Anti-TNF antibody compositions for use in methods for treatment of psoriatic arthritis

Abstract

To provide a composition comprising anti-TNF antibodies or fragments thereof for use as therapeutics for treatment of diseases mediated by TNFα, a method for treatment, and anti-TNF antibodies.SOLUTION: The present invention provides a composition for use in a treatment for patients with active Psoriatic Arthritis, the composition comprising at least one pharmaceutically acceptable carrier or diluent and at least one isolated mammalian anti-TNF antibody having a heavy chain (HC) comprising a specific amino acid sequence and a light chain (LC) comprising a specific amino acid sequence.SELECTED DRAWING: None

Description

Technical Field

[0001] (Reference to Electronically Submitted Sequence Listing) This application was electronically submitted via EFS-Web on January 22, 2019, as an ASCII-formatted sequence listing with the file name "JBI6045USPS P1Sequence Listing", and includes a sequence listing having a size of 21 kb. The sequence listing submitted via EFS-Web is part of this specification and is hereby incorporated by reference in its entirety into this specification.

[0002] (Field of the Invention) The present invention relates to compositions and methods using an anti-TNF antibody, for example, an anti-TNF antibody having a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 3 6 and a light chain (LC ) comprising the amino acid sequence of SEQ ID NO: 37, for the treatment of psoriatic arthritis (PsA).

Background Art

[0003] TNFα is a soluble homotrimer of a 17 kD protein subunit. A membrane-bound 26 kD precursor form of TNF also exists.

[0004] Cells other than monocytes or macrophages also produce TNFα. For example, human non-monocytic tumor cell lines produce TNFα as well as CD4+ and CD8+ peripheral blood T lymphocytes, and some cultured T and B cell lines also produce TNFα.

[0005] TNFα causes tissue damage such as cartilage and bone degradation, induction of adhesion molecules, induction of procoagulant activity in vascular endothelial cells to increase neutrophil and lymphocyte adhesion, and to stimulate the release of platelet-activating factor from macrophages, neutrophils and vascular endothelial cells.​ causes the use.

[0006] TNFα is associated with infections, immune disorders, tumor pathologies, autoimmune pathologies, and graft-versus-host disease is. The association between TNFα and cancer and infectious pathologies is often related to the catabolic state of the host is high. Cancer patients are usually troubled by weight loss associated with loss of appetite.

[0007] The significant debilitation associated with cancer and other diseases is known as "cachexia". Cachexia is progressive weight loss, loss of appetite, and persistent decline in fat-free mass in response to the growth of malignant tumors including. The cachectic state contributes to the morbidity and mortality of many cancers. There is evidence that TNFα is involved in cachexia in cancer, infectious pathologies and other catabolic states.

[0008] TNFα is thought to play a central role in gram-negative sepsis and endotoxin shock, including fever, malaise, loss of appetite, and cachexia. Endotoxin strongly activates monocyte / macrophage production and the secretion of TNFα and other cytokines. TNFα and other monocyte-derived cytokines mediate the metabolic and neurohormonal responses to endotoxin do. Administration of endotoxin to human volunteers results in acute diseases with symptoms such as influenza, including fever, tachycardia, increased metabolic rate, and stress hormone release. The circulation of TNFα increases in patients suffering from gram-negative sepsis.

[0009] Therefore, TNFα is associated with inflammatory diseases, autoimmune diseases, viral, bacterial, and parasitic infections , malignant tumors, and / or neurodegenerative diseases, and is a useful target for specific biological therapies in diseases such as rheumatoid arthritis and Crohn's disease. Suppression of inflammation, and related Beneficial effects of good retreatment after recurrence in rheumatoid arthritis and Crohn's disease have been reported in non-blinded trials using monoclonal antibodies against TNFα Beneficial results in rheumatoid arthritis by suppression of inflammation have also been reported in randomized double-blind placebo-controlled trials.

[0010] Neutralizing antisera or mAbs against TNF have been shown to suppress detrimental physiological changes and prevent death after lethal challenge in experimental endotoxemia and bacteremia in mammals other than humans. This effect has been shown, for example, in murine lethality assays and primate pathologic model systems.

[0011] The putative receptor-binding sites of hTNF have been disclosed, and the receptor-binding sites of TNFα consisting of amino acids 11-13, 37-42, 49-57, and 155-157 of TNF have been disclosed.

[0012] Non-human mammals, chimeras, polyclonal (e.g., antisera), and / or monoclonal antibodies (Mab) and fragments (e.g., proteolytic digestion or their fusion protein products) are, in some cases, promising therapeutic agents being investigated for the treatment of certain diseases. However, such antibodies or fragments may induce an immune response when administered to humans. Such an immune response can result in immune complex-mediated clearance of the antibody or fragment from the bloodstream, rendering repeated dosing inappropriate for treatment, thereby reducing the therapeutic benefit to the patient and limiting readministration of the antibody or fragment. For example, repeated dosing of antibodies or fragments containing non-human portions can result in serum sickness and / or anaphylaxis. To avoid these and other problems, as is well known in the art, chimerization and humanization, among other approaches, have been taken to reduce the immunogenicity of such antibodies and their portions. However, these and other approaches still result in antibodies or fragments that have some immunogenicity, low affinity, low binding activity, or are associated with problems in cell culture, scale-up, production, and / or low yield. Therefore, such antibodies or fragments may not be ideally suitable for manufacture or use as therapeutic proteins. However, these and other approaches still result in antibodies or fragments that have some immunogenicity, low affinity, low binding activity, or are associated with problems in cell culture, scale-up, production, and / or low yield. Therefore, such antibodies or fragments may not be ideally suitable for manufacture or use as therapeutic proteins. However, these and other approaches still result in antibodies or fragments that have some immunogenicity, low affinity, low binding activity, or are associated with problems in cell culture, scale-up, production, and / or low yield. Therefore, such antibodies or fragments may not be ideally suitable for manufacture or use as therapeutic proteins. However, these and other approaches still result in antibodies or fragments that have some immunogenicity, low affinity, low binding activity, or are associated with problems in cell culture, scale-up, production, and / or low yield. Therefore, such antibodies or fragments may not be ideally suitable for manufacture or use as therapeutic proteins. However, these and other approaches still result in antibodies or fragments that have some immunogenicity, low affinity, low binding activity, or are associated with problems in cell culture, scale-up, production, and / or low yield. Therefore, such antibodies or fragments may not be ideally suitable for manufacture or use as therapeutic proteins. However, these and other approaches still result in antibodies or fragments that have some immunogenicity, low affinity, low binding activity, or are associated with problems in cell culture, scale-up, production, and / or low yield. Therefore, such antibodies or fragments may not be ideally suitable for manufacture or use as therapeutic proteins. SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0013] Therefore, there is a need for an anti-TNF antibody or a fragment thereof for use as a therapeutic agent for treating TNFα-mediated diseases. Therefore, there is a need for an anti-TNF antibody or a fragment thereof for use as a therapeutic agent for treating TNFα-mediated diseases. MEANS FOR SOLVING THE PROBLEM

[0014] For simplicity, the general and preferred embodiments are defined by the independent and dependent claims appended hereto, which are incorporated herein by reference. Other preferred embodiments, features, and advantages will become apparent from the following detailed description of the invention in conjunction with the accompanying drawings. For simplicity, the general and preferred embodiments are defined by the independent and dependent claims appended hereto, which are incorporated herein by reference. Other preferred embodiments, features, and advantages will become apparent from the following detailed description of the invention in conjunction with the accompanying drawings. For simplicity, the general and preferred embodiments are defined by the independent and dependent claims appended hereto, which are incorporated herein by reference. Other preferred embodiments, features, and advantages will become apparent from the following detailed description of the invention in conjunction with the accompanying drawings. For simplicity, the general and preferred embodiments are defined by the independent and dependent claims appended hereto, which are incorporated herein by reference. Other preferred embodiments, features, and advantages will become apparent from the following detailed description of the invention in conjunction with the accompanying drawings.

[0015] In certain embodiments, the invention provides a composition for use in treating a patient having active psoriatic arthritis, the composition comprising at least one pharmaceutically acceptable carrier or diluent, a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36, and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37. In certain embodiments, the invention provides a composition for use in treating a patient having active psoriatic arthritis, the composition comprising at least one pharmaceutically acceptable carrier or diluent, a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36, and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37. In certain embodiments, the invention provides a composition for use in treating a patient having active psoriatic arthritis, the composition comprising at least one pharmaceutically acceptable carrier or diluent, a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36, and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37. At least one isolated mammalian anti-TNF antibody having [description of antibody characteristics] and, the treatment comprising administering the composition to a patient by IV infusion, wherein at week 52 of the treatment, patients treated with the anti- TNF antibody are identified as patients having remission-low disease activity in the disease activity of psoriatic arthritis (DAPSA), patients identified as having moderate disease activity in DAPSA patients identified as having inactive disease activity in the psoriatic arthritis activity score (PASDAS), patients identified as having moderate disease activity in PASDAS patients identified as having minimal disease activity (MDA), patients, patients identified as not having MDA, patients identified as having very low disease activity (VLDA), patients identified as not having VLDA, patients identified as having remission in the clinical disease activity index (CDAI), and patients identified as having low disease activity in CDAI, and the composition has a significant mean change from baseline in the total modified van der Heijde-Sharp (vdH-S) score in patients selected from the group consisting of patients. Provided is a composition having a

[0016] In certain embodiments, the invention is a composition for use in the treatment of a patient having active psoriatic arthritis, comprising at least one pharmaceutically acceptable carrier or diluent, and at least one isolated mammalian anti-TNF antibody having a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a light chain (LC ) comprising the amino acid sequence of SEQ ID NO: 37, the treatment comprising administering the composition to the patient by IV infusion, wherein at week 52 of the treatment ​wherein the patient treated with the anti-TNF antibody is in the disease activity of PsA (DAPSA) Patients identified as having remission-low disease activity, patients identified as having moderate disease activity in DAPSA Patients identified as having inactive disease activity in the PsA Activity Score (PASDAS), patients identified as having moderate disease activity in PASDAS Patients identified as having inactive disease activity, patients identified as having moderate disease activity in PASDAS, patients identified as having minimal disease activity (MDA), and patients identified as not having MDA Patients identified as having very low disease activity (VLDA), patients identified as not having VLDA, patients identified as having remission in the Clinical Disease Activity Index (CDAI), and Patients identified as having low disease activity in CDAI, and the total modified van der Heijde-Sharp (vdH-S) score in patients selected from the group consisting of Patients having a significant mean change from the baseline of the vdH-S score, and the significant mean change from the baseline of the total modified vdH-S score is vdH-S = -0.88 ± 2.3 (SD) in patients identified as having remission-low disease activity in DAPSA vdH-S = -0.48 ± 1.82 (SD) in patients identified as having moderate disease activity in DAPSA, vdH-S = -1.01 ± 2.384 (SD) in patients identified as having inactive disease activity in PASDAS vdH-S = -0.20 ± 1.965 (SD) in patients identified as having moderate disease activity in PASDAS, vdH-S = -1.16 ± 2.46 (SD) in patients identified as having MDA vdH-S = 0.0 in patients identified as not having MDA and having a significant mean change from the baseline of the total modified vdH-S score, and the significant mean change from the baseline of the total modified vdH-S score is vdH-S = -0.88 ± 2.3 (SD) in patients identified as having remission-low disease activity in DAPSA, vdH-S = -0.48 ± 1.8 2 (SD) in patients identified as having moderate disease activity in DAPSA, vdH-S = -1.01 ± 2.384 (SD) in patients identified as having inactive disease activity in PASDAS vdH-S = -0.20 ± 1.965 (SD) in patients identified as having moderate disease activity in PASDAS, vdH-S = -1.16 ± 2 .46 (SD) in patients identified as having MDA, vdH-S = 0.0 in patients identified as not having MDA in patients identified as having inactive disease activity in PASDAS, vdH-S = -1.01 ± 2.384 (SD), vdH-S = -0.20 ± 1.965 (SD) in patients identified as having moderate disease activity in PASDAS, vdH-S = -1.16 ± 2 .46 (SD) in patients identified as having MDA, vdH-S = 0.0 in patients identified as not having MDA in patients identified as having MDA, vdH-S = -1.16 ± 2.46 (SD), vdH-S = 0.0 in patients identified as not having MDA vdH-S in patients identified as having 3 ± 2.44 (SD) and VLDA = -1.49 ± 2.22 (SD), vdH-S in patients identified as not having VLDA = -0.30 ± 2.52 (SD), vdH-S in patients identified as having remission in CDAI = -1.06 ± 2.41 (SD), and vdH-S in patients identified as having low disease activity in CDAI = -0.81 ± 2.12 (SD) selected from the group consisting of, provide a composition. In certain embodiments, the invention is a composition for use in the treatment of a patient having active psoriatic arthritis, comprising at least one pharmaceutically acceptable carrier or diluent, and a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37.

[0017] In certain embodiments, the invention is a composition for use in the treatment of a patient having active psoriatic arthritis, comprising at least one pharmaceutically acceptable carrier or diluent, and at least one isolated mammalian anti-TNF antibody having a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37, wherein the treatment comprises administering the composition to the patient by IV infusion, and at week 52 of the treatment, the patients treated with the anti-TNF antibody have remission-low disease activity as identified in patients having active disease, moderate disease activity as identified in patients having moderate disease activity in DAPSA, inactive disease activity as identified in patients having inactive disease activity in the PsA activity score (PASDAS), moderate disease activity as identified in patients having moderate disease activity in PASDAS, minimal disease activity (MDA) as identified in patients having MDA, patients identified as not having MDA, patients identified as having very low disease activity (VLDA), patients identified as not having VLDA, clinical disease activity in patients having remission-low disease activity as identified in patients having remission-low disease activity in DAPSA, moderate disease activity as identified in patients having moderate disease activity in DAPSA, inactive disease activity as identified in patients having inactive disease activity in the PsA activity score (PASDAS), moderate disease activity as identified in patients having moderate disease activity in PASDAS, minimal disease activity (MDA) as identified in patients having MDA, patients identified as not having MDA, patients identified as having very low disease activity (VLDA), patients identified as not having VLDA, clinical disease activity in patients having remission-low disease activity as identified in patients having remission-low disease activity in DAPSA, moderate disease activity as identified in patients having moderate disease activity in DAPSA, inactive disease activity as identified in patients having inactive disease activity in the PsA activity score (PASDAS), moderate disease activity as identified in patients having moderate disease activity in PASDAS, minimal disease activity (MDA) as identified in patients having MDA, patients identified as not having MDA, patients identified as having very low disease activity (VLDA), patients identified as not having VLDA, clinical disease activity in patients having remission-low disease activity as identified in patients having remission-low disease activity in DAPSA, moderate disease activity as identified in patients having moderate disease activity in DAPSA, inactive disease activity as identified in patients having inactive disease activity in the PsA activity score (PASDAS), moderate disease activity as identified in patients having moderate disease activity in PASDAS, minimal disease activity (MDA) as identified in patients having MDA, patients identified as not having MDA, patients identified as having very low disease activity (VLDA), patients identified as not having VLDA, clinical disease activity in patients having remission-low disease activity as identified in patients having remission-low disease activity in DAPSA, moderate disease activity as identified in patients having moderate disease activity in DAPSA, inactive disease activity as identified in patients having inactive disease activity in the PsA activity score (PASDAS), moderate disease activity as identified in patients having moderate disease activity in PASDAS, minimal disease activity (MDA) as identified in patients having MDA, patients identified as not having MDA, patients identified as having very low disease activity (VLDA), patients identified as not having VLDA, clinical disease activity in patients having remission-low disease activity as identified in patients having remission-low disease activity in DAPSA, moderate disease activity as identified in patients having moderate disease activity in DAPSA, inactive disease activity as identified in patients having inactive disease activity in the PsA activity score (PASDAS), moderate disease activity as identified in patients having moderate disease activity in PASDAS, minimal disease activity (MDA) as identified in patients having MDA, patients identified as not having MDA, patients identified as having very low disease activity (VLDA), patients identified as not having VLDA, clinical disease activity in patients having remission-low disease activity as identified in patients having remission-low disease activity in DAPSA, moderate disease activity as identified in patients having moderate disease activity in DAPSA, inactive disease activity as identified in patients having inactive disease activity in the PsA activity score (PASDAS), moderate disease activity as identified in patients having moderate disease activity in PASDAS, minimal disease activity (MDA) as identified in patients having MDA, patients identified as not having MDA, patients identified as having very low disease activity (VLDA), patients identified as not having VLDA, clinical disease activity in patients having remission-low disease activity as identified in patients having remission-low disease activity in DAPSA, moderate disease activity as identified in patients having moderate disease activity in DAPSA, inactive disease activity as identified in patients having inactive disease activity in the PsA activity score (PASDAS), moderate disease activity as identified in patients having moderate disease activity in PASDAS, minimal disease activity (MDA) as identified in patients having MDA, patients identified as not having MDA, patients identified as having very low disease activity (VLDA), patients identified as not having VLDA, clinical disease activity in patients having remission-low disease activity as identified in patients having remission-low disease activity in DAPSA, moderate disease activity as identified in patients having moderate disease activity in DAPSA, inactive disease activity as identified in patients having inactive disease activity in the PsA activity score (PASDAS), moderate disease activity as identified in patients having moderate disease activity in PASDAS, minimal disease activity (MDA) as identified in patients having MDA, patients identified as not having MDA, patients identified as having very low disease activity (VLDA), patients identified as not having VLDA, clinical disease activity Patients identified as having remission in the index (CDAI), and in patients selected from the group consisting of patients identified as having low disease activity in CDAI There is a significant mean change from baseline in the total modified van der Heijde-Sharp (vdH-S) score in patients selected from the group consisting of and there is a significant mean change from baseline in the total modified vdH-S score such that vdH-S = -0.88 ± 2.3 (SD) in patients identified as having remission-low disease activity in DAPSA, vdH-S = -0.48 ± 1.82 (SD) in patients identified as having moderate disease activity in DAPSA, vdH-S = -1.01 ± 2.384 (SD) in patients identified as having inactive disease activity in PASDAS, vdH-S = -0.20 ± 1.965 (SD) in patients identified as having moderate disease activity in PASDAS, vdH-S = -1.16 ± 2.46 (SD) in patients identified as having MDA, vdH-S = 0.03 ± 2.44 (SD) in patients identified as not having MDA, vdH-S = -1.49 ± 2.22 (SD) in patients identified as having VLDA, vdH-S = -0.30 ± 2.52 (SD) in patients identified as not having VLDA, vdH-S = -1.06 ± 2.41 (SD) in patients identified as having remission in CDAI, and vdH-S = -0.81 ± 2.12 (SD) in patients identified as having low disease activity in CDAI, and a composition is provided, wherein the composition is administered such that the antibody is administered at a dose of 2 mg / kg at week 0 and week 4 and then every 8 weeks (q8w). selected from the group consisting of, and the composition is administered such that the antibody is administered at a dose of 2 mg / kg at week 0 and week 4 and then every 8 weeks (q8w).​​​​​​​

