the immunomodulatory proteins by means of higher eukaryotes is increased by inserting an enhancer sequence into the vector. Incrementers are cis-acting elements of DNA, usually from 10 to 300 p.b. that act on a promoter to increase its transcription. Examples include the SV40 enhancer on the late side of the duplication origin, from 100 to 270 p.b., an early promoter enhancer of cytomegalovirus, the polyoma enhancer on the late side of the duplication origin, and adenovirus enhancers. Various mammalian cell culture systems can also be used to express recombinant protein. Examples of mammalian expression systems include the COS-7 lines of monkey kidney fibroblasts, described by Gluzman (Cell 23: 175 (1981)), and other cell lines capable of expressing a compatible vector, for example cell lines. C127, 3T3, CHO, Hela and BHK. The mammalian expression vectors will comprise a suitable duplication origin, a promoter and enhancer, and also any necessary ribosome binding site, polyadenylation site, splice donor and receptor sites, transcription termination sequences, and flanking sequences of 5 'not transcribed. The DNA sequences derived from the SV40 splice, and the polyadenylation sites can be used to provide the required non-transcribed genetic elements. In a specific embodiment, constructs designed to express a portion of an immunomodulatory protein are used, such as the extracellular domains of neutrokine-alpha receptors (eg, TACI, BCMA and BAFF-R). The person skilled in the art would be able to use the polynucleotide and polypeptide sequences provided as SEQ ID NO: 5 and SEQ ID NO: 6, respectively, SEQ ID NO: 7 and SEQ ID NO: 8, respectively, or SEQ ID NO: 9 and SEQ ID NO: 10, respectively, to design polynucleotide primers and generate said expression construct. Host cells are used to express polynucleotides that encode an immunomodulatory protein. Such host cells include primary, secondary and immortalized host cells of vertebrate origin, particularly of mammalian origin. In some cases, the host cells will be engineered to suppress or replace endogenous genetic material (e.g., the neutrocin-alpha coding sequence), or to include genetic material (e.g., heterologous polynucleotide sequences). In some cases, the host cell is modified in order to promote or alter the expression of the endogenous polynucleotide that encodes the immunomodulatory protein. For example, known techniques can be used to operatively associate heterologous control regions (e.g., promoter or enhancer), and endogenous polynucleotide sequences via homologous recombination (see, e.g., U.S. Patent No. 5,641,670, issued on June 24, 1997; International Publication No. WO 96/29411, published September 26, 1996; International Publication No. WO 94/12650, published August 4, 1994; Koller et al., Proc. Nati Acad. Sci. USA 86: 8932-8935 (1989) and Zijlstra et al., Nature 342: 435-438 (1989), the descriptions of which are hereby incorporated by reference in their entirety). The host cells described herein can be used in a convenient manner to produce the immunomodulatory protein. Alternatively, cell-free translation systems can also be used to produce an immunomodulatory polypeptide using RNAs derived from the DNA constructs of the present invention. The required AUG framework can be expressed or synthesized in a modified form, such as a fusion protein (comprising the polypeptide linked via a peptide bond to a heterologous protein sequence (of a different protein)), and can include not only signals of secretion, but also additional heterologous functional regions. Said fusion protein can be made by ligating polynucleotides encoding the immunomodulatory protein and the desired nucleic acid sequence encoding the desired amino acid sequence, by known methods, in the proper reading frame, and expressing the fusion protein product by the known methods. Alternatively, said fusion protein can be made by synthetic protein techniques, for example using a peptide synthesizer. Thus, for example, a region of additional amino acids, particularly charged amino acids, may be added to the N-terminus of the polypeptide to improve stability and persistence in the host cell, during purification, or during subsequent handling and storage. Also, portions of peptide may be added to the polypeptide to facilitate its purification. Such regions can be removed before the final preparation of the polypeptide. The addition of portions of peptide to the polypeptides to engender secretion or excretion, to improve stability and to facilitate purification, among other things, are familiar and routine techniques in the field. In one embodiment, a polynucleotide encoding an immunomodulatory protein can be fused to signal sequences that will direct the localization of an immunomodulatory protein to particular compartments of a prokaryotic or eukaryotic cell, or direct the secretion of the immunomodulating protein from a prokaryotic or eukaryotic cell. . For example, it may be required, in E coli, to direct the expression of the protein to the periplasmic space. Examples of signal sequences or proteins (or fragments thereof) to which the polypeptides of the invention can be fused to direct the expression of the polypeptide to the periplasmic space of the bacteria, include without limitation, the signal sequence pe1 B, the signal sequence of the maltose binding protein (MBP), MBP, the ompA signal sequence, the periplasmic signal sequence of the heat-labile enterotoxin B subunit of E. coli, and the phosphatase signal sequence alkaline Several vectors are commercially available for the construction of fusion proteins that direct the localization of a protein, such as the pMAL series of vectors (particularly the pMAL-p series), available from New England Biolabs. In a specific embodiment, the polynucleotides encoding an immunomodulatory protein can be fused to the signal sequence of pelB pectate lyase to increase the efficiency of expression and purification of said peptides in Gram negative bacteria. See, for example, U.S. Pat. UU Nos. 5,576,195 and 5,846,818, the contents of which are incorporated herein by reference in their entirety. Examples of signal peptides that can be fused with an immunomodulatory protein to direct their secretion in mammalian cells include, without limitation, the signal sequence MPIF-1 (amino acids 1-21 of GenBank registration No. AAB51134), the signal sequence of stancine (MLQNSAVLLLLVISASA, SEQ ID NO: 27), and a consensus signal sequence ( MPTWAWWLFLVLLLALWAPARG, SEQ ID NO: 28). A suitable signal sequence that can be used in conjunction with baculovirus expression systems is the gp67 signal sequence (amino acids 1-19 of GenBank registration No. AAA72759). A preferred fusion protein comprises a heterologous immunoglobulin region that is useful for stabilizing and purifying proteins. For example, EP-A 0 464 533 (Canadian counterpart of document 2045869) discloses fusion proteins comprising several portions of the constant region of immunoglobulin molecules together with another human protein or part thereof. In many cases, the Fe part in a fusion protein is completely advantageous for use in therapy and diagnosis, and thus results, for example, in improved pharmacokinetic properties (EP-A-0232 262). On the other hand, for some uses, it would be desirable to be able to suppress the Fe part after the fusion protein has been expressed, detected and purified in the advantageous manner described. This is the case when the Fe portion proves to be an impediment to its use in therapy and diagnosis, for example, when the fusion protein is used as an antigen for immunizations. In drug discovery, for example, human proteins such as hIL-5 have been fused with Fe portions for the purpose of high throughput identification tests to identify hIL-5 antagonists. See, D. Bennett et al., J. Molecular Recognition 8: 52-58 (1995) and K. Johanson et al., J. Biol. Chem. 270: 9459-9471 (1995). Immunomodulatory proteins can be used in the methods of the present invention include naturally purified products, synthetic chemical process products, and products produced by recombinant techniques of a prokaryotic or eukaryotic host, including, for example, bacterial cells, yeasts, higher plants , insect and mammal. Depending on the host employed in a recombinant production process, the immunomodulatory proteins may be glycosylated or they may be non-glycosylated. In addition, immunomodulatory proteins may also include an initial modified methionine residue, in some cases as a result of host-mediated processes. The immunomodulatory proteins that can be used in the methods of the present invention can be chemically synthesized using known techniques (see for example Creighton, 1983, "Proteins: Structures and Molecular Principles," W.H. Freeman &; Co., N.Y., and Hunkapiller, M. et al., 1984, Nature 310: 105-111). For example, a peptide corresponding to a fragment of an immunomodulatory protein can be synthesized using a peptide synthesizer. In addition, if desired, analogs of chemical amino acids or non-classical amino acids may be introduced as a substitution or addition in the polynucleotide sequence encoding the immunomodulatory protein. Non-classical amino acids include without limitation, the D isomers of the common amino acids, 2,4-diaminobutyric acid, alpha-aminoisobutyric acid, 4-aminobutyric acid, Abu, 2-aminobutyric acid, g-Abu, e-Ahx, 6-aminobutyric acid, -aminohexanoic, Aib, 2-aminoisobutyric acid, 3-aminopropionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, homocitrulin, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, b-alanine, fluoroamino acids, designer amino acids such as b-methyl amino acids, Ca-methyl amino acids, Na-methyl amino acids, and amino acid analogs in general. In addition, the amino acid can be D (dextrorotatory) or L (levorotatory). The immunomodulatory proteins that can be used in the methods of the present invention can be differentially modified during or after translation, for example by glycosylation, acetylation, phosphorylation, amidation, modification by known protecting / blocking groups, proteolytic cleavage, binding with a antibody molecule or other cellular ligand, etc. Any of many chemical modifications can be made by known techniques, including without. specific chemical cutoff with cyanogen bromide, trypsin, chymotrypsin, papain, V8 protease, NaBH4? acetylation, formylation, oxidation, reduction, metabolic synthesis in the presence of tunicamycin, etc. Additional post-translational modifications include for example N-linked or O-linked carbohydrate chains, N-terminal or C-terminal processing, binding of chemical moieties to the amino acid skeleton, chemical modifications of the N-carbohydrate chains linked or O-linked, and addition or deletion of an N-terminal methionine residue as a result of prokaryotic host cell expression. The polypeptides can also be modified with a detectable label, such as an enzymatic, fluorescent, radioisotopic or affinity label, to allow detection and isolation of the protein Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, beta-galactosidase, glucose oxidase or acetylcholinesterase, examples of suitable prosthetic groups include streptavidin / biotin and avidin / biotin complexes; examples of fluorescent materials include biotin, umbelliferone, fluorescein, fluorescein isocyanate, rhodamine, dichlorotriazinylaminofluorescein, dansyl chloride, phycoerythrin, an example of a luminescent material includes luminol; examples of bioluminescent materials include liciferase, luciferin and aequorin; and examples of suitable radioactive material include a radioactive metal ion, for example alpha emitters such as for example 213Bi, or other radioisotopes, such as for example iodine (131l, 125l, 123l, 121l), carbon (14C), sulfur (35S ), tritium (3H), indium (115ml, 113ml, 12ln, 111ln), and technetium (99Tc, 99mTc), thallium (201Ti), gallium (68Ga, 67Ga), palladium (103Pd), molbdenum (99Mo), xenon ( 133Xe), fluorine (18F), 153Sm, 177Lu, 159Gd, 149Pm, 140La, 175Yb, 166Ho, 90Y, 7Sc, 186Re, 188Re, 142Pr, 05Rh, 97Ru, 68Ge, 57Co, 65Zn, 85Sr, 32P, 153Gd, 169Yb, 51Cr, 54Mn, 75Se, 113Sn, and 117Standard. In specific embodiments, the immunomodulatory proteins that can be used in the methods of the present invention can be labeled with europium. For example, immunomodulatory proteins (for example neutrokine-alpha antagonists) can be labeled with europium using the Eu DELPIA labeling kit (catalog No. 1244-302)., Perkin Elmer Life Sciences, Boston, Massachusetts), following the manufacturer's instructions. In specific embodiments, the immunomodulatory proteins are linked, for example, to chelators useful for conjugating radiometal ions, including, without limitation, 111 I, 177 L, 90 Y, 166 Ho, and 153 Sm, with polypeptides. In a preferred embodiment, the radiometal ion associated with the macrocyclic chelators attached to an immunomodulatory protein is 111ln. In another preferred embodiment, the radiometal one associated with the macrocyclic chelator bound to the immunomodulatory protein is 90Y. In specific embodiments, the macrocyclic chelator is 1, 4,7,10-tetraazacyclododecane-N, N ', N ", N'" - tetraacetic acid (DOTA). In other specific embodiments, DOTA is linked to an immunomodulatory protein by means of a linker molecule. Examples of linker molecules useful for conjugating DOTA with a polypeptide are known - see, for example, DeNardo et al., Clin Cancer Res. 4 (10): 2483-90, 1998; Peterson and others, Bioconjug. Chem. 10 (4): 553-7, 1999; and Zimmerman and others, Nucí. Med. Biol. 26 (8): 943-50, 1999, which are incorporated herein by reference in their entirety. In addition, the US patents are incorporated herein by reference in their entirety. UU Nos. 5,652,361 and 5,756,065, which describe chelating agents that can be conjugated with antibodies, and methods of preparation and use thereof. Although patents Nos. 5,652,361 and 5,756,065 focus on the conjugation of chelating agents with antibodies, one skilled in the art could easily adapt the method described therein to conjugate chelating agents with other polypeptides. In one embodiment, a immunomodulatory protein that can be used in the methods of the present invention can be labeled with biotin. Chemically modified derivatives of immunomodulatory proteins can be used in the methods of the present invention, which can provide additional advantages such as increased solubility, stability and time of in vivo or in vitro circulation of the polypeptide, or reduced immunogenicity (see US Pat. No. 4,179,337). The chemical portions to be modified can be selected from various water-soluble polymers such as polyethylene glycol, ethylene glycol / propylene glycol copolymers, carboxymethyl cellulose, dextran, polyvinyl alcohol, etc. The polypeptides can be modified at random positions within the molecule or at predetermined positions within the molecule, and can include one, two or more chemical moieties attached. The polymer can be of any molecular weight and can be branched or unbranched. For polyethylene glycol, the preferred molecular weight for ease of handling and manufacturing is between about 1 kDa and about 100 kDa (the term "about" indicates that in polyethylene glycol preparations some molecules will weigh more and others weigh less than the indicated molecular weight ). Other sizes may be used, depending on the desired therapeutic profile (e.g., the desired sustained release duration, effects on biological activity if any, ease of handling, degree or lack of antigenicity, and other known effects of polyethylene glycol for a therapeutic or analogous protein). For example, polyethylene glycol can have an average molecular weight of about 200, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000 , 9500, 10,000, 10,500, 11, 000, 11, 500, 12,000, 12,500, 13,000, 13,500, 14,000, 14,500, 15,000, 15,500, 16,000, 16,500, 17,000, 17,500, 18,000, 18,500, 19,000, 19,500, 20,000, 25,000 , 30,000, 35,000, 40,000, 50,000, 55,000, 60,000, 65,000, 70,000, 75,000, 80,000, 85,000, 90,000, 95,000, or 100,000 kDa. As indicated above, the polyethylene glycol may have a branched structure. For example, in U.S. Pat. UU No. 5,643,575; Morpurgo and others, Appl. Biochem. Biotechnol. 56: 59-72 (1996); Vorobjev et al., Nucleosides Nucleotides 18: 2745-2750 (1999); and Caliceti et al., Bioconjug. Chem. 10: 638-646 (1999), the descriptions of which are incorporated herein by reference, describe branched polyethylene glycols. The polyethylene glycol molecules (or other chemical moieties) must bind to the protein considering the effects on the functional or antigenic domains of the protein. There are several joining methods available to the person skilled in the art, for example EP 0 401 384, which is incorporated herein by reference (coupling to PEG or G-CSF); see also Malik et al., Exp. Hematol. 20: 1028-1035 (1992) (which report pegylation of GM-CSF using tresyl chloride). For example, polyethylene glycol can be covalently linked through amino acid residues by means of a reactive group, such as a free amino or carboxyl group. Reactive groups are those to which an activated polyethylene glycol molecule can be attached. Amino acid residues having a free amino group may include, for example, lysine residues and N-terminal amino acid residues; those having a free carboxyl group may include aspartic acid residues, glutamic acid residues and the C-terminal amino acid residue. Sulfhydryl groups can also be used as a reactive group to join the polyethylene glycol molecules. For binding purposes, binding to an amino group, such as N-terminal or lysine binding, is preferred. As suggested above, the polyethylene glycol can be bound to the proteins by means of a linkage with any several amino acid residues. For example, polyethylene glycol can be bound to proteins by means of covalent bonds with residues of lysine, histatin, aspartic acid, glutamic acid or cysteine. One or more reaction chemistries can be used to bind the polyethylene glycol to specific amino acid residues of the protein (eg lysine, histidine, aspartic acid, glutamic acid or cysteine), or to more than one type of amino acid residue of the protein ( for example lysine, histidine, aspartic acid, glutamic acid, cysteine, and combinations thereof). Chemically modified proteins can be specifically searched at the N-terminus. Using the polyethylene glycol as an illustration, from a variety of polyethylene glycol molecules one can select (by molecular weight, branching, etc.) the ratio of polyethylene glycol molecules to protein molecules ( or peptide) in the reaction mixture, the type of pegylation reaction to be performed, and the method for obtaining the N-terminally selected pegylated protein. The method for obtaining the N-terminally pegylated preparation (i.e., separating this portion from other mono-pegylated portions if necessary), can be by purification of the N-terminal pegylated material from a population of pegylated protein molecules. The modification of selective proteins chemically modified at the N-terminus can be carried out by reductive alkylation, which exploits the differential reactivity of the different types of primary amino groups (lysine against the N-terminus) available for modification in a particular protein. Under suitable reaction conditions, a substantially selective modification of the N-terminal protein with a polymer containing the carbonyl group can be obtained. As indicated above, the pegylation of the proteins of the invention can be effected by various methods. For example, polyethylene glycol can be attached to the protein directly or via an intermediate linker. Systems without linker for linking polyethylene glycol to proteins are described in Delgado et al., Crit. Rev. Thera. Drug Carrier Sys. 9: 249-304 (1992); Francís and others, Intern. J. of Hematol. 68: 1-18 (1998); US patent UU No. 4,002,531; US patent UU No. 5,349,052; WO 95/06058; and WO 98/32466, the disclosures of which are incorporated herein by reference. A system for linking polyethylene glycol directly to the amino acid residues of the proteins directly without an intermediate linker employs three-fold MPEG, which is produced by the modification of monomethoxy polyethylene glycol (MPEG) using tresyl chloride (CIS02CH2CF3). By the reaction of the protein with the three-layered MPEG, the polyethylene glycol binds directly to the amino groups of the protein. In this manner, the invention includes protein-polyethylene glycol conjugates produced by reacting the proteins of the invention with a polyethylene glycol molecule having a 2,2,2-trifluoroethanesulfonyl group. Polyethylene glycol can also be bound to proteins using several different intermediate linkers. For example, the US patent. UU No. 5,612,460, the entire disclosure of which is incorporated herein by reference, discloses urethane linkers for linking polyethylene glycol to proteins. Protein-polyethylene glycol conjugates can also be produced in which the polyethylene glycol is bound to the protein by means of a linker, by reaction of the protein with compounds such as MPEG-succinimidylsuccinate, MPEH activated with 1,1 '-carbonyldiimidazole, MPEG-2,4,5-trichlorophenylcarbonate, MPEG-p-nitrophenol carbonate, and various MPEG-succinate derivatives. Several more polyethylene glycol derivatives and reaction chemistries for linking polyethylene glycol to proteins are described in WO 98/32466, the complete disclosure of which is incorporated herein by reference. The pegylated protein products produced using the reaction chemistries set forth herein are included within the scope of the invention. The number of polyethylene glycol moieties attached to each protein of the invention (i.e., the degree of substitution) may also vary. For example, the pegylated proteins of the invention may be linked on average to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 17, 20, or more polyethylene glycol molecules. Similarly, the average degree of substitution within scales such as 1-3, 2-4, 3-5, 4-6, 5-7, 6-8, 7-9, 8-10, 9-11, 10- 12, 11-13, 12-14, 13-15, 14-16, 15-17, 16-18, 17-19, or 18-20 portions of polyethylene glycol per protein molecule. Methods for determining the degree of substitution are discussed, for example, in Delgado et al., Crit. Rev. Thera. Drug Carrier Sys. 9: 249-304 (1992). Immunomodulatory proteins that can be used in the methods of the present invention can be recovered and purified by known methods including, without limitation, ammonium sulfate or ethanol precipitation, acid extraction, anion exchange or cation chromatography, Phosphocellulose, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. High performance liquid chromatography ("HPLC") is most preferably used for purification.