[0018] In certain embodiments, the invention is for use in the treatment of a patient having psoriatic arthritis, a composition comprising at least one pharmaceutically acceptable carrier or diluent, and a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a light chain (LC ) comprising the amino acid sequence of SEQ ID NO: 37, at least one isolated mammalian anti-TNF antibody, wherein the treatment comprises administering the composition to the patient by IV infusion, and at the 52nd week of the treatment, the anti-TN F antibody-treated patients were identified as patients having remission-low disease activity in disease activity of PsA (DAPSA), patients identified as having moderate disease activity in DAPSA, patients identified as having inactive disease activity in PsA activity score (PASDAS), patients identified as having moderate disease activity in PASDAS, patients identified as having minimal disease activity (MDA), patients identified as not having MDA, patients identified as having very low disease activity (VLDA), patients identified as not having VLDA, patients identified as having remission in clinical disease activity index (CDAI), and patients identified as having low disease activity in CDAI, and a significant mean change from baseline in the total modified van der Heijde-Sharp (vdH-S) score in patients selected from the group consisting of and a significant mean change from baseline in the total modified vdH-S score is in patients identified as having remission-low disease activity in DAPSA, vdH-S = -0.88 ± 2.3 (SD), having moderate disease activity in DAPSA in patients identified as having inactive disease activity in PASDAS, patients identified as having moderate disease activity in PASDAS, patients identified as having minimal disease activity (MDA), patients identified as not having MDA, patients identified as having very low disease activity (VLDA), patients identified as not having VLDA, patients identified as having remission in clinical disease activity index (CDAI), and patients identified as having low disease activity in CDAI, and a significant mean change from baseline in the total modified van der Heijde-Sharp (vdH-S) score in patients selected from the group consisting of patients without MDA, patients with very low disease activity (VLDA), patients without VLDA, patients with remission in clinical disease activity index (CDAI), and patients with low disease activity in CDAI, and a significant mean change from baseline in the total modified van der Heijde-Sharp (vdH-S) score in patients selected from the group consisting of index (CDAI), and patients with remission in CDAI, and patients with low disease activity in CDAI, and a significant mean change from baseline in the total modified van der Heijde-Sharp (vdH-S) score in patients selected from the group consisting of and a significant mean change from baseline in the total modified vdH-S score is in patients selected from the group consisting of patients having a significant mean change from baseline in the total modified van der Heijde-Sharp (vdH-S) score, and a significant mean change from baseline in the total modified vdH-S score is in patients identified as having remission-low disease activity in DAPSA, vdH-S = -0.88 ± 2.3 (SD), having moderate disease activity in DAPSA in patients identified as having remission-low disease activity in DAPSA, vdH-S = -0.88 ± 2.3 (SD), in patients having moderate disease activity in DAPSA ​vdH-S = -0.48 ± 1.82 (SD), PASD in patients identified as such vdH-S = -1.01 ± 2.384 (SD), PASD in patients identified as having moderate disease activity in AS vdH-S = -0.20 ± 1.965 (SD), in patients identified as having MDA vdH-S = -1.16 ± 2.46 (SD), in patients identified as having MD vdH-S = 0.03 ± 2.44 (SD) in patients identified as not having MDA vdH-S = -1.49 ± 2.22 (SD) in patients identified as having VLDA vdH-S = -0.30 ± 2.52 (SD) in patients identified as not having VLDA vdH-S = -1.06 ± 2.41 (SD) in patients identified as having remission in CDAI and vdH-S = -0.81 ± 2.12 (SD) in patients identified as having low disease activity in CDAI consisting of a group selected from, and the composition is administered such that the antibody is administered at a dose of 2 mg / kg at week 0 and week 4, and then every 8 weeks (q8w), and the composition is administered over 30 ± 1 0 minutes, to provide a composition.

[0019] In certain embodiments, the invention is a composition for use in the treatment of a patient having active psoriatic arthritis, comprising at least one pharmaceutically acceptable carrier or diluent, and at least one isolated mammalian anti-TNF antibody having a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a light chain (LC ) comprising the amino acid sequence of SEQ ID NO: 37, wherein the treatment comprises administering the composition to the patient by IV infusion, and at week 52 of the treatment, the anti- ​​​ Patients treated with TNF antibodies who achieved remission - low in disease activity in Psoriatic Arthritis (DAPSA) Patients identified as having low disease activity, patients identified as having moderate disease activity in DAPSA Patients identified as having inactive disease activity in Psoriatic Arthritis Activity Score (PASDAS), patients identified as having moderate disease activity in PASDAS Patients identified as having inactive disease activity in PASDAS, patients identified as having moderate disease activity in PASDAS Patients identified as having Minimal Disease Activity (MDA), patients identified as not having MDA Patients identified as having very low disease activity (VLDA), patients identified as not having VLDA Patients identified as having remission in Clinical Disease Activity Index (CDAI), and patients identified as having low disease activity in CDAI Selected from the group consisting of patients having a significant mean change from baseline in the total modified van der Heijde - Sharp (vdH - S) score in patients A significant mean change from baseline in the total modified vdH - S score is vdH - S = - 0.88 ± 2.3 (SD) in patients identified as having remission - low disease activity in DAPSA vdH - S = - 0.48 ± 1.82 (SD) in patients identified as having moderate disease activity in DAPSA, vdH - S = - 1.01 ± 2.384 (SD) in patients identified as having inactive disease activity in PASDAS, vdH - S = - 0.20 ± 1.965 (SD) in patients identified as having moderate disease activity in ASDAS vdH - S = - 1.16 ± 2.46 (SD) in patients identified as having MDA S = - 1.01 ± 2.384 (SD) in patients identified as having inactive disease activity in PASDAS, vdH - S = - 0.20 ± 1.965 (SD) in patients identified as having moderate disease activity in ASDAS vdH - S = - 0.20 ± 1.965 (SD) in patients identified as having moderate disease activity in ASDAS S = - 0.20 ± 1.965 (SD) in patients identified as having moderate disease activity in ASDAS vdH - S = - 1.16 ± 2.46 (SD) in patients identified as having MDA vdH-S = 0.03 ± 2.44 (SD) in patients identified as those without DA ) and vdH-S = -1.49 ± 2.2 (SD) in patients identified as those with VLDA, and vdH-S = -0.3 0 ± 2.52 (SD) in patients identified as those without VLDA, vdH-S = -1.06 ± 2.41 (SD) in patients identified as those with remission in CDAI, and vdH-S = -0.81 ± 2.12 (SD) in patients identified as those with low disease activity in CDAI, consisting of a group selected therefrom, wherein the composition is administered such that the antibody is administered at a dose of 2 mg / kg at week 0 and week 4, and then every 8 weeks (q8w), and the patient is an adult patient 18 years of age or older , to provide a composition.

[0020] In certain embodiments, the present invention is a composition for use in the treatment of a patient having active psoriatic arthritis comprising at least one pharmaceutically acceptable carrier or diluent, and at least one isolated mammalian anti-TNF antibody having a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a light chain (LC ) comprising the amino acid sequence of SEQ ID NO: 37, wherein the treatment comprises administering the composition to the patient by IV infusion, and at week 52 of the treatment , patients treated with the anti-TN F antibody are patients identified as those having remission - low disease activity in the disease activity of PsA (DAPSA), patients identified as those having moderate disease activity in DAPSA , patients identified as those having inactive disease activity in the PsA activity score (PASDAS), patients identified as those having moderate disease activity in PASDAS , patients identified as those having minimal disease activity (MDA), patients identified as those having... Patients identified as those without MDA, with very low disease activity (VLDA) Patients identified as such, patients identified as those without VLDA, clinical disease activity Patients identified as those in remission in the Clinical Disease Activity Index (CDAI), and in the CDAI Patients selected from the group consisting of patients with low disease activity, in whom there is a significant Mean change from baseline in the total modified van der Heijde - Sharp (vdH - S) score, and a significant mean change from baseline in the total modified vdH - S score is , vdH - S=-0.88±2.3 (SD) in patients identified as those with remission - low disease activity in DAPSA, vdH - S=-0.48±1.82 (SD) in patients identified as those with moderate disease activity in DAPSA , vdH - S=-1.01±2.384 (SD) in patients identified as those with inactive disease activity in PASD AS, vdH - S=-0.20±1.965 (SD) in patients identified as those with moderate disease activity in PASDAS, vdH - S=-1.16±2.46 (SD) in patients identified as those with MDA in patients identified as such, vdH - S=0.03±2.44 (SD) in patients identified as those without MDA in patients identified as such, vdH - S=-1.49±2.22 (SD) in patients identified as those with VLDA, vdH - S=-0.30±2.52 (SD) in patients identified as those without VLDA, vdH - S=-1.06±2.41 (SD) in patients identified as those in remission in CDAI and vdH - S=-0.30±2.52 (SD) in patients with low disease activity in CDAI and vdH - S=-1.06±2.41 (SD) in patients identified as those with low disease activity in CDAI, and vdH - S=-1.49±2.22 (SD) in patients identified as those with VLDA, vdH - S=-0.30±2.52 (SD) in patients identified as those without VLDA, vdH - S=-1.06±2.41 (SD) in patients identified as those in remission in CDAI and vdH - S=-1.06±2.41 (SD) in patients identified as those with low disease activity in CDAI, and Composed of vdH-S = -0.81 ± 2.12 (SD) in patients identified as such Selected from the group, the composition is such that the antibody is administered at weeks 0 and 4, and then every 8 weeks (q8w) at a dose of 2 mg / kg, and the treatment further comprises administering the composition with or without methotrexate (MTX), to provide a composition .

[0021] In certain embodiments, the invention is a method for treating a TNF-related condition in a patient wherein the TNF-related condition is active psoriatic arthritis, and the method comprises determining the total modified van der Heijde-Sharp (vdH-S) score of the patient before treating the patient and treating the patient by intravenously (IV) injecting a composition comprising an anti-TNF antibody having a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37, and determining the total vdH-S score of the patient at week 52 of the treatment , wherein the patient treated with the composition comprising the anti-TNF antibody is identified as a patient having remission-low disease activity in the disease activity of PsA (DAPSA) , a patient identified as having moderate disease activity in DAPSA, a patient identified as having inactive disease activity in the PsA activity score (PASDAS) , a patient identified as having moderate disease activity in PASDAS, a patient identified as having minimal disease activity (MDA) , a patient identified as not having MDA, a patient identified as having very low disease activity (VLDA) , a patient identified as not having VLDA, a patient having remission in the clinical disease activity index (CDAI) , a patient identified as having moderate disease activity in PASDAS, a patient identified as having minimal disease activity (MDA) , a patient identified as not having MDA, a patient identified as having very low disease activity (VLDA) , a patient identified as not having VLDA, a patient having remission in the clinical disease activity index (CDAI) , a patient identified as having very low disease activity (VLDA), a patient identified as not having VLDA , a patient having remission in the clinical disease activity index (CDAI) Patients identified as such, and patients identified as having low disease activity in the CDAI Provided is a method of achieving a significant mean change from the baseline of the total modified vdH-S score in a patient selected from the group consisting of patients so identified.

[0022] In certain embodiments, the invention is a method for treating a TNF-related condition in a patient wherein the TNF-related condition is active psoriatic arthritis, the method comprising determining the patient's total modified van der Heijde-Sharp (vdH-S) score prior to treating the patient and administering by intravenous (IV) infusion a composition comprising an anti-TNF antibody having a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37 to treat the patient, and determining the patient's total vdH-S score at week 52 of the treatment wherein the patient treated with the composition comprising the anti-TNF antibody is a patient identified as having remission-low disease activity in disease activity of PsA (DAPSA) a patient identified as having moderate disease activity in DAPSA, a patient identified as having inactive disease activity in PsA activity score (PASDAS) a patient identified as having moderate disease activity in PASDAS, a patient identified as having minimal disease activity (MDA), a patient identified as not having MDA a patient identified as having very low disease activity (VLDA), a patient identified as not having VLDA, a patient identified as having remission in the clinical disease activity index (CDAI) and patients identified as having low disease activity in the CDAI ​​​​​​The baseline of the total modified vdH-S score in patients selected from the group of patients to whom it applies Achieve a significant mean change from the baseline of the total modified vdH-S score A significant mean change from the baseline is identified as having remission-low disease activity in DAPSA vdH-S = -0.88 ± 2.3 (SD) in patients identified as having moderate disease activity in DAPSA vdH-S = -0.48 ± 1.82 ([SD) in patients identified as having moderate disease activity in PASDAS vdH-S = -1.01 ± 2.384 (SD) in patients identified as having inactive disease activity in PASDAS vdH-S = -0.20 ± 1.965 (SD) in patients identified as having moderate disease activity in PASDAS vdH-S = -1.16 ± 2.46 (SD) in patients identified as having MDA vdH-S = 0.03 ± 2.44 (SD) in patients identified as not having MDA vdH-S = -1.49 ± 2.22 (SD) in patients identified as having VLDA vdH-S = -0.30 ± 2.52 (SD) in patients identified as not having VLDA vdH-S = -1.06 ± 2.41 (SD) in patients identified as having remission in CDAI vdH-S = -0.81 ± 2.12 (SD) in patients identified as having low disease activity in CDAI Provided is a composition selected from the group consisting of

[0023] In certain embodiments, the present invention is a method for treating a TNF-related condition in a patient wherein the TNF-related condition is active psoriatic arthritis and the method comprises, prior to treating the patient Determining the total modified van der Heijde-Sharp (vdH-S) score, and an array A heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a light chain (LC) having the amino acid sequence of SEQ ID NO: 37 is administered by intravenous (IV) injection To treat a patient, and determine the patient's total vdH-S score at week 52 of treatment Including, a patient treated with a composition comprising an anti-TNF antibody is defined as a patient having remission-low disease activity in disease activity of PsA (DAPSA), D A patient identified as having moderate disease activity in APSA, PsA activity score A patient identified as having inactive disease activity in PASDAS, PA A patient identified as having moderate disease activity in SDAS, minimal disease activity( A patient identified as having MDA), a patient identified as not having MDA, A patient identified as having very low disease activity (VLDA), a patient identified as not having VLDA A patient identified as having remission in the clinical disease activity index (CDAI) and A patient identified as having low disease activity in CDAI, and the baseline of the total modified vdH-S score in a patient selected from the group consisting of Patients achieve a significant mean change from baseline, and a significant Mean change from baseline in the total modified vdH-S score is vdH-S = -0.88 ± 2.3 (SD) in patients identified as having remission-low disease activity in DAPSA vdH-S = -0.48 ± 1.82 (SD In patients identified as having moderate disease activity in DAPSA ) and vdH-S = -0.48 ± 1.82 (SD) in patients identified as having moderate disease activity in DAPSA In patients identified as having moderate disease activity in DAPSA, and vdH-S = -0.48 ± 1.82 (SD ) in patients identified as having inactive disease activity in PASDAS vdH-S = -1.01 ± 2.384 (SD), moderate disease activity in PASDAS vdH-S = -0.20 ± 1.965 (SD) in patients identified as having it, vdH-S = -1.16 ± 2.46 ( SD) in patients identified as having MDA, vdH-S = 0.03 ± 2. 44 (SD) in patients identified as having VLDA, vdH-S = -1.4 9 ± 2.22 (SD) in patients identified as not having VLDA, vdH-S = -0.30 ± 2.52 (SD) in patients identified as having remission in CDAI , and vdH-S = -1.06 ± 2.41 (SD) in patients identified as having low disease activity in non-active disease activity CDA I, and vdH-S = -0. 81 ± 2.12 (SD), selected from the group consisting of, wherein the composition is such that the anti-TNF antibody is administered at a dose of 2 mg / kg at week 0 and week 4, and then every 8 weeks (q8w) thereafter is administered as, provides a method.

[0024] In certain embodiments, the present invention is a method for treating a TNF-related condition in a patient wherein the TNF-related condition is active psoriatic arthritis, and the method comprises determining the total modified van der Heijde-Sharp (vdH-S) score of the patient before treating the patient and treating the patient by administering, by intravenous (IV) infusion, a composition comprising an anti-TNF antibody having a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37, and determining the total vdH-S score of the patient at week 52 of the treatment (LC) and treating the patient thereby ​​comprising determining that a patient treated with a composition comprising an anti-TNF antibody is identified as a patient having remission - low disease activity in disease activity of PsA (DAPSA), a patient identified as having moderate disease activity in DAPSA, a patient identified as having inactive disease activity in PsA activity score (PASDAS), a patient identified as having moderate disease activity in PASDAS, a patient identified as having minimal disease activity (MDA), a patient identified as not having MDA, a patient identified as having very low disease activity (VLDA), a patient identified as not having VLDA, a patient identified as having remission in clinical disease activity index (CDAI), and a patient identified as having low disease activity in CDAI, and achieving a significant mean change from baseline in the total modified vdH - S score in a patient selected from the group consisting of the patients, and the significant mean change from baseline in the total modified vdH - S score is vdH - S = - 0.88 ± 2.3 (SD) in a patient identified as having remission - low disease activity in DAPSA, vdH - S = - 0.48 ± 1.82 (SD) in a patient identified as having moderate disease activity in DAPSA, vdH - S = - 1.01 ± 2.384 (SD) in a patient identified as having inactive disease activity in PASDAS, vdH - S = - 0.20 ± 1.965 (SD) in a patient identified as having moderate disease activity in PASDAS, vdH - S = - 1.16 ± 2.46 (SD) in a patient identified as having MDA, vdH - S = 0.03 ± 2. in a patient identified as not having MDA a patient identified as having remission - low disease activity in disease activity of PsA (DAPSA), D a patient identified as having moderate disease activity in DAPSA, PsA activity score a patient identified as having inactive disease activity in PsA activity score (PASDAS), PA a patient identified as having moderate disease activity in PASDAS, minimal disease activity( MDA), a patient identified as not having MDA, a patient identified as having very low disease activity (VLDA), a patient identified as not having VLDA a patient identified as having remission in clinical disease activity index (CDAI), and a patient identified as having low disease activity in CDAI from the group consisting of the patients, and achieving a significant mean change from baseline in the total modified vdH - S score in a patient selected a significant mean change from baseline in the total modified vdH - S score is vdH - S = - 0.88 ± 2.3 (SD) in a patient identified as having remission - low disease activity in DAPSA a patient identified as having moderate disease activity in DAPSA is vdH - S = - 0.48 ± 1.82 (SD ), a patient identified as having inactive disease activity in PASDAS is vdH - S = - 1.01 ± 2.384 (SD) in a patient identified as having moderate disease activity in PASDAS is vdH - S = - 0.20 ± 1.965 (SD) in a patient identified as having MDA, vdH - S = - 1.16 ± 2.46( SD), a patient identified as not having MDA is vdH - S = 0.03 ± 2. vdH-S = -1.4 in patients identified as those with 44 (SD) and VLDA vdH-S in patients identified as those without VLDA, 9 ± 2.22 (SD) =-0.30 ± 2.52 (SD), vdH-S = -1.06 ± 2.41 (SD) in patients identified as those with remission in CDAI, and vdH-S = -0. 81 ± 2.12 (SD) in patients identified as those with low disease activity in inactive disease activity CDA I, selected from the group consisting of administered such that the anti-TNF antibody is administered at a dose of 2 mg / kg at week 0 and week 4, and then every 8 weeks (q8w) thereafter, and the composition is administered over 30 ± 10 minutes, provides a method. administered such that the anti-TNF antibody is administered at a dose of 2 mg / kg at week 0 and week 4, and then every 8 weeks (q8w) thereafter, and the composition is administered over 30 ± 10 minutes, provides a method. administered such that the anti-TNF antibody is administered at a dose of 2 mg / kg at week 0 and week 4, and then every 8 weeks (q8w) thereafter, and the composition is administered over 30 ± 10 minutes, provides a method.

[0025] In certain embodiments, the invention is a method for treating a TNF-related condition in a patient wherein the TNF-related condition is active psoriatic arthritis, the method comprising determining the total modified van der Heijde-Sharp (vdH-S) score of the patient before treating the patient and treating the patient by intravenously (IV) infusing a composition comprising an anti-TNF antibody having a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37, and determining the total vdH-S score of the patient at week 52 of the treatment wherein the patient treated with the composition comprising the anti-TNF antibody is identified as a patient having remission-low disease activity in disease activity of PsA (DAPSA), a patient identified as having moderate disease activity in D APSA, a patient identified as having inactive disease activity in PsA activity score (PASDAS), PA and comprising a patient identified as having remission-low disease activity in disease activity of PsA (DAPSA), a patient identified as having moderate disease activity in D APSA, a patient identified as having inactive disease activity in PsA activity score (PASDAS), PA a patient identified as having inactive disease activity in PsA activity score (PASDAS), PA Patients identified as having moderate disease activity in SDAS, patients identified as having minimal disease activity ( MDA), patients identified as not having MDA, patients identified as having very low disease activity (VLDA), patients identified as not having VLDA, patients identified as having remission in the Clinical Disease Activity Index (CDAI) and patients identified as having low disease activity in CDAI achieve a significant mean change from baseline in the total modified vdH-S score in patients selected from the group consisting of patients, and a significant mean change from baseline in the total modified vdH-S score is vdH-S = -0.88 ± 2.3 (SD) in patients identified as having remission - low disease activity in DAPSA, vdH-S = -0.48 ± 1.82 (SD ) in patients identified as having moderate disease activity in DAPSA, vdH-S = -1.01 ± 2.384 (SD) in patients identified as having inactive disease activity in PASDAS, vdH-S = -0.20 ± 1.965 (SD) in patients identified as having moderate disease activity in PASDAS, vdH-S = -1.16 ± 2.46 ( SD) in patients identified as having MDA, vdH-S = 0.03 ± 2. 44 (SD) in patients identified as not having MDA, vdH-S = -1.4 9 ± 2.22 (SD) in patients identified as having VLDA, vdH-S = -0.30 ± 2.52 (SD) in patients identified as not having VLDA, vdH-S = -1.06 ± 2.41 (SD) in patients identified as having remission in CDAI, and inactive disease activity CDA In patients identified as having low disease activity in I, vdH-S = -0. Selected from the group consisting of 81 ± 2.12 (SD), wherein the composition is such that the anti-TNF antibody is at week 0 And week 4, and thereafter every 8 weeks (q8w) at a dose of 2 mg / kg Administered as such, and the patient is an adult patient 18 years of age or older, a method is provided.

[0026] In certain embodiments, the invention is a method for treating a TNF-related condition in a patient Wherein the TNF-related condition is active psoriatic arthritis and the method comprises, prior to treating the patient Determining the total modified van der Heijde-Sharp (vdH-S) score of the patient, and a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 And a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37 Administering, by intravenous (IV) infusion, a composition comprising an anti-TNF antibody having Treating the patient by, and determining the total vdH-S score of the patient at week 52 of treatment Including, patients treated with a composition comprising an anti-TNF antibody, patients identified as having remission-low disease activity in the disease activity of PsA (DAPSA), D Patients identified as having moderate disease activity in APSA, patients identified as having inactive disease activity in the PsA activity score (PASDAS), PA Patients identified as having moderate disease activity in SDAS, patients identified as having minimal disease activity ( MDA), patients identified as not having MDA, Patients identified as having very low disease activity (VLDA), patients identified as not having VLDA Patients identified as having remission in the clinical disease activity index (CDAI), and Patients identified as not having very low disease activity (VLDA), patients identified as not having VLDA Patients identified as having remission in the clinical disease activity index (CDAI), and a patient identified as such, and one identified as having low disease activity in the CDAI the baseline of the total modified vdH-S score in a patient selected from the group consisting of patients to achieve a significant mean change from, and a significant mean change from the baseline of the total modified vdH-S score is such that the vdH-S = -0.88 ± 2.3 (SD) in patients identified as having remission-low disease activity in DAPSA, vdH-S = -0.48 ± 1.82 (SD ) in patients identified as having moderate disease activity in DAPSA, vdH-S = -1.01 ± 2.384 (SD) in patients identified as having inactive disease activity in PASDAS , vdH-S = -0.20 ± 1.965 (SD ) in patients identified as having moderate disease activity in PASDAS, vdH-S = -1.16 ± 2.46( SD) in patients identified as having MDA, vdH-S = 0.03 ± 2. 44 (SD) in patients identified as not having MDA, vdH-S = -1.4 9 ± 2.22 (SD) in patients identified as having VLDA, vdH-S = -0.30 ± 2.52 (SD) in patients identified as not having VLDA, vdH-S = -1.06 ± 2.41 (SD) in patients identified as having remission in CDAI, and vdH-S = -0. 81 ± 2.12 (SD) in patients identified as having low disease activity in non-active disease activity CDA I, and is selected from the group consisting of, and the composition is administered such that the anti-TNF antibody is administered at a dose of 2 mg / kg at weeks 0 and 4 and then every 8 weeks (q8w) , and the method is administered with or without methotrexate (MTX) such that the composition is administered as described, and the method is administered with or without methotrexate (MTX) such that the composition is administered as described, and the method is administered with or without methotrexate (MTX) such that the composition is administered at weeks 0 and 4 and then every 8 weeks (q8w) at a dose of 2 mg / kg is administered, and the method is administered with or without methotrexate (MTX) such that the composition Provide a method further comprising administering an agent.

[0027] In certain embodiments, the invention is a method for treating a TNF-related condition in a patient wherein the TNF-related condition is active psoriatic arthritis and the method comprises determining the patient's total modified van der Heijde-Sharp (vdH-S) score prior to treating the patient and administering by intravenous (IV) infusion a composition comprising an anti-TNF antibody having a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37 to treat the patient, and determining the patient's total vdH-S score at week 52 of the treatment wherein a patient treated with the composition comprising the anti-TNF antibody is identified as a patient having remission-low disease activity in disease activity of PsA (DAPSA), a patient identified as having moderate disease activity in D APSA, a patient identified as having inactive disease activity in PsA activity score (PASDAS), a patient identified as having moderate disease activity in PA SDAS, a patient identified as having minimal disease activity ( MDA), a patient identified as not having MDA, a patient identified as having very low disease activity (VLDA), a patient identified as not having VLDA, a patient identified as having remission in clinical disease activity index (CDAI) and a patient identified as having low disease activity in CDAI, and achieving a significant mean change from baseline of the total modified vdH-S score in a patient selected from the group consisting of patients identified as such, and a significant from baseline of the total modified vdH-S score wherein a patient treated with the composition comprising the anti-TNF antibody is identified as a patient having remission-low disease activity in disease activity of PsA (DAPSA), a patient identified as having moderate disease activity in D APSA, a patient identified as having inactive disease activity in PsA activity score (PASDAS), a patient identified as having moderate disease activity in PA SDAS, a patient identified as having minimal disease activity ( MDA), a patient identified as not having MDA, a patient identified as having very low disease activity (VLDA), a patient identified as not having VLDA, a patient identified as having remission in clinical disease activity index (CDAI) and a patient identified as having low disease activity in CDAI, and achieving a significant mean change from baseline of the total modified vdH-S score in a patient selected from the group consisting of patients identified as such, and a significant No mean change was identified as remission-low disease activity in DAPSA patients with vdH-S = -0.88 ± 2.3 (SD), vdH-S = -0.48 ± 1.82 (SD ) in patients identified as having moderate disease activity in DAPSA, vdH-S = -1.01 ± 2.384 (SD ) in patients identified as having inactive disease activity in PASDAS, vdH-S = -0.20 ± 1.965 (SD ) in patients identified as having moderate disease activity in PASDAS, vdH-S = -1.16 ± 2.46( SD) in patients identified as having MDA, vdH-S = 0.03 ± 2. 44 (SD) in patients identified as not having MDA, vdH-S = -1.4 9 ± 2.22 (SD) in patients identified as having VLDA, vdH-S = -0.30 ± 2.52 (SD) in patients identified as not having VLDA, vdH-S = -1.06 ± 2.41 (SD) in patients identified as having remission in CDAI, and vdH-S = -0. 81 ± 2.12 (SD) in patients identified as having low disease activity in inactive disease activity CDA I, and is selected from the group consisting of, the composition being such that the anti-TNF antibody is administered at a dose of 2 mg / kg at weeks 0 and 4 and then every 8 weeks (q8w) thereafter administered as such, the method being, before, simultaneously with, or after said (a) administration, a detectable label or reporter, TNF antagonist, antirheumatic agent, muscle relaxant, narc otic, non-steroidal anti-inflammatory drug (NSAID), analgesic, anesthetic, sedative agent is not administered simultaneously with the anti-TNF antibody Agents, local anesthetics, neuromuscular blockers, antibacterial agents, psoriasis treatment agents, corticosteroids, anabolic steroids, erythropoietin, immunization substances, immunoglobulins, immunosuppressive agents, growth hormones, hormone replacement agents, radiopharmaceuticals, antidepressants, antipsychotics, stimulants, asthma treatment agents, β - agonists, inhaled steroids, epinephrine or analogs, cytokines, or cytokine antagonists, administering at least one composition comprising an effective amount of at least one compound or protein selected from at least one of them, further comprising providing a method.

[0028] In certain embodiments, the invention is at least one isolated mammalian anti - TNF antibody for use in the treatment of patients having active psoriatic arthritis, wherein the at least one isolated mammalian anti - TNF antibody has a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37, and the treatment comprises administering to the patient at least one isolated mammalian anti - TNF antibody by IV infusion, and at the 52nd week of the treatment, patients treated with the anti - TNF antibody are identified as patients having remission - low disease activity in the disease activity of PsA (DAPSA ), patients identified as having moderate disease activity in DAPSA, patients identified as having inactive disease activity in the PsA activity score (PASDAS ), patients identified as having moderate disease activity in PASDAS, patients identified as having minimal disease activity (MDA), patients identified as not having MDA, patients identified as having very low disease activity (VLDA), patients identified as not having VLDA ), the treatment comprising administering to the patient at least one isolated mammalian anti - TNF antibody by IV infusion, and at the 52nd week of the treatment, patients treated with the anti - TNF antibody are identified as patients having remission - low disease activity in the disease activity of PsA (DAPSA ), patients identified as having moderate disease activity in DAPSA, patients identified as having inactive disease activity in the PsA activity score (PASDAS ), patients identified as having moderate disease activity in PASDAS, patients identified as having minimal disease activity (MDA), patients identified as not having MDA, patients identified as having very low disease activity (VLDA), patients identified as not having VLDA ), patients identified as having moderate disease activity in DAPSA, patients identified as having inactive disease activity in the PsA activity score (PASDAS ), patients identified as having moderate disease activity in PASDAS, patients identified as having minimal disease activity (MDA), patients identified as not having MDA, patients identified as having very low disease activity (VLDA), patients identified as not having VLDA ), patients identified as having moderate disease activity in PASDAS, patients identified as having minimal disease activity (MDA), patients identified as not having MDA, patients identified as having very low disease activity (VLDA), patients identified as not having VLDA ), patients identified as having minimal disease activity (MDA), patients identified as not having MDA, patients identified as having very low disease activity (VLDA), patients identified as not having VLDA ), patients identified as having very low disease activity (VLDA), patients identified as not having VLDA Patients who are identified as having remission in the Clinical Disease Activity Index (CDAI), and patients who are identified as having low disease activity in the CDAI, and a total modified van der Heijde-Sharp (vdH-S) score from baseline in patients selected from the group consisting of patients having a significant mean change, at least one isolated mammalian anti-TNF antibody is provided.

[0029] In certain embodiments, the invention is at least one isolated mammalian anti-TNF antibody for use in the treatment of patients having active psoriatic arthritis, wherein at least one isolated mammalian anti-TNF antibody has a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37, and the treatment comprises administering to the patient at least one isolated mammalian anti-TNF antibody by IV infusion, wherein at week 52 of the treatment, patients treated with the anti-TNF antibody are patients identified as having remission-low disease activity in the disease activity of PsA (DAPSA ), patients identified as having moderate disease activity in DAPSA, patients identified as having inactive disease activity in the PsA Activity Score (PASDAS ), patients identified as having moderate disease activity in PASDAS, patients identified as having minimal disease activity (MDA), patients identified as not having MDA, patients identified as having very low disease activity (VLDA), patients identified as not having VLDA, patients identified as having remission in the Clinical Disease Activity Index (CDAI), and patients identified as having low disease activity in the CDAI, and a group consisting of patients patients identified as having remission in the Clinical Disease Activity Index (CDAI), and patients identified as having low disease activity in the CDAI, and a group consisting of patients The total modified van der Heijde-Sharp (vdH-S) score in the selected patients has a significant mean change from baseline, and the significant mean change from baseline of the total modified vdH-S score is such that vdH-S = -0.88 ± 2.3 (SD) in patients identified as having remission-low disease activity in DAPSA, vdH-S = -0.48 ± 1 .82 (SD) in patients identified as having moderate disease activity in DAPSA, vdH-S = -1.01 ± 2.384 (SD) in patients identified as having inactive disease activity in PASDAS, vdH-S = -0.20 ± 1.9 65 (SD) in patients identified as having moderate disease activity in PASDAS, vdH-S = -1.16 ± 2.46 (SD) in patients identified as having MDA, vdH-S = 0 .03 ± 2.44 (SD) in patients identified as not having MDA, vdH-S = -1.49 ± 2.22 (SD) in patients identified as having VLDA, vdH-S = -0.30 ± 2.52 (SD) in patients identified as not having VLDA, vdH-S = -1.06 ± 2.41 (SD) in patients identified as having remission in CDAI, and vdH-S = -0.81 ± 2.12 (SD) in patients identified as having low disease activity in CDAI, and provides a composition selected from the group consisting of. In certain embodiments, the invention is at least one isolated mammalian anti-TNF antibody for use in the treatment of patients having active psoriatic arthritis, wherein at least one isolated

[0030] mammalian anti-TNF antibody ​​​​The mammalian anti-TNF antibody comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: and a light chain (LC) comprising the amino acid sequence of SEQ ID NO:37, and the treatment comprises administering to the patient at least one administering an isolated mammalian anti-TNF antibody by IV infusion to a first At week 52, patients treated with anti-TNF antibodies showed a significant improvement in PsA disease activity (DAPSA ) in remission - patients identified as having low disease activity in DAPSA; Patients identified as having moderate disease activity, PsA activity score (PASDAS ) as having inactive disease activity, and Patients identified as having moderate disease activity, or minimal disease activity (MDA) Patients identified as having MDA, patients identified as not having MDA, patients with very low disease activity Patients identified as having VLDA and those identified as not having VLDA Patients who are identified as having remission on the Clinical Disease Activity Index (CDAI) and those identified as having low disease activity on the CDAI. Total modified van der Heijde-Sharpe (vdH-S) score in patients selected from had a significant mean change from baseline in total modified vdH-S score A significant mean change from baseline was observed in patients with remission (low disease activity) on DAPSA. vdH-S in identified patients = -0.88 ± 2.3 (SD), in DAPSA vdH-S=-0.48±1 in patients identified as having moderate disease activity .82 (SD), identified as having inactive disease activity on the PASDAS vdH-S in patients = -1.01 ± 2.384 (SD), moderate in PASDAS vdH-S = -0.20 ± 1.9 in patients identified as having disease activity 65 (SD), vdH-S = -1.16 in patients identified as having MDA ± 2.46 (SD), vdH-S = 0 in patients identified as not having MDA .03 ± 2.44 (SD), vdH- S = -1.49 ± 2.22 (SD) in patients identified as not having VLDA vdH-S = -0.30 ± 2.52 (SD) in patients identified as having remission in CDAI vdH-S = -1.06 ± 2.41 (SD) in patients identified as having low disease activity in CDAI vdH-S = -0.81 ± 2.12 (SD), selected from the group consisting of, at least one isolated mammalian anti-TNF antibody is administered at a dose of 2 mg / kg at week 0 and week 4, then every 8 weeks (q8w) thereafter to provide at least one isolated mammalian anti-TNF antibody.