Formulations and administration The invention provides methods of treatment, inhibition and prophylaxis, by administering an effective amount of a pharmaceutical composition comprising an immunomodulatory agent, such as a Neutrocin-alpha antagonist, to a subject. In a specific embodiment, the Neutrocin-alpha antagonist is an anti-Neutrocin-alpha antibody. In a specific embodiment, the Neutrocin-alpha antagonist is a TACI-Fc protein. In a specific embodiment, the Neutrocin-alpha antagonist is a BAFF-R-Fc protein. In a specific embodiment, the Neutrocin-alpha antagonist is an anti-Neutrocin-alpha antibody peptide. In a specific embodiment, the Neutrocin-alpha antagonist is a fragment or protein variant of Neutrocin-alpha that functions as a dominant negative. In a preferred embodiment, the immunomodulatory agent is substantially purified (e.g. substantially free of substances that limit its effect or produce undesirable side effects). The subject is preferably an animal, which includes without limitation animals such as cows, pigs, horses, chickens, cats, dogs, etc., preferably a mammal, preferably a human. An immunomodulatory agent will be formulated and dosed in a manner consistent with good medical practice, taking into account the clinical condition of the individual patient (especially the side effects of treatment with the immunomodulatory agent alone), the site of delivery of the composition containing the agent immunomodulator, the method of administration, the administration schedule, and other factors known to physicians. Thus, the "therapeutically effective amount" of an immunomodulatory agent for the purposes of the present is determined by means of said considerations. Various delivery systems are known and can be used to administer a pharmaceutical composition comprising an immunomodulatory agent, for example, encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the compound, receptor-mediated endocytosis (see, for example, Wu and Wu, J. Biol. Chem. 262: 4429-4432 (1987)), construction of a nucleic acid as part of a retroviral vector or other vector, etc. Methods of introduction include, without limitation, the intradermal, intraular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. A pharmaceutical composition comprising an immunomodulatory agent can be administered by any convenient route, for example, by infusion or bolus injection, by absorption through the epithelial or mucocutaneous coatings (e.g., oral, rectal and intestinal mucosa, etc.) , and can be administered together with other biologically active agents. The administration can be systemic or local. In addition, it may be desirable to introduce pharmaceutical compositions comprising an immunomodulatory agent into the central nervous system by any suitable route, including intraventricular and intrathecal injection; Intraventricular injection can be facilitated by the use of an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir. Pulmonary administration can also be used, for example, by an inhaler or nebulizer, and formulation with a spray agent. In a specific embodiment, the present invention is directed to pharmaceutical formulations of therapeutic agents (e.g., immunomodulatory agents known in the art or described herein). In particular, the present invention is directed to pharmaceutical formulations of therapeutic agents that are proteinaceous in nature (eg, proteins and antibodies). A pharmaceutical formulation of the invention contains pharmaceutically acceptable excipients. In general, a pharmaceutical formulation of the invention is formulated in such a way that a therapeutic agent retains its physical activity, chemical and biological. A pharmaceutical formulation of the invention can be stored at the appropriate temperatures. For example, a pharmaceutical formulation of the invention can be stored at 2-8 ° C, at -40 ° C, or at -80 ° C. In a specific embodiment, a stable formulation is one in which less than about 1% aggregation of the therapeutic agent is observed for 2 years, less than about 1% of oxidation of the therapeutic agent is observed for 2 years, or less than about 4% deamidation of the therapeutic agent is observed for 2 years. The amount of therapeutic agent present in a pharmaceutical formulation of the invention is determined for example by taking into account the desired dose volumes and modes of administration. In one embodiment of the invention, the concentration of therapeutic agent in a pharmaceutical formulation of the invention is about 1-160 mg / ml, about 10-155 mg / ml, about 20-150 mg / ml, about 30-145 mg / ml, approximately 40-140 mg / ml, approximately 50-135 mg / ml, approximately 60-130 mg / ml, approximately 70-125 mg / ml, approximately 80-120 mg / ml, approximately 90-115 mg / ml , approximately 95-110 mg / ml, approximately 100-105 mg / ml, or approximately 100 mg / ml. Intermediate scales of the aforementioned concentrations, for example about 11-154 mg / ml, are also considered part of the invention. For example, scales of values with a combination of any of the above-mentioned values as upper or lower limits are considered included. In this context, "approximately" includes the scales particularly cited, and scales that are larger or smaller by several mg (5, 4, 3, 2 or 1) mg / ml, at the upper or lower limits of the scale. The aqueous pharmaceutical formulations of the invention comprise a buffer solution for pH. In one embodiment of the invention, the buffer used in the pharmaceutical formulations of the invention has a pH ranging from about 5 to about 7. In a preferred embodiment, the buffer used in the pharmaceutical formulations of the invention has a pH that varies from approximately 5.8 to approximately 6.2. In another preferred embodiment, the buffer used in the pharmaceutical formulations of the invention has a pH of about 6.0. The intermediate scales of the aforementioned pH's are considered part of the invention. For example, scales of values with a combination of any of the above-mentioned values as upper or lower limits are considered included. In this context, "approximately" includes the scales particularly cited, and scales that are larger or smaller in 0.5, 0.4, 0.3, 0.2, or 0.1 pH units, at the upper or lower limits of the scale. Examples of buffers that will control pH within the preferred ranges include acetate (for example sodium acetate), succinate (for example sodium succinate), gluconate, histidine, citrate, Tris, phosphate, glycylglycine and other organic acid buffers. Additional exemplary buffers are pharmaceutically acceptable and can be made from suitable acids, bases and salts thereof, such as those defined below. The pharmaceutically acceptable acids include organic and inorganic acids that are innocuous to the concentration and form in which they are formulated. For example, suitable inorganic acids include hydrochloric, perchloric, hydrobromic, hydroiodic, nitric, sulfuric, sulfonic, sulfinic, sulfanilic, phosphoric, carbonic, etc. Suitable organic acids include straight and branched chain alkyl, aromatic, cyclic, cycloaliphatic, arylaliphatic, heterocyclic, saturated, unsaturated, mono-, di- and tri-carboxylic acids, including, for example, formic, acetic acid, 2- hydroxyacetic, trifluoroacetic, phenylacetic, trimethylacetic, t-butylacetic, anthranilic, propanoic, 2-hydroxypropanoic, 2-oxopropanoic, propandioic, cyclopentanepropionic, cyclopentanepropionic, 3-phenylpropionic, butanoic, butanedioic, benzoic, 3- (4-hydroxybenzoyl) benzoic, 2-acetoxy-benzoic, ascorbic, cinnamic, lauryl-sulfuric, stearic, muconic, mandelic, succinic, embonic, fumaric, malic, maleic, hydroximic, malonic, lactic, citric, tartaric, glycolic, glyconic, gluconic, pyruvic, glyoxal, oxalic, mesylic, succinic, salicylic, phthalic, pamoic, palmic, thiocyanic, methanesulfonic, ethanesulfonic, 1,2-ethanedisulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 4-chorobenzenesulfonic, naphalene-2-sulphonic, p-toluenesulfonic, camphorsulfonic, 4-methylbicyclo [2.2.2] -oct -2-en-1 -carboxylic, glucoheptonic, 4,4'-methylenebis-3- (hydroxy-2-ene-1-carboxylic), hydroxynaphthoic, etc. The pharmaceutically acceptable bases include organic and inorganic bases which are innocuous to the concentration and form in which they are formulated. For example, suitable bases include those formed of metals forming inorganic bases, such as lithium, sodium, potassium, magnesium, calcium, ammonium, iron, zinc, copper, manganese, aluminum, N-methylglucamine, morpholine, piperidine, and bases harmless organic compounds including primary, secondary and tertiary amines, substituted amines, cyclic amines and basic ion exchange resins [e.g., N (R ') 4+ (wherein R' is independently H or C? - alkyl, example, ammonium, Tris)], eg, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine , methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred harmless organic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline, and caffeine. Additional pharmaceutically acceptable acids and bases which are usable in the present invention are those derived from amino acids, for example, histidine, glycine, phenylalanine, aspartic acid, glutamic acid, lysine and asparagine. Pharmaceutically acceptable buffers include those derived from acid and base addition salts of the acids and bases indicated above. In one embodiment of the invention, the buffer of a pharmaceutical formulation of the invention is succinate, histidine, citrate or phosphate. In a preferred embodiment, the buffer of a pharmaceutical formulation of the invention is histidine. In another preferred embodiment, the buffer of a pharmaceutical formulation of the invention is citrate. In another embodiment of the invention, the concentration of buffer is a pharmaceutical formulation of the invention is about 5-50 mM, about 5-20 mM, about 5-15 mM, or about 10 mM. Intermediate scales of the aforesaid concentrations, for example about 6-48 mM, are also considered part of the invention. For example, value scales with a combination of any of the aforementioned values as upper or lower limit are considered included. In this context, "approximately" includes scales particularly cited, and scales that are larger or smaller by several mM (5, 4, 3, 2, or 1), at the upper or lower limit of the scale. A surfactant may also be added to the pharmaceutical formulation of the invention. Exemplary surfactants include nonionic surfactants such as polysorbates (for example polysorbate 20 or 80) or poloxamers (for example poloxamer 188). Other pharmaceutically acceptable surfactants are well known and are also contemplated. In a specific embodiment, an amount of surfactant is added in an amount sufficient to reduce the aggregation of a therapeutic agent (such as that which occurs by agitation or delivery), to minimize the formation of particles in a pharmaceutical formulation of the invention, or to reduce the non-specific adsorption of a therapeutic agent. In a preferred embodiment, a pharmaceutical formulation of the invention includes a surfactant agent that is a polysorbate. In a preferred embodiment, a pharmaceutical formulation of the invention contains the surfactant agent polysorbate 20. In a preferred embodiment, a pharmaceutical formulation of the invention contains between 0.005% methylnaltrexone and about 0.07% polysorbate 20. In another preferred embodiment, a pharmaceutical formulation of the invention contains between about 0.01% and about 0.05% polysorbate 20. In another preferred embodiment, a pharmaceutical formulation of the invention contains between about 0.01% and about 0. 03% polysorbate 20. In another preferred embodiment, it is found about 0.01% polysorbate 20 in a pharmaceutical formulation of the invention. In this context, "approximately" includes the scales particularly mentioned, and the scales that are greater or lesser in 0.01%, 0.009%, 0.008%, 0.007%, 0.006% or 0.005% in the upper or lower limit of the scale, with the condition that the percentage of polysorbate 20 is not less than 0.007%. In another preferred embodiment, a pharmaceutical formulation of the invention contains the surfactant polysorbate 80. In a preferred embodiment, a pharmaceutical formulation of the invention contains between about 0.0015% and about 0.07% polysorbate 80. In another preferred embodiment, a pharmaceutical formulation of the invention contains between about 0.003% and about 0.05% polysorbate 80. In another preferred embodiment, a pharmaceutical formulation of the invention contains between about 0.005% and about 0.03% polysorbate 80. In another preferred embodiment, a pharmaceutical formulation of the invention contains between about 0.01% and about 0.03% polysorbate 80. In another preferred embodiment, about 0.01% polysorbate 80 is found in a pharmaceutical formulation of the invention. In this context, "approximately" includes the scales particularly mentioned, and the scales that are greater or lesser in 0.01%, 0.009%, 0.008%, 0.007%, 0.006% or 0.005% in the upper or lower limit of the scale, with the condition that the percentage of polysorbate 80 is not less than 0.0015%. A tonicity modifier can also be added to a pharmaceutical formulation of the invention. Useful tonicity modifiers include salts and amino acids. Salts that are pharmaceutically acceptable and suitable for pharmaceutical formulations of the invention include sodium chloride, sodium succinate, sodium sulfate, potassium chloride, magnesium chloride, magnesium sulfate, and calcium chloride. Preferred salts for use in the pharmaceutical formulations of the invention are NaCl and MgCl 2; NaCl can improve the stability of a therapeutic agent by protecting the deamidation and aggregation agent. In a preferred embodiment, a pharmaceutical formulation of the invention contains NaCl. In another preferred embodiment, a pharmaceutical formulation of the invention contains between about 150 and about 500 mM NaCl. In another preferred embodiment, a pharmaceutical formulation of the invention contains approximately 150 mM NaCl. In this context, "approximately" includes the scales cited in particular and scales that are greater or lesser in 1, 2, 3, 4, 5, 10, 25 or 50 mM, at the upper or lower limit of the scale. In a preferred embodiment, the pharmaceutical formulations of the invention are isotonic. By isotonic it is understood that a pharmaceutical formulation of the invention has essentially the same osmotic pressure as human blood. Isotonic formulations will generally have an osmotic pressure of from about 250 to about 350 mOsm, preferably from about 290 to about 310 mOsm. In this context, "approximately" includes the scales cited in particular and scales that are higher or lower in several mOsm (5, 4, 3, 2 or 1) at the upper or lower limit of the scale. Isotonicity can be measured using an osmometer of the vapor pressure type or the freezing type with ice. In one embodiment, a pharmaceutical formulation of the invention contains the above-identified agents (ie, the therapeutic agent, buffer, surfactant and tonicity modifier), and is essentially free of one more preservatives such as benzyl alcohol, phenol, m-cresol, clortobutanol and benzethonium chloride. In another embodiment, a preservative may be included in a pharmaceutical formulation of the invention, particularly when the formulation is a multidose formulation. One or more other pharmaceutically acceptable excipients, carriers or stabilizers, such as those described in "Remington's Pharmaceutical Sciences" 16th edition, Osol, A. Ed. (1980), may be included in a pharmaceutical formulation of the invention, provided that no adversely affect the desired characteristics of the formulation. Acceptable excipients, carriers or stabilizers are harmless to recipients at the doses and concentrations used and include: additional buffering agents; cosolvents; antioxidants that include ascorbic acid and methionine; chelating agents such as EDTA; metal complexes (eg, Zn-protein complexes); biodegradable polymers such as polyesters: preservatives; cryoprotectants; lyoprotectants; volume agents, and the like. Examples of suitable cryoprotectants include polyols, polyethylene glycol (PEG), bovine serum albumin (BSA), glutamic acid, other amino acids, and the like. Additional suitable cryoprotective agents include sugars and sugar alcohols such as sucrose, mannose, trehalose, glucose, sorbitol, mannitol, and the like. Suitable lyoprotectants may include sugars including sucrose, trehalose, lactose, maltose, and the like. Suitable volume agents include mannitol, glycine, sorbitol, and the like. In a specific embodiment, a pharmaceutical formulation of the invention does not comprise a cryoprotectant. In a further embodiment, a pharmaceutical formulation of the invention does not comprise sucrose. EDTA, which is commonly used to stabilize a protein formulation, can also be included in a pharmaceutical formulation of the invention. EDTA, as a chelating agent, can inhibit the metal-catalyzed oxidation of the sulfhydryl groups, thereby reducing the formation of disulfide-linked aggregates. A preferred concentration of EDTA is from about 0.01% to about 0.2%. A pharmaceutical formulation of the invention can also be combined with one or more other therapeutic agents as necessary for the particular indication to be treated, preferably those with complementary activities that do not adversely affect a therapeutic agent in a pharmaceutical formulation of the invention. Combinations are contemplated wherein the additional therapeutic agents are formulated as a mixture with the immunomodulatory agents. In addition, combinations are contemplated wherein the additional therapeutic agents are formulated independently but are intended for simultaneous or overlapping administration with an immunomodulatory agent. Such additional therapeutic agents are present in combination, conveniently in amounts that are effective for the intended purposes. Additional therapeutic agents that can be combined with the formulation of the invention are additionally described herein. The present invention provides, in a preferred embodiment, a pharmaceutical formulation comprising, or alternatively consisting of, 10 mM histidine buffer, 150 mM NaCl and 0.01% polysorbate 80, pH 6.0 (± 0.5). In another preferred embodiment, a pharmaceutical formulation of the invention comprises or alternatively consists of, an antibody in an amount of about 1 mg / ml to about 160 mg / ml, preferably about 80 mg / ml to about 120 mg / ml, 10 mM histidine buffer, 150 mM NaCl and 0.01% polysorbate 80, pH 6.0 (± 0.5). In another preferred embodiment, a pharmaceutical formulation of the invention for intravenous administration comprises, or alternatively consists of, an antibody in an amount of about 1 mg / ml to about 160 mg / ml, preferably about 80 mg / ml to about 120 mg / ml, 10 mM histidine buffer, 150 mM NaCl, and 0.01% polysorbate 80, pH 6.0 (± 0.5). In another preferred embodiment, a pharmaceutical formulation of the invention for subcutaneous administration comprises, or alternatively consists of, an antibody in an amount of about 1 mg / ml to about 160 mg / ml, preferably about 80 mg / ml to about 120. mg / ml, 10 mM histidine buffer, 150 mM NaCl, and 0.01% polysorbate 80, pH 6.0 (± 0.5). In this context, "approximately" includes scales particularly cited, and scales that are greater or lesser by several mg / ml (5, 4, 3, 2, or 1), at the upper or lower limit of the scale. In a preferred embodiment, a pharmaceutical formulation of the invention comprises, or alternatively consists of, 100 mg / ml of an antibody, 10 mM of histidine buffer, 150 mM of NaCl, and 0.01% of polysorbate 80, pH 6.0 (± 0.5. ). In another preferred embodiment, a pharmaceutical formulation of the invention for intravenous administration comprises, or alternatively consists of, 100 mg / ml of an antibody, 10 mM of histadine buffer, 150 mM of NaCl, and 0.01% of polysorbate 80, pH 6.0 (± 0.5). In another preferred embodiment, a pharmaceutical formulation of the invention for subcutaneous administration comprises, or alternatively consists of, 100 mg / ml of an antibody, 10 mM histidine buffer, 150 mM NaCl, and 0.01% polysorbate 80, pH 6.0 (± 0.5). The present invention provides, in a preferred embodiment, a pharmaceutical formulation comprising, or alternatively consisting of, 0.74 mg / ml of L-histidine, 1.1 mg / ml of L-histidine monohydrochloride, 8.8 mg / ml of NaCl, and 0.1 mg / ml polysorbate 80, pH 6.0 (± 0.5). In another preferred embodiment, a pharmaceutical formulation of the invention comprises, or alternatively consists of, an antibody in an amount of about 1 mg / ml to about 160 mg / ml, preferably about 80 mg / ml to about 120 mg / ml. , 0.74 mg / ml of L-histidine, 1.1 mg / ml of L-histidine monohydrochloride, 8.8 mg / ml of NaCl, and 0.1 mg / ml of polysorbate 80, pH 6.0 (± 0.5). In another preferred embodiment, a pharmaceutical formulation of the invention for intravenous administration comprises, or alternatively consists of, an antibody in an amount of about 1 mg / ml to about 160 mg / ml, preferably about 80 mg / ml to about 120 mg / ml, 0.74 mg / ml L-histidine, 1.1 mg / ml monohydrochloride L-histidine, 8.8 mg / ml of NaCl, and 0.1 mg / ml of polysorbate 80, pH 6.0 (± 0.5). In another preferred embodiment, a pharmaceutical formulation of the invention for subcutaneous administration comprises, or alternatively consists of, an antibody in an amount of about 1 mg / ml to about 160 mg / ml, preferably about 80 mg / ml to about 120. mg / ml, 0.74 mg / ml of L-histidine, 1.1 mg / ml of L-histidine monohydrochloride, 8.8 mg / ml of NaCl, and 0.1 mg / ml of polysorbate 80, pH 6.0 (± 0.5). In this context, "approximately" includes scales particularly cited, and scales that are greater or lesser by several mg / ml (5, 4, 3, 2, or 1), at the upper or lower limit of the scale.

In a preferred embodiment, a pharmaceutical formulation of the invention comprises, or alternatively consists of, 100 mg / ml of an antibody, 0.74 mg / ml of L-histidine, 1.1 mg / ml of L-histidine monohydrochloride, 8.8 mg / ml of NaCl, and 0.1 mg / ml of polysorbate 80, pH 6.0 (± 0.5). In another preferred embodiment, a pharmaceutical formulation of the invention for intravenous administration comprises, or alternatively consists of, 100 mg / ml of an antibody, 0.74 mg / ml of L-histidine, 1.1 mg / ml of L-histidine monohydrochloride, 8.8 mg / ml of NaCl, and 0.1 mg / ml of polysorbate 80, pH 6.0 (± 0.5). In another preferred embodiment, a pharmaceutical formulation of the invention for subcutaneous administration comprises, or alternatively consists of, 100 mg / ml of an antibody, 0.74 mg / ml of L-histidine, 1.1 mg / ml of L-histidine monohydrochloride, 8.8 mg / ml of NaCl, and 0.1 mg / ml of polysorbate 80, pH 6.0 (± 0.5). In a preferred embodiment, the antibody in a pharmaceutical formulation of the invention a monoclonal antibody. In another preferred embodiment, the antibody in a pharmaceutical formulation of the invention is an IgG antibody. In another preferred embodiment, the antibody in a pharmaceutical formulation of the invention is an IgG1 antibody. In another preferred embodiment, the antibody in a pharmaceutical formulation of the invention is an IgG1 /? Antibody. In another preferred embodiment, the antibody in a pharmaceutical formulation of the invention is a human or humanized antibody. In a preferred embodiment, a pharmaceutical formulation of the invention is stable for at least 6 months at 2-8 ° C. In another preferred embodiment, a pharmaceutical formulation of the invention is stable for at least 9 months at 2-8 ° C. C. In another preferred embodiment, a pharmaceutical formulation of the invention is stable for at least 1 year at 2-8 ° C. In another preferred embodiment, a pharmaceutical formulation of the invention is stable for at least 1.5 years at 2- 8 ° C. In another preferred embodiment, a pharmaceutical formulation of the invention is stable for at least 2 years at 2-8 ° C. In another preferred embodiment, a pharmaceutical formulation of the invention is stable for at least 3 years at 2-8 ° C. In another preferred embodiment, a pharmaceutical formulation of the invention is stable for at least 4 years at 2-8 ° C. In another preferred embodiment, a pharmaceutical formulation of the invention is stable for at least At least 5 years at 2-8 ° C. In a preferred embodiment, an antibody in a pharmaceutical formulation of the invention can exhibit significant stability during repeated freeze-thaw cycles, and after said treatment can remain stable after being thawed. . In general, a formulation designed to be rapidly frozen is frozen, for example, in liquid nitrogen. Thawing can be at a temperature range, for example from about 0 ° C to about 25 ° C, which is slow thawing; or from about 26 ° C to 40 ° C, which is rapid thawing. In this context, "approximately" includes scales particularly cited, and scales that are greater or lesser in several degrees Celsius (5, 4, 3, 2, or 1) at the upper or lower limit of the scale. An example of rapid thawing is the thawing of a pharmaceutical formulation of the invention in a water bath at 37 ° C. In a preferred embodiment, an antibody in a pharmaceutical formulation of the invention is stable during at least one freeze-thaw cycle. In another preferred embodiment, an antibody in a pharmaceutical formulation of the invention is stable for at least two freeze-thaw cycles. In another preferred embodiment, an antibody in a pharmaceutical formulation of the invention is stable for at least three freeze-thaw cycles. In another preferred embodiment, an antibody in a pharmaceutical formulation of the invention is stable for at least four freeze-thaw cycles. In another preferred modality, an antibody in a pharmaceutical formulation of the invention is stable for at least five freeze-thaw cycles. In another preferred embodiment, an antibody in a pharmaceutical formulation of the invention is stable for at least ten freeze-thaw cycles. It may be convenient to determine an optimal freeze-thaw rate of a pharmaceutical formulation of the invention to preserve stability, or it may be convenient to identify a pharmaceutical formulation of the invention that provides the greatest stability for an antibody that will be subjected to a particular freeze-thaw cycle. Accordingly, in one embodiment of the invention this parameter is determined. For example, a pharmaceutical formulation of the invention can be analyzed for stability under a variety of freeze-thaw conditions, such as rapid freezing, slow freezing, rapid thawing, slow thawing, in various combinations, to determine the procedure that will produce the least amount of degradation products (for example, that has the greatest stability). A concentration study has shown that an IgG1 /? it can be concentrated to at least 160 mg / ml in a pharmaceutical formulation of the invention comprising 10 mM histidine buffer, 150 mM NaCl, and 0.01% polysorbate 80, pH 6.0, without deleterious effects on purity (determined by SEC-HPLC) and aggregation (no particle formation was observed) (data not shown). In addition, an increase in viscosity was observed with the concentration. As the viscosity increases, the administration difficulties increase. Studies have shown that samples with viscosities less than 7.75 cP can be easily injected through a 30G 1.25 cm needle in less than 10 seconds. As shown in Table X, even at a IgG1 /? Antibody concentration. of 160 mg / ml, the viscosity of the pharmaceutical formulation is less than 7.75 cP and therefore still easily injected by means of a syringe.

TABLE X Viscosity as a function of IgG1 antibody concentration /? To use the formulations for in vivo administration, they should preferably be sterile. This is easily achieved by filtration through sterile filtration membranes before or after the preparation of the formulation. In a preferred embodiment, the antibody of the invention is formulated in 10 mM sodium citrate, 1.9% glycine, 0.5% sucrose, 0.01% polysorbate 80, pH 6.5 (± 0.3). In another preferred embodiment, the antibody of the invention is formulated for intravenous administration in 10 mM sodium citrate, 1.9% glycine, 0.5% sucrose, 0.01% polysorbate 80, pH 6.5 (± 0.3). In a preferred embodiment, the antibody of the invention is formulated in 10 mM sodium citrate, 8% sucrose, 0.04% (w / v) polysorbate 80 (pH 6.5) (± 0.3). In another preferred embodiment, the antibody of the invention is formulated for intravenous administration in 10 mM sodium citrate, 8% sucrose, 0.04% (w / v) polysorbate 80 (pH 6.5). In another preferred embodiment, the antibody of the invention is formulated for subcutaneous administration in 10 mM sodium citrate, 8% sucrose, 0.04% (w / v) polysorbate 80 (pH 6.5). Generally the formulations are prepared by contacting the neutrokine-alpha antagonist or other immunomodulatory agent known or described herein, uniformly and intimately with liquid carriers or finely divided solid carriers, or both. Then, if necessary, the product is given the desired pharmaceutical form.

Preferably, the vehicle is a parenteral vehicle, preferably a sotonic solution with the blood of the recipient. Examples of such vehicles include water, Ringer's solution and dextrose solution. Also useful herein are non-aqueous vehicles such as fixed oils and ethyl oleate, and also liposomes. The vehicle conveniently contains minor amounts of additives such as substances that increase the sotonicity and chemical stability. Such materials are harmless to the recipients at the doses and concentrations used and include buffers such as phosphate, citrate, succinate, acetic acid and other organic acids or their salts; antioxidants such as ascorbic acid; low molecular weight polypeptides (less than about 10 residues), for example polyarginine or tripeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinyl pyrrolidone; amino acids such as glycine, glutamic acid, aspartic acid, or arginine; monosaccharides, disaccharides or other carbohydrates including cellulose or its derivatives, glucose, mannose, sucrose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counterions such as sodium; preservatives such as cresol, phenol, chlorobutanol, benzyl alcohol and parabens, or nonionic surfactants such as polysorbates, poloxamers or PEG. Compositions comprising immunomodulatory polypeptides are normally formulated in such vehicles at a concentration of from about 0.001 mg / ml to 100 mg / ml, or from 0.1 mg / ml to 100 mg / ml, preferably 1-10 mg / ml or 1-10. mg / ml, at a pH of about 3 to 10, or 3 to 8, preferably 5-8, most preferably 6-7. It will be understood that the use of the above excipients, vehicles or stabilizers will result in the formation of salts of the polypeptide. Most preferably, the compositions for use in therapeutics are sterile. Sterility is easily achieved by filtration through sterile filtration membranes (eg, 0.2 micron membranes). The therapeutic compositions are generally placed in a container having a sterile access port, for example an intravenous solution bag or a bottle having a pierceable plug with a hypodermic injection needle.

Pharmaceutical compositions comprising immunomodulatory agents that can be used in the methods of the present invention will ordinarily be stored in single dose or multiple dose containers., for example, sealed vials or flasks, as an aqueous solution or as a lyophilized formulation for reconstitution. As an example of a lyophilized formulation, 10 ml bottles are filled with 5 ml of an aqueous solution of sterilized 1% (w / v) neutrocine polypeptide by filtration, and the resulting mixture is lyophilized. The infusion solution is prepared by reconstituting the lyophilized neutrokine-alpha polypeptide using bacteriostatic injectable water. Alternatively, pharmaceutical compositions comprising the immunomodulatory agents that can be used in the methods of the present invention are stored in individual dose containers in lyophilized form. The infusion solution is reconstituted using a sterile injectable vehicle. In specific embodiments, the immunomodulatory agents that can be used in the present invention are radiolabelled polypeptides such as a radiolabeled form of neutrocine-alpha or anti-CD20 antibody. Said pharmaceutical compositions comprising radiolabelled molecules can also comprise radioprotectors and plasma expanders such as sodium ascorbate, gentran 40 and glycerol. In specific embodiments, compositions that can be used in the methods of the present invention comprise iodinated forms of neutrophil-alpha polypeptides, or fragments or variants thereof, which are formulated in 10.0 mM sodium citrate, 140.0 mM chloride of sodium, 8.7 mM of HEPES, 4% (w / v) of sodium ascorbate, 3.3% (w / v) of Genetran-40. In specific embodiments, a composition that can be used in the methods of the present invention comprises at least 1 mg / mL of an iodinated form of amino acid residues 134-285 of SEQ ID NO: 2, 10.0 mM citrate sodium, 140.0 mM sodium chloride, 8.7 mM HEPES, 4% (w / v) sodium ascorbate, 3.3% (w / v) Gentran-40. In specific embodiments, a composition that can be used in the methods of the present invention comprises at least 2 mg / mL of an iodinated form of amino acid residues 134-285 of SEQ ID NO: 2, 10.0 mM citrate sodium, 140.0 mM sodium chloride, 8.7 mM HEPES, 4% (w / v) sodium ascorbate, 3.3% (w / v) Gentran-40. In specific embodiments, a composition that can be used in the methods of the present invention comprises at least 3 mg / mL of an iodinated form of amino acid residues 134-285 of SEQ ID NO: 2, 10.0 mM citrate sodium, 140.0 mM sodium chloride, 8.7 mM HEPES, 4% (w / v) sodium ascorbate, 3.3% (w / v) Gentran-40. In specific embodiments, a composition that can be used in the methods of the present invention comprises at least 4 mg / mL of an iodinated form of amino acid residues 134-285 of SEQ ID NO: 2, 10.0 mM citrate sodium, 140.0 mM sodium chloride, 8.7 mM HEPES, 4% (w / v) sodium ascorbate, 3.3% (w / v) Gentran-40. In specific embodiments, a composition that can be used in the methods of the present invention comprises about 4.6 mg / mL of an iodinated form of amino acid residues 134-285 of SEQ ID NO: 2, 10.0 mM of sodium citrate, 140.0 mM sodium chloride, 8.7 mM HEPES, 4% (w / v) sodium ascorbate, 3.3% (w / v) Gentran-40. In specific embodiments, a composition that can be used in the methods of the present invention comprises approximately between 0.1 mg / mL and 20 mg / mL of an iodinated form of amino acid residues 134-285 of SEQ ID NO: 2, 10.0 mM sodium citrate, 140.0 mM sodium chloride, 8.7 mM HEPES, 4% (w / v) sodium ascorbate, 3.3% (w / v) Gentran-40. In specific embodiments, a composition that can be used in the methods of the present invention comprises between 1 mg / mL and 10 mg / mL of an iodinated form of amino acid residues 134-285 of SEQ ID NO: 2, 10.0 mM of sodium citrate, 140.0 mM of sodium chloride, 8.7 mM of HEPES, 4% (w / v) of sodium ascorbate, 3.3% (w / v) of Gentran-40. In specific modalities, a composition that can be used in the methods of the present invention comprises between 2 mg / mL and 8 mg / mL of an iodinated form of amino acid residues 134-285 of SEQ ID NO: 2, 10.0 mM citrate sodium, 140.0 mM sodium chloride, 8.7 mM HEPES, 4% (w / v) sodium ascorbate, 3.3% (w / v) Gentran-40. In specific embodiments, a composition that can be used in the methods of the present invention comprises between 3 mg / mL and 6 mg / mL of an iodinated form of amino acid residues 134-285 of SEQ ID NO: 2, 10.0 mM of sodium citrate, 140.0 mM sodium chloride, 8.7 mM HEPES, 4% (w / v) sodium ascorbate, 3.3% (w / v) Gentran-40. In preferred embodiments, a composition that can be used in the methods of the present invention comprises an anti-neutrocin-alpha antibody. In other embodiments, a composition that can be used in the methods of the present invention comprises an antibody that specifically binds to neutrocine-alpha. In other embodiments, a composition that can be used in the methods of the present invention comprises an anti-neutrocin-alpha antagonist antibody. In other embodiments, a composition that can be used in the methods of the present invention comprises an antibody that specifically binds to neutrocine-alpha and neutralizes the biological activity of neutrocine-alpha. In other embodiments, a composition that can be used in the methods of the present invention comprises an anti-neutrocin-alpha antibody that binds with a recombinant neutrocin-alpha protein purified from a cell culture, wherein said recombinant neutrocin-alpha protein is encoded by a polynucleotide encoding at least amino acids 134 to 285 of SEQ ID NO: 2. In other embodiments, a composition that can be used in the methods of the present invention comprises an antibody that specifically binds to neutrocin-alpha, wherein said antibody binds to a purified recombinant neutrocin-alpha protein from a cell culture, wherein said recombinant neutrocin-alpha protein is encoded by a polynucleotide encoding at least amino acids 134 to 285 of SEQ ID NO: 2.