[0031] In certain embodiments, the invention is at least one isolated mammalian anti-TNF antibody for use in the treatment of patients with active psoriatic arthritis wherein at least one isolated mammalian anti-TNF antibody has a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37 and the treatment comprises administering to the patient at least one isolated mammalian anti-TNF antibody by IV infusion, and at week 52 of the treatment patients treated with the anti-TNF antibody are identified as patients having remission-low disease activity in PsA disease activity (DAPSA ), in DAPSA ​​Patients identified as having moderate disease activity, patients identified as having inactive disease activity in the PsA Activity Score (PASDAS ), patients identified as having moderate disease activity in PASDAS, patients identified as having Minimal Disease Activity (MDA) , patients identified as having MDA, patients identified as not having MDA, patients identified as having very low disease activity (VLDA), patients identified as not having VLDA, patients identified as having remission in the Clinical Disease Activity Index (CDAI) , patients identified as having low disease activity in CDAI, and the total modified van der Heijde - Sharp (vdH - S) score in patients selected from the group consisting of patients having a significant mean change from baseline, and the significant mean change from baseline of the total modified vdH - S score is vdH - S = - 0.88 ± 2.3 (SD) in patients identified as having remission - low disease activity in DAPSA, and vdH - S = - 0.48 ± 1 .82 (SD) in patients identified as having moderate disease activity in DAPSA, vdH - S = - 1.01 ± 2.384 (SD) in patients identified as having inactive disease activity in PASDAS, and vdH - S = - 0.20 ± 1.9 65 (SD) in patients identified as having moderate disease activity in PASDAS, vdH - S = - 1.16 ± 2.46 (SD) in patients identified as having MDA, vdH - S = 0 .03 ± 2.44 (SD) in patients identified as not having MDA, vdH - S = - 1.49 ± 2.22 (SD) in patients identified as having VLDA, and vdH - S = - 0.20 ± 1.9 65 (SD) in patients identified as having moderate disease activity in PASDAS, vdH - S = - 1.16 ± 2.46 (SD) in patients identified as having MDA, vdH - S = 0 .03 ± 2.44 (SD) in patients identified as not having MDA, vdH - S = - 1.49 ± 2.22 (SD) in patients identified as having VLDA, and vdH - S = - 0.20 ± 1.9 65 (SD) in patients identified as not having VLDA, vdH-S = -0.30 ± 2.52 (SD), as those having remission in CDAI vdH-S = -1.06 ± 2.41 (SD) in the patients identified, and in CDAI vdH-S = -0.81 ± 2.12 (SD) in the patients identified as those having low disease activity, selected from the group consisting of at least one isolated mammalian anti-TNF antibody is administered at a dose of 2 mg / kg at week 0 and week 4, and then every 8 weeks (q8w), and at least one isolated mammalian anti-T NF antibody is administered over 30 ± 10 minutes, providing at least one isolated mammalian anti-T NF antibody.

[0032] In certain embodiments, the invention is at least one isolated mammalian anti-TNF antibody for use in the treatment of patients having active psoriatic arthritis, wherein at least one isolated mammalian anti-TNF antibody has a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37, and the treatment comprises administering to the patient at least one isolated mammalian anti-TNF antibody by IV infusion, and at week 52 of the treatment, the patients treated with the anti-TNF antibody are identified as those having remission - low disease activity in the disease activity of PsA (DAPSA ), patients identified as those having moderate disease activity in DAPSA, patients identified as those having inactive disease activity in the PsA activity score (PASDAS ), patients identified as those having moderate disease activity in PASDAS, patients identified as those having minimal disease activity (MDA), patients identified as those not having MDA, very low disease activity )), patients identified as those having moderate disease activity in DAPSA, patients identified as those having inactive disease activity in the PsA activity score (PASDAS ), patients identified as those having moderate disease activity in PASDAS, patients identified as those having minimal disease activity (MDA), patients identified as those not having MDA, very low disease activity ), patients identified as those having inactive disease activity in the PsA activity score (PASDAS), patients identified as those having moderate disease activity in PASDAS, patients identified as those having minimal disease activity (MDA), patients identified as those not having MDA, very low disease activity ), patients identified as those having moderate disease activity in PASDAS, patients identified as those having minimal disease activity (MDA), patients identified as those not having MDA, very low disease activity activity​ Patients identified as having very low disease activity (VLDA), patients identified as not having VLDA, patients identified as having remission in the Clinical Disease Activity Index (CDAI), and patients identified as having low disease activity in the CDAI from the group consisting of patients selected from the group consisting of patients having a significant mean change from baseline in the total modified van der Heijde - Sharp (vdH - S) score in patients and having a significant mean change from baseline in the total modified vdH - S score, where the significant mean change from baseline in the total modified vdH - S score is vdH - S = - 0.88 ± 2.3 (SD) in patients identified as having remission - low disease activity in DAPSA, vdH - S = - 0.48 ± 1 .82 (SD) in patients identified as having moderate disease activity in DAPSA, vdH - S = - 1.01 ± 2.384 (SD) in patients identified as having inactive disease activity in PASDAS, vdH - S = - 0.20 ± 1.9 65 (SD) in patients identified as having moderate disease activity in PASDAS, vdH - S = - 1.16 ± 2.46 (SD) in patients identified as having MDA, vdH - S = 0 .03 ± 2.44 (SD) in patients identified as not having MDA, vdH - S = - 1.49 ± 2.22 (SD) in patients identified as having VLDA, vdH - S = - 0.30 ± 2.52 (SD) in patients identified as not having VLDA, vdH - S = - 1.06 ± 2.41 (SD) in patients identified as having remission in CDAI, and vdH - S = - 0.81 ± in patients identified as having low disease activity in CDAI ​​​​​​​​​Selected from the group consisting of 2.12(SD), at least one isolated mammalian anti-TNF antibody is administered at a dose of 2 mg / kg at week 0 and week 4, and then every 8 weeks (q8w), wherein the non-active disease active patient is an adult patient 18 years of age or older, providing at least one isolated mammalian anti-TNF antibody.

[0033] In certain embodiments, the invention is at least one isolated mammalian anti-TNF antibody for use in the treatment of patients with active psoriatic arthritis, wherein at least one isolated mammalian anti-TNF antibody has a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37, and the treatment comprises administering to the patient at least one isolated mammalian anti-TNF antibody by IV infusion, and at week 52 of the treatment, patients treated with the anti-TNF antibody are identified as patients having remission - low disease activity, patients identified as having moderate disease activity in DAPSA (Psoriatic Arthritis Disease Activity Score), patients identified as having non-active disease activity in PASDAS (Psoriatic Arthritis Activity Score for Disease Activity), patients identified as having moderate disease activity in PASDAS, patients identified as having minimal disease activity (MDA), patients identified as not having MDA, patients identified as having very low disease activity (VLDA), patients identified as not having VLDA, patients identified as having remission in Clinical Disease Activity Index (CDAI), and patients identified as having low disease activity in CDAI, and the total modified van der Heijde-Sharp (vdH-S) score in patients selected from the group consisting of patients so identified, wherein the anti-TNF antibody is administered at a dose of 2 mg / kg at week 0 and week 4, and then every 8 weeks (q8w), wherein the non-active disease active patient is an adult patient 18 years of age or older, providing at least one isolated mammalian anti-TNF antibody. patients identified as having moderate disease activity in PASDAS, patients identified as having minimal disease activity (MDA), patients identified as not having MDA, patients identified as having very low disease activity (VLDA), patients identified as not having VLDA, patients identified as having remission in Clinical Disease Activity Index (CDAI), and patients identified as having low disease activity in CDAI, and the total modified van der Heijde-Sharp (vdH-S) score in patients selected from the group consisting of patients so identified, wherein the anti-TNF antibody is administered at a dose of 2 mg / kg at week 0 and week 4, and then every 8 weeks (q8w), wherein the non-active disease active patient is an adult patient 18 years of age or older, providing at least one isolated mammalian anti-TNF antibody. from the group consisting of patients so identified. with a significant mean change from the baseline of the total modified vdH-S score, and the significant mean change from the baseline of the total modified vdH-S score is, as those having remission-low disease activity in DAPSA identified in patients with vdH-S = -0.88 ± 2.3 (SD) in DAPSA, identified in patients with vdH-S = -0.48 ± 1 .82 (SD) in patients identified as those having moderate disease activity in DAPSA, vdH-S = -1.01 ± 2.384 (SD) in patients identified as those having inactive disease activity in PASDAS, vdH-S = -0.20 ± 1.9 65 (SD) in patients identified as those having moderate disease activity in PASDAS, vdH-S = -1.16 ± 2.46 (SD) in patients identified as those having MDA, vdH-S = 0 .03 ± 2.44 (SD) in patients identified as those not having MDA, vdH-S = -1.49 ± 2.22 (SD) in patients identified as those having VLDA, vdH-S = -0.30 ± 2.52 (SD) in patients identified as those not having VLDA, vdH-S = -1.06 ± 2.41 (SD) in patients identified as those having remission in CDAI, and vdH-S = -0.81 ± 2.12 (SD) in patients identified as those having low disease activity in CDAI, selected from the group consisting of, at least one isolated mammalian anti-TNF antibody is administered at a dose of 2 mg / kg at week 0 and week 4, and then every 8 weeks (q8w), and the treatment further comprises administering the inactive disease activity anti-TNFα antibody with or without methotrexate (MTX), providing at least one isolated mammalian anti-TNF antibody.

Brief Description of the Drawings

[0034]

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Mode for Carrying Out the Invention

[0035] The present invention relates to a composition comprising a heavy chain (HC) containing SEQ ID NO: 36 and a light chain (LC) containing SEQ ID NO: 37, and a production process for producing such an anti-TNF antibody. A process is provided.

[0036] As used herein, "anti-tumor necrosis factor α antibody", "anti-TNF antibody", "anti-TNF antibody portion" or "anti-TNF antibody fragment", and / or "anti-TNF antibody variant", etc., at least one complementarity determining region (CDR) of the heavy chain or light chain or its ligand-binding portion, the variable region of the heavy chain or light chain, the heavy chain or or a light chain constant region, a framework region, or any portion thereof, or at least one portion of a TNF receptor or a binding protein, etc., but not limited thereto, an immune globulin molecule, including a molecule containing at least a part of an immune globulin molecule. Such an antibody optionally further affects a specific ligand, and these are not limited thereto, but such an antibody regulates, reduces, increases, antagonizes, activates, reduces, alleviates, blocks, inhibits, suppresses, and / or interferes with at least one TNF activity or binding, or TNF receptor activity or binding, in vitro, in situ, and / or in vivo. As a non-limiting example, a preferred anti-TNF antibody, a specified portion or variant of the present invention can bind to at least one TNF or a specified portion, variant or domain thereof. A preferred anti-TNF antibody, a specified portion or variant can also, if desired, affect at least one of TNF activities or functions such as RNA, DNA, or protein synthesis, TNF release, TNF receptor signaling, membrane TNF cleavage, TNF activity, TNF production, and / or synthesis, etc., but not limited thereto. The term "antibody" further intends to include antibodies, digestion fragments thereof, specific portions and variants, including antibody mimetics thereof, or portions of antibodies or specific fragments or parts thereof that mimic the structure and / or function of antibodies, including single-chain antibodies and fragments thereof. Functional fragments include antigen-binding fragments that bind to mammalian TNF. For example, Fab (e.g., by papain digestion), Fab' (e.g., by pepsin digestion and partial reduction), and F(ab') ) A preferred anti-TNF antibody, a specified portion or variant can also, if desired, affect at least one of TNF activities or functions such as RNA, DNA, or protein synthesis, TNF release, TNF receptor signaling, membrane TNF cleavage, TNF activity, TNF production, and / or synthesis, etc., but not limited thereto. The term "antibody" further intends to include antibodies, digestion fragments thereof, specific portions and variants, including antibody mimetics thereof, or portions of antibodies or specific fragments or parts thereof that mimic the structure and / or function of antibodies, including single-chain antibodies and fragments thereof. Functional fragments include antigen-binding fragments that bind to mammalian TNF. For example, Fab (e.g., by papain digestion), Fab' (e.g., by pepsin digestion and partial reduction), and F(ab') The term "antibody" is further intended to include antibodies, digestion fragments thereof, specific portions and variants, including antibody mimetics thereof, or portions of antibodies or specific fragments or parts thereof that mimic the structure and / or function of antibodies, including single-chain antibodies and fragments thereof. Functional fragments include antigen-binding fragments that bind to mammalian TNF. For example, Fab (e.g., by papain digestion), Fab' (e.g., by pepsin digestion and partial reduction), and F(ab') (e.g., by pepsin digestion). Antigen-binding fragments that bind to mammalian TNF include, for example, Fab (e.g., by papain digestion), Fab' (e.g., by pepsin digestion and partial reduction), and F(ab') ) 2(e.g., by pepsin digestion), facb (e.g., by plasmin digestion), p Fc’ (e.g., by pepsin or plasmin digestion), Fd (e.g., pepsin digestion, partial reduction and reassembly), Fv or scFv (e.g., by molecular biological techniques) fragments, among others but not limited thereto, that can bind to TNF or a portion thereof antibody fragments are encompassed by the present invention (see, e.g., Colligan, Immunol ogy supra).

[0037] Such fragments can be produced by enzymatic cleavage, synthesis or recombinant techniques, as known in the art and / or as described herein. Antibodies can be produced in various truncated forms using antibody genes in which one or more stop codons have been introduced upstream of the natural termination site. For example, F(ab’) combinations of genes encoding the heavy chain portions can be designed to include DNA sequences encoding the CH 2 domains and / or hinge regions of the heavy chain. Various portions of the antibody can be chemically conjugated by conventional techniques or prepared as contiguous proteins using genetic engineering techniques. 1 When used herein, the term “human antibody” means that substantially all portions of the protein (e.g., CDRs, frameworks, C

[0038] domains (e.g., C 1, C L 2, and C H 3), hinge (VL, V H ), C H 2) have substantially human sequences with only minor sequence variations or mutations H ), VH) have substantially human sequences with only minor sequence variations or mutations H and are present in a human ​refers to an antibody that is non-immunogenic in the same way as in primates (such as monkeys, baboons, chimpanzees, etc.), rodents (such as mice, rats, rabbits, guinea pigs, hamsters, etc.), and other mammalian animals. The specified antibody refers to an antibody specific to such species, subgenera, genera, subfamilies, and families. Furthermore, chimeric antibodies include any of the above combinations. Such changes or mutations may, in some cases and preferably retain or reduce immunogenicity in humans or other species compared to the unmodified antibody. Therefore, human antibodies are different from chimeric or humanized antibodies. Human antibodies are indicated to be producible by non-human animals, or prokaryotic or eukaryotic cells that can express a functionally reconstituted human immunoglobulin (e.g., heavy chain and / or light chain ) gene. Moreover, when a human antibody is a single-chain antibody, it may contain a linker peptide not found in natural human antibodies. For example, Fv may contain a linker peptide such as 2 to about 8 glycine or other amino acid residues that connect the variable region of the heavy chain and the variable region of the light chain. Such a linker peptide is considered to be of human origin.

[0039] Also, bispecific (e.g., DuoBody®), heterospecific, heteroconjugate, or similar antibodies, which are monoclonal, preferably human or humanized antibodies having binding specificities for at least two different antigens, may be used. In this case, one of the binding specificities is for at least one TNF protein, and the other is for any other antigen. Methods for producing bispecific antibodies are known in the art. Conventionally, the recombinant production of bispecific antibodies involves two immunoglobulin heavy chain-light chain pairs. is based on co-expression, where the two heavy chains have different specificities (Milstein a nd Cuello, Nature, 305:537(1983)). Due to the random combination of immunoglobulin heavy chains and light chains, these hybridomas (quadromas) generate a possible mixture of 10 different antibody molecules, only 1 of which has the correct dual specific structure. Usually, the purification of the correct molecule, which is carried out by an affinity chromatography step, is low in product yield and time-consuming, so different methods have been developed to facilitate the production of bispecific antibodies.

[0040] Full-length bispecific antibodies can be conveniently generated, for example, in an in vitro cell-free environment or using co-expression, by introducing substitutions at the heavy chain CH3 interface in each half-molecule to favor the heterodimer formation of two antibody half-molecules with different specificities, using Fab arm exchange (or half-molecule exchange) between two monospecific bivalent antibodies. The Fab arm exchange reaction is the result of a disulfide bond isomerization reaction and the dissociation-association of the CH3 domain . The heavy chain disulfide bond in the hinge region of the parental monospecific antibody is reduced. One of the resulting free cysteines in the parental monospecific antibody forms an intramolecular disulfide bond with the cysteine residue of the second parental monospecific antibody molecule, and at the same time, the CH3 domain of the parental antibody is released and reformed by dissociation- association. The CH3 domain of the Fab arm may be modified to favor heterodimer formation over homodimer formation. The resulting product is a bispecific antibody with two Fab arms or half-molecules that can bind to different epitopes respectively.

[0041] ​​​​As used herein, "homodimer formation" means the interaction of two heavy chains having the same CH3 amino acid sequence. As used herein, "homodimer" means an antibody having two heavy chains having the same CH3 amino acid sequence. As used herein, "heterodimer formation" means the interaction of two heavy chains having non-identical CH3 amino acid sequences. As used herein, "heterodimer" means an antibody having two heavy chains having non-identical CH3 amino acid sequences. The "knob-in-hole" strategy (see, e.g., WO 2006 / 028936) can be used to generate full-length bispecific antibodies. Briefly, the selected amino acids that form the interface of the CH3 domain in human IgG are mutated at positions that affect CH3 domain interaction to promote heterodimer formation. An amino acid with a small side chain (hole) is introduced into the heavy chain of an antibody that specifically binds to the first antigen, and an amino acid with a large side chain (knob) is introduced into the heavy chain of an antibody that specifically binds to the second antigen. After co-expression of the two antibodies, the heterodimer is formed as a result of the preferential interaction between the heavy chain having the "hole" and the heavy chain having the "knob".

[0042] Exemplary CH3 substitution pairs that form knobs and holes are T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V (modifications in the first CH3 domain of the first heavy chain). As used herein, "heterodimer formation" means the interaction of two heavy chains having non-identical CH3 amino acid sequences. As used herein, "heterodimer" means an antibody having two heavy chains having non-identical CH3 amino acid sequences. As used herein, "heterodimer" means an antibody having two heavy chains having non-identical CH3 amino acid sequences.

[0043] The "knob-in-hole" strategy (see, e.g., International Publication No. WO 2006 / 028936) can be used to generate full-length bispecific antibodies. Briefly, the selected amino acids that form the interface of the CH3 domain in human IgG are mutated at positions that affect CH3 domain interaction to promote heterodimer formation. An amino acid with a small side chain (hole) is introduced into the heavy chain of an antibody that specifically binds to the first antigen, and an amino acid with a large side chain (knob) is introduced into the heavy chain of an antibody that specifically binds to the second antigen. After co-expression of the two antibodies, the heterodimer is formed as a result of the preferential interaction between the heavy chain having the "hole" and the heavy chain having the "knob". As used herein, "heterodimer formation" means the interaction of two heavy chains having non-identical CH3 amino acid sequences. As used herein, "heterodimer" means an antibody having two heavy chains having non-identical CH3 amino acid sequences. Briefly, the selected amino acids that form the interface of the CH3 domain in human IgG are mutated at positions that affect CH3 domain interaction to promote heterodimer formation. An amino acid with a small side chain (hole) is introduced into the heavy chain of an antibody that specifically binds to the first antigen, and an amino acid with a large side chain (knob) is introduced into the heavy chain of an antibody that specifically binds to the second antigen. After co-expression of the two antibodies, the heterodimer is formed as a result of the preferential interaction between the heavy chain having the "hole" and the heavy chain having the "knob". As used herein, "heterodimer formation" means the interaction of two heavy chains having non-identical CH3 amino acid sequences. As used herein, "heterodimer" means an antibody having two heavy chains having non-identical CH3 amino acid sequences. As used herein, "heterodimer" means an antibody having two heavy chains having non-identical CH3 amino acid sequences. An amino acid with a small side chain (hole) is introduced into the heavy chain of an antibody that specifically binds to the first antigen, and an amino acid with a large side chain (knob) is introduced into the heavy chain of an antibody that specifically binds to the second antigen. After co-expression of the two antibodies, the heterodimer is formed as a result of the preferential interaction between the heavy chain having the "hole" and the heavy chain having the "knob". As used herein, "heterodimer" means an antibody having two heavy chains having non-identical CH3 amino acid sequences. An amino acid with a small side chain (hole) is introduced into the heavy chain of an antibody that specifically binds to the first antigen, and an amino acid with a large side chain (knob) is introduced into the heavy chain of an antibody that specifically binds to the second antigen. After co-expression of the two antibodies, the heterodimer is formed as a result of the preferential interaction between the heavy chain having the "hole" and the heavy chain having the "knob". Exemplary CH3 substitution pairs that form knobs and holes are T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V (modifications in the first CH3 domain of the first heavy chain). Exemplary CH3 substitution pairs that form knobs and holes are T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V (modifications in the first CH3 domain of the first heavy chain). Exemplary CH3 substitution pairs that form knobs and holes are T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V (modifications in the first CH3 domain of the first heavy chain). Exemplary CH3 substitution pairs that form knobs and holes are T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V (modifications in the first CH3 domain of the first heavy chain). (represented as the modified position in the second CH3 domain of the positioned / second heavy chain).

[0044] Other strategies, such as using electrostatic interactions by substituting positively charged residues on one CH3 surface and negatively charged residues on the second CH3 surface to promote heavy chain heterodimer formation are used as described in U.S. Patent Application Publication No. 2010 / 0015133, U.S. Patent Application Publication No. 2009 / 0 182127, U.S. Patent Application Publication No. 2010 / 028637, or U.S. Patent Application Publication No. 2011 / 0123532. Other strategies may be used as described in U.S. Patent Application Publication No. 2012 / 0149876 or U.S. Patent Application Publication No. 2013 / 0195849. Specifically, the following substitutions: L351Y_F405A_Y407V / T394W, T366I_K3 92M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351 Y_Y407A / T366V_K409F, Y407A / T366A_K409F, or T350V_L351Y_F405A_Y407V / T350V_T366L_K392 L_T394W (represented as the modified position in the first CH3 domain of the first heavy chain / the modified position in the second CH3 domain of the second heavy chain) can promote it.

[0045] In addition to the methods described above, bispecific antibodies can be prepared by introducing asymmetric mutations into the CH3 regions of two single-specific homodimeric antibodies and isomerizing disulfide bonds in an in vitro cell-free environment according to the method described in International Publication No. 2011 / 131746. Under reducing conditions, it can be generated by forming a bispecific heterodimer antibody from two parental monospecific homodimer antibodies. In this method, the first monospecific bivalent antibody and the second monospecific bivalent antibody are modified to have certain substitutions in the CH3 domain that promote the stability of the heterodimer, but these antibodies are incubated together under reducing conditions where the cysteine in the hinge region is sufficient to isomerize the disulfide bond, thereby generating a bispecific antibody by Fab arm exchange. The incubation conditions can optimally be returned to non-reducing conditions. Exemplary reducing agents that can be used are 2-mercaptoethylamine (2-MEA), dithiothreitol (DTT), dithio erythritol (DTE), glutathione, tris(2-carboxyethyl)phosphine (TCEP), L-cysteine, and beta-mercaptoethanol, preferably a reducing agent selected from the group consisting of 2-mercaptoethylamine, dithiothreitol, and tris(2-carboxyethyl l)phosphine. For example, at a temperature of at least 20 °C, in the presence of at least 25 mM of 2-MEA or at least 0.5 mM of dithio threitol, at pH 5-8, for example, at pH 7.0 or pH 7.4, an incubation of at least 90 minutes may be used. The anti-TNF antibodies (also referred to as TNF antibodies) useful in the methods and compositions of the present invention can optionally be characterized by high affinity binding to TNF and, optionally and preferably, low toxicity. Specifically, individual regions such as variable regions, constant regions, and frameworks can be arbitrarily characterized.

[0046] The components, individually and / or collectively, optionally and preferably, have low immunogenicity The antibody, its identified fragment, or variant of the present invention, which has is useful in the present invention. The antibodies that can be used in the present invention are based on the ability to measurably relieve symptoms and to treat patients over a long period of time with low and / or acceptable toxicity, and can be characterized by optionality. Low or acceptable immunogenicity, and / or high affinity, and other suitable properties can contribute to the treatment results obtained. "Low immunogenicity" as used herein is defined as an increase in HAHA, HACA or HAMA responses in less than about 75%, or preferably less than about 50%, of the patients being treated, and / or low titers (less than about 300, preferably less than about 100 when measured by a double antigen enzyme immunoassay) in the patients being treated (Elliott et al., Lancet 3 44:1125-1127 (1994), which is hereby incorporated by reference in its entirety). ) (Elliott et al., Lancet 3 44:1125-1127 (1994), which is hereby incorporated by reference in its entirety).

[0047] Usefulness: The isolated nucleic acids of the present invention can be measured or act in cells, tissues, organs or animals (including mammals and humans) to diagnose, monitor, regulate, treat, relieve, prevent the occurrence of, or reduce the symptoms of at least one TNF condition selected from, but not limited to, immune disorders or diseases, circulatory disorders or diseases, infectious conditions, malignant and / or neurological disorders or diseases. They can be used to help generate at least one anti-TNF antibody or its identified variant. Such methods can be used for such regulation, treatment, relief, prevention, or reduction of symptoms, effects, or mechanisms

[0048] administering to a cell, tissue, organ, animal or patient in need thereof, a composition or pharmaceutical composition comprising at least one anti-TNF antibody The effective amount may include. The effective amount is determined using known methods described herein or known in the relevant art, and is, for example, about 0.001 to 500 mg / kg per single (e.g., bolus), multiple or continuous administration or an amount to achieve a serum concentration of 0.01 to 5000 μg / mL per single, multiple or continuous administration, or any effective range or value therein. Citation. All publications or patents cited in this specification are hereby incorporated by reference in their entirety, showing the highest level at the time of the present invention, and / or providing an explanation and usability of the present invention. Publications refer to any scientific publication or patent gazette or any other information available in any media format, including those recorded in electronic or printed form The following documents are hereby incorporated by reference in their entirety: Ausubel, et al., ed. , Current Protocols in Molecular Biology, John Wiley & Sons, Inc., NY, NY (1987 - 2001), Sambrook, et al., Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor, NY (1989), Harlow and Lane, antibodies , a Laboratory Manual, Cold Spring Harbor, NY (1989), Colligan, et al., eds., Current Protocols in Immunology, John Wiley & Sons, Inc., NY, NY (1991 - 2002). Inc., NY, NY (1991 - 2002). , Current Protocols in Molecular Biology, John Wiley & Sons, Inc., NY, NY (1987 - 2001), Sambrook, et al., Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor, NY (1989), Harlow and Lane, antibodies , a Laboratory Manual, Cold Spring Harbor, NY (1989), Colligan, et al., eds., Current Protocols in Immunology, John Wiley & Sons, Inc., NY, NY (1991 - 2002). Inc., NY (1994 - 2001), Colligan et al., Curre nt Protocols in Protein Science, John Wil ey & Sons, NY, NY, (1997 - 2001).

[0049] Antibodies of the present invention: all of the heavy - chain variable CDR regions of SEQ ID NOs: 1, 2, and 3, and / or all of the light - chain variable CDR regions of SEQ ID NOs: 4, 5, and 6, at least one anti - TNF antibody of the present invention can, if desired, be produced by a cell line, a mixed cell line, an immortalized cell or a clonal population of immortalized cells, as is well - known in the art. For example, Ausubel , et al., ed., Current Protocols in Molecul ar Biology, John Wiley & Sons, Inc., NY, NY ([[]] 1987 - 2001), Sambrook, et al., Molecular Clo ning: A Laboratory Manual, 2nd Edition, Col d Spring Harbor, NY (1989), Harlow and Lane , antibodies, a Laboratory Manual, Cold Spr ing Harbor, NY (1989), Colligan, et al., eds. , Current Protocols in Immunology, John Wi ley & Sons, Inc., NY (1994 - 2001), Colligan e t al., Current Protocols in Protein Scien ce, John Wiley & Sons, NY, NY, (1997 - 2001) can be referred to Desired to be irradiated, each of which is incorporated herein by reference in its entirety.

[0050] Human antibodies specific for human TNF protein or fragments thereof can be isolated and / or TNF protein, or portions thereof (including synthetic molecules such as synthetic peptides), etc. against suitable immunogenic antigens. Other specific or general mammalian antibodies can similarly occur. The preparation of immunogenic antigens and the production of monoclonal antibodies can be carried out using any suitable technique.

[0051] In one approach, hybridomas are prepared by fusing suitable immortalized cell lines (e.g., Sp2 / 0 , Sp2 / 0-AG14, NSO, NS1, NS2, AE-1, L.5, >243, P3 X63Ag8.653, Sp2 SA3, Sp2 MAI, Sp2 SS1, Sp2 S A5, U937, MLA 144, ACT IV, MOLT4, DA-1, JURKAT , WEHI, K-562, COS, RAJI, NIH 3T3, HL-60, MLA 1 44, NAMAIWA, NEURO 2A, etc., but not limited to these myeloma cell lines, or heteromylomas, their fusion products, or any cells or fused cells derived therefrom, or any other suitable cell lines known in the art . For example, see www.atcc.org, www.lif etech.com, etc. Antibody-producing cells such as isolated or cloned spleen, peripheral blood, lymph, tonsils, or other immune or B cell-containing cells, but not limited to these, or recombinant or endogenous, virus, bacteria, algae, prokaryotes, ​​​Amphibians, insects, reptiles, fish, mammals, rodents, horses, sheep, goats, cattle, primates , eukaryotes, genomic DNA, cDNA, rDNA, mitochondrial DNA or RN A, chloroplast DNA or RNA, hnRNA, mRNA, tRNA, single-stranded, double-stranded or triple-stranded, hybridized, etc., or combinations thereof, as either endogenous or heterologous nucleic acids, having any other cell that expresses a heavy or light chain constant or variable or framework or CDR sequence. See, for example, Ausubel, supra, and Chapter 2 of Colligan, Immunology. Both references are hereby incorporated by reference in their entirety.

[0052] Antibody-producing cells can also be obtained from the peripheral blood of humans or other suitable animals immunized with the antigen of interest, or preferably from the spleen or lymph nodes. Any other suitable host cell can be used to express a heterologous nucleic acid or endogenous nucleic acid encoding an antibody, a specified fragment or a variant thereof. Fusion cells (hybridomas) or recombinant cells can be isolated using selective culture conditions or other suitable known methods and cloned by limiting dilution or cell sorting or other known methods. Cells that produce antibodies having the desired specificity can be selected by a suitable assay (e.g., ELISA).

[0053] Recombinant antibodies can be selected from peptide or protein libraries (e.g., display libraries of bacteriophages, ribosomes, oligonucleotides, RNA, cDNA, etc., but not limited thereto), e.g., Cambridge antibody ​​​​​ Technologies, Cambridge, UK, MorphoSys , Martinsried / Planegg, DE, Biovation, Aberdeen , Scotland, UK, BioInvent, Lund, Sweden, Dyax Corp., Enzon, Affymax / Biosite, Xoma, Berkeley , CA, Ixsys. For example, European Patent No. 368,684, International Application PCT / G B91 / 01134, International Application PCT / GB92 / 01755, International Application PCT / G B92 / 002240, International Application PCT / GB92 / 00883, International Application PCT / GB93 / 00605, US Patent Application No. 08 / 350260 (5 / 12 / 94), US International Application PCT / GB94 / 01422, International Application PCT / GB94 / 02662, US International Application PCT / GB97 / 01835, (CAT / MRC), International Publication No. 90 / 144 43, International Publication No. 90 / 14424, International Publication No. 90 / 14430, International Application PCT / U S94 / 1234, International Publication No. 92 / 18619, International Publication No. 96 / 07754 (S cripps), European Patent No. 614 989 (MorphoSys), International Publication No. 95 / 16027 (BioInvent), International Publication No. 88 / 06630, International Publication No. 9 0 / 3809 (Dyax), US Patent No. 4,704,692 (Enzon), International Application PCT / US91 / 02989 (Affymax), International Publication No. 89 / 06283 , European Patent No. 371998, European Patent No. 550400, (Xoma), European Patent No. 2 29046, International Application PCT / US91 / 07149 (Ixsys), or probabilistic Peptides or proteins produced - U.S. Patent Nos. 5,723,323, 5,763 192, 5,814,476, 5,817,483, 5,824,514, 5,976,862, International Publication No. 86 / 05803, European Patent No. 590,689 (Ixs ys, now Applied Molecular Evolution (AME), each of which is hereby incorporated by reference in its entirety), or known in the art and / or described herein, and can generate a repertoire of human antibodies, depending on immunization of transgenic animals (e.g., SCID mice, Nguyen et al., Microbiol. Immunol. 41:901 - 907 (199 7), Sandhu et al., Crit. Rev. Biotechnol. 16: 95 - 118 (1996), Eren et al., Immunol. 93:154 - 161 (1998) (each of which is incorporated by reference in its entirety), as well as related patents and applications), other suitable methods for generating or isolating antibodies of the required specificity can be used, including but not limited to such techniques as ribosome display (Ha nes et al., Proc. Natl. Acad. Sci. USA, 94:493 7 - 4942 (May 1997), Hanes et al., Proc. Natl. Acad. Sci. USA, 95:14130 - 14135 (Nov. 1998)), single cell antibody generation techniques (e.g., selected lymphocyte antibody method ("SLAM") (U.S. Patent No. 5, 627,052, Wen et al., J. Immunol. 17:887 - 892 (1987), Babcook et al., Proc. Natl. Acad. Sci USA, 93:7843 - 7848 (1996)), and related patents and applications), (1987), Babcook et al., Proc. Natl. Acad. Sci .USA 93:7843-7848(1996)), germ microdroplets, and flow cytometry (Powell et al., Biotechnol. 8:33 3-337(1990), One Cell Systems, Cambridge, M A, Gray et al., J. Imm. Meth. 182:155-163(199 5), Kenny et al., Bio / Technol. 13:787-790(1 995), B cell selections (Steenbakkers et al., Molec. Bi ol. Reports 19:125-134(1994), Jonak et al. , Progress Biotech, Vol. 5, In Vitro Immuniz ation in Hybridoma Technology, Borrebaeck , ed., Elsevier Science Publishers B.V., Am sterdam, Netherlands(1988)) are mentioned, but are not limited to these.

[0054] Methods for engineering or humanizing non-human antibodies or human antibodies can likewise be used and are well-known in the art. Generally, humanized or engineered antibodies have one or more amino acid residues from a non-human source, such as, but not limited to, mice, rats, rabbits, non-human primates, or other mammals. These human amino acid residues are often referred to as "import" residues and are typically taken from the "import" variable regions, constant regions, or other domains of known human sequences. to these. residues have. These human amino acid residues are often referred to as "import" residues and are typically taken from the "import" variable regions, constant regions, or other domains of known human sequences. from the "import" variable region, constant region, or other domains of known human sequences.