The pharmaceutical compositions containing immunomodulatory agents can be administered orally, rectally, parenterally, subcutaneously, intracisternally, intravaginally, intraperitoneally, topically (for example as powders, ointments, drops or transdermal patches), buccally, or as an atomization oral or nasal (for example by inhaling a vapor or powder). The term "parenteral," as used herein, refers to modes of administration that include intravenous, intramuscular, intraperitoneal, intracisternal, subcutaneous, and intraarticular injection and infusion. In a preferred embodiment, compositions containing immunomodulatory agents are administered subcutaneously. In another preferred embodiment, the compositions containing the immunomodulatory agents are administered intravenously. The compositions containing immunomodulatory agents can also be administered by sustained release systems. Suitable examples of sustained release compositions include suitable polymeric materials (such as for example semi-permeable polymer matrices in the form of shaped articles, for example films or microcapsules), suitable hydrophobic materials (for example as an emulsion in an acceptable oil) or resins. of ion exchange, and sparingly soluble derivatives (such as for example a sparingly soluble salt). Sustained-release matrices include polylactides (U.S. Patent No. 3,773,919, EP 58,481), or polymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman, U. et al., Biopolymers 22: 547- 556 (1983)), poly (2-hydroxyethyl methacrylate) (R. Langer et al., J. Biomed, Mater. Res. 15: 167-277 (1981), and R. Langer, Chem. Tech. 12: 98-105. (1982)), ethylene vinyl acetate (R. Langer et al., Id.), Or poly-D - (-) - 3-hydroxybutyric acid (EP 133,988). In a specific embodiment, compositions containing immunomodulatory agents are formulated in a biodegradable polymeric drug delivery system, for example as described in US Pat. UU Nos. 4,938,763; 5,278,201; 5,278,202; 5,324,519; 5,340,849; and 5,487,897, and in international publications Nos. WO01 / 35929, WO00 / 24374, and WO00 / 06117, which are incorporated herein by reference in their entirety. In specific embodiments, compositions containing immunomodulatory agents are formulated using the ATRIGEL® Biodegradable system from Atrix Laboratories, Inc. (Fort Collins, Colorado). In other specific embodiments, compositions containing immunomodulatory agents are formulated using the ProLease® sustained release system, available from Alkermes, Inc. Cambridge, Massachusetts). Examples of biodegradable polymers that may be used in pharmaceutical formulations include, without limitation, polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polycarbonates, polycarbonates, polyoxycarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerate, polyalkylene oxalates, polyalkylene succinates, poly (malic acid), poly (amino acids), poly (methyl vinyl ether), poly (maleic anhydride), polyvinyl pyrrolidone, polyethylene glycol, polyhydroxy cellulose, chitin, chitosan, and copolymers, terpolymers, or combinations or mixtures of the above materials . Preferred polymers are those that have a lower degree of crystallization and are more hydrophobic. These polymers and copolymers are more soluble in biocompatible solvents than highly crystalline polymers such as polyglycolide and chitin, which also have a high degree of hydrogen bonding. Preferred materials with the desired solubility parameters are polylactides, polycaprolactones and copolymers thereof with glycolide in which there are more amorphous regions to increase solubility. In specific preferred embodiments, the biodegradable polymers that can be used in the formulation of compositions containing immunomodulatory agents are poly (lactide-co-glycolides). The properties of polymers, such as molecular weight, hydrophobicity and lactide / glycolide ratio can be modified to obtain the desired drug release profile (see for example Ravivarapu et al., Journal of Pharmaceutical Sciences 89: 732-741 (2000), which is incorporated herein) as a whole reference It is also preferred that the solvent for the biodegradable polymer be harmless, water-miscible and otherwise biocompatible Examples of such solvents include, without limitation, N-methyl-2-pyrrolidone, 2- pyrrolidone, C2 to C6 alkanols, C1 to C15 alcohols, diols, triols, and tetraols, such as ethanol, glycerin, propylene glycol, butanol; C3 to C15 alkyl ketones such as acetone, diethyl ketone and methyl ethyl ketone; esters of C3 to C15 such as methyl acetate, ethyl acetate ethyl lactate; alkylketones such as methyl ethyl ketone, C1 to 15 amides such as dimethylformamide, dimethylacetamide and caprolactam; C3 to C20 ethers such as tetrahydrofuran or solketal; tweens, triacetin, propylene carbonate, decylmethyl sulfoxide, dimethyl sulfoxide, oleic acid, 1-dodecylazacycloheptan-2-one. Other preferred solvents are benzyl alcohol, benzyl benzoate, dipropylene glycol, tributyrin, ethyl oleate, glycerin, glyofural, isopropyl myristate, isopropyl palmitate, oleic acid, polyethylene glycol, propylene carbonate and triethyl citrate. The most preferred solvents are N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, triacetin and propylene carbonate, due to their solvation and compatibility ability. Additionally, formulation compositions containing immunomodulatory agents and a biodegradable polymer may also include release rate modifying agents or pore forming agents. Examples of release rate modifying agents include, without limitation, fatty acids, triglycerides, other similar hydrophobic compounds, organic solvents, plasticizer compounds, and hydrophilic compounds. Suitable release rate modifying agents include, for example, esters of mono-, di-, and tri-carboxylic acids, such as 2-ethoxyethyl acetate, methyl acetate, ethyl acetate, diethyl phthalate, dimethyl phthalate. dibutyl phthalate, dimethyl adipate, dimethyl succinate, dimethyl oxalate, dimemethyl citrate, triethyl citrate, acetyl tributyl citrate, acetyltrietyl citrate, glycerol triacetate, di (n-butyl) cebacate, etc .; polyhydric alcohols such as propylene glycol, polyethylene glycol, glycerin, sorbitol etc .; fatty acids; glycerol triesters, such as triglycerides, epoxidized soybean oil, and other epoxidized vegetable oils; sterols such as cholesterol; alcohols such as C6-C12 alkanols, 2-ethoxyethanol, etc. The release rate modifying agent can be used individually or in combination with other of these agents. Suitable combinations of release rate modifying agents include, without limitation, glycerin / propylene glycol, sorbitol / glycerin, ethylene oxide / propylene oxide, butylene glycol / adipic acid, etc. Preferred release rate modifying agents include, without limitation, dimethyl citrate, triethyl citrate, ethyl heptanoate, glycerin and hexanediol. Suitable pore formers that can be used in the polymer composition include, without limitation, sugars such as sucrose and dextrose, salts such as sodium chloride and sodium carbonate, polymers such as hydroxypropylcellulose, carboxymethylcellulose, polyethylene glycol and polyvinylpyrrolidone. Solid crystals that provide a defined pore size, such as a salt or sugar, are preferred. In specific embodiments, compositions containing immunomodulatory agents are formulated using the BEMA ™ BioErodible mucoadhesive system, the MCA ™ mucocutaneous absorption system, the SMP ™ solvent microparticle system, or the BCP ™ biocompatible polymer system from Atrix Laboratories, Inc. . (Fort Collins, Colorado). Sustained-release compositions also include compositions entrapped in liposomes (see, in general, Langer, Science 249: 1527-1533 (1990); Treat et al., In "Liposomes in the Therapy of Infectious Disease and Cancer", Lopez-Berestein and Fidler ( eds.), Liss, New York, pp. 317-327 and 353-365 (1989)). Liposomes can be prepared by methods known per se: DE 3,218,121; Epstein et al., Proc. Nati Acad. Sci. (USA) 82: 3688-3692 (1985); Hwang et al., Proc. Nati Acad. Sci. (USA) 77: 4030-4034 (1980); EP 52,322; EP 36,676; EP 88,046; EP 143,949; EP 142,641; Japanese patent application; 83-118008; US patents UU Nos. 4,485,045 and 4,544,545, and EP 102,324. Ordinarily, the liposomes are of the small unilamellar type (approximately 200-800 Angstroms), in which the lipid content is greater than about 30 mole percent cholesterol; the selected proportion is adjusted for an optimal immunomodulatory therapy. In another embodiment, sustained release compositions include known crystal formulations. In a further embodiment, the compositions comprising an immunomodulatory agent are delivered by means of a pump (see Langer, cited above, Sefton, CRC Crit Ref Biomed, Eng 14: 201 (1987), Buchwald et al., Surgery 88 : 507 (1980); Saudek et al., N. Engl. J.

Med. 321: 574 (1989)). Other controlled release systems are set forth in the Langer review (Science 249: 1527-1533 (1990) .For parenteral administration, in one embodiment, the immunomodulatory agent is generally formulated by blending it to any desired degree of purity, in a form of injectable unit dose (solution, suspension or emulsion), with a pharmaceutically acceptable vehicle, i.e., one that is harmless to the recipients at the doses and concentrations used, and is compatible with the other ingredients of the formulation. Active is a immunomodulatory protein, preferably the formulation does not include oxidizing agents or other compounds known to be harmful to the polypeptides In a specific embodiment, it may be convenient to administer the compounds or pharmaceutical compositions locally in the area where the treatment is required. This can be achieved, for example, without limitation, by means of a local infusion du During surgery, topical application, for example in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous material, non-porous, or gelatinous, including membranes such as sialastic membranes, or fibers. Preferably, when administering a protein that includes an antibody of the invention, care must be taken to use materials that do not absorb the protein.

In another embodiment, the immunomodulatory agent can be delivered in a vesicle, in particular in a liposome (see Langer, Science 249: 1527-1533 (1990); Treat et al., In "Liposomes in the Therapy of Infectious Disease and Cancer", Lopez-Berestein in Fldler (eds.), Liss, New York, pp. 353-365 (1989), Lopez-Berestein, id., Pp. 317-327, see generally, ibid.). In another embodiment, the immunomodulatory agent can be delivered in a controlled release system. In one embodiment a pump can be used (see Langer, cited above, Sefton, CRC Crit Ref Biomed Eng 14: 201 (1987), Buchwaid et al., Surgery 88: 507 (1980), Saudek et al., N. Engl J Med. 321: 574 (1989)). In another embodiment, polymeric materials can be used (see "Medical Applications of Controlled Relay," Langer and Wise (eds.), CRC Press, Boca Raton, Florida (1974), "Controlled Drug Bioavailability, Drug Product Design and Performance", Smolen and Ball (eds.), Wiley, New York (1984), Ranger and Peppas, J., Macromol, Sci. Rev. Macromol, Chem. 23:61 (1983), see also Levy et al., Science 228: 190 ( 1985), During et al, Ann Neurol 25: 351 (1989), Howard et al, J. Neurosurg 71: 105 (1989)). In yet another embodiment, a controlled release system can be placed close to the therapeutic agent, ie, the brain, thus requiring only a fraction of the systemic dose (see, eg, Goodson, in "Medical Applications of Controlled Release", cited above, vol 2, pp. 115-138 (1984)). Other controlled-release systems are discussed in Langer's review (Science 249: 1527-1533 (1990)). In a specific embodiment wherein the compound of the invention is a nucleic acid encoding a protein, the nucleic acid can be administered in vivo to promote the expression of its encoded protein, constructing it as part of a suitable nucleic acid expression vector and administering it in such a way that it is made intracellular, for example using a retroviral vector (see U.S. Patent No. 4,980,286), or by direct injection, or using a bombardment of microparticles (e.g., a gene gun, Biolistic , Dupont), or coating with lipids or cell surface receptors or transfection agents, or by administering them in bond with a homeobox-like peptide that is known to enter the nucleus (see for example Joliot et al., Proc. Nati. Acad. Sci. USA 88: 1864-1868 (1991)), etc. Alternatively, a nucleic acid can be introduced intracellularly and incorporated into the DNA of the host cell for expression, by means of homologous recombination. The present invention also provides pharmaceutical compositions. Said compositions comprise a therapeutically effective amount of a compound and a pharmaceutically acceptable carrier. In a specific embodiment, the term "pharmaceutically acceptable" means approved by a regulatory agency of the federal or state government, or listed in the US pharmacopoeia. UU or another pharmacopoeia generally recognized for use in animals, more particularly in humans. The term "vehicle" refers to a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered. Said pharmaceutical vehicles can be sterile liquids, such as water and oils, which include those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is a preferred vehicle when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous solutions of dextrose and glycerol can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice flour, gypsum, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene glycol, water, ethanol, etc. If desired, the composition may also contain minor amounts of wetting agents or emulsifiers, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained release formulations, etc. The composition can be formulated as a suppository, with binders and traditional vehicles, such as triglycerides. The oral formulation may include normal vehicles such as the pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical vehicles are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. Said compositions will contain a therapeutically effective amount of the compound, preferably in purified form, together with a suitable amount of vehicle, in order to provide the proper form of administration to the patient. The formulation must be adapted to the mode of administration. In a preferred embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to humans. Typically, compositions for intravenous administration are isotonic, sterile, aqueous buffer solutions. When necessary, the composition may also include a solubilizing agent and a local anesthetic such as lignocaine, to alleviate pain at the site of injection. Generally, the ingredients are separately provided or mixed together in unit dosage form, for example as a dry lyophilized powder or a water-free concentrate, in a hermetically sealed container, such as a vial or sachet, which indicates the amount of active agent When the composition is to be administered by infusion, it can be dispensed into an infusion bottle containing water or sterile pharmaceutical grade saline. When the composition is administered by injection, a sterile injectable water vial or sterile saline solution can be provided, so that the ingredients can be mixed prior to administration. Immunomodulatory agents can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with anions such as hydrochloric, phosphoric, acetic, oxalic, tartaric acid derivatives, etc., and those formed with cations such as those derived from sodium, potassium hydroxides., ammonium, calcium, and ferric, and of isopropylamine, triethylamine, 2-ethylaminoethanol, histidine, procaine, etc. The amount of immunomodulatory agent that will be effective in the methods of the invention as described herein, can be determined by standard clinical techniques. In addition, in vitro tests can optionally be used to help identify optimal dosing scales. The exact dose to be used in the formulation will also depend on the route of administration and the severity of the disease or disorder, and should be decided according to the physician's criteria and the circumstances of each patient. Effective doses of the dose-response curves derived from in vitro test systems or animal models can be extrapolated. For antibodies, the dose administered to a patient is normally 0.1 mg / kg to 100 mg / kg of the patient's body weight. Preferably, the dose administered to a patient is between 0.1 mg / kg and 20 mg / kg of the patient's body weight, preferably from 1 mg / kg to 10 mg / kg of the patient's body weight. In preferred embodiments, the patient is administered a dose of 1, 4, 10, or 20 mg / kg intravenously. In general, human antibodies have a longer half-life in the human body than antibodies from other species, due to the immune response to foreign polypeptides. In this way, lower doses of human antibodies and less frequent administration are often possible. Furthermore, the dose and frequency of administration of the antibodies of the invention can be reduced by increasing the incorporation and penetration of the antibodies to the tissue (for example in the brain), by means of modifications such as for example lipidation. As a general proposition, the total pharmaceutically effective amount per dose of a polypeptide administered parenterally will be on the scale of about 1 microgram / kg / day to 10 mg / kg / day of the patient's body weight, although as noted above, this will be subject to therapeutic discretion. More preferably, this dose is at least 0.01 mg / kg / day, and preferably for humans it is between 0.01 and 1 mg / kg / day. In another embodiment, a polypeptide is administered to a human at a dose of between 0.0001 and 0.045 mg / kg / day, preferably at a dose between 0.0045 and 0.045 mg / kg / day, most preferably at a dose of about 45 micrograms / kg / day in humans; and at a dose of about 3 mg / kg / day in mice. If given continuously, the polypeptide is normally administered at a dosage of about 1 microgram / kg / hour to about 50 micrograms / kg / hour, by 1-4 injections per day, or by continuous subcutaneous infusion, for example using a minipump. An intravenous bag solution can also be used. The duration of treatment necessary to observe the changes, and the interval after treatment for the responses to occur, vary depending on the desired effect. The compositions comprising immunomodulatory agents can be administered as a continuous infusion, multiple injections separated per day (for example three or more times a day, or twice a day), a single injection per day, or as separate injections administered intermittently (per example twice a day, once a day, every third day, twice a week, weekly, every two weeks, monthly, every two months, and every four months). If administered continuously, a polypeptide is normally administered at a dosage of about 0.001 to 10 microgram / kg / hour, at about 50 microgram / kg / hour, through 1-4 injections per day, or by continuous subcutaneous infusion, for example using a mini pump Effective dosages of the compositions comprising the immunomodulatory agents to be administered can be determined by well-known procedures that handle parameters such as biological half-life, bioavailability and toxicity. Such a determination is within the ability of those skilled in the art, especially in light of the detailed description provided herein. The bioexposure of an organism to an immunomodulatory agent may also have an important function in determining a therapeutically or pharmacologically effective dosage regimen. Dosage variations, such as repetition of administrations at a relatively low dose of immunomodulatory agent over a relatively long period, may have an effect that is therapeutically or pharmacologically distinguishable from that obtained with repeated administrations of a relatively high dose of an immunomodulatory agent. for a relatively short period. Using the dose conversion factors per equivalent surface area provided by Freireich, EJ et al (Cancer Chemotherapy Reports 50 (4): 219-44 (1966)), the skilled person will be able to conveniently convert the data obtained from the use of the immunomodulatory agent in a given experimental system, to an accurate estimate of a pharmaceutically effective amount of immunomodulatory agent to be administered per dose in another experimental system. Experimental data obtained by administering the immunomodulatory agent in mice, for example, can be converted by the conversion factors provided by Freireich et al, to accurate estimates of the pharmaceutically effective doses of neutrocine-alpha in the rat, monkey, dog and human. The following conversion table (table III) is a summary of the data provided by Freireich and others. Table III gives approximate factors for converting the expressed doses as a function of mg / kg of a species to an equivalent dose per surface area expressed in mg / kg in another tabulated species.

TABLE III Conversion factors of equivalent dose per surface area Rat Mouse Monkey Human Dog DE (20 g) (150 g) (3.5 Kg) (8 Kg) (60 Kg) Mouse 1 1/2 1/4 1/6 1/12 Rat 2 1 1/2 1/4 1 / 7 Monkey 4 2 1 3/5 1/3 Dog 6 4 5/3 1 1/2 Human 12 7 3 2 1 So, for example, using the conversion factors provided In Table III, a dose of 50 mg / kg in the mouse is converted to an appropriate dose of 12.5 mg / kg in the monkey, because (50 mg / kg) x (1/4) = 12.5 mg / kg.

As an additional example, the doses of 0.02, 0.08, 0.8, 2, and 8 mg / kg in the mouse are equivalent to effective doses of 1667 micrograms / kg, 6.67 micrograms / kg, 66.7 micrograms / kg, 166.7 micrograms / kg, and 0.667 mg / kg, respectively, in the human.

In some modalities, the administration of radiolabeled forms of neutrocin-alpha or anti-neutrocin-alpha antibody. The Radiometric dose to be applied may vary substantially. The composition radiolabeled neutrokine-alpha or anti-neutrocine-alpha antibody can be Administer at a dose of approximately 0.1 to approximately 100 mCi for 70kg of body weight. In another embodiment, the radiolabeled composition of neutrokine-alpha or anti-neutrocin-alpha antibody can be administered at a dose of about 0.1 to about 50mCi per 70kg of body weight. In another embodiment, the radiolabelled composition of neutrophil-alpha or anti-neutrocin-alpha antibody can be administered at a dose of from about 0.1 to about 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40 , 50, 60, 70, 80, 90, or 100 mCi per 70 kg of body weight. The radiolabeled composition of neutrokine-alpha or anti-neutrocin-alpha antibody can be administered at a dose of about 0.1 to about 10 mCi / kg body weight. In another embodiment, the radiolabeled composition of neutrokine-alpha or anti-neutrocin-alpha antibody can be administered at a dose of 0.25 to about 5 mCi / kg of body weight. In specific modalities, the radiolabeled composition of neutrophil-alpha or anti-neutrocin-alpha antibody can be administered at a dose of 0.35, 0.70, 1.35, 1.70, 2.0, 2.5 or 3.0 mCi / kg. The radiolabeled composition of neutrokine-alpha or anti-neutrocin-alpha antibody can be administered at a dose of about 1 to about 50 mCi / m2. In another embodiment, the radiolabeled composition of neutrokine-alpha or anti-neutrocin-alpha antibody can be administered at a dose of about 10 to about 30 mCi / m2. In specific embodiments, the radiolabeled composition of neutrokine-alpha or anti-neutrocin-alpha antibody can be administered at a dose of 10, 15, 20, 25, or 30 mCi / m2. The total concentration of neutrokine-alpha protein, neutrocin-alphaSV protein, anti-neutrocin-alpha antibody or antineutrocin-alphaSV antibody in a radiolabelled composition of neutrokine-alpha or anti-neutrocin-alpha antibody may also vary, for example about 1 microgram / kg to approximately 1 mg / kg. In specific embodiments, the total concentration of neutrocin-alpha protein, neutrocin-alphaSV protein, anti-neutrocin-alpha antibody or anti-neutrocine-alphaSV antibody in a radiolabelled composition of neutrocin-alpha or anti-neutrocin-alpha antibody, may be 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 micrograms / kg. For example, it is known that lymphomas are radiosensitive tumors. For image immunodiagnostic analysis, trace labeling with the complex can be used, typically 1-20 mg of the neutrocyan-alpha protein are labeled with approximately 1 to 60 mCi of radioisotope. The dose may be a little dependent on the isotope used for the image; quantities can be used at the highest end of the scale, preferably from 40 to 60 mCi, with 99mTc; quantities may be used at the lower end of the scale, preferably 1-20 mCi, with 111 ln. For image analysis purposes, the subject may be given about 1 mg to about 30 mg of the neutrokine-alpha complex. For radioimmunotherapeutic purposes, the neutrophil-alpha complex is administered to a subject in an amount sufficient for the dose received throughout the body to be up to 1100 cGy, but preferably less than or equal to 500 cGy. The total amount of neutrokine-alpha protein administered to a subject, including the neutrocine-alpha protein, neutrokine-alpha conjugate and neutrokine-alpha complex, can vary from 1.0 μg / kg to 1.0 mg / kg of the patient's body weight. In another embodiment, the total amount of neutrokine-alpha protein administered to a subject can vary from 20 μg / kg to 100 mg / kg of body weight of a subject. A quantity of radioactivity that would provide approximately 500 cGy to the entire body of a human is estimated to be approximately 825 mCi of 131l. The amounts of radioactivity to be administered depend in part on the chosen isotope. For 90Y therapy, from about 1 to about 200 mCi of radioactivity are considered appropriate, with preferable amounts being from 1 to 150 mCi, preferably from 1 to 100 mCi (for example 60 mCi). The preferred means for estimating tissue doses of the amount of radioactivity administered is an image analysis or other pharmacokinetic regimen with a dose of tracer, in order to obtain approximations of the predicted dosimetry. To determine the appropriate dose of the radiopharmaceutical agent to be administered to an individual, it is necessary to consider the amount of radiation that the individual organs will receive in comparison with the maximum tolerance for said organs. This information is known to experts in the field; see for example Emami et al., International Journal of Radiation Oncology, Biology, Physics 21: 109-22 (1991); and Meredith, Cancer Biotherapy & Radiopharmaceuticals 17: 83-99 (2002), both are incorporated herein by reference in their entirety.