[0055] Known human Ig sequences are disclosed in numerous publications and websites, for example, www.ncbi.nlm.nih.gov / entrez / query.fcgi; www.atcc.org / phage / hdb.html; www.sciquest.com / ; www.abcam.com / ; www.antibodyresource.com / onlinecomp.htm l; www.public.iastate.edu / ~pedro / research_ tools.html; www.mgen.uni-heidelberg.de / SD / IT / IT.htm l; www.whfreeman.com / immunology / CH05 / kuby0 5.htm; www.library.thinkquest.org / 12429 / Immune / Antibody.html; www.hhmi.org / grants / lectures / 1996 / vlab; www.path.cam.ac.uk / ~mrc7 / mikeimages.htm l; www.antibodyresource.com / ; www.mcb.harvard.edu / BioLinks / Immunology .html. www.immunologylink.com / ; www.pathbox.wustl.edu / ~hcenter / index.ht ml; www.biotech.ufl.edu / ~hcl / ; www.pebio.com / pa / 340913 / 340913.html; www.nal.usda.gov / awic / pubs / antibody / ; www.m.ehime-u.ac.jp / ~yasuhito / Elisa.htm l; www.biodesign.com / table.asp; www.icnet.uk / axp / facs / davies / links.html ; www.biotech.ufl.edu / ~fccl / protocol.html ; www.isac-net.org / sites_geo.html; www.aximt1.imt.uni-marburg.de / ~rek / AEPS tart.html; www.baserv.uci.kun.nl / ~jraats / links1.ht ml; www.recab.uni-hd.de / immuno.bme.nwu.edu / ; www.mrc-cpe.cam.ac.uk / imt-doc / public / IN TRO.html; www.ibt.unam.mx / vir / V_mice.html;imgt.cn usc.fr:8104 / 、 www.biochem.ucl.ac.uk / ~martin / abs / index .html;antibody.bath.ac.uk / 、 www.abgen.cvm.tamu.edu / lab / www.abgen.html; www.unizh.ch / ~honegger / AHOseminar / Slide 01.html; www.cryst.bbk.ac.uk / ~ubcg07s / ; www.nimr.mrc.ac.uk / CC / ccaewg / ccaewg.htm ; www.path.cam.ac.uk / ~mrc7 / humanisation / T AHHP.html; www.ibt.unam.mx / vir / structure / stat_aim. html; www.biosci.missouri.edu / smithgp / index.h tml; www.cryst.bioc.cam.ac.uk / ~fmolina / Web-p ages / Pept / spottech.html; www.jerini.de / frproducts.html; www.patents.ibm.com / ibm.html.Kabatetal. , Sequences of Proteins of Immunological Interest, U.S. Dept. Health (1983) exists, and each is hereby incorporated by reference in its entirety into this specification.

[0056] Such imported sequences can be used to reduce immunogenicity or to reduce, enhance or modify binding, affinity, association rate constant, dissociation rate constant, binding activity, specificity, half-life, or any other suitable property, as is known in the art. Generally, some or all of the non-human or human CDR sequences are maintained while the non-human sequences of the variable and constant regions are replaced with human or other amino acids. Antibodies can also be humanized while retaining high affinity for the antigen and other desirable biological properties, if desired. To achieve this purpose, if desired, the humanized antibody is compared with the parental sequence and human ​​ Analysis process of the parental array and various conceptual humanized products using a three-dimensional model of the chemical array It can be prepared accordingly. Three-dimensional immunoglobulin models are generally available and are well known to those skilled in the art. A computer program is available to illustrate and display a highly likely three-dimensional conformation for a selected immunoglobulin sequence candidate. By examining these displays, it becomes possible to analyze the highly likely functions shown by residues in the function of the immunoglobulin sequence candidate, i.e., to analyze the residues that affect the antigen-binding ability of the immunoglobulin candidate. In this way, FR residues can be selected and combined from the consensus sequence and the import sequence so that desirable antibody characteristics, such as an increase in affinity for the target antigen(s), are achieved. Generally, CDR residues directly and almost substantially affect antigen binding. The humanization or engineering of the antibodies of the present invention is based on Winter (Jones et al., Nature 321:522 (1986), Riechmann et al., Nature 332:323 (1988), Verhoeyen et al., Science 239:1534 (1988)), Sims et al., J . Immunol. 151:2296 (1993), Chothia and Lesk , J. Mol. Biol. 196:901 (1987), Carter et al., Proc. Natl. Acad. Sci. U.S.A. 89:4285 (1992), P resta et al., J. Immunol. 151:2623 (1993), U.S. Patent Nos. 5,723,323, 5,976,862, 5,824,514, 5,817 . Immunol. 151:2296 (1993), Chothia and Lesk , J. Mol. Biol. 196:901 (1987), Carter et al., Proc. Natl. Acad. Sci. U.S.A. 89:4285 (1992), P resta et al., J. Immunol. 151:2623 (1993), U.S Patent Nos. 5,723,323, 5,976,862, 5,824,514, 5,817 No. 483, No. 5814476, No. 5763192, No. 5723323, and No. 5,766886, No. 5714352, No. 6204023, No. 618037 0, No. 5693762, No. 5530101, No. 5585089, No. 52 25539, No. 4816567, International Application PCT / : US98 / 16280, U S96 / 18978, US91 / 09630, US91 / 05939, US94 / 01234, GB89 / 01334, GB91 / 01134, GB92 / 0175 5, International Publication No. 90 / 14443, No. 90 / 14424, No. 90 / 14430 No., European Patent No. 229246 (each of which is incorporated herein by reference in its entirety, including the documents cited therein), etc., but not limited thereto, and can be carried out using any known method. The anti-TNF antibody can also, if desired, be generated by immunizing transgenic animals (e.g., mice, rats, hamsters, non-human primates, etc.) that can generate a repertoire of human antibodies described herein and / or known in the art. Cells producing human anti-TNF antibodies can be isolated from such animals and immortalized using suitable methods such as those described herein.

[0057] The anti-TNF antibody can also, if desired, be generated by immunizing transgenic animals (e.g., mice, rats, hamsters, non-human primates, etc.) that can generate a repertoire of human antibodies described herein and / or known in the art. Cells producing human anti-TNF antibodies can be isolated from such animals and immortalized using suitable methods such as those described herein. (e.g., mice, rats, hamsters, non-human primates, etc.) and can also be generated by immunizing transgenic animals that can generate a repertoire of human antibodies described herein and / or known in the art. Cells producing human anti-TNF antibodies can be isolated from such animals and immortalized using suitable methods such as those described herein. Cells producing human anti-TNF antibodies can be isolated from such animals and immortalized using suitable methods such as those described herein.

[0058] Transgenic mice capable of generating a repertoire of human antibodies that bind to human antigens can be generated by known methods (e.g., but not limited to U.S. Patent Nos. 5,770,428 and 5,569 issued to Lonberg et al., but not limited thereto, and can be carried out using any known method. No. 825, the same as No. 5,545,806, the same as No. 5,625,126, the same as No. 5,625,8 25, the same as No. 5,633,425, the same as No. 5,661,016, and the same as No. 5,789, 650, International Publication No. 98 / 50433 by Jakobovits et al., Jakobovi ts et al.'s International Publication No. 98 / 24893, Lonberg et al.'s International Publication No. 98 / 2488 4, Lonberg et al.'s International Publication No. 97 / 13852, Lonberg et al.'s International Publication No. 94 / 25585, Kucherlapate et al.'s International Publication No. 96 / 34096, Kucherlapate et al.'s European Patent No. 0463151 (B1), Kucherla pate et al.'s European Patent No. 0710719 (A1), Surani et al.'s US Patent No. 5,5 45,807, Bruggemann et al.'s International Publication No. 90 / 04036, Brugg emann et al.'s European Patent No. 0438474 (B1), Lonberg et al.'s European Patent No. 0 814259 (A2), Lonberg et al.'s UK Patent No. 2272440 (A), Lonberg et al. Nature 368:856 - 859 (1994), T aylor et al., Int. Immunol. 6(4)579 - 591 (199 4), Green et al, Nature Genetics 7:13 - 21 (1 994), Mendez et al., Nature Genetics 15:14 6 - 156 (1997), Taylor et al., Nucleic Acids Research 20(23):6287 - 6295 (1992), Tuaillon et al., Proc Natl Acad Sci USA 90(8)3720 -3724 (1993), Lonberg et al., Int Rev Immun ol 13(1):65-93(1995), and Fishwald et al., N at Biotechnol 14(7):845-851(1996), which are hereby incorporated by reference in their entirety). Generally, these mice contain at least one transgene containing DNA derived from at least one human immunoglobulin locus that has been functionally reconstituted or is capable of undergoing functional reconstitution. The endogenous immunoglobulin locus of such mice can be disrupted or deleted to remove the ability of the mice to produce antibodies encoded by the endogenous genes. Screening for antibodies specific for similar proteins or fragments can be successfully accomplished using peptide display libraries. This method involves screening a large number of samples of peptides for individual members having the desired function or structure. Antibody screening of peptide display libraries is well known in the art. The length of the displayed peptide sequences can be from 3 to 5 000 or more amino acids, frequently 5 to 100 amino acids in length, and often about 8 to 25 amino acids in length. In addition to direct chemical synthesis methods for creating peptide libraries, several recombinant DNA methods have also been described. One type involves the display of peptide sequences on the surface of bacteriophages or cells. Each bacteriophage or cell

[0059] contains a nucleotide sequence encoding a specific displayed peptide sequence. Such methods are described in International Publication Nos. 91 / 17271, 91 / 18980, 91 contains a nucleotide sequence encoding a specific displayed peptide sequence. Such methods are described in International Publication Nos. 91 / 17271, 91 / 18980, 91 contains a nucleotide sequence encoding a specific displayed peptide sequence. Such methods are described in International Publication Nos. 91 / 17271, 91 / 18980, 91 contains a nucleotide sequence encoding a specific displayed peptide sequence. Such methods are described in International Publication Nos. 91 / 17271, 91 / 18980, 91 contains a nucleotide sequence encoding a specific displayed peptide sequence. Such methods are described in International Publication Nos. 91 / 17271, 91 / 18980, 91 contains a nucleotide sequence encoding a specific displayed peptide sequence. Such methods are described in International Publication Nos. 91 / 17271, 91 / 18980, 91 contains a nucleotide sequence encoding a specific displayed peptide sequence. Such methods are described in International Publication Nos. 91 / 17271, 91 / 18980, 91 contains a nucleotide sequence encoding a specific displayed peptide sequence. Such methods are described in International Publication Nos. 91 / 17271, 91 / 18980, 91 contains a nucleotide sequence encoding a specific displayed peptide sequence. Such methods are described in International Publication Nos. 91 / 17271, 91 / 18980, 91 contains a nucleotide sequence encoding a specific displayed peptide sequence. Such methods are described in International Publication Nos. 91 / 17271, 91 / 18980, 91 contains a nucleotide sequence encoding a specific displayed peptide sequence. Such methods are described in International Publication Nos. 91 / 17271, 91 / 18980, 91 It is described in / No. 19818 and No. 93 / 08278. The peptide library is Other systems for creating have both in vitro chemical synthesis and recombinant modes. See International Application Publication Nos. 92 / 05258, 92 / 14843, and 96 / 19 256. Also see U.S. Patent Nos. 5,658,754 and 5,643, 768. Peptide display libraries, vectors, and screening kits are commercially available from suppliers such as Invitrogen (Carlsbad, CA) and Cambridg e antibody Technologies (Cambridgeshire, U K). For example, U.S. Patent Nos. 4 704692, 4939666, 4946778, 5260203 , 5455030, 5518889, 5534621, 5656 730, 5763733, 5767260, 5856456, Dy ax-assigned U.S. Patent Nos. 5223409, 5403484, 55716 98, 5837500, Affymax-assigned U.S. Patent No. 5427908 , 5580717, Cambridge antibody Technolo gies-assigned U.S. Patent No. 5885793, Genentech-assigned U.S. Patent No. 5750373, Xoma-assigned U.S. Patent Nos. 5618920, 5 595898, 5576195, 5698435, 5693493 , 5698417, the above Colligan, the above Ausubel, or the above Sambrook. Each of the above patents and publications is incorporated herein by reference in its entirety. is incorporated herein.

[0060] The antibodies of the present invention may also be used in transgenic animals, such as goats, cows, horses, sheep, etc., which produce such antibodies in their milk. To provide a transgenic animal or mammal, a nucleic acid encoding at least one Such animals can be prepared using one or more anti-TNF antibodies. For example, but not limited to, those disclosed in U.S. Pat. No. 90, No. 5,849,992, No. 4,873,316, No. 5,849,99 No. 2, No. 5,994,616, No. 5,565,362, No. 5,304,489 Nos. 5,313,633 and 5,313,725, each of which is incorporated herein by reference in its entirety.

[0061] The antibodies of the present invention can be used to detect the specific Transgenic plants and cultured plant cells (e.g., In order to provide at least Further, the present invention can be prepared using one or more anti-TNF antibody-encoding nucleic acids. For example, transgenic vectors expressing recombinant proteins using inducible promoters can be used. Tobacco leaves have been successfully used to provide large amounts of recombinant proteins. For example, Cr amer et al.,Curr.Top.Microbol.Immunol.24 0:95-118 (1999) and references cited therein. Transgenic maize is a plant that is genetically engineered to be free of proteins or natural resources produced in other recombinant systems. A mammalian protein having biological activity equivalent to that of the protein purified from a commercial source is prepared. It has been used for expression at the production level. For example, Hood et al., Adv . Exp. Med. Biol. 464:127 - 147(1999) and the references cited therein are referred to. Antibodies have also been produced in large quantities from transgenic plant seeds containing antibody fragments such as single-chain antibodies (s cFv), including tobacco seeds and potato tubers . For example, Conrad et al., Plant Mol. Biol. 38:101 - 109(1998) and the references cited therein are referred to. Therefore, the antibodies of the present invention can also be produced using transgenic plants by known methods . For example, Fischer et al., Biotechnol. Appl. Bio chem. 30:99 - 108(Oct., 1999), Ma et al., Tren ds Biotechnol. 13:522 - 7(1995), Ma et al., P lant Physiol. 109:341 - 6(1995), Whitelam et al., Biochem. Soc. Trans. 22:940 - 944(1994), and the references cited therein are also referred to. Generally, references regarding the expression of antibodies in plants are also referred to. Each of the above-mentioned documents is incorporated herein by reference in its entirety

[0062] The antibodies of the present invention can bind to human TNF with a wide range of affinities (K D ). In a preferred embodiment, at least one human mAb of the present invention can bind to human TN F with high affinity. For example, the human mAb can bind human TNF at about 10 M or less, for example 0.1 - 9.9(or any range or value therein)×10 - 7 M-7 , 1 0 -8 , 10 -9 , 10 -10 , 10 -11 , 10 -12 , 10 -13 or any of them range or value of K, etc. (but not limited thereto) D can be conjugated with D .

[0063] The affinity or binding activity of an antibody to an antigen can be determined experimentally using any suitable method . (For example, see Berzofsky, et al., "Antibody- Antigen Interactions," In Fundamental Imm unology, Paul, W.E., Ed., Raven Press: New Yo rk, NY (1984), Kuby, Janis Immunology, W.H. Fr eeman and Company: New York, NY (1992), and the methods described in this specification). The affinity measured for a particular antibody-antigen interaction may vary when measured under different conditions (e.g., salt concentration, pH). Therefore , the measurement of affinity and other antigen-binding parameters (e.g., K K K D、 K a K d ) is preferably performed using standard solutions of the antibody and antigen, and standard buffers such as those described in this specification .

[0064] Nucleic acid molecules. Nucleotide sequences encoding at least 70 - 100% of at least one contiguous amino acid among SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, specified fragments , variants or their consensus sequences, or at least one of these sequences ​​Using the information provided in this specification, such as the deposited vectors containing, all of the heavy chain variable CDR regions of SEQ ID NOs: 1, 2, and 3 and / or all of the light chain variable CDR regions of SEQ ID NOs: 4, 5, and 6, the nucleic acid molecules of the present invention encoding at least one anti-TNF antibody can be obtained using the methods described herein or known in the art. All of the heavy chain variable CDR regions and / or all of the light chain variable CDR regions The nucleic acid molecules of the present invention encoding at least one anti-TNF antibody containing can be obtained using the methods described herein or known in the art.

[0065] The nucleic acid molecules of the present invention can be in the form of mRNA, hnRNA, tRNA, or any other form of RNA, such as or in the form of DNA obtained by cloning or synthetically generated cDNA and genomic DNA, including but not limited to these, or any combination thereof. The DNA can be triple-stranded, double-stranded, or single-stranded, or any combination thereof. Any portion of at least one strand of the DNA or RNA can be the coding strand, also known as the sense strand, or the non-coding strand, also called the antisense strand.

[0066] The isolated nucleic acid molecules of the present invention can optionally have one or more introns in an open reading frame (ORF), for example, but not limited to, at least one specific portion of at least one CDR, such as CDR1, CDR2, and / or CDR3 of at least one heavy chain (e.g., SEQ ID NOs: 1-3) or light chain (e.g., SEQ ID NOs: 4-6), a nucleic acid molecule containing the coding sequence of an anti-TNF antibody or variable region (e.g., SEQ ID NOs: 7, 8), and nucleic acid molecules that are substantially different from the above-described nucleic acid molecules but, due to the degeneracy of the genetic code, encode at least one anti-TNF antibody described herein and / or known in the art. It may comprise a nucleic acid molecule comprising a nucleotide sequence encoding at least one anti-TNF antibody still . Of course, the genetic code is well known in the art. Thus, it would be routine for one of ordinary skill in the art to generate such degenerate nucleic acid variants encoding the particular anti-TNF antibodies of the invention . See, for example, Ausubel et al. supra, such nucleic acid variants are included in the invention. Non-limiting examples of the isolated nucleic acid molecules of the invention include those encoding the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CD R2, LC CDR3, of the HC variable region and the LC variable region, corresponding non-limiting examples of the nucleic acids are SEQ ID NOs: 10, 11, 12, 13, 14, 15.

[0067] As shown herein, the nucleic acid molecules of the invention comprising nucleic acids encoding anti-TNF antibodies may themselves encode the amino acid sequences of antibody fragments, sequences encoding the full length of the antibody or a portion of the antibody , coding sequences of antibodies, fragments or portions, and additional sequences, e.g ., with or without the aforementioned additional coding sequences, such as at least one intron, non-coding 5' and 3' sequences, e.g., splicing and polyadenylation signals (e.g ., ribosome binding and stability of mRNA), transcribed non-translated sequences involved in transcription, mRNA processing that play a role in and including, but not limited to, additional non-coding sequences together with at least one signal leader or coding sequence of a fusion peptide, additional amino acids, e.g., additional coding sequences encoding amino acids that provide additional functions can be listed but are not limited thereto. Thus, the sequences encoding the antibodies are mar It can be fused to the CAR array. For example, the marker array is a sequence encoding a peptide that promotes the purification of an antibody containing a fragment or portion thereof that has been fused thereto. It is a sequence encoding a peptide that promotes the purification of an antibody containing a fragment or portion thereof that has been fused thereto.