A "high-dose" protocol, for example on a scale of 200 to 600 cGy (or higher) for the whole body, may require the support of a bone marrow replacement protocol, since the bone marrow is the tissue that It limits the dose of radiation due to its toxicity. In specific embodiments, a patient receives multiple administrations of a composition (e.g., antibody that specifically binds to neutrocine-alpha or other immunomodulatory agent known in the art or described herein). A group of multiple administrations is referred to as a cycle. A single cycle may comprise, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more administrations. For any administration, the dose may be fixed or variable to allow initial drug loading or to compensate for specific patient differences in mass, body surface area, disease activity, disease response, drug tolerance, time to recovery, pharmacokinetic parameters, or pharmacological responses. The time between any two administrations within a given cycle can be fixed or variable to accommodate the specific differences of the patient in terms of disease activity, response to the disease, drug tolerance, recovery time, pharmacokinetic parameters, or pharmacological response. . In specific modalities, patients are given an initial loading dose that is twice the amount given in subsequent administrations. In other modalities, the time between any two administrations may be 1, 2, 3, 4, 5, 6, or 7 days (one week) or more. In specific modalities, the time between any two administrations may be 1, 2, 3, 4, 5, 6, 7, or 8 weeks or more. Patients can also receive multiple treatment cycles. If more than one cycle is required, the time between any two treatment cycles can be fixed or variable to accommodate the patient-specific differences in disease activity, disease response, drug tolerance, recovery time, pharmacokinetic parameters, or pharmacological responses. In specific modalities, the time between any two cycles may be 1, 2, 3, 4, 5, 6, weeks or greater. In specific modalities, the time between any two cycles may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months, or more. In specific modalities, the time between any two cycles may be 1, 2, 3, 4, 5 years, or more. In specific modalities, a patient receives an initial bolus administration followed by one or more cycle treatments. In one embodiment, the initial bolus administration comprises a dose of 2 mg / kg or greater of a neutrokine-alpha antagonist antibody administered intravenously to a patient. In one embodiment, the initial bolus administration comprises a dose of 5 mg / kg or greater of a neutralizing antibody to neutrokine-alpha administered intravenously to a patient. In preferred embodiments, the initial bolus administration is a dose of 10 mg / kg or greater of a neutral-alpha antagonist antibody administered intravenously to a patient. In other embodiments, the initial bolus administration is a dose of 15 mg / kg or greater of an alpha-neutrophilic antagonist antibody administered intravenously to a patient. In one embodiment, the initial bolus administration comprises a dose of 20 mg / kg or greater of the antibody of the invention administered intravenously to a patient. In other embodiments, the initial bolus specific comprises an anti-CD20 antibody. In other specific embodiments, the initial bolus comprises an agent that depletes B cells. The invention also provides a pharmaceutical package or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions. Optionally associated with said containers, there may be an advertisement in the form prescribed by a governmental agency that regulates the manufacture, use or sale of pharmaceutical or biological products, said advertisement indicates the agency's approval of the manufacture, use or sale for human administration. An immunomodulatory agent can be administered alone or in combination with other therapeutic agents, including without limitation one or more additional immunomodulatory agents, chemotherapeutic agents, antibiotics, antivirals, steroidal agents and non-steroidal anti-inflammatory agents, conventional immunotherapeutic agents and cytokines. Combinations may be administered concomitantly, for example as a mixture, separately but simultaneously or concurrently; or sequentially. This includes presentations in which the combined agents are administered together as a therapeutic mixture, and also methods in which the combined agents are administered separately but simultaneously, for example by intravenous lines separated from the same individual. Administration "in combination" further includes administration first of a separate one of the given compounds or agents, followed by the second. In the following paragraphs it is described that an immunomodulatory agent can be administered in combination with another compound. In certain cases, the additional compound alone is an immunomodulatory agent. The description of said paragraphs is intended to express specifically that two or more different immunomodulatory agents may be administered in combination with one another in conjunction with the methods of the present invention. For example, it is specifically contemplated that an anti-neutrocin-alpha antibody may be used in conjunction with an anti-CD20 antibody in conjunction with the methods of the present invention. Conventional nonspecific immunosuppressive agents that can be administered in combination with an immunomodulatory agent include, without limitation, steroids, cyclosporine, cyclosporin analogs, cyclophosphamide, cyclophosphamide IV, methylprednisolone, prednisolone, azathioprine, FK-506, 15-deoxyspergualin and other agents immunosuppressants that act by suppressing the function of responder T cells. Other immunosuppressive agents that can be administered in combination with an immunomodulatory agent include, without limitation, prednisolone, methotrexate, thalidomide, methoxsalen, rapamycin, leflunomide, mizoribine (BREDININ ™), brequinar, deoxyspergualin and azaspirana (SKF 105685). In specific embodiments, an immunomodulatory agent is administered in combination with an immunosuppressant. Immunosuppressive preparations that can be administered with an immunomodulatory agent include, without limitation, ORTHOCLONE OKT® 3 (muromonab-CD3), SANDIMMUNE ™, NEORAL ™, SANGDYA ™ (cyclosporin), PROGRAF® (FK506, tacrolimus), CELLCEPT® (mycophenolate motefil, of which the active metabolite is mycophenolic acid), IMURAN ™ (azathioprine), glucorticosteroids, adrenocortical steroids such as DELTASONE ™ (prednisone) and HYDELTRASOL ™ (prednisolone), FOLEX ™ and MEXATE ™ (methotrexate), OXSORALEN-ULTRA ™ (methoxsalen) and RAPAMUNE ™ (sirolimus). In a specific embodiment, immunosuppressants can be used to prevent rejection of an organ or bone marrow transplant. In another embodiment, an immunomodulatory agent is administered in combination with a steroid therapy. Steroids that can be administered in combination with an immunomodulatory agent include, without limitation, oral corticosteroids, prednisone, and methylprednisolone (e.g., methylprednisolone iv). In a specific embodiment, an immunomodulatory agent is administered in combination with prednisone. In a further specific embodiment, an immunomodulatory agent is administered in combination with prednisone and an immunosuppressive agent. Immunosuppressive agents that can be administered with an immunomodulatory agent and prednisone are those described herein and include, without limitation, azathioprine, cyclophosphamide and iv cyclophosphamide. In another specific embodiment, an immunomodulatory agent is administered in combination with methylprednisolone. In a further specific embodiment, an immunomodulatory agent is administered in combination with methylprednisolone and an immunosuppressive agent. Immunosuppressive agents that can be administered with an immunomodulatory agent and methylprednisolone are those described herein and include, without limitation, azathioprine, cyclophosphamide and cyclophosphamide IV. In a preferred embodiment, an immunomodulatory agent is administered in combination with an antimalarial. Antimalarials that can be administered with an immunomodulatory agent include, without limitation, hydroxychloroquine (eg, PLAQUENIL ™), chloroquine, or quinacrine. In a preferred embodiment, an immunomodulatory agent is administered in combination with an NSAID. In a non-exclusive embodiment, an immunomodulatory agent is administered in combination with one, two, three, four, five, ten or more of the following drugs: NRD-101 (Hoechst Marion Roussel), diclofenac (Dimetharid), potassium oxaprozin ( Monsanto), mecasermin (Chíron), T-614 (Toyama), pemetrexed disodium (Eli Lilly), atreleuton (Abbott), valdecoxib (Monsanto), eltenac (Byk Gulden), campath, AGM-1470 (Takeda), CDP-571 (Celltech Chiroscience), CM-101 (CarboMed), ML-3000 (Merckle), CB-2431 (KS Biomedix), CBF-BS2 (KS Biomedix), IL-1 Ra gene therapy (Valentis), JTE-522 ( Japan Tobacco), paclitaxel (Angíotech), DW-166HC (Dong Wha), darbufelone mesylate (Warner-Lambert), soluble receptor for TNF 1 (synergen; Amgen), IPR-6001 (Institute for Pharmaceutical Research), trocade (Hoffman-La Roche), EF-5 (Scotia Pharmaceuticals), BIIL-284 (Boehringer Ingelheim), BIF-1149 (Boehringer Ingelheim), LeukoVax (Inflammatics), MK-663 (Merck), ST-1482 (Sigma-Tau) and butixocort propionate (WarnerLambert). In one embodiment, an immunomodulatory agent is administered in combination with one or more of the following drugs: Infliximab (also known as Remicade ™ Centocor, Inc.), Trocade (Roche, RO-32-3555), Leflunomide (also known as Arava Hoechst Marion Roussel ™), Kineret ™ (an IL-1 receptor antagonist also known as Anakinra from Amgen, Inc.), SCIO-469 (p38 kinase inhibitor from Scios, Inc.), Humira® (adalimumab from Abbott Laboratories) ), or ASLERA ™ (prasterone, dehydroepiandrosterone, GL701) from Genelabs Technologies Inc. In another embodiment, an immunomodulatory agent is administered in combination with one, two, three, four, five or more of the following drugs: methotrexate, sulfasalazine, aurothiomalate sodium, auranofin, cyclosporine, penicillamine, azathioprine, an antimalarial drug (for example, such as those described here), cyclophosphamide, chlorambucil, gold, ENBREL ™ (Etanercept), anti-TNF antibody, LJP 394 (La Jolla Pharmaceutic to the Company, San Diego, California) and prednisolone. In another embodiment, an immunomodulatory agent is administered in combination with an antimalarial agent, methotrexate, anti-TNF antibody, ENBREL ™ or sulfasalazine. In one embodiment, an immunomodulatory agent is administered in combination with methotrexate. In another embodiment, an immunomodulatory agent is administered in combination with an anti-TNF antibody. In another embodiment, an immunomodulatory agent is administered in combination with methotrexate and anti-TNF antibody. In another embodiment, an immunomodulatory agent is administered in combination with sulfasalazine. In another embodiment, an immunomodulatory agent is administered in combination with methotrexate, anti-TNF antibody and sulfasalazine. In another embodiment, an immunomodulatory agent is administered in combination with ENBREL ™. In another embodiment, an immunomodulatory agent is administered in combination with ENBREL ™ and methotrexate. In another embodiment, an immunomodulatory agent is administered in combination with ENBREL ™, methotrexate and sulfasalazine. In another embodiment, an immunomodulatory agent is administered in combination with ENBREL ™ and sulfasalazine. In other embodiments, one or more antimalarial agents are combined with one of the combinations mentioned above. In a specific embodiment, an immunomodulatory agent is administered in combination with an antimalarial agent (e.g. hydroxychloroquine), ENBREL ™, methotrexate and sulfasalazine. In another specific embodiment, an immunomodulatory agent is administered in combination with an antimalarial agent (e.g. hydroxychloroquine), sulfasalazine, anti-TNF antibody and methotrexate. In a further embodiment, an immunomodulatory agent is administered alone or in combination with one or more intravenous immunoglobulin preparations. Intravenous immunoglobulin preparations that can be administered with an immunomodulatory agent include, without limitation, GAMMAR ™, IVEEGAM ™, SANDOGLOBULIN ™, GAMMAGARD S / D ™, and GAMIMUNE ™. In a specific embodiment, an immunomodulatory agent is administered in combination with intravenous immunoglobulin preparations in transplantation therapy (e.g., bone marrow transplantation). In a further embodiment, an immunomodulatory agent is administered alone or in combination with an anti-inflammatory agent. Anti-inflammatory agents that can be administered with an immunomodulatory agent include, without limitation, glucocorticoids and nonsteroidal antiinflammatories, aminoarilcarboxylic acid derivatives, arylacetic acid derivatives, arylbutyric acid derivatives, arylcarboxylic acids, arylpropionic acid derivatives, pyrazoles, pyrazolones, salicylic acid derivatives, thiazinecarboxamides, e-acetamidocaproic acid, S-adenosylmethionine, 3-amino-4-hydroxybutyric acid, amixetrine, bendazac, benzydamine, bucolome, diphenpiramide, ditazole, emorfazone, guayazulene, nabumetone, nimesulide, orgotein, oxaceprol, paraniline, perisoxal, pifoxime, proquazone, proxazole and tenidap. In specific embodiments, an immunomodulatory agent is administered alone or in combination with anti-CD4 antibody. In one embodiment, coadministration of an immunomodulatory agent with an anti-CD4 antibody is contemplated for the treatment of rheumatoid arthritis. In one embodiment, coadministration of an immunomodulatory agent with an anti-CD4 antibody is contemplated for the treatment of systemic lupus erythematosus. In specific embodiments, an immunomodulatory agent is administered alone or in combination with anti-IL-15 antibody. In one embodiment, co-administration of an immunomodulatory agent with an anti-IL-15 antibody for the treatment of rheumatoid arthritis is contemplated. In one embodiment, coadministration of an immunomodulatory agent with an anti-IL-15 antibody is contemplated for the treatment of systemic lupus erythematosus. In specific embodiments, an immunomodulatory agent is administered alone or in combination with CTLA4-Ig and LEA29Y. In one embodiment, coadministration of an immunomodulatory agent with CTLA4-lg and LEA29Y is contemplated for the treatment of rheumatoid arthritis. In one embodiment, the co-administration of an immunomodulatory agent with CTLA4-Ig and LEA29Y for the treatment of systemic lupus erythematosus is contemplated. In specific embodiments, an immunomodulatory agent is administered alone or in combination with an anti-IL-6 receptor antibody. In one embodiment, co-administration of an immunomodulatory agent with an anti-IL-6 receptor antibody for the treatment of rheumatoid arthritis is contemplated. In one embodiment, the coadministration of an immunomodulatory agent with an anti-IL-6 receptor antibody for the treatment of systemic lupus erythematosus is contemplated. In specific embodiments, an immunomodulatory agent is administered alone or in combination with anti-C5 antibody (complement component). In one embodiment, coadministration of an immunomodulatory agent with an anti-C5 antibody for the treatment of rheumatoid arthritis is contemplated. In one embodiment, coadministration of an immunomodulatory agent with an anti-C5 antibody is contemplated for the treatment of systemic lupus erythematosus. In specific embodiments, an immunomodulatory agent is administered alone or in combination with inhibitors of the complement cascade. Inhibitors of the complement cascade include, without limitation, anti-properdin antibodies (Gliatech); TP-10, a type I soluble recombinant complement receptor (AVANT Immunotheragenetics Inc.); Pexelizmab, a C5 complement inhibitor (Alexion Pharmaceuticals Inc.); and 5G1.1, a monoclonal antibody that prevents the cutting of the complement component C5 in its proinflammatory components. In one embodiment, coadministration of an immunomodulatory agent with inhibitors of the complement cascade is contemplated for the treatment of inflammation, rheumatoid arthritis or systemic lupus erythematosus. In another embodiment, an immunomodulatory agent is administered in combination with a chemotherapeutic agent. Chemotherapeutic agents that can be administered with an immunomodulatory agent include, without limitation, antibiotic derivatives (eg, doxorubicin, bleomycin, daunorubicin, and dactinomycin); antiestrogens (e.g., tamoxifen); antimetabolites (eg, fluorouracil, 5-FU, methotrexate, floxuridine, interferon alfa-2b, glutamic acid, plicamycin, mercaptopurine and 6-thioguanine); cytotoxic agents (e.g., carmustine, BCNU, lomustine, CCNU, cytosine arabinoside, cyclophosphamide, estramustine, hydroxyurea, procarbazine, mitomycin, busulfan, cis-platinum and vincristine sulfate); hormones (eg, medroxyprogesterone, estramustine sodium phosphate, ethinylestradiol, estradiol, megestrol acetate, methyltestosterone, diethylstilbestrol diphosphate, chlorotrianisine and testolactone); Nitrogen mustard derivatives (for example, mephalene, chlorambucil, mechlorethamine (nitrogen mustard) and totepa); steroids, and combinations (e.g., sodium phosphate of betamethasone); and others (eg, dicarbazine, asparaginase, mitotane, vincristine sulfate, vinblastine sulfate, etoposide). In a specific embodiment, an immunomodulatory agent is administered in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), or any combination of one or more of the components of CHOP. In another embodiment, an immunomodulatory agent is administered in combination with anti-CD20 antibodies, such as human monoclonal anti-CD20 antibodies. In another embodiment, an immunomodulatory agent is administered in combination with anti-CD20 and CHOP antibodies, or anti-CD20 antibodies and any combination of one or more of the CHOP components, particularly cyclophosphamide or prednisone. In a specific embodiment, a immunomodulatory agent is administered in combination with Rituxmab. In a further embodiment, an immunomodulatory agent is administered with Rituxmab and CHOP, or Rituxmab and any combination of one or more of the components of CHOP, particularly cyclophosphamide or prednisone. In a specific embodiment, an immunomodulatory agent is administered in combination with tositumomab (anti-CD20 antibody from Coulter Pharmaceuticals, San Francisco, California). In a further embodiment, an immunomodulatory agent is administered with tositumomab and CHOP, or tositumomab and any combination of one or more of the components of CHOP, particularly cyclophosphamide or prednisone. Tositumomab may optionally be associated with 1311. Optionally, anti-CD20 antibodies may be associated with radioisotopes, toxins or cytotoxic pro-drugs. In another specific embodiment, an immunomodulatory agent is administered in combination Zevalin ™. In a further embodiment, an immunomodulatory agent is administered with Zevalin ™ and CHOP, or Zevalin ™ and any combination of one or more of the components of CHOP, particularly cyclophosphamide or prednisone. Zevalin ™ can be associated with one or more radioisotopes. Particularly preferred isotopes are 90Y and 111ln. In additional embodiments, an immunomodulatory agent is administered in combination with Rituximab (Rituxan ™) or Ibritumomab Tiuxetan (Zevalin ™, for example, (ln-111) Ibritumomab Tiuxetan or (Y-90) Ibritumomab Tiuxetan). In a specific embodiment, an immunomodulatory agent is administered in combination with Rituximab or Ibritumomab Tiuxetan for the treatment of non-Hodgkin's lymphoma. In specific modalities, an immunomodulatory agent is administered as a chronic treatment that is supplemented with the administration of anti-CD20 after an attack of the disease, for example, after an attack of lupus. In additional embodiments, an immunomodulatory agent is administered in combination with imatinib mesylate (Gleevec®: 4 - [(4-methyl-1-piperazinyl) methyl] -N- [4-methyl-3 - [[4- ( 3-pyridinyl) -2-pyrimidinyl] amino] -phenyl] benzamide). In additional embodiments, an immunomodulatory agent is administered in combination with bortezomib (Velcade ™ [(1 R) -3-methyl-1 - [[(2S) -1 -oxo-3-phenyl-2 - [(pyrazole)] L-carbonyl) amino] propyl] amino] butyl] boronic). In additional embodiments, an immunomodulatory agent is administered in combination with Alemtuzumab (Campath®). In additional embodiments, an immunomodulatory agent is administered in combination with fludarabine phosphate (Fludara®: 9H-Purin-6-amine, 2-fluoro-9- (5-0-phosphono-β-D-arabinofuranosyl) (2-fluoro) -ara-AMP)). An immunomodulatory agent can be administered in combination with one or more therapeutic agents useful in the treatment of multiple myeloma, including without limitation, alkylating agents, anthracyclines, carmustine (DTI-015, BCNU, BiCNU, Gliadel Wafer®), cyclophosphamide (Cytoxan ®, Neosar®, CTX), dexamethasone (Decadron®), doxorubicin (Adriamycin®, Doxil®, Rubex®), melphalan (L-PAM, Alkeran®, phenylalanine mustard), prednisone, thalidomide and vincristine (Oncovorin®, Onco TCS®, VCR, Leurocristina®). Preferred combinations of therapeutic agents useful in the treatment of multiple myeloma, which may be administered in combination with an immunomodulatory agent, include without limitation cyclophosphamide + prednisone, melphalan + prednisone (MP), vincristine + Adriamycin® + dexamethasone (VAD), vincristine + carmustine + melphalan + cyclophosphamide + prednisone (VBMCP; protocol M2), and vincristine + melphalan + cyclophosphamide + prednisone alternating with vincristine + carmustine + doxorubicin + prednisone (VMCP? / BAP). An immunomodulatory agent can be administered in combination with one or more therapeutic agents useful in the treatment of non-Hodgkin's lymphoma include, without limitation, 2-chlorodeoxyadenosine, amifostine (Ethyol®, Ethiofos®, WR-272), bexarotene (Targretin®, Targretin gel®, Targretin oral®, LGD1069), bleomycin (Blenoxane®), busulfan (Busulfex®, Myleran®), carboplatin (Paraplatin®, CBDCA), carmustine (DTI-015, BCNU, BiCNU, Gliadel Wafer®), chlorambucil ( Leukeran®), cisplatin (Platinol®, CDDP), cladribine (2-CdA, Leustatin®), cyclophosphamide (Cytoxan®, Neosar®, CTX), cytarabine (Cytosar-U®, ara-C, cytosine arabinoside, DepoCyt®) , dacarbazine (DTIC), daunorubicin (Daunomycin, DaunoXome®, Daunorubicin®, Cerubidine®), denileukin diftitox (Ontak®), dexamethasone (Decadron®), dolasetron mesylate (Anzemet®), doxorubicin (Adriamycin®, Doxil®, Rubex ®), erythropoietin (EPO®, Epogen®, Procrit®), etoposide phosphate (Etopophos®), etoposide (VP-16 , Vedasid®), fludarabine (Fludara®, FAMP), granisetron (Kytril®), hydrocortisone, idarubicin (Idamicin®, DMDR, IDA), ifosfamide (IFEX®), interferon alfa (Alfaferone®, Alpha-IF®), interferon alpha 2a (Intron A®), mechlorethamine (nitrogen mustard, HN2, Mustargen®), melphalan (L-PAM, Alkeran®, mustard phenylalanine), Methotrexate® (MTX, Mexate®, Folex®), methylprednisolone (Solumedrol®) , mitoxantrone (Novantrone®, DHAD), ondansetron (Zofran®), pentostatin (Nipent®, 2-deoxicoformycin), perfosfamide (4-hydroperoxy cyclophosphamide, 4-HC), prednisone, procarbazine (Matulane®), Rituximab® (Rituxan®, anti-CD20 mAb), Thiotepa (triethylene-thiophosphoramide, Thioplex®), topotecan (Hycamtin®, SK &F-104864, NSC-609699, Evotopin®), vincblastin (Velban®, VLB), vincristine (Oncovin®, Onco TCS®, VCR, Leurocristine®) and vindesine (Eldisine®, Fildesin®). Preferred combinations of therapeutic agents useful in the treatment of non-Hodgkin's lymphoma, which may be administered in combination with an immunomodulatory agent, include without limitation, Adriamicyn® + blenoxane + vinblastine + dacarbazine (ABVD), anti-idiotype therapy (BsAb) + interferon alfa, anti-idiotype therapy (BsAb) + chlorambucil, anti-idiotypic therapy (BsAb) + interleukin 2, BCNU (Carmustine) + etoposide + Ara-C (cytarabine) + melphalen (BEAM), bleomycin + etoposide + adriamycin + cyclophosphamide + vincristine + procarbazine + prednisone (BEACOPP), briostatin + vincristine, cyclophosphamide + BCNU (carmustine) + VP-16 (etoposide) (CBV), cyclophosphamide + vincristine + prednisone (CVP), Cyclophosphamide + Adriamycin® (hydroxyldaunomycin) + vincristine ( Oncovorin) + prednisone (CHOP), cyclophosphamide + Novantrone® (Mitoxantrone) + vincristine (Oncovorin) + prednisone (CNOP), cyclophosphamide + doxorubicin + teniposide + prednisone, cyclophosphamide + Adriam icina® (Hydroxydaunomycin) + vincristine (Oncovorin) + prednisone + rituximab (CHOP + Rituximab), cyclophosphamide + doxorubicin + teniposide + prednisone + alpha interferon, cytarabine + bleomycin + vincristine + methotrexate (CytaBOM), dexamethasone + cytarabine + cisplatin (DHAP) , dexamethasone + ifosfamide + cisplatin + etoposide (DICE), doxorubicin + vinblastine + mechlorethamine + vincristine + bleomycin + etoposide + prednisone (Stanford V), etoposide + vinblastine + adriamycin (EVA), etoposide + methylprednisone + cytarabine + cisplatin (ESHAP), etoposide + prednisone + ifosfamide + cisplatin (EPIC), fludarabine, mitoxantrone + dexamethasone (FMD), fludarabine, dexamethasone, cytarabine (ara-C), + cisplatin (Platinol®) (FluDAP), phosphamide + cisplatin + etoposide (ICE) , mechlorethamine + Oncovin® (vincristine) + procarbazine + prednisone (MOPP), mesna + ifosfamide + idarubicin + etoposide (MIZE), methotrexate with leucovorin rescue + bleomycin + adriamycin + cyclophosphamide + Oncovorin + dexamethasone (m-BACOD), prednisone + methotrexate + adriamycin + cyclophosphamide + etoposide (ProMACE), thiotepa + busulfan + cyclophosphamide, thiotepa + busulfan + melphalan, topotecan + paclitaxel, and vincristine (Oncovin®) + Adriamycin® + dexamethasone (VAD). Additional examples of therapeutic agents useful in the treatment of non-Hodgkin's lymphoma, which may be administered in combination with an immunomodulatory agent, include, without limitation, A007 (4-4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone), AG-2034 ( AG-2024, AG-2032, GARFT inhibitor [glycinamide ribonucleoside transformylase]), Aldesleukin (IL-2, Proleukin®), Alemtuzumab (Campath®), Alitretinoin (Panretin®, LGN-1057), Altretamine (Hexalen®, hexamethylmelamine , Hexastat®), aminocamptothecin (9-AC, 9-aminocamptothecin, NSC 603071), anti-CD19 / CD3 mAb (anti-CD19 / CD3 scFv, anti-NHL mAb), anti-idiotype therapy (BsAb), arabinosilguanine (Ara -G, GW506U78), arsenic trioxide (Trisenox®, ATO), B43-Genistein (anti-CD19 Ab conjugate / genistein), conjugates of B7 antibody, Betathin (Beta-LT), BLyS antagonists, Bryostatin-1 (Bryostatin ®, BMY-45618, NSC-339555), CHML (heterogeneous cytotropic molecular lipids), clofarabine (chloro-fluoro-araA), Daclizumab ( Zenapax®), Depsipeptide (FR901228, FK228), Dolastatin-10 (DOLA-10, NSC-376128), Epirubicin (Ellence®, EPI, 4 'epi-Doxorubicin), Epratuzumab (Lymphocide®, Humanized anti-CD22, HAT) , ligand of Fly3 / flk2 (Mobista®), G3139 (Genasense®, GentaAnticode®, Bcl-2 antisense), Hu1 D10 (anti-HLA-DR mAb, SMART 1 D10), HumaLYM (anti-CD20 mAb), Ibritumomab tiuxetan (Zevalin®), Interferon gamma (Gamma-interferon, Gamma 100®, Gamma-IF), Irinotecan (Camptosar®, CPT-11, Topotecin®, CaptoCPT-1), ISIS-2053, ISIS-3521 (PKC-alpha antisense), Lmb-2 immunotoxin (recombinant anti-CD25 immunotoxin, anti-Tac (Fv) -PE38), Leuvectin® (cofeofectin + IL-2 gene, IL-2 gene therapy), Lym-1 (131 -1 LYM-1), Lymphoma vaccine (Genitope), Nelarabine (Compound 506, U78), Neugene compounds (Oncomyc-NG®, Resten-NG®, antisense myc), NovoMAb-G2 scFv (IgM NovoMAb-G2), 06-benzylguanine (BG, Procept®), oxaliplatin (Eloxatine®, Eloxatin®), paclitaxel (Paxene®, Taxol®), paclitaxel-DH A (Taxoprexin®), Peldesin (BCX-34, PNP inhibitor), Rebeccamycin and Rebeccamycin analogs, SCH-66336, Sobuzoxane (MST-16, Perazolin®), SU5416 (Semaxanib®, VEGF inhibitor), TER-286 , thalidomide, TNP-470 (AGM-1470), tositumomab (Bexxar®), Valspodar (PSC 833), Vaxid (B-cell lymphoma DNA vaccine), vinorelbine (Navelbine®), WF10 (macrophage regulator) and XR -9576 (XR-9351, P-glycoprotein / MDR inhibitor). An immunomodulatory agent can be administered in combination with one or more therapeutic agents useful in the treatment of acute lymphocytic leukemia, including without limitation, amsacrine, carboplatin (Paraplatin®, CBDCA), carmustine (DTI-015, BCNU, BiCNU, Gliadel Wafer ®), colecaliferol, cyclophosphamide (Cytoxan®, Neosar®, CTX), cytarabine (Cytosar-U®, ara-C, cytosine arabinoside, DepoCyt®), daunorubicin (Daunomycin, DaunoXome®, Daunorubicin®, Cerubidine®), dexamethasone ( Decadron®), doxorubicin (Adriamycin®, Doxil®, Rubex®), etoposide (VP-16, Vepesid®), Filgrastam® (Neupogen®, G-CSF, Leukine®), fludarabine (Fludara®, FAMP), idarubicin ( Idamicin®, DMDR, IDA), ifosfamide (IFEX®), imatinib mesylate (STI-571, Imatinib®, Glivec®, Gleevec®, Abl tyrosine kinase inhibitor), gamma interferon (Gamma-interferon, Gamma 100®, Gamma -IF), L-asparaginase (Elspar®, Crastinin®, Asparaginase medac®, Kidrolase®), mercaptopurine (6-mercaptopurin) a, 6-MP), Methotrexate® (MTX, Mexate®, Folex®), mitoxantrone (Novantrone®, DHAD), Pegaspargase® (Oncospar®), prednisone, retinoic acid, teniposide (VM-26, Vumon®), thioguanine (6-thioguanine, 6-TG), topotecan (Hycamtin®, SK & amp;; F-104864, NSC-609699, Evotopin®), Tretinoin (Retin-A®, Atragen®, ATRA, Vesanoid®) and vincristine (Oncovorin®, Onco TCS®, VCR, Leurocristine®). Additional examples of therapeutic agents useful in the treatment of acute lymphocytic leukemia that can be administered in combination with an immunomodulatory agent include, without limitation, aminocamptothecin (9-AC, 9-aminocamptothecin, NSC 603071), aminopterin, annamycin (AR-522, annamicin LF, Aronex®), arabinosilguanine (Ara-G, GW506U78, Nelzarabine®), arsenic trioxide (Trisenox®, ATO, Atrivex®), B43-Genistein (anti-CD19 Ab / genistein conjugate), B43-PAP (Ab anti-CD19 / phytolac antiviral protein conjugate), Cordycepin, CS-682, decitabine (5-aza-2'-deoxythidine), Dolastatin-10 (DOLA-10, NSC-376128), G3139 (Genasense®, GentaAnticode® , Antisense Bcl-2), Irofulven (MGI-114, Ivofulvan, acylfulvene analogue), MS-209, phenylbutyrate, quinine, TNP-470 (AGM-1470, Fumagillin), trimetrexate (Neutrexin®), Troxacitabine (BCH- 204, BCH-4556, Troxatyl®), UCN-01 (7-hydroxistaurosporin), WHI-P131 and WT1 vaccine.

Preferred combinations of the therapeutic agents useful in the treatment of acute leukemia that can be administered in combination with an immunomodulatory agent include, without limitation, carboplatin + mitoxantrone, carmustine + cyclophosphamide + etoposide, cytarabine + daunorubicin, cytarabine + doxorubicin, cytarabine + idarubicin, cytarabine + interferon gamma, cytarabine + L-asparaginase, cytarabine + mitoxantrone, cytarabine + fludarabine and mitoxantrone, etoposide + cytarabine, etoposide + ifosfamide, etoposide + mitoxantrone, ifosfamide + etoposide + mitoxantrone, ifosfamide + teniposide, methotrexate + mercaptopurine, methotrexate + mercaptopurine + vincristine + prednisone, phenylbutyrate + cytarabine, phenylbutyrate + etoposide, phenylbutyrate + topotecan, phenylbutyrate + tretinoin, quinine + doxorubicin, quinine + mitoxantrone + cytarabine, thioguanine + cytarabine + amsacrine, thioguanine + etoposide + idarubicin, thioguanine + retinoic acid + cholecaliferol, vincristine + prednisone, vincristine + prednisone and L-asparaginase, vincristine + dexamethasone / prednisone + asparaginase + daunorubicin / doxorubicin, vincristine + dexamethasone / prednisone + asparaginase + daunorubicin / doxorubicin + filgrastim, vincristine + dexamethasone / prednisone + asparaginase + daunorubicin / doxorubicin + cyclophosphamide + methotrexate, and vincristine + dexamethasone / prednisone + asparaginase + daunorubicin / doxorubicin + cyclophosphamide + methotrexate + filgrastim. An immunomodulatory agent can be administered in combination with one or therapeutic agents useful in the treatment of chronic lymphocytic leukemia, including, without limitation, chlorambucil (Leukeran®), cladribine (2-CdA, Leustatin®), cyclophosphamide (Cytoxan®, Neosar ®, CTX), cytarabine (Cytosar-U®, ara-C, cytosine arabinoside, DepoCyt®, cytarabine ocphosphate, ara-CMP), doxorubicin (Adriamycin®, Doxil®, Rubex®), fludarabine (Fludara®, FAMP), pentostatin (Nipent®, 2-deoxicoformycin), prednisone and vincristine (Oncovorin®, Onco TCS®, VCR, Leurocristine®). Additional examples of therapeutic agents useful in the treatment of chronic lymphocytic leukemia that can be administered in combination with an immunomodulatory agent, include, without limitation, alemtuzumab (Campath®), aminocamptothecin (9-AC, 9-aminocamptothecin, NSC 603071), aminopterin , annamicin (AR-522, annamicin LF, Aronex®), arabinosilguanine (Ara-G, GW506U78, Nelzarabine®, compound 506U78), arsenic trioxide (Trisenox®, ATO, Atrivex®), Bryostatin-1 (Bryostatin®, BMY -45618, NSC-339555), CS-682, Dolastatin-10 (DOLA-10, NSC-376128), filgrastim (Neupogen®, G-CSF, Leucine), Flavopiridol (NSC-649890, HMR-1275), G3139 ( Genasense®, GentaAnticode®, Bcl-2 antisense), Irofulven (MGI-114, Ivofulvan, acylfulvene analog), MS-209, phenylbutyrate, Rituximab® (Rituxan®, anti-CD20 mAb), thalidomide, theophylline, TNP- 470 (AGM-1470, Fumagillin), UCN-01 (7-hydroxystaurosporine) and WHI-P131. Preferred combinations of therapeutic agents useful in the treatment of chronic lymphocytic leukemia that can be administered in combination with an immunomodulatory agent, include, without limitation, fludarabine + prednisone, and cyclophosphamide + doxorubicin + vincristine + prednisone (CHOP). In a further embodiment, an immunomodulatory agent is administered in combination with cytokines. Cytokines that can be administered with an immunomodulatory agent include, without limitation, GM-CSF, G-CSF, IL2, IL3, IL4, IL5, IL6, IL7, IL10, IL12, IL13, IL15, anti-CD40, CD40L, IFN -alpha, IFN-beta, IFN-gamma, TNF-alpha, and TNF-beta. In another embodiment, an immunomodulatory agent can be administered with any interleukin, including without limitation IL-1alpha, IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7. , IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL -20, IL-21, and IL-22. In preferred embodiments, an immunomodulatory agent is administered in combination with IL4 and IL10. The present inventors have observed that both IL4 and IL10 promote the proliferation of B cells mediated by neutrokine-alpha. The present inventors have observed that in vitro, IFN gamma and IL-10 promote cell surface expression of neutrokine-alpha in monocytes and macrophages (macrophages were obtained by culturing primary monocytes with 20 ng / ml of M-CSF for 12-15 days), while treatment with IL-4 decreased cell surface expression of neutrokine-alpha in monocytes and macrophages. IL-4 administered with IL-10 resulted in the complete inhibition of cell surface expression induced by IL-10 of neutrocine-alpha. IL-4 administered with IFN-gamma resulted in an increase in cell surface expression of neutrocine-alpha. Treatment of macrophages with IFN-gamma and IL-10 resulted in a 3-fold increase in soluble (active) neutrokine-alpha released into the culture medium, compared to untreated macrophages. In a further embodiment, an immunomodulatory agent is administered with a chemokine. In another embodiment, an immunomodulatory agent is administered with chemokine beta-8, chemokine beta-1, or macrophage inflammatory protein 4. In a preferred embodiment, an immunomodulatory agent is administered with chemokine beta-8. In a further embodiment, an immunomodulatory agent is administered in combination with an IL-4 antagonist. Antagonists of IL-4 that can be administered with an immunomodulatory agent include, without limitation: soluble IL-4 receptor polypeptides, multimeric forms of soluble IL-4 receptor polypeptides; anti-IL-4 receptor antibodies that bind to the IL-4 receptor without transducing the biological signal elicited by IL-4, anti-IL-4 antibodies that block the binding of IL-4 to one or more IL-4 receptors 4, and IL-4 muteins that bind to IL-4 receptors but do not transduce the biological signal elicited by IL-4. Preferably, the antibodies used according to this method are monoclonal antibodies (which include antibody fragments, such as for example those described herein). In a further embodiment, an immunomodulatory agent is administered in combination with hematopoietic growth factors. Haematopoietic growth factors that can be administered with an immunomodulatory agent include, without limitation, LEUKINE ™ (SARGRAMOSTIM ™) and NEUPOGEN ™ (FILGRASTIM ™). In a further embodiment, an immunomodulatory agent is administered in combination with fibroblast growth factors. Fibroblast growth factors that can be administered with an immunomodulatory agent include, without limitation, FGF-1, FGF-2, FGF-3, FGF-4, FGF-5, FGF-6, FGF-7, FGF-8 , FGF-9, FGF-10, FGF-11, FGF-12, FGF-13, FGF-14, and FGF-15. In a further embodiment, an immunomodulatory agent is administered in combination with an antihypertensive agent. Antihypertensives that can be administered with an immunomodulatory agent include, without limitation, calcium channel blocking agents, such as nifedipine (ADALAT ™, PROCARDIA ™); peripheral vasodilators, such as hydralazine (APRESOLINE ™); beta-adrenergic blocking agents, such as propranolol (INDERAL ™); alpha / beta adrenergic blockers, such as labetolol (NORMODYNE ™, TRANDATE ™); agents that inhibit the production of angiotensin II, such as captopril (CAPOTEN ™); agents that directly inhibit the activity of angiotensin II, such as losartan (COZAAR ™); and thiazide diuretics, such as hydrochlorothiazide (HIDRODIURIL ™, ESIDREX ™). The immunomodulatory agents can be administered alone or in combination with other adjuvants. Adjuvants that can be administered with an immunomodulatory agent include without limitation, alum, alum plus deoxycholate (ImmunoAg), MTP-PE (Biocine Corp.), QS21 (Genentech, Inc.), BCG and MPL. In a specific embodiment, an immunomodulatory agent is administered in combination with alum. In another specific embodiment, an immunomodulatory agent is administered in combination with QS-21. Additional adjuvants that can be administered with an immunomodulatory agent include, without limitation, monophosphoryl lipid immunomodulator, AdjuVax 100a, QS-21, QS-18, CRL1005, aluminum salts, MF-59 and Virosomal adjuvant technology. Vaccines that can be administered with an immunomodulatory agent include, without limitation, vaccines to protect against MMR (measles, mumps, rubella), polio, chicken pox, tetanus / diphtheria, hepatitis A, hepatitis B, Haemophilus influenzae B, whooping cough, pneumonia , influenza, Lyme disease, rotavirus, cholera, yellow fever, Japanese encephalitis, polio, rabies, typhoid and pertussis, or PNEUMOVAX-23 ™. In another specific embodiment, an immunomodulatory agent is used in combination with PNEUMOVAX-23 ™. In one embodiment, an immunomodulatory agent is administered in combination with another member of the TNF family. TNF-related, TNF-related or TNF-like molecules that can be administered with an immunomodulatory agent include, without limitation, soluble forms of TNF-alpha, lymphotoxin alfa (LT-alpha, also known as TNF-beta), LT-beta (found in the heterotrimeric complex LT-alpha2-beta), OPGL, FasL, CD27L, CD30L, CD40L, 4-1 BBL, DcR3, OX40L, TNF-gamma (international publication No. WO 96/14328), TRAIIJAIM-I ( international publication No.

WO 97/33899), LIGHT / AIM-II (International Publication No. WO 97/34911), APRIL (J. Exp. Med. 188 (6): 1185-1190), endoc-alpha (International Publication No. WO 98 / 07880), FASTR / TR6 (International Publication No. WO 98/30694), Osteoprotegrin (OPG), and Neutrocine-alpha (International Publication No. WO 98/18921, OX40, and nerve growth factor (NGF), and soluble forms of Fas, CD30, CD27, CD40 and 4-IBB, TR2 (international publication No. WO 96/34095), DR3 (international publication No. WO 97/33904), TRAIL-R1 / DR4 (international publication No. WO 98/32856), TRAIL-R3, TR5 (international publication No. WO 98/30693), TR6 (international publication No. WO 98/30694), TRAIL-R2 / TR7 (international publication No. WO 98/41629), TRANK , TR9 (international publication No. WO 98/56892), TRAIL-R4 / TR10 (international publication No. WO 98/54202), 312C2 (international publication No. WO 98/06842), and TR12. In another embodiment, an agent The immunomodulator is administered in combination with n one or more neutrocine-alpha receptors (eg, TACI, BCMA and BAFF-R). In preferred embodiments, the neutrocine-alpha receptor is soluble. In other preferred embodiments, the neutrokine-alpha receptor is fused to the Fe region of an immunoglobulin molecule, such as the Fe region of an IgG molecule. For example, amino acid residues 1-154 of TACI (GenBank Registration No. AAC51790), amino acids 1-48 of BCMA (GenBank Registration No. NP 001183, or amino acids 1 to 81 of BAFF-R (No. GenBank registration numbers NP_443177 can be fused to the Fe region of an IgG molecule and used in combination with another immunomodulating agent known in the art or described herein In another embodiment, a BAFF-R-Fc protein that can be administered in combination with an immunomodulatory agent comprises amino acids 1-70 of SEQ ID NO: 10 fused with the Fe region of an IgG1 immunoglobulin molecule Optionally, amino acid 20 (valine) of BAFF-R is substituted with aspargin, and amino acid 27 (leucine) of BAFF-R is substituted with proline In a preferred embodiment, an immunomodulatory agent is administered in combination with anti-CD40L antibodies or anti-CD40 antibodies In a further embodiment, an immunomodulatory agent is administered alone or in combination with one or more anti-angiogenic agents. Anti-angiogenic agents that can be administered with an immunomodulatory agent include, without limitation, Angiostatin (Entremed, Rockville, Maryland), Troponin-1 (Boston Life Sciences, Boston, Massachusetts), and anti-invasive factor, retinoic acid and its derivatives, paclitaxel (Taxol), Suramin, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2, VEGI, plasminogen activator inhibitor 1, plasminogen activator inhibitor 2, and various forms of the lighter transition metals of the "group d". The lighter transition metals of "group d" include, for example, species of vanadium, molybdenum, tungsten, titanium, niobium and tantalum. Said transition metal species can form transition metal complexes. Suitable complexes of the above-mentioned transition metal species include oxo transition metal complexes. Representative examples of vanadium complexes include oxo vanadium complexes such as vanadate and vanadyl complexes. Suitable vanadate complexes include metavanadate and orthovanadate complexes such as for example ammonium metavanadate, sodium metavanadate and sodium orthovanadate. Suitable vanadyl complexes include, for example, vanadyl acetylacetonate and vanadyl sulfate, including vanadyl sulfate hydrates such as vanadyl sulfate mono- and trihydrate. Representative examples of tungsten and molybdenum complexes also include oxo complexes. Suitable tungsten oxo complexes include tungsten oxide and tungsten complexes. Suitable tungstate complexes include ammonium tungstate, calcium tungstate, sodium tungstate dihydrate and tungstic acid. Suitable tungsten oxides include tungsten oxide (IV) and tungsten oxide (VI). Suitable oxo molybdenum complexes include complexes of molybdate, molybdenum oxide and molybdenyl. Suitable molybdate complexes include ammonium molybdate and its hydrates, sodium molybdate and its hydrates, and potassium molybdate and its hydrates. Suitable molybdenum oxides include molybdenum oxide (VI), molybdenum oxide (VI) and molybdic acid. Suitable molybdenyl complexes include, for example, molybdenyl acetylacetonate. Other suitable complexes of tungsten and molybdenum include the hydroxo derivatives thereof, derived for example from glycerol, tartaric acid and sugars. A wide variety of other anti-angiogenic factors can also be used in the context of the present invention. Representative examples include, without limitation, platelet factor 4; protamine sulfate; Sulphated chitin derivatives (prepared from queen crab shells; Murata et al., Cancer Res. 51: 22-26, 1991); sulfated polysaccharide and peptidoglycan complex (SP-PG; the function of this compound can be enhanced by the presence of steroids such as estrogen and tamoxifen citrate); staurosporine; modulators of matrix metabolism including, for example, proline analogs, cishydroxyproline, d, L-3,4-dehydroproline, tiaproline, alpha.alpha.-dipyridyl, aminopropionitrile fumarate; 4-propyl-5- (4-pyridinyl) -2 (3H) -oxazolone; methotrexate; mitoxantrone; heparin; Interferons; serum macroglobulin 2; ChlMP-3 (Pavloff et al., J. Biol. Chem. 267: 17321-17326, 1992); Chemostatin (Tomkinson et al., Biochem J. 286: 475-480, 1992); cyclodextrin tetradecasulfate; eponemycin; camptothecin; fumagillin (Ingber et al., Nature 348: 555-557, 1990); sodium and gold thiomalate ("GST", Matsubara and Zif, J. Clin.Invest.79: 1440-1446, 1987); serum anticolagenase; alpha2-antiplasmin (Holmes et al., J. Biol. Chem. 262 (4): 1659-1664, 1987); Bisantrene (National Cancer Insti); disodic lobenzarit (disodium salt of N- (2) -carboxyphenyl-4-chloroanthronilic acid or "CCA"; Takeuchí et al., Agents Actions 36: 312-316, 1992); and metalloproteinase inhibitors such as BB94.

Additional anti-angiogenic factors that can also be used in the context of the present invention include thalidomide (Celgene, Warren, New Jersey); angiostatic steroid; AGM-1470 (H. Brem and J. Folkman, J Pediatr Surg. 28: 445-51 (1993)); an alpha v beta 3 integrin antagonist (C. Storgard et al., J Clin Invest. 103: 47-54 (1999)); carboxyminolmidazole; carboxyamidotriazole (CAI) (National Cancer Institute, Bethesda, Maryland); Conbretastatin A-4 (CA4P) (OXIGENE, Boston, Massachusetts); Squalamine (Magainin Pharmaceuticals, Plymouth Meeting, Pennsylvania); TNP-470, (Tap Pharmaceuticals, Deerfield, Illinois); ZD-0101 AstraZeneca (London, United Kingdom); APRA (CT2584); Benefin, Byrostatin-1 (SC359555); CGP-41251 (PKC 412); CM101; Dexrazoxane (ICRF187) DMXAA; endostatin; flavopridiol; genestein; GTE; IrmTher; Iressa (ZD1839) octreotide (Somatostatin); Panretín; pentacylamine; Photopoint; PI-88 Prinomastat (AG-3540) Purlytin; Suradista (FCE26644); tamoxifen (Nolvadex); tazarotene; tetrathiomolybdate; Xeioda (Capecitabine); and 5-fluorouracil. Anti-angiogenic agents that can be administered in combination with an immunomodulatory agent can function through a variety of mechanisms including, without limitation, inhibition of extracellular matrix proteolysis, blocking the function of extracellular matrix adhesion molecules of endothelial cell, antagonism of the function of angiogenesis inducers such as growth factors, and inhibition of integrin receptors expressed on proliferative endothelial cells. Examples of antiangiogenic inhibitors that affect proteolysis of the extracellular matrix and that can be administered in combination with an immunomodulatory agent, include without limitation, AG-3540 (Agouron, La Jolla, California), BAY-12-9566 (Bayer, West Haven , Connecticut), BMS-275291 (Bristol Myers Squibb, Princeton, New Jersey), CGS-27032A (Novartis, East Hanover, New Jersey), Marimastat (British Biotech, Oxford, United Kingdom), and Metastat (Aeterna, St-Foy , Quebec). Examples of anti-angiogenic inhibitors that act by blocking the function of adhesion molecules of the endothelial cell extracellular matrix, and which can be administered in combination with an immunomodulatory agent, include without limitation, EMD-121974 (Merck KcgaA Darmstadt, Germany) and Vitaxin (Ixsys, La Jolla, California / Medimmune, Gaithersburg, Maryland). Examples of anti-angiogenic agents that act by antagonizing or directly inhibiting angiogenesis inducers and that can be administered in combination with an immunomodulatory agent, include without limitation, Angiozyme (Ribozyme, Boulder, Colorado), Anti-VEGF antibody (Genentech, S. San Francisco , California), PTK-787 / ZK-225846 (Novartis, Basel, Switzerland), SU-101 (Sugen, S. San Francisco, California), SU-5416 (Sugen / Pharmacia Upjohn, Bridgewater, New Jersey), and SU -6668 (Sugen). Other angiogenic agents act to directly inhibit angiogenesis. Examples of indirect inhibitors of angiogenesis that can be administered in combination with the immunomodulatory agent include, without limitation, IM-862 (Cytran, Kirkland, Washington), interferon-alpha, IL-12 (Roche, Nutley, New Jersey) and polysulfate Pentosan (Georgetown University, Washington, DC). In particular embodiments, the use of an immunomodulatory agent in combination with anti-angiogenic agents is contemplated for the treatment, prevention or alleviation of an autoimmune disease, such as for example one of the autoimmune diseases described herein. In a particular embodiment, the use of an immunomodulatory agent in combination with an anti-angiogenic agent for the treatment, prevention or relief of arthritis is contemplated. In a more particular embodiment, the use of an immunomodulatory agent in combination with an antiangiogenic agent for the treatment, prevention or relief of rheumatoid arthritis is contemplated. In another modality, an immunomodulatory agent is administered in combination with an anticoagulant. Anticoagulants that can be administered with an immunomodulatory agent include, without limitation, heparin, warfarin and aspirin. In a specific embodiment, an immunomodulatory agent is administered in combination with heparin or warfarin. In another specific embodiment, an immunomodulatory agent is administered in combination with warfarin. In another specific embodiment, an immunomodulatory agent is administered in combination with warfarin and aspirin. In another specific embodiment, an immunomodulatory agent is administered in combination with heparin. In another specific embodiment, an immunomodulatory agent is administered in combination with heparin and aspirin.