[0068] A polynucleotide that selectively hybridizes to the polynucleotides described herein. The present invention provides an isolated nucleic acid that hybridizes under selective hybridization conditions to the polynucleotides disclosed herein. Thus, the polynucleotides of this embodiment can be used to isolate, detect, and / or quantify nucleic acids containing such polynucleotides. For example, the polynucleotides of the present invention can be used to identify, isolate, or amplify partial-length or full-length clones in a deposited library. In some embodiments, the polynucleotide is an isolated or otherwise genomic or cDNA sequence that is complementary to the cDNA of a human or mammalian nucleic acid library. It can be used to identify, isolate, or amplify partial-length or full-length clones in a deposited library. In some embodiments, the polynucleotide is an isolated or otherwise genomic or cDNA sequence that is complementary to the cDNA of a human or mammalian nucleic acid library. It can be used to isolate, detect, and / or quantify nucleic acids containing such polynucleotides. For example, the polynucleotides of the present invention can be used to identify, isolate, or amplify partial-length or full-length clones in a deposited library. In some embodiments, the polynucleotide is an isolated or otherwise genomic or cDNA sequence that is complementary to the cDNA of a human or mammalian nucleic acid library. For example, the polynucleotides of the present invention can be used to identify, isolate, or amplify partial-length or full-length clones in a deposited library. It can be used to identify, isolate, or amplify partial-length or full-length clones in a deposited library. In some embodiments, the polynucleotide is an isolated or otherwise genomic or cDNA sequence that is complementary to the cDNA of a human or mammalian nucleic acid library. In some embodiments, the polynucleotide is an isolated or otherwise genomic or cDNA sequence that is complementary to the cDNA of a human or mammalian nucleic acid library. It is a cDNA sequence.

[0069] Preferably, the cDNA library contains at least 80% of the full-length sequence, preferably at least 85% or 90% of the full-length sequence, and more preferably at least 95% of the full-length sequence. This cDNA library can be normalized to increase the expression level of rare sequences. Low or medium stringency hybridization conditions are typical, but not limited to, using sequences with low sequence identity to the complementary sequence. For sequences with higher identity, medium and high stringency conditions can optionally be used. Low stringency conditions are selective for sequences having about 70% sequence identity. Preferably, the cDNA library contains at least 80% of the full-length sequence, preferably at least 85% or 90% of the full-length sequence, and more preferably at least 95% of the full-length sequence. This cDNA library can be normalized to increase the expression level of rare sequences. Low or medium stringency hybridization conditions are typical, but not limited to, using sequences with low sequence identity to the complementary sequence. For sequences with higher identity, medium and high stringency conditions can optionally be used. Low or medium stringency hybridization conditions are typical, but not limited to, using sequences with low sequence identity to the complementary sequence. For sequences with higher identity, medium and high stringency conditions can optionally be used. Low stringency conditions are selective for sequences having about 70% sequence identity. It can be used to enable hybridization and identify orthologous or paralogous sequences. It can be used.

[0070] Optionally, the polynucleotide of the present invention will encode at least a portion of an antibody encoded by the polynucleotides described herein. The polynucleotide of the present invention includes nucleic acid sequences available for selective hybridization to a polynucleotide encoding an antibody of the present invention. See, for example, Ausubel, supra, Colligan, supra. Each is incorporated herein by reference in its entirety. ... ... ... ... It is incorporated herein by reference in its entirety.

[0071] Construction of nucleic acids. The isolated nucleic acids of the present invention can be made using (a) recombinant methods, (b) synthetic techniques, (c) purification techniques, or combinations thereof, as is well known in the art. ... It can be done.

[0072] In addition to the polynucleotides of the present invention, the nucleic acids can conveniently contain sequences. For example, a multiple cloning site containing one or more endonuclease restriction sites can be inserted into the nucleic acid to facilitate isolation of the polynucleotide. Also, a translatable sequence can be inserted to facilitate isolation of the translated polynucleotide of the present invention. For example, a hexahistidine marker sequence provides a convenient means for purifying the protein of the present invention. The nucleic acids of the present invention (excluding the coding sequences) are, optionally, vectors, adapters, or linkers for cloning and / or expressing the polynucleotides of the present invention. ... ... ... ... ... ...

[0073] Additional sequences can be added to such cloning and / or expression sequences for cloning and... optimizing their function in splicing / or expression, useful for isolating polynucleotides or improving the introduction of polynucleotides into cells. The use of cloning vectors, expression vectors, adapters, and linkers is well known in the art. (See, e.g., Ausubel supra, or Sambrook supra).

[0074] Recombinant methods for constructing nucleic acids. Isolated nucleic acid compositions of the invention, such as RNA, cDNA, genomic DNA, or any combination thereof, can be obtained from biological sources using any number of cloning procedures known to those of skill in the art. In some embodiments, oligonucleotide probes that selectively hybridize to the polynucleotides of the invention under stringent conditions are used to identify the desired sequences in cDNA or genomic DNA libraries. The isolation of RNA, and the construction of cDNA and genomic libraries are well known to those of skill in the art. (See, e.g., Ausubel supra, or Sambrook supra).

[0075] Methods for screening and isolating nucleic acids. Using a probe based on the sequence of the polynucleotides of the invention as disclosed herein, cDNA or genomic libraries can be screened. The probe can be used to hybridize to genomic DNA or cDNA sequences to isolate homologous genes from the same or different organisms. Those of skill in the art can use various degrees of hybridization stringency in the assay, and either the hybridization or wash medium can be made stringent. It will be apparent what can be done. As the hybridization conditions become more stringent the degree of complementarity between the probe and the target when double-stranded formation occurs should increase. The degree of stringency can be controlled by one or more of temperature, ionic strength, pH, and the presence of a partially denaturing solvent such as formamide. For example, the stringency of hybridization can be successfully altered by changing the polarity of the reaction solution, for example, by manipulating the formamide concentration within the range of 0% to 50%. The degree of complementarity (sequence identity) required for a detectable binding varies depending on the stringency of the hybridization medium and / or the washing medium. The degree of complementarity is optimally 100%, or 70 - 100%, or any range or value therein. However, it should be understood that minor differences in the sequences in the probe and primer can be compensated for by reducing the stringency of the hybridization and / or the washing medium. Methods for amplifying RNA or DNA are well known in the art and can be used in accordance with the present invention without undue experimentation based on the teachings and guidance presented herein.

[0076] Known methods of DNA or RNA amplification include polymerase chain reaction (PCR) and related amplification processes (e.g., U.S. Pat. Nos. 4,683,195, 4,683,202, 4,800,159, 4,965,188 to Mullis et al.,

[0077] 4,795,699 and 4,921,794 to Tabor et al., and U.S. Pat. Nos. 4,795,699 and 4,921,794 to Tabor et al., and 4,795,699 and 4,921,794 to Tabor et al., and U.S. Pat. Nos. 4,795,699 and 4,921,794 to Tabor et al., and U.S. Patent No. 5,142,033, U.S. Patent No. 5,122,464 to Wilson et al., U.S. Patent No. 5,091,310 to Innis, U.S. Patent No. 5 ,066,584 to Gyllensten et al., U.S. Patent No. 4,889,818 to Gelfand et al., Silve r et al., U.S. Patent No. 4,994,370, U.S. Patent No. 4,766,067 to Biswas No. (see Ringold, U.S. Patent No. 4,656,134), and double-stranded D NA-mediated amplification using antisense RNA against a target sequence as a template for double-stranded DNA synthesis (see, for example, U.S. Patent No. 5,130,238 to Malek et al., having the trade name NASBA ), but not limited to these (the entire contents of these documents are incorporated herein by reference). (See, for example, Ausubel supra, or Sambrook supra ).) For example, the polymerase chain reaction (PCR) technique can be used to amplify the sequences of the polynucleotides and related genes of the present invention directly from genomic DNA or cDNA libraries .)

[0078] For example, the polymerase chain reaction (PCR) technique can be used to amplify the sequences of the polynucleotides and related genes of the present invention directly from genomic DNA or cDNA libraries . PCR and other in vitro amplification methods can also be useful, for example, for cloning nucleic acid sequences encoding proteins to be expressed, detecting the presence of desired mRNA in a sample , for nucleic acid sequencing, or for making nucleic acids for use as probes for other purposes. Examples of techniques sufficient to guide one of ordinary skill in the art in in vitro amplification methods are Berger supra, Sambrook supra, and Ausubel supra , as well as U.S. Patent No. 4,683,202 (1987) to Mullis et al., and Inni s, et al., PCR Protocols A Guide to Method .) .) , as well as U.S. Patent No. 4,683,202 (1987) to Mullis et al., and Inni s, et al., PCR Protocols A Guide to Method s and Applications, Eds., Academic Press I nc, San Diego, CA (1990). Commercially available kits for genomic PCR amplification are known in the art. For example, see the Advantage-GC Genomic PCR Kit (Clontech). In addition, for example, the yield of long PCR products can be improved using T4 gene 32 protein (Boehringer Mannheim).

[0079] Synthetic methods for constructing nucleic acids. The isolated nucleic acids of the present invention can also be prepared by direct chemical synthesis by known methods (see, for example, Ausubel et al. above). Chemical synthesis generally generates single-stranded oligonucleotides that can be converted to double-stranded DNA by hybridization with complementary sequences or by polymerization with a DNA polymerase using the single-strand as a template. Those skilled in the art will recognize that while chemical synthesis of DNA may be limited to sequences of about 100 or more bases, longer sequences can be obtained by ligation reactions of shorter sequences.

[0080] Recombinant expression cassettes. The present invention further provides recombinant expression cassettes comprising the nucleic acids of the present invention. Using the nucleic acid sequences of the present invention, for example, cDNA or genomic sequences encoding the antibodies of the present invention, recombinant expression cassettes can be constructed that can be introduced into at least one desired host cell. Recombinant expression cassettes typically comprise a polynucleotide of the present invention operably linked to a transcriptional initiation regulatory sequence that directs the transcription of the polynucleotide in the intended host cell. Both heterologous and non-heterologous (i.e., endogenous) promoters can be used to drive the expression of the nucleic acids of the present invention in the appropriate host cells. ​​​​​​​​​​​​​​​ can direct the expression of an acid.

[0081] In some embodiments, an isolated nucleic acid that functions as a promoter, enhancer, or other element is used to upregulate or downregulate the expression of a polynucleotide of the invention by introducing it at an appropriate position (upstream, downstream, or within an intron) of a non-heterologous form of the polynucleotide of the invention. For example, in vivo or in vitro, the endogenous promoter can be altered by mutation, deletion, and / or substitution.

[0082] Vectors and host cells. The invention also relates to vectors containing the isolated nucleic acid molecules of the invention, host cells genetically engineered with recombinant vectors, and the production of at least one anti-TNF antibody by recombinant techniques well known in the art. For example, reference is made to Sambrook et al. and Ausubel et al., each of which is incorporated herein by reference in its entirety.

[0083] The polynucleotide can optionally be ligated to a vector containing a selectable marker for growth of the host. Generally, plasmid vectors are introduced into precipitates such as calcium phosphate precipitates or complexes with charged lipids. If the vector is a virus, it is packaged in vitro using an appropriate packaging cell line and then can be transfected into host cells.

[0084] The DNA insert should be operably linked to an appropriate promoter. An expression construct further includes a transcription start site, a transcription termination site, and a ribosome binding site for translation within the transcribed region. The coding portion of the mature transcript expressed by the construct is preferably ​​​​​​​​​​​​​​ Alternatively, it will include the translation start site at first and the stop codon (e.g., , UAA, UGA or UAG) will be properly located at the end of the translated mRNA. In mammalian or eukaryotic cell expression, UAA and UAG are preferred.

[0085] The expression vector preferably includes at least one selectable marker, but this is optional . Such markers include, for example, methotrexate (MTX ) for eukaryotic cell culture, dihydrofolate reductase (DHFR, U.S. Patent Nos. 4,399,216, 4, 634,665, 4,656,134, 4,956,288, 5,1 49,636, 5,179,017, ampicillin, neomycin (G418) , mycophenolic acid or glutamine synthetase (GS) (U.S. Patent Nos. 5,122,4 64; 5,770,359, 5,827,739) resistance genes, and tetracycline or ampicillin resistance genes for culture in E. coli and other bacteria or prokaryotes, but are not limited thereto (the above patents are hereby incorporated by reference in their entirety into this specification ). Suitable culture media and conditions for the above host cells are known in the art . Suitable vectors will be readily apparent to those skilled in the art. The introduction of the vector construct into the host cell is affected by calcium phosphate transfection, DEAE-dextran-mediated transfection, cationic lipid-mediated transfection , electroporation, transduction, infection or other known methods . For such methods, see Sambrook, supra, Chapters 1-4 and 16-18 , such as the above-mentioned Ausubel, Chapters 1, 9, 13, 15, 16, etc., are described in the relevant technical field. It is described.

[0086] At least one antibody of the present invention can be expressed in a modified form such as a fusion protein, and may include not only a secretion signal but also additional heterologous functional regions. For example, a region of additional amino acids, especially charged amino acids, is added to the N-terminus of the antibody to improve stability and persistence in host cells during purification or subsequent processing and storage. In addition, a peptide moiety can be added to the antibody of the present invention to facilitate purification. Such regions can be removed before the final preparation of the antibody or at least one of its fragments. Such methods are described in many standard laboratory manuals such as the above-mentioned Sambrook, Chapters 17.29 - 17.42 and 18.1 - 18.74, and the above-mentioned Ausubel, Chapters 16, 17 and 18, etc. It is described. Before the final preparation of the antibody or at least one of its fragments, such regions can be removed. Such methods are described in many standard laboratory manuals such as the above-mentioned Sambrook, Chapters 17.29 - 17.42 and 18.1 - 18.74, and the above-mentioned Ausubel, Chapters 16, 17 and 18, etc. Sambrook, Chapters 17.29 - 17.42 and 18.1 - 18.74, and the above-mentioned Ausubel, Chapters 16, 17 and 18, etc. are described in many standard laboratory manuals. It is described.

[0087] Those skilled in the art are proficient in a number of expression systems available for the expression of nucleic acids encoding the proteins of the present invention. It is described.

[0088] As another method, the nucleic acid of the present invention can be expressed in a host cell by (operationally) switching it on within the host cell containing the endogenous DNA encoding the antibody of the present invention. Such methods are well-known in the relevant technical field as described in U.S. Patent Nos. 5,580,734, 5,641,670, 5,733,746, and 5,733,761, which are hereby incorporated by reference in their entirety. It is described in U.S. Patent Nos. 5,580,734, 5,641,670, 5,733,746, and 5,733,761, which are hereby incorporated by reference in their entirety.

[0089] An example of a cell culture useful for the production of an antibody, its identified part or variant is mammalian cells This is the case. Mammalian cell lines often take the form of a monolayer of cells, but suspensions of mammalian cells or bioreactors can also be used. Several suitable host cell lines capable of expressing intact glycosylated proteins have been developed in the art, including COS -1 (e.g., ATCC CRL 1650), COS-7 (e.g., ATCC CRL-1 651), HEK293, BHK21 (e.g., ATCC CRL-10), CHO (e.g. ATCC CRL1610) and BSC-1 (e.g., ATCC CRL-26) cell lines , Cos-7 cells, CHO cells, hep G2 cells, P3X63Ag8.653, SP2 / 0-Ag14, 293 cells, HeLa cells, etc., which are, for example, available from Amer ican Type Culture Collection, Manassas, VA and are readily available. Preferred host cells include CHO cells, as well as cells derived from the lymphatic system such as myeloma and lymphoma cells. Particularly preferred host cells are CHO cells, P3X63Ag8.653 cells (ATCC accession number CRL-1580) and SP2 / 0-Ag14 cells (ATCC accession number CRL-1851).

[0090] Expression vectors for these cells include an origin of replication, a promoter (e.g., late or early SV 40 promoter, CMV promoter (U.S. Patent Nos. 5,168,062; 5,3 85,839), HSV tk promoter, pgk (phosphoglycerate kinase) promoter, EF-1α promoter (U.S. Patent No. 5,266,491), at least one human immunoglobulin promoter, an enhancer, and / or a ribosome binding site sites, RNA splice sites, polyadenylation sites (e.g., the SV40 large T Ag poly addition site), and processing information sites such as transcription termination sequences, etc., but are not limited thereto, and may include one or more of the expression control sequences. For example, see Ausubel et al. above and Sambrook et al. above. Other cells useful for the production of the nucleic acid or protein of the present invention are known, and / or are available, for example, from the catalog of cell lines and hybridomas of the American Type Culture Collection or other known or commercial sources. When eukaryotic host cells are used, typically, a polyadenylation or transcription termination sequence is incorporated into the vector. An example of a termination sequence is the polyadenylation sequence from the bovine growth hormone gene. Sequences for accurate splicing of transcription can also be included, similarly.

[0091] An example of a splicing sequence is the VP1 intron derived from SV40 (Sprague , et al., J. Virol. 45:773-781 (1983)). In addition, as is known in the art, gene sequences for controlling replication in host cells can be incorporated into the vector. , et al., J. Virol. 45:773-781 (1983)). In addition, as is known in the art, gene sequences for controlling replication in host cells can be incorporated into the vector.

[0092] Purification of antibodies. Anti-TNF antibodies can be purified by protein A purification, ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxyapatite chromatography, and lectin chromatography. It can be recovered and purified from recombinant cell cultures by well-known methods not limited to these. This can be done. High performance liquid chromatography ( “HPLC”) can also be used for purification. For example, see Colligan, Current Protocols in Immuno logy or Current Protocols in Protein Scien ce, John Wiley & Sons, NY, NY (1997 - 2001), for example, see Chapters 1, 4, 6, 8, 9, 10, each of which is hereby incorporated by reference in its entirety. into this specification.

[0093] The antibodies of the present invention include naturally purified products, products of chemical synthesis procedures, and, for example, products produced by recombinant techniques from eukaryotic hosts including yeast, higher plants, insects, and mammalian cells. Depending on the host used in the recombinant production procedure, the antibodies of the present invention may or may not be glycosylated, but are preferably glycosylated. Such methods are described in many standard laboratory manuals such as the above Sambrook, Sections 17.37 - 17.42, the above Ausubel, Chapters 10, 12, 13, 16, 18, and 20, the above Colligan, Protein Science, Chapters 12 - 14, etc., all of which are hereby incorporated by reference in their entirety into this specification.