In another embodiment, an immunomodulatory agent is administered in combination with an agent that suppresses the production of anti-cardiolipin antibodies. In specific embodiments, an immunomodulatory agent is administered in combination with an agent that blocks or reduces the ability of anti-cardiolipin antibodies to bind to a plasma beta-2-glycoprotein I protein linked to a phospholipid (b2GPI). In some embodiments, an immunomodulatory agent is administered in combination with antiretroviral agents, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors. Nucleoside reverse transcriptase inhibitors that can be administered in combination with an immunomodulatory agent include, without limitation, RETROVIR ™ (zidovudine / AZT), VIDEX ™ (didanosine / ddl), HMD ™ (zalcitabine / ddC), ZERIT ™ (stavudine) / d4T), EPIVIR ™ (lamivudine / 3TC), and COMBIVIR ™ (zidovudine / lamivudine). Non-nucleoside reverse transcriptase inhibitors that can be administered in combination with an immunomodulatory agent include, without limitation, VIRAMUNE ™ (nevirapine), RESCRIPTOR ™ (delavirdine) and SUSTIVA ™ (efavirenz). Protease inhibitors that can be administered in combination with an immunomodulatory agent include, without limitation, CRIXIVAN ™ (indinavir), NORVIR ™ (ritonavir), INVIRASE ™ (saquinavir) and VIRACEPT ™ (nelfinavir). In some embodiments, an immunomodulatory agent is administered in combination with antiretroviral agents, nucleoside / nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), or protease inhibitors (Pls). NRTIs that can be administered in combination with an immunomodulatory agent include, without limitation, RETROVIR ™ (zidovudine / AZT), VIDEX ™ (didanosine / ddl), HMD ™ (zalcitabine / ddC), ZERIT ™ (stavudine / d4T), EPIVIR ™ (lamivudine / 3TC), and COMBIVIR ™ (zidovudine / lamivudine). NNRTIs that can be administered in combination with an immunomodulatory agent include, without limitation, VIRAMUNE ™ (nevirapine), RESCRIPTOR ™ (delavirdine) and SUSTIVA ™ (efavirenz). Protease inhibitors that can be administered in combination with an immunomodulatory agent include, without limitation, CRIXIVAN ™ (indinavir), NORVIR ™ (ritonavir), INVIRASE ™ (saquinavir) and VIRACEPT ™ (nelfinavir). Additional NRTIs include LODENOSINE ™ (F-ddA), an acid stable adenosine NRTI, Triangle / Abbott; COVIRACIL ™ (emtricitabine / FTC; structurally related to lamivudine (3TC) but with 3 to 10 times more activity in vitro; Triangle / Abbott ) dOTC (BCH-10652, also structurally related to lamivudine but retains activity against a substantial proportion of lamivudine-resistant isolates Bíochem Pharma) Adefovir (approval rejected by the FDA for anti-HIV therapy, Gilead Sciences) PREVEON® (Adefovir Dipivoxil, the active prodrug of adefovir, its active form is PMEA-pp), TENOFOVIR ™ (bis-POC PMPA, a prodrug of PMPA, Gilead), DAPD / DXG (active metabolite of DAPD, Triangle / Abbott); D-D4FC (related to 3TC, with activity against viruses resistant to AZT / 3TC); GW420867X (Glaxo Wellcome); ZIAGEN ™ (abacavir / 159U89; Glaxo Wellcome Inc.); CS-87 (3'-azido-2 ', 3'-dideoxyuridine; WO 99/66936); and (SATE) -carrying prodrug forms of ß-L-FD4C and ß-L-FddC (WO 98/17281). Additional NNRTIs include COACTINON ™ (Emivirine / MKC-442, potent NNRTI of the HEPT class, Triangle / Abbott); CAPRAVIRINE ™ (AG-1549 / S-1153, a next-generation NNRTI with activity against viruses containing the K103N mutation, Agouron); PNU-142721 (it has an activity 20 to 50 times higher than its predecessor delavirdine and is active against K103N mutants, Pharmacia &Upjohn); DPC-961 and DPC-963 (second-generation derivatives of efavirenz, designed to be active against viruses with the K103N mutation, DuPont); GW-420867X (has an activity 25 times higher than HBY097 and is active against K103N mutants, Glaxo Wellcome); CALANOLIDE A (natural agent of latex tree; active against viruses that contain the Y181C or K103N mutation, or both); and Propolis (WO 99/49830). Additional protease inhibitors include LOPINAVIR ™ (ABT378 / r; Abbott Laboratories); BMS-232632 (an azapeptide, Bristol-Myres Squibb); TIPRANAVIR ™ (PNU-140690, a non-peptic dihydropyrone, Pharmacia &Upjohn); PD-178390 (a non-peptic dihydropyrone; Parke-Davis); BMS 232632 (an azapeptide, Bristol-Myers Squibb); L-756,423 (an analogue of indinavir, Merck); DMP-450 (a cyclic urea compound; Avid &DuPont); AG-1776 (a peptidomimetic with activity in vitro against viruses resistant to protease inhibitor, Agouron); VX-175 / GW-433908 (prodrug of amprenavir phosphate, Vertex &Glaxo Welcome); CGP61755 (Ciba); and AGENERASE ™ (amprenavir, Glaxo Wellcome Inc.). Additional antiretroviral agents include fusion inhibitors / gp41 linkers. Gp41 fusion / linker inhibitors include T-20 (a peptide from residues 643-678 of the ectodomain of the transmembrane protein gp41 of HIV, which binds to gp41 in its resting state and prevents transformation to the fusogenic state; Trimeris), and T-1249 (a second generation fusion inhibitor, Trimeris). Additional antiretroviral agents include fusion inhibitors / chemokine receptor antagonists. The chemokine receptor fusion antagonists / antagonists include CXCR4 antagonists such as AMD 3100 (a biciclam), SDF-1 and its analogs, and ALX40-4C (a cationic peptide), T22 (an 18 amino acid peptide, Trimeris) and the T22 analogs: T134 and T140; CCR5 antagonists such as RANTES (9-68), AOP-RANTES, NNY-RANTES, and TAK-779; and CCR5 / CXCR4 antagonists such as NSC 651016 (a distamycin analog). Antagonists of CCR2B, CCR3 and CCR6 are also included. Chemokine receptor agonists such as RANTES, SDF-1, MIP-1a, MIP-1β, etc. may also inhibit fusion. Additional antiretroviral agents include integrase inhibitors. Integrase inhibitors include dicaffeoylquinic acids (DFQA); L-chicoric acid (a dicaffeoyltartaric acid (DCTA)); Quinalizarin (QLC) and related anthraquinones; ZINTEVIR ™ (AR 177, an oligonucleotide that probably acts on the cell surface instead of being a true integrase inhibitor, Arondex); and naphthols such as those described in WO 98/50347. Additional retroviral agents include hydroxyurea-type compounds, such as BCX-34 (a purine nucleoside phosphorylase inhibitor; Biocryst); ribonucleotide reductase inhibitors such as DIDOX ™ (Molecules for Health); inosine monophosphate dehydrogenase inhibitors (IMPDH) such as VX-497 (Vertex); and mycolic acids such as Celicept (mycophenolate mofetil; Roche). Additional retroviral agents include viral integrase inhibitors, nuclear translocalization inhibitors of the viral genome such as arylene bis (methyl ketone) compounds; inhibitors of HIV entry such as AOP-RANTES, NNY-RANTES, RANTES-IgG fusion protein, soluble complexes of RANTES and glycosaminoglycans (GAG), and AMD-3100; nucleocapsid zinc finger inhibitors such as dithiane compounds; targets of Tat and Rev of HIV; and drug enhancers such as ABT-378. Other antiretroviral therapies and ancillary therapies include cytokines and lymphokines such as MIP-1a, MIP-1β, SDF-1a, IL-2, PROLEUKIN ™ (aldesleukin / L2-7001, Chiron), IL-4, IL-8, IL-10, IL-12, and IL-13; interferons such as IFN-a2a; antagonists of TNFs, NFKB, GM-CSF, M-CSF, and IL-10; agents that modulate immune activation such as cyclosporin and prednisone; vaccines such as Remune ™ (HIV Immunogen), APL 400-003 (Apollon), recombinant gp120 and fragments, recombinant bivalent envelope glycoprotein (B / E), rgp120CM235, MN rgp120, SF-2 rgp120, soluble gp120 / CD4 complex, protein Delta JR-FL, synthetic branched peptide derived from the discontinuous C3 / C4 domain of gp120, competent fusion immunogens, and Gag, Pol, Nef and Tat vaccines; gene-based therapies, such as genetic suppressor elements (GSEs; WO 98/54366), and intrakines (genetically modified CC chemokines, directed to the ER to block surface expression of newly synthesized CCR5 (Yang et al., PNAS 94: 11567- 72 (1997), Chen et al., Nat. Med. 3: 1110-16 (1997)), antibodies such as anti-CXCR4 antibody 12G5, anti-CCR5 antibodies 2D7, 5C7, PA8, PA9, PA10, PA11, PA12, and PA14, anti-CD4 antibodies Q4120 and RPA-T4, anti-CCR3 antibody 7B11, anti-gp120 17b, 48d, 447-52D, 257-D, 268-D and 50.1 antibodies, anti-Tat antibodies , anti-TNF-a antibodies, and monoclonal antibody 33A, hydrocarbon aryl receptor (AR) agonists and antagonists such as TCDD, 3,3 ', 4,4', 5-pentachlorobiphenyl, 3,3 ', 4,4 '-tetrachlorobiphenyl, and a-naftoflavone (WO 98/30213), and antioxidants such as the ethyl ester of? -L-glutamyl-L-cysteine (? -GCE; WO 99/56764). In other embodiments, an immunomodulatory agent is You can manage in com bination with an agent against opportunistic infection. Agents against opportunistic infection that can be administered in combination with an immunomodulatory agent, include without limitation TRIMETHOPRIM-SULFAMETHOXAZOLE ™, DAPSONE ™, PENTAMIDINE ™ ATOVAQUONE ™, ISONIAZID ™, RIFAMPIN ™, PYRAZINAMIDE ™ ETHAMBUTOL ™, RIFABUTIN ™, CLARITHROMYCIN ™, AZITHROMYCIN ™ GANCICLOVIR ™, FOSCARNET ™, CIDOFOVIR ™, FLUCONAZOLE ™ ITRACONAZOLE ™, KETOCONAZOLE ™, ACYCLOVIR ™, FAMCICOLVIR ™ PYRIMETHAMINE ™, LEUCOVORIN ™, NEUPOGEN ™ (filgrastim / G-CSF), and LEUKINE ™ (sargramostim / GM-CSF) . In a specific embodiment, an immunomodulatory agent is used in any combination with TRIMETHOPRIM-SULFAMETHOXAZOLE ™, DAPSONE ™, PENTAMIDINE ™ or ATOVAQUONE ™, to prophylactically treat, prevent or diagnose an opportunistic pneumonia infection caused by Pneumocystis carinii. In another specific embodiment, the immunomodulatory agent is used in any combination with ISONIAZID ™, RIFAMPIN ™, PYRAZINAMIDE ™ or ETHAMBUTOL ™ to prophylactically treat, prevent or diagnose an opportunistic complex infection caused by Mycobacterium avium. In another specific embodiment, the immunomodulatory agent is used in any combination with RIFABUTIN ™, CLARITHROMYCIN ™ or AZITHROMYCIN ™ to prophylactically treat, prevent or diagnose an opportunistic infection caused by Mycobacterium tuberculosis. In another specific embodiment, the immunomodulatory agent is used in combination with GANCICLOVIR ™, FOSCARNET ™ or CIDOFOVIR ™ to prophylactically treat, prevent or diagnose an opportunistic infection caused by cytomegalovirus. In another specific embodiment, the immunomodulatory agent is used in any combination with FLUCONAZOLE ™, ITRACONAZOLE ™ or KETOCONAZOLE ™ to treat prophylactically, prevent or diagnose an opportunistic infection caused by fungi. In another specific embodiment, the immunomodulatory agent is used in any combination with ACYCLOVIR ™ or FAMCILCOVIR ™ to prophylactically treat, prevent or diagnose an opportunistic infection caused by herpes simplex virus type I or type II. In another specific embodiment, the immunomodulatory agent is used in any combination with PYRIMETHAMINE ™ or LEUCOVORIN ™ to prophylactically treat, prevent or diagnose an opportunistic infection caused by Toxoplasma gondii. In another specific embodiment, the immunomodulatory agent is used in any combination with LEUCOVORIN ™ or NEUPOGEN ™ to prophylactically treat, prevent or diagnose a bacterial opportunistic infection. In a further embodiment, an immunomodulatory agent is administered in combination with an antiviral agent. Antiviral agents that can be administered with an immunomodulatory agent include, without limitation, acyclovir, ribavirin, amantadine and remantidine. In a further embodiment, an immunomodulatory agent is administered in combination with an antibiotic agent. Antibiotic agents that can be administered with an immunomodulatory agent include, without limitation, amoxicillin, aminoglycosides, beta-lactam (glycopeptide), beta-lactamases, clindamycin, chloramphenicol, cephalosporins, ciprofloxacin, ciprofloxacin, erythromycin, fluoroquinolones, macrolides, metronidazole, penicillins , quinolones, rifampin, streptomycin, sulfonamide, tetracyclines, trimethoprim, trimethoprim-sulfamethoxazole, and vancomycin. Additionally, an immunomodulatory agent can be administered alone or in combination with other therapeutic regimens including, without limitation, radiation therapy. Such combination therapy can be administered sequentially or concomitantly.

Equipment The invention also provides a pharmaceutical package or equipment comprising one or more containers with one or more of the ingredients of the pharmaceutical compositions. With said containers a tag may optionally be associated in the manner prescribed by a governmental agency that regulates the manufacture, use or sale of pharmaceutical or biological products; said label reflects the approval of the agency to manufacture, use or sell the product for human administration. In addition, the polypeptides of the present invention can be used in conjunction with other therapeutic compounds. In a specific modality, the equipment contains a label in the form prescribed by a governmental agency that regulates the manufacture, use or sale of pharmaceutical or biological products; said label reflects the approval of the agency to manufacture, use or sell the product for human administration in patients who have an ANA titre greater than or equal to 1: 80, or 30 Ul or more of anti-dsDNA antibodies in their plasma or serum blood EXAMPLES Having described the invention, it will be more readily understood by reference to the following examples, which are provided by way of illustration and are not considered to be limiting.

EXAMPLE 1 Summary of results of a clinical trial of the use of an antibody (belimumab) that neutralizes the protein neutrocin-alpha to treat systemic lupus erythematosus fSLE) A prospective, randomized, double-blind, placebo-controlled trial analyzed belimumab, an antibody that neutralizes the neutrocyan-alpha protein, added to a standard of therapy for SLE. 449 subjects with SLE were used according to the ACR criterion (Tan and others, Arthritis Rheum 25: 1271-7, (1982), and Hochberg et al., Arthritis Rheum 40: 1725, (1997)), with a history of autoantibodies measurable and SELENA SLEDAI or > 4 in the selection test. They were given intravenously the study agent (1, 4, 10 mg / kg of belimumab) or placebo on days 0, 14, 28, and then every 28 days for 52 weeks. Subjects who completed the 52-week treatment period were given the option to continue the study for a 24-week extension period. Belimumab was formulated in 10mM sodium citrate, 1.9% glycine, 0.5% sucrose 0.01% (w / v) polysorbate 80, pH 6.5 (± 0.3). Subjects receiving the placebo dose received the formulation (10 mM sodium citrate, 1.9% glycine, 0.5% sucrose, 0.01% (w / v) polysorbate 80, pH 6.5 (± 0.3)) without belimumab. Efficacy was determined every 1-2 months by SELENA SLEDAI (SS), the SLE attack rate, Global Physician Determination (PGA). The BILAG and SF-36 disease activity scores were also regularly determined. The predefined primary efficacy endpoints were the percentage reduction in the SS score at week 24 and the time to attack during 52 weeks, defined by the SLE attack rate. The biological markers included ANA, anti-dsDNA antibody (Ab), C3 / C4, Ig isotypes, and peripheral B cell FACS. B cells were analyzed every 1-2 months by four-color FACS (CD19, CD20, CD27, CD69, CD38, CD138 and CD45). Serum autoantibody concentrations were obtained, including anti-dsDNA, Ig isotypes, total protein and albumin, in the same visits. The likelihood ratio of chi2, the Wilcoxon test or the f test were used to analyze changes in biological markers. The average age of the subjects in this study was 42 years; the average duration of SLE in these subjects was 8.8 years. The reference value of the disease activity of these subjects was relatively high, 67% of the subjects having an SS score of 8 points or higher (mean SS score: 9.6). 93% of the subjects enrolled in this study were females. 70% of the subjects were Caucasian; 24% of the subjects were African-American; 3% of the subjects were Asian; and 18% of the subjects were Hispanic (overlapping categories). 98% of the subjects had a historically positive score for ANA and 71.5% of the subjects were ANA + at the beginning (ANA titre> 1: 80 or Ab anti-dsDNA> 30 IU / ml in the screening / day test) 0). 50% of the subjects had an anti-dsDNA titre = 30 IU / ml at the beginning. The most common concomitant medications for SLE used as a reference point included the following: steroids (approximately 70% of the subjects), aminoquinolines (for example antimalarials) (70%), COX-2 inhibitors (28%), COX inhibitors -1 (26%), azatrioprine (20%), methotrexate (16%), and mycophenolate mofetil (16%). 34% and 42% of active and placebo subjects, respectively, were receiving clinically significant doses of systemic corticosteroids (defined as a dose of prednisone or prednisone equivalent of> 7.5 mg / day) at the reference point. There were no significant differences in the characteristics of the reference point or termination ratio in all treatment arms (81% completed). The primary efficacy endpoints do not reach a statistical significance, but the SS score was significantly reduced by 29% at week 52 in the ANA + subjects (p = 0.0435, see Figure 1). SLE attacks decreased in the subjects of belimumab during weeks 24-52 using a reference point of 24 weeks (logarithm of the range p = 0.036). Although no significant differences were observed in composite numerical BILAG scores (calculated BILAG composite converting organ system grades to numerical scores as follows: A = 9, B = 3, C = 1, D = 0, E = 0) , in subjects ANA +, the analysis of the scores of the 8 individual organ domains revealed less increases in the score in two organ domains (musculoskeletal, p <0.008, neurological p <0.038) and a tendency towards fewer increases in score in three organ domains (cardiovascular and respiratory, p = 0.060, general p <0.15, renal, p <0.15) in subjects treated with belimumab week 52. The PGA score improved at week 16 (p = 0.016) until the week 52 (p <0.002, all active against placebo). Improvements occurred despite increases in prednisone in the placebo compared to those treated with belimumab (increases to> 7.5mg / day, ~ 15% compared to ~ 7%). In ANA + subjects, a significant reduction in the frequency of increase in prednisone was observed, from the low dose of < 7.5mg / day up to the high dose of > 7.5 mg / day, already at week 8 (p <0.05 during weeks 8-12 and during weeks 32-40). There was no efficacy response per dose, suggesting that all doses are equally active. No clinically significant differences in safety were observed, including adverse effects (AE), severity of AE, infections or laboratory toxicity in all arms of belimumab compared with placebo. Fewer subjects with belimumab had pleuritis (3.3% versus 8%, p <0.05), while more had urticaria (4% vs. 0%, p <0.05). Infusion reactions were rare, reporting only 1 severe event. Immunogenicity to belimumab was observed in 1 subject (1 mg / kg). As shown in table IX, the analysis of the subjects ANA + week 52, revealed that treatment with belimumab resulted in significant stabilization of the disease with respect to placebo, measured by the BILAG index (row 3) and by PGA (row 4). In addition, the response ratios between the treatment groups in the trial were also analyzed using a combined response endpoint (row 1), which was combined with a measure of global disease activity measured by the SS score, with a measure of a general patient condition determined by the PGA disease activity index and a measure of disease in specific organ systems, as measured by the BILAG scale. It was rated that a patient responds to treatment at the combined end point if he had a reduction in the SELENA SLEDAI > 4, without worsening your PGA score defined as an increase of < 0.3 points in the PGA score, and without worsening in any specific organ system defined as no new BILAG A organ domain score, or without two new BILAG B organ domain scores. The analysis of ANA + subjects using the point The composite endpoint described above revealed a significant response to belimumab (p = 0.0058).

Additionally, in ANA + subjects, significant improvements of the PGA scores and physical component scores SF-36 (SF-36 PCS) were observed early in the treatment. The change in mean percentage of the reference PGA showed a significant improvement (p <0.05) as early as week 4 in subjects ANA + treated with belimumab, compared to subjects ANA + treated with placebo. The values for the mean percentage of change in the PGA score at 8 weeks, 16 weeks, 48 weeks and 52 weeks also reflected a significant improvement in ANA + subjects treated with belimumab, compared to the ANA + subjects treated with placebo (p < 0.05 at 8, 16 and 48 weeks, p <0.01 at week 52). The SF-36 PCS media also showed significant improvements in the quality of life of ANA + subjects treated with belimumab, compared to subjects ANA + treated with placebo at weeks 12, 24, 48 and 52 (p <0.05 at each point of treatment). weather). Significant reductions in B cell counts (expressed as the mean percentage of change over the reference value) were observed in subjects treated with belimumab during the course of the study, including CD19 + B cells (p <0.01 for each measurement taken during the weeks 8-52), activated B cells (CD20 + / CD69 +, p <0.01 for each measurement taken during weeks 8-52), intact B cells (CD20 + / CD27-, p <0.01 for each measurement taken during weeks 8 -52), and plasmacytoid B cells (CD20 + / CD138 +; p < 0.01 for each measurement taken during weeks 16-52). B-cell counts at week 24 showed that belimumab (all treated treaties) significantly reduced B cells at week 24 compared to subjects treated with placebo. At week 24, a significant reduction in cell counts (expressed as the mean percent change over the reference value, p <0.0001) was observed for CD19 + B cells, intact B cells (CD20 + / CD27-), activated B cells (CD20 + / CD69 +), and plasmacytoid B cells (CD20 + / CD138 +). Belimumab (all combined treaties) significantly reduced B cell counts at week 52 (median). At week 52, the mean percentage of change in CD20 + B cells was 54% * for all treatment groups, combined with a significant reduction already observed at week 8 (p <0.0001). At week 52, the mean percentage of change in plasmacytoid B cells (CD20 + / CD138 +) was 62% * for all treatment groups combined. The average percentage of change in activated B cells (B CD20 + / CD69 + cells) was 70% * at week 52 (* all p <0.002). At week 52, CD19 + B cells and intact B cells (CD20 + / CD27-) were significantly reduced, while the population of memory cells was preserved. In contrast, plasma cells (CD20- / CD138 +) increased 72.5% over the reference value (2.7%) in subjects treated with belimumab, compared to 30.6% in placebo / standard therapy (p = 0.02) week 52. In addition, belimumab-induced reduction in B cell counts continued through week 76. At week 76, the mean percentage of change in CD20 + B cells was 61% in all treatment groups combined. At week 76, the mean percentage change in plasmacytoid B cells (CD20 + / CD138 +) was 60% in all the treatment groups combined. The mean percentage change in activated B cells (CD20 + / CD69 + B cells) at week 76 was 84% in all treatment groups combined. Among the subjects who initially had an anti-dsDNA titre >; 30 IU / ml, as early as week 4, a significant reduction of the anti-dsDNA titre (expressed as the mean percentage of change over the reference value) was observed in the subjects treated with belimumab, in comparison with the subjects treated with placebo (p. < 0.01 for each measurement taken during weeks 4-12; p < 0.03 for each measurement taken during weeks 16-24 &p < 0.01 for each measurement taken during weeks 32-52). Belimumab reduced anti-dsDNA Ab at week 52 by 30% (p <0.002, positive reference value) compared to 9% in placebo. This effect was sustained, since a measurement at week 76 showed a 28% reduction in anti-dsDNA Ab. Already in week 8, significant reductions induced by belimumab were observed in the serum concentrations of IgG, IgA, IgE and IgM (expressed as average percentage of change over the reference value) (p <0.0001) in the subjects treated with belimumab, compared to controls treated with placebo. Week 52 IgG, IgA, IgE and IgM were reduced in the serum (10%, 14%, 34% and 29%, respectively). The reductions continued during week 76 (12% 15%, 35% and 34%, respectively). In addition, for those subjects with Ig isotype concentrations elevated at the reference point, 41% (52/128, p = 0.0014) of the subjects who received belimumab returned to normal levels of the Ig isotype, while only 16% (7/45) of the control subjects was normalized. A significant increase in C4 complement concentrations (expressed as the mean percentage change over the reference value) was observed in each measurement taken during weeks 4-52 among patients with low C4 complement at the reference point in the treated arms with belimumab (p <0.01). By week 52, C4 had increased 33% (p = 0.0126, low reference value of C4) in arms treated with belimumab. Again, the effect of belimumab was sustained, improving C4 to 46% at week 76 in arms treated with belimumab. Week 52, 14.5% (24/165) of the anti-cDNA + subjects who received belimumab were converted to negatives compared to 3.5% (2/58) in the placebo (p = 0.012). At week 76, three additional anti-dsDNA + subjects who received belimumab were converted to negatives. Belimumab was well tolerated and showed significant bioactivity. Belimumab improved PGA scores, reduced B cell counts, increased C4, reduced anti-dsDNA, and reduced or normalized Ig isotype concentrations. The belimumab delayed the appearance of attacks after 6 months. In subjects with ANA + at the beginning, the SS score significantly improved at week 52. Finally, a combined response endpoint revealed a significant response to treatment with belimumab in ANA + subjects (see Table IX).

TABLE IX Response rate in subjects ANA + week 52 Placebo 1 0 4 0 10 0 All value mg / kg mg / kg mg / kg active pa N = 86 N = 78 N = 79 N = 78 N = 235 1 Response rate (% 25 38 34 36 108 0 0058 of subjects with reduction in (29 1%) (48 7%) (43 0%) (46 2%) (46 0%) SELENA SLEDAI > 4, and without worsening of the BILAG index (without new BILAG A organ domain score, or two new BILAG B organ domain scores) and without worsening of PGA (<0 3 increase points) 2% of subjects with reduction in 34 41 38 37 116 0 1169 SELENA SLEDAI > 4 (39 5%) (52 6%) (48 1%) (47 4%) (49 4%) 3 Percentages of subjects without 70 69 75 71 215 0 0152 worsening according to (81 4%) (88 5%) (94 9%) (91 0%) (91 5%) BILAG index (no new organ domain score) BILAG A or without two new BILAG organ domain scores B) / 4% of subjects without 66 70 70 72 212 0 0027 worsening of PGA (< 0 3 (76 7%) (89 7%) (88 6% ) (92 3%) (90 2%) points of increase of the reference value) a P-value of the probability relation test for paired comparison between all the assets against placebo combined EXAMPLE 2 Qualification of proteinuria for SELENA SLEDAI Malfunction of the kidney is often associated with systemic lupus erythematosus. The person skilled in the art knows a variety of standard measurements that can be used to determine renal function, for example the progression to end-stage renal disease, sustained duplication of creatinine in the serum, creatinine clearance, iotalamate clearance, concentration of protein in a single urine sample and protein concentration in a 24-hour urine sample. The proteinuria change calculated in the "24-hour urine samples" is one of the qualified categories in the SELENA SLEDAI. Measurements of proteinuria can be made by any known method. In a specific embodiment, a single urine specimen is collected and the amount of protein or creatinine clearance measured, see for example Lemann et al., Clin Chem., 33: 297-9, 1987; and Schwab et al., Arch Intern Med., May; 147 (5): 943-4, 1987. In a specific embodiment, the urine is collected for 24 hours and the amount of protein or creatinine clearance determined. In a specific modality, a single urine specimen is collected, the ratio between the amount of protein and the creatinine clearance is determined, and this ratio is used to estimate the amount of protein in a 24-hour urine sample; see for example Ruggenenti et al., BMJ 316 (7130): 504-9, 1998. Thus, in this example, a "24-hour urine sample" can refer to the grams of protein in the urine based on a sample of 24-hour urine, or an estimate of the grams of protein in a 24-hour urine sample. An estimate of the grams of protein in a 24-hour urine sample can be based for example on the ratio between the amount of protein in a single urine specimen and the creatinine clearance in a single urine sample. In the standard SELENA SLEDAI scoring system, a patient exhibiting a new onset of proteinuria or a recent increase in proteinuria, which results in a proteinuria value in the current 24-hour urine sample that is at least 0.5 grams more high that the proteinuria value determined in the immediately preceding 24-hour urine sample, will be assigned a score of 4 for proteinuria on the published SELENA SLEDAI scale; see for example Bombardier et al., Arthritis Rheum. Jun; 35 (6): 630-40, 1992. Therefore, under the standard SELENA SLEDAI scoring system, a subject who is assigned 4 proteinuria points of reference value will have an improvement of SELENA SLEDAI in a subsequent visit , provided that the proteinuria does not continue to increase more than 0.5 g in a 24-hour urine sample (ie, the patient will have 4 points discounted from his total score even in case of stable proteinuria or increments 0.5 g / 24). A modification of the proteinuria scoring rules of SELENA SLEDAI is described below. As in the standard scoring system of SELENA SLEDAI a patient exhibiting a new onset of proteinuria or a recent increase in proteinuria, which results in a proteinuria value in the current 24-hour urine sample that is at least 0.5 g more high that the proteinuria value determined in the immediately preceding 24-hour urine sample will be assigned a score of 4 for proteinuria. Furthermore, if the patient's proteinuria value has not improved (ie, there has not been a decrease in proteinuria in the current 24-hour urine sample of at least 0.5 g compared to the proteinuria value determined in the sample 24-hour urine immediately preceding), the patient will continue to be assigned a score of 4 for proteinuria. However, if the patient's proteinuria value has improved (ie, there has been a decrease in proteinuria in the current 24-hour urine sample of at least 0.5 g, as compared to the proteinuria value determined for the urine sample) 24 hours immediately preceding), the patient will be assigned a score of 0 for proteinuria. In a specific modality, the measurement of previous proteinuria was made in a 24-hour urine sample that was obtained <; 26 weeks before the current measurement.

EXAMPLE 3 Summary of the results of a clinical trial of the use of an antibody (belimumab) that neutralizes the neutrocyan-alpha protein to treat rheumatoid arthritis (RA) A double-blind, randomized, multicenter, phase 2, placebo-controlled study was conducted in subjects with RA. The subjects were randomized into 4 treatment groups (placebo, 1 mg / kg, 4 mg / kg and 10 mg / kg). They were given placebo or belimumab at doses of 1, 4, and 10 mg / kg on days 0, 14, and 28, and subsequently every 28 days for 24 weeks, followed by an optional 24-week extension period. Belimumab was formulated in 10 mM sodium citrate, 1.9% glycine, 0.5% sucrose, 0.01% (w / v) polysorbate 80, pH 6.5 (± 0.3). Subjects receiving placebo received the formulation (10 mM sodium citrate, 1.9% glycine, 0.5% sucrose, 0.01% (w / v) polysorbate 80, pH 6.5 (± 0.3)) without belimumab. A total of 283 subjects participated in the study. Belimumab was administered to 214 subjects at a dose of 1, 4, or 10 mg / kg during the 24-week treatment phase of the study. Sixty-nine subjects received placebo. A statistically superior ACR20 response was obtained in the treatment group of 1 mg / kg (p = 0.0097), as well as in all the active treatment groups combined (p = 0.0213). The ACR20 is an index developed by the American College of Rheumatology (ACR) to evaluate the patient's response to the treatment of rheumatoid arthritis. An ACR20 response is defined as a reduction of at least 20% in the account of painful joints and the swollen joint count, in addition to an improvement of at least 20% in 3 of 5 other determinations of symptoms or manifestations of the disease (ie, determination of patient's pain, overall determination of the patient, overall determination of the physician, self-determined disability by the patient, acute phase reagent [ESR or CRP]). In addition, the result for the treatment group of 1 mg / kg remained statistically significant under adjustment for multiple comparisons using the Bonferroni closed procedure (p <0.0166). As in subjects with SLE, belimumab was associated with improved ACR20 responses in subjects with positive autoantibody disease (rheumatoid factor [RF] or cyclic cyclic peptide [CCP]) as well as in subjects positive for C-reactive protein (CRP) ) in reference point. Biological activity was observed including statistically significant reductions of CD20 + B cells, intact B cells, activated B cells, and RF; Memory cells increased within the first month of treatment and declined slowly as treatment continued. Belimumab was well tolerated in all doses. A dose-response relationship was not evident in this study for efficacy, safety and biomarker effects. Continued treatment during the study extension period was well tolerated. The response of ACR20 increased to approximately 40% at week 48. Effects on biomarkers increased or were sustained with continued treatment, while memory cells continued to decline towards baseline values. The serum concentrations in this study were within the expected scale based on the data from phase 1, and the concomitant medications (ie, methotrexate, leflunomide or hydroxchlorofin) had no significant effect on exposure to belimumab.

EXAMPLE 4 Neutrokine-alpha extends the lifetime of B cells through two independent signaling pathways Neutrokine-alpha, also called BLyS (B lymphocyte stimulator), BAFF, TALL-1, THANK, TNFSF13B and zTNF4, is essential for the survival of peripheral B lymphocytes at rest (Rolink, AG and Melchers, F. (2002 ) Curr Opin Immunol 14, 266-275). The importance of neutrocine-alpha in the homeostasis of intact B cells is best demonstrated by the finding that mice deficient in neutrocine-alpha, produced by targeted gene deletion or introduction of soluble decoy receptors, have surprising B cell deficits. of the follicular and peripheral zone, the main populations of mature peripheral B cells (Gross, JA et al. (2001), Immunity 15, 289-302; Schiemann, B. et al. (2001), Science 293, 2111-2114). In contrast, the ectopic expression of neutrokine-alpha of a transgene, notably expands the B cells of the follicular and peripheral zone without affecting T cells, B1 cells, peripheral B cells early transition (T1), or cells B under development in the bone marrow (Mackay, F. et al. (2003), Annu Rev Immunol 21, 231-264). Neutrocin-alpha is also required for the maintenance of many B-cell tumors, and uncontrolled stimulation of neutrokine-alpha rescues autoreactive B cells from suppression, thus promoting the production of autoantibodies (Kalled, SL (2005), Immunol Rev 204, 43-54). In this way, neutrocin-alpha has a critical function in the homeostasis of both normal and pathogenic B cells. This example details the results of experiments conducted to understand the mechanism by which neutrocin-alpha promotes the survival of B cells. Experimental procedures. Mice: Pim-1 + / + 2+ +, Pim-I "^^, Pim-1 + / + 2" and "and Pim-1 '2" 7"mice were generated from the Pim-1 + supply / "2 + /" by Paul Rothman Columbia University, New York, NY The C57BIJ6 mice were from the Jackson Laboratory, Bar Harbor ME, or the National Cancer Institute Production Program, NCI-Fredrick, Fredrick MD The animals were bred and held at the Harvard Medical School of the University of Pennsylvania, or at the Medical School of the Univiversity of Massachusetts, according to the guidelines of the Insti- tional Animal Care and Use Committee B cell purification: splenic B cells were obtained by treatment of splenocytes with anti-thy1.2 and complement, followed by purification of B cells at rest using a gradient and harvesting the cells at the interface of 60-70% In some experiments CD23 + B cells were obtained by positive selection and magnetic separation of suspensions of splenocytes using biotinylated anti-CD23 antibody (BD Biosciences-Pharmingen, San Diego California) and streptavidin-coated microglots (Miltenyi Biotec, Auburn California). The CD23 + B cells were not selected for size in a Percoll since environmental activation in vivo results in the loss of CD23. B cells prepared by means of antibody and Percoll were > 90% B220 +, while the CD23 + B cells were > 95% pure. Cell cultures: Purified B cells or CD23 + B cells were cultured in RPMI-1640 supplemented with 2-mercaptoethanol, MEM-non-essential amino acids, glutamine, penicillin and streptomycin (complete medium, CM). For B-cell survival testing and other tests, recombinant human neutrocin-alpha made in Human Genome Sciences, Rockville Maryland, was used at 50-100 ng / ml. The human neutrokine-alpha labeled with FLAG was from Dr. Randolph Noelle, Dartmouth Medical School. Murine neutrocine-alpha was purchased from Alexis Biochemicals, San Diego California, and human alpha interferon (IFNa) from PBL Biomedical, Píscataway, NJ. Rapamycin was used at a final concentration of 50nM, added to cultures of a stock solution dissolved in methanol. Control B cells in the experiments using rapamycin were treated with methanol as vehicle control. For kinetic tests the B cells were prepared and refrigerated overnight at 4 ° C. 5-6 x 10 6 purified B cells were centrifuged per sample on 24-well plates that had been coated with 5 ug / ml anti-M2FLAG monoclonal antibody (Sigma), washed, blocked with 1% BSA in PBS, followed by the addition of FLAG-tagged human alpha-neutrocin, 2 ug / well, one hour before washing and addition of cells. Non-stimulated control B cells were centrifuged in wells treated with anti-FLAG antibody alone. B cells were also activated by incubation with anti-murine IgM (5 ug / ml), anti-CD40 (0.5 ug / ml), or 100ng / ml human recombinant neutrocin-alpha added to the kinetic test buffer (salt solution) balanced by Hank plus 2% BSA). Antibodies and Western Blotting: Anti-Pim 2 (1 D12) was obtained, Mouse Pim 1 (19F7), goat anti-actin (1-19), mouse anti-lg, rabbit anti-lg and goat anti-lg coupled with HRP, from Santa Cruz Biotechnology, Santa Cruz California. Anti-phosphoserine 473 rabbit Akt, phosphorethrin 389 p70S6 kinase, phosphothreonine 24/32 FKHR / FKRHL1, phosphoGSK3a / p, GSK, p70S6K, FKHR and Akt were purchased from Cell Signaling, Beverly Massachusetts. Rabbit mouse anti-Mcl-1 was purchased from Rockland, Wilmington Massachusetts. Whole cell lysates were prepared by washing B cells in ice-cold PBS and used in RIPA (150 mM NaCl, 1% NP-40, 0.5% sodium deoxycholate, 0.1% SDS, 50 mM Tris, pH8 .0), supplemented with protease inhibitors (minitab, Roche, Indianapolis, Indiana) and phosphatase inhibitor cocktails I and II (Sigma). 10-50 ug of protein was resolved on bis-tris polyacrylamide NuPage 4-12% gels (Invitrogen, Carlsbad, California) and transferred to nitrocellulose. The blots were blocked with 3% BSA (Sigma, IgG free), 0.2% Tween-20, in PBS, and incubated with primary antibody in the same buffer overnight at 4 ° C. The blots were washed with PBS-2% Tween-20, incubated with secondary antibody conjugated with HRP and developed using ECLplus (Amersham Bioscience, Piscataway New Jersey). The blots were scraped to probe again by incubation for 20 minutes at 65 ° C in PBS supplemented with 1% SDS and 100 μM and β-mercaptoethanol. Then the blots were washed and blocked as above. Survival tests: B cells at 5 x 106 / ml were cultured in 24-well tissue plates in CM at 37 ° C. B cells were supplemented with 50-100ng / ml of rhu-neutrocine-alpha, 50nM of rapamycin, 200 U of human IFNα, or a combination of these reagents. Previously, B cells were treated with 50 nM rapamycin or vehicle one hour before the culture with the test supplements, new rapamycin was added after 48 hours of culture. Survival was monitored daily by counting viable cells using tripane blue exclusion, each determination made in triplicate. Results Research on the mechanism by which neutrokine-alpha promotes B cell survival revealed that neutrokine-alpha activates the Akt / mTOR pathway in B cells. Purified B cells were stimulated during 0, 5, 20, 60 or 120 minutes with 100 ng / ml of recombinant or murine human neutrocin-alpha, or anti-lg (positive control), at 37 ° C in previously gasified medium. Lysates were prepared from the frozen samples and analyzed by Western Blot. Such stimulation of primitive B cells with recombinant neutrocin-alpha results in the activation of the Akt pathway determined by an increase in phosphorylation of the serine 473 and trenin 308 residues of Akt. Additional experiments in which purified B cells were stimulated with FLAG-labeled neutrophine-alpha bound to the plate, soluble neutral-alpha (100 ng / ml), or 0.5 μg / ml of anti-CD40 (positive control), showed that the Akt itself had been activated as observed by the phosphorylation of the Akt substrates, GSKβ and the hair transcription factors FOXOI and FOX03a. The mTOR is the main effector at the end of the Akt route. After neutrokine-alpha stimulation, mTOR activation in primary B cells was also shown by the phosphorylation of mTOR substrates, p70 S6 kinase and the 4E-BP1 translation inhibitor. The phosphorylation patterns were studied by means of Western blotting. Rapamycin is a potent mTOR inhibitor and a potent suppressor of B cell proliferation and differentiation. Small resting B cells from normal donors were cultured for four days with and without 100 ng / ml rhu-neutrocine-alpha, vehicle or 50 nM of rapamycin, which was used to pre-treat the B cells before culture, added directly to the cultures after initiation, and was added again every two days. Viable cells were determined on day 4. The associated culture of complete B cells or CD23 + with neutrocine-alpha and rapamycin does not prevent the neutrocine-alpha-mediated increase in survival, measured by the number of viable cells present after four days in the culture. This result suggests that another survival route may be active in B cells treated with neutrocin-alpha. Pims are a family of three serine / threonine kinases that can protect hematopoietic cells from rapamycin-resistant apotosis induced by a variety of activators (Fox, CJ et al., (2003) Genes Dev 17, 1841-1854. Fox, CJ, and others (2005), J Exp Med 201, 259-266). It was shown by means of Western blot that after two days treatment with 100 ng / ml of rhu-neutrocine-alpha, the primary B cells positively regulate the expression of Pim1 and Pim2. To test the implication of Pim1 and Pim2 in B cell survival mediated by neutrokine-alpha, wild type CD23 + B cells or heterozygous Pim 1"/ + 2" / + donors, doubly deficient Pim V1 '2 ~' ~ ' or deficient in Pim 2 (Pim 1 + / "2 ~ '~), were cultured in CM for 4 days with vehicle, 100 ng / ml of rhu-neutrocin-alpha, and with or without 50 nM of rapamycin. determined daily by exclusion with tripane blue Interestingly, the B cells of mice doubly deficient in Pim1 and Pim 2 (B-cells Pim-1"A2" A) exhibited greater survival when exposed to alpha-neutrocin. it could be explained if mTOR and Pim1 and 2 operated in different signaling routes that each mediated the promotion of cell survival by means of neutrocin-alpha.

To test the theory that two separate routes are involved, the effect of rapamycin on neutrokine-mediated survival in Pirn-I "7 ^" B cells was tested. The addition of rapamycin suppressed the ability of neutrokine-alpha to increase the survival of B-cells Pim-1"'" 2"'". Further investigation showed that Pim-1 + / "2" / "B cells, deficient only in the Pim2 function, were as sensitive to rapamycin as Pim-I B cells" 7 ^ "7", indicating that Pim-1 1 is not necessary for the effects of neutrocin-alpha on the survival of B cells. All together, these data show that there are 2 independent routes that work to mediate neutrokine-alpha-mediated survival, and that any of the routes alone it's enough for this neutrocin-alpha activity. Additional experiments indicated that expression of Mcl-1, a member of the Bcl-2 family that plays a role in the promotion of peripheral B and T cell homeostasis, is required for an effective increase in B cell survival ( protection against the induction of apoptosis) (data not shown). Accordingly, a composition comprising an inhibitor of the akt / mTOR pathway (for example rapamycin) and a Pim 2 pathway inhibitor, can be used to mimic the effects induced by a neutrocin-alpha antagonist. Thus, a composition comprising an inhibitor of the akt / mTOR pathway (eg, rapamycin) and an inhibitor of the Pim 2 pathway, can be used as a neutrokine-alpha antagonist to inhibit the survival of B cells, or to treat one or more of the diseases or disorders described herein. For example, a composition comprising an inhibitor of the akt / mTOR pathway (e.g. rapamycin) and an inhibitor of the Pim 2 pathway can be used to decrease the lifespan of B cells. Additionally, a composition can be used comprising an inhibitor of the akt / mTOR pathway (for example rapamycin) and an inhibitor of the Pim 2 pathway, to treat an autoimmune disease. In specific embodiments, a composition comprising an inhibitor of the akt mTOR pathway (e.g. rapamycin) and a Pim 2 pathway inhibitor, can be used to treat autoimmune diseases mediated by B cells. In other specific embodiments, it can be used a composition comprising an inhibitor of the akt mTOR pathway (e.g. rapamycin) and an inhibitor of the Pim 2 pathway, to treat autoimmune diseases in which autoantibodies prevail. In specific embodiments, a composition comprising an akt / mTOR pathway inhibitor (e.g. rapamycin) and an inhibitor of the Pim 2 pathway can be used to treat rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjogren's syndrome, type 1 diabetes, idiopathic thrombocytopenic purpura, Gullian-Barre syndrome, Hashimoto's thyroiditis, or Graves' disease. Additionally, a composition comprising a Mc1-1 inhibitor can be used to mimic the effects induced by a neutrokine-alpha antagonist. In this manner, a composition comprising a Mc1-1 inhibitor can be used as a neutral-alpha antagonist to inhibit the survival of B cells or to treat one or more of the diseases or disorders described herein. For example, a composition comprising a Mc1-1 inhibitor can be used to reduce the lifespan of B cells. Additionally, a composition comprising a Mc1-1 inhibitor can be used to treat an autoimmune disease. In specific embodiments, a composition comprising an inhibitor of Mc1-1 can be used to treat autoimmune diseases mediated by B cells. In other specific embodiments, a composition comprising a Mc1-1 inhibitor can be used to treat autoimmune diseases in the cells. which autoantibodies prevail. In specific embodiments, a composition comprising an inhibitor of Mc1-1 can be used to treat rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjogren's syndrome, type 1 diabetes, idiopathic thrombocytopenic purpura, Gullian-Barre syndrome. , Hashimoto's thyroiditis, or Graves' disease.

EXAMPLE 5 Characterization of antibody formulations 1 mg / ml of IgG1 /? Antibody was analyzed. formulated in 10 mM of histidine and 10 mM of citrate buffers, by differential scanning calorimetry, to determine the thermal stability of the antibody in each formulation. The particular antibody used in this study was an IgG1 /? Antibody, which is specific for neutrokine-alpha and is capable of neutralizing the activity of neutrokine-alpha. The analysis revealed that the melting temperature was higher in the two buffers on the pH scale of 6.0 to 7.5, and the higher melting temperature generally indicates higher thermal stability. The melting temperature of the citrate buffer was about 2 ° C higher than the histidine buffer on this pH scale, suggesting that the citrate buffer can give a more stable antibody formulation. However, the thermal reversibility of the antibody was higher in the histidine buffer than in the citrate buffer. This suggests that the antibody has greater biophysical stability in histidine than in citrate, despite its lower melting temperature. This was confirmed by stability studies of the antibody formulations in which 10mM of histidine resulted in less aggregation than 10mM of citrate when stored at 2-8 ° C for 18 months. During the stability study, the buffering capacity of the two shock absorbers was determined by repeated pH measurements. In addition to providing greater biophysical stability for the antibody, it seems that histidine provides greater buffering capacity at pH 6.0-6.5, than citrate at a pH scale of 6.5-7.0. In the 18-month stability study, the histidine formulations remained at a stable pH over time at all temperatures tested (2-8 ° C, 25 ° C, and 40 ° C). In contrast, the citrate formulations had wider variations at higher temperatures (data not shown).

EXAMPLE 6 Study of long-term stability of an antibody formulation To determine the shelf life of an antibody formulation, a long-term stability study of 100mg / ml antibody in 10 mM histidine, 150 mM NaCl, 0.01% (w / v) polysorbate 80, pH was performed. 6.0 The particular antibody used in this study was an IgG1 /? Antibody, which is specific for neutrokine-alpha and is capable of neutralizing the activity of neutrokine-alpha. 2 ml aliquots were stored vertically in 5 ml glass bottles for 24 months at -80 ° C, 2-8 ° C, 25 ° C and 40 ° C. Samples were stored at -80 ° C as control, 2-8 ° C to determine shelf life, and accelerated conditions (25 ° C and 40 ° C) to monitor any possible degradation path that may occur. Periodically for 24 months, the samples were analyzed by multiple tests, including visual inspection, pH, concentrations, SDS-PAGE, SEC-HPLC, ion-exchange HPLC (IE-HPLC), bioassay, capillary isoelectric focusing (clEF), peptide, RP-HPLC and ISOQUANT®. The analysis of the samples stored for 24 months at 2-8 ° C and -80X by SEC-HPLC, IE-HPLC and RP-HPLC, was visually comparable in the three methods, with only minor differences being observed. The sample of 2-8 ° C decreased in its purity according to SEC-HPLC at a rate of approximately 0.03% per month, and increased in early elution in the peaks of IE-HPLC (mainly due to deamidation), at an approximate speed of 0.14% per month (data not shown). The sample of 2-8 ° C showed only small changes in aggregation (<1%), deamidation (~ 4%), and oxidation (1%) of the antibody after 24 months of storage. However, significant degradation was observed in all tests of samples stored under accelerated conditions. The degradation observed by SEC-HPLC under accelerated conditions included both aggregation and fragmentation. The IE-HPLC tests showed that storage at accelerated conditions results in an increase in early elution peaks. Deamidation and fragmentation were observed by peptide mapping at 25 ° C; deamidation, oxidation, fragmentation and transposition of aspartate to isoaspartate was observed at 40 ° C. In this way, 100 mg / ml of an IgG1 /? Antibody. in a pharmaceutical formulation of the invention it is stable at 2-8 ° C for at least 24 months of storage.

EXAMPLE 7 In vitro test to test the inhibition of neutrokine-alpha-neutrokine receptor-alpha interaction A test that can be used to test if a compound works as an antagonist of neutrocine-alpha is described below. Specifically, this test measures the ability of the compound to inhibit soluble neutrokine-alpha to its cognate receptor in IM9 cells. Preparation of Biotinylated Neutrocin-alpha 100 μg of human or mouse neutrocine-alpha was dialyzed overnight at 4 ° C against 50 mM sodium bicarbonate (sodium acid carbonate), pH 8.5, using a slide-a-lyzer cassette (Pierce) The next day NHS-biotin (Pierce) was dissolved in DMSO at 13.3 mg / ml. This was then added to the neutrocin-alpha at a molar ratio of 20: 1 biotin: neutrocine-alpha, mixed and incubated on ice for 2 hours. Then, the biotinylated neutrocin-alpha was dialyzed back into sterile PBS (Sigma) using a slide-a-lyzer cassette overnight at 4 ° C. Biological activity of biotinylated neutrocin-alpha was confirmed using the inhibition test of receptor binding (see below). Maintenance of IM9 cells IM9 cells are a line of human B lymphocyte cells that express neutrokine-alpha receptors. IM9 cells can be maintained in RPMI-1640 supplemented with 4 mM L-glutamine, 10% FCS, 10 U penicillin, 100 g / ml streptomycin (all Sigma reagents). The cells were thawed from the frozen stock and can be used in the tests after 5 days in culture when they reached a density of 4-8 x 105 / ml. Inhibitor assay of receptor binding 96-well flat bottom plates (Costar) were coated with 100 μg per well of a 1: 10 dilution of poly-L-lysine (Sigma) in PBS for one hour at room temperature. Then, the plates were washed twice with water, allowed to air dry and placed at 4 ° C overnight. Then 100 μg of IM9 cells were added to each well (at 106 / ml in RPMI-1640 culture medium). Then, the plates were centrifuged at 3200 rpm for 5 minutes to pellet the cells. The medium was carefully aspirated and 200 μg of MPBS (PBS containing 3% Marvel blocking solution) was added to each well. Then the plates were allowed to block for 1 hour at room temperature. In a separate 96-well plate, 10 μl of biotinylated neutrocin-alpha (at 162.5 ng / ml) in MPBS was added to each well to each well to give a final concentration of 25 ng / ml. 55 μl of each test compound was added to each well. The final volume in each well was 65 μl. Preferably, the test compound is also diluted in MPBS. The plates were then incubated at room temperature for 30 minutes. The plates coated with IM9 were washed twice in PBS, drained and immediately 50 μl of the biotinylated phage / neutrocin-alpha mixture were added and incubated at room temperature for 1 hour. The plates were washed three times in PBST and three times in PBS, drained and 50 μl of streptavidin-Delfia (Wallac) was added to each well at a dilution of 1: 1000 in the manufacturer's buffer. The plates were then incubated at room temperature for one hour and washed 6 times in Delfia wash solution (Wallac). After draining the plates, 100 μl per well of Delphia enhancing solution (Wallac) was added. Plates were gently decanted to promote micelle formation, incubated at room temperature for 10 minutes and fluorescence was read at a Wallac 1420 workstation at 6520 nm. Appropriate controls to include in this test include a sample of only neutrocin-alpha to show what is the maximum binding of the biotinylated neutrocin-alpha to its receptor in this test, and the sample that does not contain biotinylated neutrocin-alpha to show the signal background in this test. An additional useful control is a nonspecific neutrokine-alpha or "irrelevant" compound-a compound that is structurally similar to the test compound but is considered not to interact with either neutrocin-alpha or any of the neutrokine-alpha receptors. . If the test compound was an anti-neutrocine-alpha antibody of the IgG isotype, an adequate "irrelevant" control would be another IgG1 antibody that is not specific for neutrokine-alpha or any of its receptors.

EXAMPLE 8 Proliferation test of human B cells for examination and selection of neutrokine-alpha antagonist molecules in vitro A bioassay is performed in duplicate to determine the effects of a putative neutrocin-alpha antagonist in a 96 well format, mixing equal volumes of neutrokine-alpha, responder cells, and putative antagonist, each of which is prepared as a reagent 3X reservation B lymphocytes are purified from human tonsils by means of MACS (depletion of anti-CD3), washed and resuspended in complete medium (CM) (RPMI 1640 with 10% FBS containing 100 U / ml penicillin, 100 μg. / ml of streptomycin, 4mM of glutamine, 5x10E-5M of beta-mercaptoethanol), at a concentration of 3 x 106 cells / mL. Staphylococcus aureus, Cowan I (SAC, CalBiochem) is added at a concentration of 3X (3X = 1: 33.333 dilution of the stock solution). Meanwhile, 8 serial dilutions (three times) of the potential antagonist are prepared in CM in such a way that the diluted antagonists are left at 3X the final concentrations to be tested in the analysis. For example, antibodies are routinely tested starting at a final concentration of 10 ug / ml and reaching about 1.5 ng / ml. Recombinant human neutrocin is prepared in CM at a 3X concentration (3X = 300 ng / mL, 30 ng / mL, and 3 ng / mL) in CM. Potential antagonists are routinely tested at various concentrations of neutrokine-alpha to avoid false negatives due to unexpectedly low activity or antagonist concentration. 50 uL of diluted antagonist are added to the wells and then 50 uL of diluted neutrokine-alpha containing 50 uL of the cell mixture. The cells are then incubated for 72 hours (37 ° C, 5% C02) in a completely humidified chamber. After 72 hours, the cells are supplemented with 0.5 μCi / well of 3H-thymidine (6.7 Ci / mmol), and incubated for a further 24 hours. The plates are harvested using a Tomtec Cell harvester and the filters are counted in a TopCount scintillation counter (Packard). Appropriate controls to include in this test include a sample in which an antagonist is not included to show which is the maximum incorporation of 3H-thymidine in this test, and a sample that does not contain neutrocin-alpha to show the background signal in this test. proof. An additional useful control is a nonspecific neutrokine-alpha or "irrelevant" compound-a compound that is structurally similar to the test compound but is considered to interact neither with neutrocin-alpha nor with any of the neutrocyte receptors. alpha. For example, if the test compound was an anti-neutrocin-alpha antibody of the IgG isotype, a suitable "irrelevant" control would be another IgG1 antibody that is not specific for neutrocin-alpha or any of its receptors. The person skilled in the art knows the modifications that can be made to this test, for example in the order of the steps or reagents used. As a specific example, B cells can be prepared with anti-IgM instead of SAC. Also, the person skilled in the art knows other tests that can be used to test the ability of a compound to act as an antagonist of neutrocine-alpha.

EXAMPLE 9 Proliferation test of murine B cells for examination and selection of neutrokine-alpha antagonist molecules in vitro To determine whether a potential neutrokine-alpha antagonist inhibits the proliferation of B cells mediated by neutrokine-alpha, a proliferation test of murine splenocytes can be performed. Briefly, murine splenocytes are isolated by flooding a spleen using a 25g needle and 10 ml of complete medium (RPMI 1640 with 10% FBS containing 100 U / ml penicillin, 100 μg / ml streptomycin, 4 mM glutamine, 5x10"5 M-β-mercaptoethanol) The cells are passed through a 100 micron nylon filter to remove the agglomerates of cells.The cell suspension is then subjected to centrifugation at 400 xg with ficoll for 25 minutes at room temperature ( 15 ml conical tube / spleen; 3ml of ficol, 10ml of cell suspension / spleen; Ficol 1083 of Sigma). The recovered cells are washed 3 times in complete medium and counted. Afterwards, the recovered cells are diluted to a concentration of 3x106 in complete medium containing a 3X concentration of SAC (3X = 1: 33.333 dilution of the reserve, the reserve is a 10% suspension of S. aureus (Cowan I strain) , available from Calbiochem). For each antibody, aliquots of 50 μl of antibody dilutions are taken in triplicate at concentrations of 30 μg / ml, 3.0 μg / ml, and 0.3 μg / ml in individual wells of a 96-well plate. Media containing no antibody is used as a negative control (and, when necessary, human isotype controls (purchased)). The neutrocin-alpha protein is diluted in complete medium at concentrations of 300ng / ml, 90ng / ml and 30ng / ml. Then, 50 μl of each of the neutrokine-alpha dilutions are added to the series of antibody dilutions on the plates. The plate containing the antibody and the neutrokine-alpha dilutions are then incubated 30 minutes at 37 ° C, with 5% CO 2, after which 50 μl of the cell suspension of splenocytes containing SAC is added to the wells. The plates are incubated for 72 hours (37 ° C, 5% C02). After 72 hours, each well is supplemented with 50 μl of complete medium containing 0.5 μCi of 3H-thymidine (6.7 Cí / mM, Amersham) and the cells are incubated for 20-24 hours at 37 ° C, 5% C02 . After incubation, the cells are harvested using a Tomtec Cell harvester and the filters are counted in a TopCount scintillation counter (Packard). The person skilled in the art will know of the modifications that can be made to this test, for example, in the order of the steps or reagents used. As a specific example, B cells can be prepared with anti-IgM instead of SAC. The person skilled in the art will also know of other tests that can be used to test the ability of a compound to act as an antagonist of neutrocine-alpha. It will be apparent that the invention can be practiced in a different manner to that which is particularly described in the description and the preceding examples. Many modifications and variations of the present invention are possible in light of the above teachings and therefore are within the scope of the appended claims. The full description of each cited publication (including patents, patent applications, journal articles, laboratory manuals, books or other documents) is incorporated herein by reference. In addition, the list of sequences appended hereto both in computer readable form and on paper is incorporated as a reference in its entirety. In addition, the complete description (including the specification, sequence listing and drawings) of each of the following documents is hereby incorporated by reference in its entirety: provisional US applications. UU Nos. 60 / 725,625, filed on October 13, 2005; 60 / 735,967, filed on November 14, 2005; 60 / 776,664, filed on February 27, 2006; 60/781, 387, filed on March 13, 2006; 60 / 787,557, filed on March 31, 2006; 60 / 797,360, filed May 4, 2006; 60 / 814,870, filed on June 20, 2006; 60 / 815,558, filed on June 22, 2006; 60 / 815,827, filed on June 23, 2006; 60 / 834,150, filed on July 31, 2006; 60 / 725,626, filed on October 13, 2005; 60 / 735,988, filed on November 14, 2005; 60 / 776,665, filed on February 27, 2006; 60 / 797,351, filed May 4, 2006; 60 / 814,869, filed on June 20, 2006; 60 / 815,559, filed on June 22, 2006; 60 / 834,152, filed on July 31, 2006; 60 / 725,627, filed on October 13, 2005; 60 / 735,964, filed on November 14, 2005; 60 / 776,658, filed on February 27, 2006; 60 / 725,629, filed on October 13, 2005; 60 / 735,963, filed on November 14, 2005; 60 / 776,660, filed on February 27, 2006; 60 / 725,628, filed on October 13, 2005; 60 / 735,987, filed on November 14, 2005; 60 / 776,659, filed on February 27, 2006; 60 / 543,261 filed on February 11, 2004, 60 / 580,387 filed on June 18, 2004, 60 / 617,191 filed on October 12, 2004, 60 / 368,548 filed on April 1, 2002, 60 / 336,726 filed on April 7, 2004. December 2001, 60/331, 478 filed on November 16, 2001, 60 / 330,835 filed on October 31, 2001, 60 / 329,747 filed on October 18, 2001, and 60 / 329,508 filed on October 17, 2001. 2001, 60 / 225,628 filed on August 15, 2000, 60 / 227,008 filed on August 23, 2000, 60 / 234,338 filed on September 22, 2000, 60 / 240,806 filed on October 17, 2000, 60 / 250,020 filed on November 30, 2000, 60 / 276,248 filed on March 6, 2001, 60 / 293,499 filed on May 25, 2001, 60 / 296,122 filed on June 7, 2001, 60 / 304,809 filed on July 13, 2001; 60 / 122,388 filed on March 2, 1999, 60 / 124,097, filed on March 12, 1999, 60 / 126,599 filed on March 26, 2000, 60 / 127,598 filed on April 2, 1999, 60 / 130,412 filed on April 16, 1999, 60 / 130,696 filed on April 23, 1999, 60/131, 278 filed on April 27, 1999, 60/131, 673 filed on April 29, 1999, 60 / 136,784 filed on April 28, 1999 May 1999, 60 / 142,659 filed on July 6, 1999, 60 / 145,824 filed on July 27, 1999, 60 / 167,239 filed on November 24, 1999, 60 / 168,624 filed on December 3, 1999, 60 / 171, 108 filed on December 16, 1999, 60/171, 626 filed on December 23, 1999, 60 / 176,015 filed on January 14, 2000, and 60 / 036,100 filed on January 14, 1997; non-provisional US applications UU Nos. Of series: 11 / 054,539 filed on February 10, 2005, 10/739, 042 filed on December 19, 2003, 10 / 735,865 filed on December 16, 2003, 10 / 270,487 filed on October 16, 2002 , 09 / 929,493, filed on August 14, 2001, 09 / 588,947 filed on June 8, 2000, 09 / 589,285 filed on June 8, 2000, 09 / 589,286 filed on June 8, 2000, 09 / 589,287 filed on June 8, 2000, 09 / 589,288 filed on June 8, 2000, 09 / 507,968 filed on February 22, 2000 2000, 09 / 255,794 filed on February 23, 1999, and 09 / 005,874 filed on January 12, 1998; and International Patent Applications Nos. PCT / US01 / 25549, filed August 15, 2001, PCT / US00 / 04336, filed February 22, 2000, and PCT / US96 / 17957, filed October 25, 2001. nineteen ninety six.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A method of treating a patient who has an ANA > 1: 80, or 30 IU / mL or more of anti-dsDNA antibodies in your plasma or blood serum, which comprises administering a therapeutically effective amount of a neutral-alpha antagonist.

2. The method according to claim 1, further characterized in that the patient has a title of ANA > 1: 80, or 30 IU / mL or more of anti-dsDNA antibodies in your plasma or blood serum.

3. The method according to claim 1, further characterized in that the neutrokine-alpha antagonist is administered in combination with an anti-CD20 antibody.

4. The method according to claim 1, further characterized in that it comprises determining, before administering the neutral-alpha antagonist, if the patient has an ANA titre > 1: 80 or 30 IU / mL or more of anti-dsDNA antibodies in your plasma or blood serum.

5. The method according to claim 4, further characterized in that the determination is made based on the clinical history of the patient.

6. The method according to claim 4, further characterized in that the determination is made based on laboratory tests.

7. The method according to claim 1, further characterized in that the neutrokine-alpha antagonist is an anti-neutrocin-alpha antibody.

8. The method according to claim 1, further characterized in that the neutrokine-alpha antagonist is a protein comprising the neutrocyan-alpha binding domain of TACI (SEQ ID NO: 6).

9. The method according to claim 1, further characterized in that the neutrokine-alpha antagonist is a protein comprising the neutrocin-alpha binding domain of BCMA (SEQ ID NO: 8).

10. The method according to claim 1, further characterized in that the neutrocin-alpha antagonist is a protein comprising the neutrocin-alpha binding domain of BAFF-R (SEQ ID NO: 10), or a variant of the Neutrokine-alpha binding domain of BAFF-R having the sequence of amino acid residues 2-70 of SEQ ID NO: 26.

11. The method according to claim 1, further characterized in that the neutrokine antagonist -alpha is a neutrokine-alpha binding peptide, an antibody peptide, a neutrokine-alpha protein variant, or an anti-neutrokine-alpha receptor antibody.

12. The method according to claim 11, further characterized in that the protein variant of neutrocine-alpha acts as a negative dominant.

13. The method according to claim 1, further characterized in that the patient has an autoimmune disease.

14. The method according to claim 13, further characterized in that the autoimmune disease is systemic lupus erythematosus (SLE).

15. The method according to claim 14, further characterized in that the neutrokine-alpha antagonist is administered in combination with an anti-CD20 antibody.

16. The method according to claim 13, further characterized by the autoimmune disease is rheumatoid arthritis, Sjögren's syndrome, scleroderma, polymyositis, dermatomyositis, Felty syndrome, mixed connective tissue disease, Raynaud's syndrome, or chronic arthritis. youth.

17. The method according to claim 7, further characterized in that the antibody comprises the amino acid sequences of a set of VH and VL domains selected from the group consisting of: (a) the VH domain and the VL domain of SEQ ID NO: 13; (b) the VH domain and the VL domain of SEQ ID NO: 14; (c) the VH domain and the VL domain of SEQ ID NO: 15; (d) the VH domain and the VL domain of SEQ ID NO: 16; (e) the VH domain and the VL domain of SEQ ID NO: 17; (f) the VH domain and the VL domain of SEQ ID NO: 18; (g) the VH domain of SEQ ID NO: 19 and the VL domain of SEQ ID NO: 20; (h) the VH domain of SEQ ID N: 21 and the VL domain of SEQ ID NO: 22.

18. A method of treating a patient with systemic lupus erythematosus, comprising: (a) determining if the patient has a title of ANA > 1: 80, or 30 IU / mL or more of anti-dsDNA antibodies in your plasma or blood serum; and (b) administering a therapeutically effective amount of a neutrocine-alpha antagonist to said patient after making said determination.

19. The method according to claim 18, further characterized in that the patient has a title of ANA > 1: 80 or 30 IU / mL or more of anti-dsDNA antibodies in your plasma or blood serum.

20. The method according to claim 18, further characterized in that the neutrokine-alpha antagonist is administered in combination with an anti-CD20 antibody.

21. The method according to claim 18, further characterized in that it also comprises, before administering the neutral-alpha antagonist, determining whether the patient has at least one characteristic selected from the group consisting of: (a) a score of SELENA SLEDAI > 6; (b) a decreased concentration of complement factor C3 in your blood plasma or serum; (c) a decreased concentration of C4 complement factor in your blood plasma or serum; (d) the patient is receiving 7.5 milligrams / day or more of prednisone; and (e) the patient is receiving or has previously received immunosuppressive therapy for the treatment of symptoms related to lupus.

22. The method according to claim 21, further characterized in that it comprises determining if the patient has a SELENA SLEDAI > 6 before administering the neutrokine-alpha antagonist.

23. The method according to claim 21, further characterized in that it comprises determining whether the patient has less than 90 milligrams / deciliter of complement factor C3 in his plasma or blood serum before administering the neutrocyan-alpha antagonist.

24. The method according to claim 21, further characterized in that it comprises determining whether the patient has less than 16 milligrams / deciliter of the complement factor C4 in his plasma or blood serum before administering the neutrocin-alpha antagonist.

25. The method according to claim 21, further characterized in that it comprises determining if the patient is receiving 7.5 milligrams / day or more of prednisone before administering the neutrokine-alpha antagonist.

26. The method according to claim 21, further characterized in that it comprises determining whether the patient is receiving or has previously received immunosuppressive therapy for the treatment of symptoms related to lupus, before administering the neutrokine-alpha antagonist.

27. The method according to claim 18, further characterized in that the determination is made based on the patient's clinical history.

28. The method according to claim 18, further characterized in that the determination is made based on laboratory tests.

29. The method according to claim 18, further characterized in that the neutrokine-alpha antagonist is an anti-neutrocin-alpha antibody.

30. The method according to claim 1, further characterized in that the neutrokine-alpha antagonist is a protein comprising the TACI neutrophil-alpha binding domain (SEQ ID NO: 6).

31. The method according to claim 18, further characterized in that the neutrokine-alpha antagonist is a protein comprising the neutrophil-alpha binding domain of BCMA (SEQ ID NO: 8).

32. The method according to claim 18, further characterized in that the neutrocin-alpha antagonist is a protein comprising the neutrocin-alpha binding domain of BAFF-R (SEQ ID NO: 10), or a variant of the neutrocin-alpha binding domain of BAFF-R having the sequence of amino acid residues 2-70 of SEQ ID NO: 26.

33.- The method according to claim 18, further characterized in that the neutrokine-alpha antagonist is a binding peptide of neutrocin-alpha, an antibody peptide, a protein variant of neutrocine-alpha, or an anti-neutrocin-alpha receptor antibody.

34.- The method according to claim 33, further characterized in that the neutrophil-alpha protein variant acts as a negative dominant.

35. A method for reducing the frequency or amount of corticosteroid administered to a patient of systemic lupus erythematosus, which comprises administering a therapeutically effective amount of a neutrophil-alpha antagonist to said patient.

36. The method according to claim 35, further characterized in that it also comprises, before administering the neutrocin-alpha antagonist, determining whether the patient has at least one characteristic selected from the group consisting of: (a) a titer of ANA > 1:80; (b) 30 IU / mL or more of anti-dsDNA antibodies in your plasma or blood serum; (c) a score of SELENA SLEDAI = 6; (d) a decreased concentration of complement factor C3 in your blood plasma or serum; (e) a decreased concentration of C4 complement factor in your blood plasma or serum; (f) the patient is receiving 7.5 milligrams / day or more of prednisone; and (g) the patient is receiving or has previously received immunosuppressive therapy for the treatment of symptoms related to lupus.

37. The method according to claim 36, further characterized in that it comprises determining if the patient has a degree of ANA > 1: 80

38. The method according to claim 36, further characterized in that it comprises determining whether the patient has 30 IU / mL or more of anti-dsDNA antibodies in his plasma or blood serum.

39.- The method according to claim 36, further characterized in that it comprises determining if the patient has a title of ANA > 1: 80 and 30 IU / mL or more of anti-dsDNA antibodies in your plasma or blood serum.

40. The method according to claim 36, further characterized in that it comprises determining if the patient has a SELENA SLEDAI score>. 6 before administering the neutrokine-alpha antagonist.

41. The method according to claim 36, further characterized in that it comprises determining whether the patient has less than 90 milligrams / deciliter of complement factor C3 in his plasma or blood serum before administering the neutrocin-alpha antagonist.

42. The method according to claim 36, further characterized in that it comprises determining whether the patient has less than 16 milligrams / deciliter of the complement factor C4 in his plasma or blood serum before administering the neutrocin-alpha antagonist.

43. - The method according to claim 36, further characterized in that it comprises determining whether the patient is receiving 7.5 milligrams / day or more of prednisone, before administering the neutral-alpha antagonist.

44. The method according to claim 36, further characterized in that it comprises determining whether the patient is receiving or has previously received immunosuppressive therapy for the treatment of symptoms related to lupus, before administering the neutral-alpha antagonist.

45. The method according to claim 36, further characterized in that the determination is made based on the clinical history of the patient.

46. The method according to claim 36, further characterized in that the determination is made based on laboratory tests.

47. The method according to claim 35, further characterized in that the neutrokine-alpha antagonist is an anti-neutrocin-alpha antibody.

48.- The method according to claim 35, further characterized in that the neutrokine-alpha antagonist is a protein comprising the TACI neutrophil-alpha binding domain (SEQ ID NO: 6).

49. The method according to claim 35, further characterized in that the neutrokine-alpha antagonist is a protein comprising the neutrocin-alpha binding domain of BCMA (SEQ ID NO: 8).

50.- The method according to claim 35, further characterized in that the neutrocin-alpha antagonist is a protein comprising the neutrocin-alpha binding domain of BAFF-R (SEQ ID NO: 10), or a variant of the Neutrokine-alpha binding domain of BAFF-R having the sequence of amino acid residues 2-70 of SEQ ID NO: 26.

51.- The method according to claim 35, further characterized in that the neutrokine antagonist -alpha is a neutrokine-alpha binding peptide, an antibody peptide, a neutrokine-alpha protein variant, or an anti-neutrokine-alpha receptor antibody.

52. The method according to claim 51, further characterized in that the protein variant of neutrocine-alpha acts as a negative dominant.

53. The method according to claim 35, further characterized in that the corticosteroid is selected from the group consisting of prednisone, prednisolone, hydrocortisone, methylprednisolone and dexamethasone.

54. The method according to claim 35, further characterized in that the corticosteroid is prednisone.

The method according to claim 54, further characterized in that the amount of prednisone administered to a patient is reduced by at least 25% to 7.5 milligrams / day or less.

56.- A method to determine if a lupus patient is responding to medical treatment, which includes: (a) determining the SELENA SLEDAI, BILAG and PGA score of the patient before the administration of the medical treatment; (b) administer medical treatment; and (c) determining the SELENA SLEDAI, BILAG and PGA score of the patient after the administration of the medical treatment; where the patient is considered to have responded to medical treatment if the SELENA SLEDAI score determined in step (c) is 4 points or more lower than the SELENA SLEDAI score determined in step (a), the BILAG score determined in step (c) does not include a new BILAG A organ domain score, nor 2 new BILAG B organ domain scores, compared to the BILAG score determined in step (a), and the score PGA determined in step (c) is less than 0.3 points higher than the PGA score determined in step (a).

57. The method according to claim 56, further characterized in that the medical treatment is a pharmaceutical composition comprising an antagonist of neutrocine-alpha.

58. The method according to claim 56, further characterized in that the neutrokine-alpha antagonist is an anti-neutrocin-alpha antibody.

59. The method according to claim 56, further characterized in that the neutrokine-alpha antagonist is a protein comprising the neutrocyan-alpha binding domain of TACI (SEQ ID NO: 6).

The method according to claim 56, further characterized in that the neutrokine-alpha antagonist is a protein comprising the neutrocin-alpha binding domain of BCMA (SEQ ID NO: 8).

61.- The method according to claim 56, further characterized in that the neutrokine-alpha antagonist is a protein comprising the neutrocin-alpha binding domain of BAFF-R (SEQ ID NO: 10), or a variant of the Neutrokine-alpha binding domain of BAFF-R having the sequence of amino acid residues 2-70 of SEQ ID NO: 26.

62.- The method according to claim 56, further characterized in that the neutrocyte antagonist -alpha is a neutrophil-alpha binding peptide, an antibody peptide, a neutrophil-alpha protein variant, or an anti-neutrocin-alpha receptor antibody.

63. The method according to claim 62, further characterized in that the protein variant of neutrocine-alpha acts as a negative dominant. 64.- An aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody, a buffer in an amount of about 5 mM to about 50 mM, NaCl in an amount of about 150 mM to about 500 mM, a surfactant in an amount from about 0.003% to about 0.05%, with a pH from about 5.5 to about 6.5. 65.- The formulation according to claim 64, further characterized in that the antibody is an IgG1 /? Antibody. human, the buffer is histidine 10 mM, the surfactant is polysorbate 80 in an amount of 0.01% w / v, the NaCl is 150 mM, and where the formulation has a pH of 6.0. 66.- The formulation according to claim 65, further characterized in that it is stable at a temperature of about 2-8 ° C for at least one year. 67.- The formulation according to claim 65, further characterized in that it is stable at a temperature of about 2-8 ° C for at least two years. 68.- The formulation according to claim 65, further characterized in that the antibody is present in an amount of 100 mg / ml. 69.- The aqueous pharmaceutical formulation according to claim 64, further characterized in that it comprises 100 mg / ml of antibody IgG1 / ?, 0.74 mg / ml of L-histidine, 1.1 mg / ml of monohydrochloride of L-histidine, 8.8 mg / ml of NaCl, and 0.1 mg / ml of polysorbate 80, and wherein the formulation has a pH of 6.0.