[0094] Anti - TNF antibody The isolated antibodies of the present invention comprising all of the heavy - chain variable CDR regions of SEQ ID NOs: 1, 2, and 3 and / or all of the light - chain variable CDR regions of SEQ ID NOs: 4, 5, and 6 can be in any suitable polynucle The amino acid sequences of the antibodies disclosed herein encoded by the oligonucleotides, or any single isolated or prepared antibody. Preferably, the human antibody or antigen-binding fragment binds to human TNF and thereby partially or substantially neutralizes at least one biological activity of the protein. An antibody or a specified portion or variant thereof that partially or preferably substantially neutralizes at least one biological activity of at least one TNF protein or fragment binds to the protein or fragment and thereby inhibits the activity mediated through binding of TNF to its TNF receptor or through other TNF-dependent or -mediated mechanisms. As used herein, the term "neutralizing antibody" refers to an antibody that can inhibit TNF-dependent activity by about 20-1 20%, preferably at least about 10, 20, 30, 40, 50, 55, 60, 65, 7 0, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 %, 100% or more, depending on the assay. The ability of an anti-TNF antibody to inhibit TNF-dependent activity is preferably evaluated by at least one suitable TNF protein or receptor a ssay described herein and / or known in the art. The human antibodies of the invention can be of any class (IgG, IgA, Ig M, IgE, IgD, etc.) or isotype and can include a κ or λ light chain. In one embodiment, the human antibody includes an IgG heavy chain or a defined fragment, e.g., Ig G1, IgG2, IgG3 or IgG4 of at least one isotype. This type of antibody can include at least one human light chain (e.g., IgG, IgA) and IgM (e.g., γ1, γ2, γ described herein and / or known in the art. This type of antibody can include at least one human light chain (e.g., IgG, IgA) and IgM (e.g., γ1, γ2, γ In one embodiment, the human antibody includes an IgG heavy chain or a defined fragment, e.g., Ig G1, IgG2, IgG3 or IgG4 of at least one isotype. Antibodies of this type are described herein and / or known in the art, and include at least one human light chain (e.g., IgG, IgA) and IgM (e.g., γ1, γ2, γ 3. A transgenic mouse or other transgenic non-human mammal containing the introduced gene [[γ4]] can be prepared by using. In another embodiment, the anti-human TNF human antibody contains an IgG1 heavy chain and an IgG1 light chain. When used herein, the term "antibody" or "antibodies" includes biosimilar antibody molecules approved under the Biologics Price Competition and Innovation Act (BPCI Act) of 2009 and similar worldwide laws and regulations. Under the BPCI Act, an antibody is "very similar" to a reference product despite minor differences in clinically inactive components, and is "expected" to provide clinical results equivalent to the reference product in terms of safety, purity, and potency. (Endocrine Practice: February 2018, Vol. 24, No. 2, pp. 195-204). These biosimilar antibody molecules provide a shortened approval pathway, and thus the applicant relies on the clinical data of the innovator's reference product to secure regulatory approval. Compared to the original innovator reference antibody approved by the FDA based on the success of clinical trials, the biosimilar antibody molecules are referred to herein as "follow-on biologics". As presented herein, SIMPONI® (golimumab) is the original innovator reference anti-TNF antibody approved by the FDA based on the success of clinical trials. Golimumab has been on the market in the United States since 2009. At least one antibody of the present invention binds to at least one TNF protein, subunit

[0095] When used herein, the term "antibody" or "antibodies" includes biosimilar antibody molecules approved under the Biologics Price Competition and Innovation Act (BPCI Act) of 2009 and similar worldwide laws and regulations. Under the BPCI Act, an antibody is "very similar" to a reference product despite minor differences in clinically inactive components, and is "expected" to provide clinical results equivalent to the reference product in terms of safety, purity, and potency. (Endocrine Practice: February 2018, Vol. 24, No. 2, pp. 195- 204). These biosimilar antibody molecules provide a shortened approval pathway, and thus the applicant relies on the clinical data of the innovator's reference product to secure regulatory approval. Compared to the original innovator reference antibody approved by the FDA based on the success of clinical trials, the biosimilar antibody molecules are referred to herein as "follow-on biologics". As presented herein, SIMPONI® (golimumab) is the original innovator reference anti-TNF antibody approved by the FDA based on the success of clinical trials. Golimumab has been on the market in the United States since 2009. At least one antibody of the present invention binds to at least one TNF protein, subunit When used herein, the term "antibody" or "antibodies" includes biosimilar antibody molecules approved under the Biologics Price Competition and Innovation Act (BPCI Act) of 2009 and similar worldwide laws and regulations. Under the BPCI Act, an antibody is "very similar" to a reference product despite minor differences in clinically inactive components, and is "expected" to provide clinical results equivalent to the reference product in terms of safety, purity, and potency. (Endocrine Practice: February 2018, Vol. 24, No. 2, pp. 195- 204). These biosimilar antibody molecules provide a shortened approval pathway, and thus the applicant relies on the clinical data of the innovator's reference product to secure regulatory approval. Compared to the original innovator reference antibody approved by the FDA based on the success of clinical trials, the biosimilar antibody molecules are referred to herein as "follow-on biologics". As presented herein, SIMPONI® (golimumab) is the original innovator reference anti-TNF antibody approved by the FDA based on the success of clinical trials.

[0096] At least one antibody of the present invention binds to at least one TNF protein, subunit 、 binds to at least one specific epitope specific to a fragment, portion, or any combination thereof. This at least one epitope can include at least one antibody-binding region that includes at least a portion of this protein, and this epitope is preferably composed of at least one extracellular portion, soluble portion, hydrophilic portion, external portion, or cytoplasmic granule portion of this protein. At least one identified epitope can include any combination of at least 1 to 3 amino acids relative to the entire identified portion of the adjacent amino acids of SEQ ID NO: 9 of at least one amino acid sequence. Generally, the human antibodies or antigen-binding fragments of the present invention include at least one human complementarity-determining region (CDR1, CDR2, and CDR3) or a variant of at least one heavy chain variable region, and an antigen-binding region that includes at least one human complementarity-determining region (CDR1, CDR2, and CDR3) or a variant of at least one light chain variable region. As a non-limiting example, the antibody or

[0097] antigen-binding portion or variant can include at least one of the heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 3 and / or the light chain CDR3 having the amino acid sequence of SEQ ID NO: 6. In certain embodiments, the antibody or antigen-binding fragment has an antigen-binding region that includes at least a portion of at least one heavy chain CDR (i.e., CDR1, CDR2, and / or CDR3) having the amino acid sequence of the corresponding CDR1, 2, and / or 3 (e.g., SEQ ID NO: 1, 2, and / or 3). In another specific embodiment, the antibody or antigen-binding portion or variant has an antigen-binding region that includes at least a portion of the amino acid sequence of the corresponding CDR1, 2, and / or 3 (e.g., SEQ ID NO: 4 of at least one heavy chain CDR (i.e., CDR1, CDR2, and / or CDR3). In certain embodiments, the antibody or antigen-binding fragment has an antigen-binding region that includes at least a portion of at least one heavy chain CDR (i.e., CDR1, CDR2, and / or CDR3) having the amino acid sequence of the corresponding CDR1, 2, and / or 3 (e.g., SEQ ID NO: 1, 2, and / or 3). In another specific embodiment, the antibody or antigen-binding portion or variant has an antigen-binding region that includes at least a portion of the amino acid sequence of the corresponding CDR1, 2, and / or 3 (e.g., SEQ ID NO: 4 of at least one heavy chain CDR (i.e., CDR1, CDR2, and / or CDR3). , 5, and / or 6) having at least one light chain CDR (i.e., CDR1, CDR2 and / or CDR3) can have an antigen-binding region that includes at least a portion thereof. In a preferred embodiment, the three heavy chain CDRs and the three light chain CDRs of the antibody or antigen-binding fragment are the corresponding CDRs of at least one of mAb TNV148, TNV14, TNV15, TNV1 96, TNV118, TNV32, and TNV86 described herein. Such antibodies can be prepared and expressed by using conventional techniques related to recombinant DNA technology to prepare (i.e., one or more) nucleic acid molecules encoding the antibody, or by chemically bonding various parts of the antibody (e.g., CDRs, frameworks) together using conventional techniques by any other suitable method. The anti-TNF antibody can include at least one of a heavy chain or light chain variable region having a defined amino acid sequence. For example, in a preferred embodiment, the anti-TNF antibody can include at least one of a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7 and / or at least one light chain variable region having the amino acid sequence of SEQ ID NO: 8,

[0098] if desired. An antibody that binds to human TNF and includes a defined heavy chain or light chain variable region can be prepared using a suitable method, e.g., phage display (Katsube, Y., et al., Int J Mol. Med, 1( 5):863-868(1998)) or a method employing transgenic animals, which are known in the art and / or described herein. For example, a functionally rearranged human immunoglobulin display (Katsube, Y., et al., Int J Mol.Med, 1( 5):863-868(1998)) or a method employing transgenic animals, such as a suitable method can be used for preparation. For example, a functionally rearranged human immunoglobulin ​​​​A transgenic mouse comprising a roblin heavy chain transgene and a transgene comprising DNA from a human immunoglobulin light chain locus capable of undergoing functional rearrangement can be immunized with human TNF or a fragment thereof to induce antibody production. If desired, antibody-producing cells can be isolated and hybridomas or other immortalized antibody-producing cells can be prepared as described herein and / or as known in the art. Alternatively, an antibody, identified portion or variant can be expressed in a suitable host cell using the coding nucleic acid or a portion thereof. The present invention also relates to antibodies, antigen-binding fragments, immunoglobulin chains and CDRs comprising amino acids in a sequence that is substantially the same as the amino acid sequences described herein. Preferably, such antibodies or antigen-binding fragments and antibodies comprising such chains or CDRs have a high affinity (e.g., K is about 10 M or less) and can bind to human TNF. Amino acid sequences that are substantially the same as the sequences described herein include sequences comprising conservative amino acid substitutions and amino acid deletions and / or insertions. Conservative amino acid substitutions refer to replacing a first amino acid with a second amino acid having similar chemical and / or physical properties (e.g., charge, structure, polarity, hydrophobicity / hydrophilicity) to that of the first amino acid. Conservative substitutions include replacing one amino acid with another amino acid within the following groups: lysine (K), arginine (R) and histidine (H); aspartate (D) and glutamate (E); asparagine (N), glutamine (Q), serine (S), threonine (T), serine (S), tyrosine (Y), cysteine (C); valine (V), leucine (L), isoleucine (I), methionine (M), alanine (A), glycine (G).

[0099] The present invention also relates to antibodies, antigen-binding fragments, immunoglobulin chains and CDRs comprising amino acids in a sequence that is substantially the same as the amino acid sequences described herein. Preferably, such antibodies or antigen-binding fragments and antibodies comprising such chains or CDRs have a high affinity (e.g., K is about 10 M or less) and can bind to human TNF. Amino acid sequences that are substantially the same as the sequences described herein include sequences comprising conservative amino acid substitutions and amino acid deletions and / or insertions. Conservative amino acid substitutions refer to replacing a first amino acid with a second amino acid having similar chemical and / or physical properties (e.g., charge, structure, polarity, hydrophobicity / hydrophilicity) to that of the first amino acid. Conservative substitutions include replacing one amino acid with another amino acid within the following groups: lysine (K), arginine (R) and histidine (H); aspartate (D) and glutamate (E); asparagine (N), glutamine (Q), serine (S), threonine D is about 10 -9 M or less) and can bind to human TNF. Amino acid sequences that are substantially the same as the sequences described herein include sequences comprising conservative amino acid substitutions and amino acid deletions and / or insertions. Conservative amino acid substitutions refer to replacing a first amino acid with a second amino acid having similar chemical and / or physical properties (e.g., charge, structure, polarity, hydrophobicity / hydrophilicity) to that of the first amino acid. Conservative substitutions include replacing one amino acid with another amino acid within the following groups: lysine (K), arginine (R) and histidine (H); aspartate (D) and glutamate (E); asparagine (N), glutamine (Q), serine (S), threonine (T), serine (S), tyrosine (Y), cysteine (C); valine (V), leucine (L), isoleucine (I), methionine (M), alanine (A), glycine (G). Conservative substitutions include replacing one amino acid with another amino acid within the following groups: lysine (K), arginine (R) and histidine (H); aspartate (D) and glutamate (E); asparagine (N), glutamine (Q), serine (S), threonine (T), serine (S), tyrosine (Y), cysteine (C); valine (V), leucine (L), isoleucine (I), methionine (M), alanine (A), glycine (G). Onin (T), tyrosine (Y), K, R, H, D, and E; alanine (A), valine (V ), leucine (L), isoleucine (I), proline (P), phenylalanine (F), tryptophan (W), methionine (M), cysteine (C), and glycine (G); F , W, and Y; C, S, and T.

[0100] Amino acid codes. The amino acids constituting the anti-TNF antibody of the present invention are often abbreviated. Amino acid notations can be indicated by their one-letter code, their three-letter code, name, or the codon(s) of three nucleotides that represent the amino acid, which is well understood in the art (see Alberts, B., et al., Molecular Biology of The Cell, Third Ed., Garland Publishing, Inc., New York, 1994).

[0101] [Table 1]

[0102] The anti-TNF antibody of the present invention may contain substitutions, deletions, or additions of one or more amino acids, either by natural mutations or human operations, as specified herein. Of course, the number of amino acid substitutions that a person skilled in the art can make depends on a number of

[0103] factors including those described above. Generally speaking, for any given anti-TNF antibody, fragment, or variant, the number of amino acid substitutions, insertions, or deletions is 40, 30, 2 0, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, as specified herein, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, Not exceeding 5, 4, 3, 2, 1, for example, 1 to 30, or any range or value therein .

[0104] Amino acids within the anti-TNF antibodies of the invention that are functionally essential can be identified by site-directed mutagenesis or The specific sequences may be identified by methods known in the art, such as alanine scanning mutagenesis. (see, e.g., Ausubel, supra, Chapter 8, 15; Cunningham, am and Wells,Science 244:1081-1085(1989) The latter procedure involves the introduction of single alanine mutations at every residue in the molecule. and the resulting mutant molecule has at least one TNF neutralizing activity, e.g. The antibodies are tested for biological activity, including but not limited to: The sites that are important for the synthesis of the nucleotides have also been identified by structural analysis such as crystallization, nuclear magnetic resonance, or photoaffinity labeling. (Smith, et al., J. Mol. Biol. 224:8 99-904 (1992) and de Vos, et al., Science 255: 306-312(1992)).

[0105] The anti-TNF antibody of the present invention has at least one of SEQ ID NOs: 1, 2, 3, 4, 5, and 6. At least one portion, sequence or combination selected from one to all of the adjacent amino acids These may include, but are not limited to, combinations.

[0106] The anti-TNF antibody may further comprise at least one adjacent amino acid sequence of SEQ ID NO: 7, SEQ ID NO: 8. It may contain at least one polypeptide that is 70 to 100% amino acids.

[0107] In one embodiment, the amino acid sequence of an immunoglobulin chain or a portion thereof (e.g., variable region, CDR) has at least about 70 to 100% identity (e.g., 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 9 0, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, or any range or value therein) with the amino acid sequence of at least one corresponding chain of SEQ ID NOs: 7 and 8 . For example, the amino acid sequence of the light chain variable region can be compared with the sequence of SEQ ID NO: 8, or the amino acid sequence of the heavy chain CDR3 can be compared with SEQ ID NO: 7 . Preferably, 70 to 100% amino acid identity (i.e., 90, 91, 9 2, 93, 94, 95, 96, 97, 98, 99, 100, or any range or value therein) is determined using suitable computer algorithms, as is known in the art .

[0108] Representative heavy and light chain variable region sequences are shown in SEQ ID NOs: 7 and 8. The antibodies of the present invention or their identified mutants can include any number of adjacent amino acid residues from the antibodies of the present invention, the number of which is selected from the group of integers consisting of 10 to 100% of the number of adjacent residues in an anti-TNF antibody . Optionally, this subsequence of adjacent amino acids is at least about 10, 20, 30 , 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 1 50, 160, 170, 180, 190, 200, 210, 220, 230, 240, 2 50, or more amino acids in length, or any range or value therein. Further, the number of such subsequences is selected from the group consisting of 1 to 20, such as at least 2, 3, 4, or 5 . The integer number can be any integer number that is supported.

[0109] As will be apparent to one of skill in the art, the present invention includes at least one biologically active compound of the present invention. Biologically active antibodies include antibodies that are naturally occurring (non-synthetic), endogenous or related At least 20%, 30% or 40% of that of the known antibody, and preferably at least 50%, 60% or 70%, and most preferably at least 80%, 90% or 95% It has a specific activity of 1000%. Methods for assay and quantification of enzyme activity and substrate specificity is well known to those skilled in the art.

[0110] In another aspect, the present invention provides a method for the preparation of a compound according to any one of the preceding claims, wherein the compound is modified by the covalent attachment of an organic moiety. The present invention relates to human antibodies and antigen-binding fragments that have been modified to have improved pharmacokinetic properties. (e.g., increased serum half-life in vivo). The organic moiety can be a linear or branched hydrophilic polymer group, a fatty acid group, or a fatty acid ester. In certain embodiments, the hydrophilic polymeric group can be a tertiary ether group. 0 to about 120,000 daltons, and polyalkane glycols (e.g., polyethylene glycols). Polyethylene glycol (PEG), polypropylene glycol (PPG), carbohydrate polymers, It may be an amino acid polymer or polyvinylpyrrolidone, and may also be a fatty acid group or a fatty acid ester. The alkyl group can contain from about 8 to about 40 carbon atoms.

[0111] The modified antibodies and antigen-binding fragments of the invention are directly or indirectly covalently attached to the antibody. The antibody or antigen-binding fragment of the present invention may contain one or more organic moieties that are attached to the antibody or antigen-binding fragment of the present invention. Each organic moiety is independently a hydrophilic polymeric group, a fatty acid group, or a fatty acid ester group. is obtained. As used herein, the term "fatty acid" includes monocarboxylic acids and dicarboxylic acids. As used herein, the term "hydrophilic polymer group" means an organic polymer that is more soluble in water than in octane. For example, polylysine is more soluble in water than in octane. Thus, an antibody modified by covalent bonding of polylysine is included in the present invention. Suitable hydrophilic polymers for modifying the antibodies of the present invention can be linear or branched, and examples thereof include polyalkylene glycols (e.g., PEG, monomethoxy-polyethylene glycol (mPEG), PPG, etc.), carbohydrates (e.g., dextran, cellulose, oligosaccharides, polysaccharides, etc.), polymers of hydrophilic amino acids (e.g., polylysine, polyarginine, polyaspartic acid, etc.), polyalkylene oxides (e.g., polyethylene oxide, polypropylene oxide, etc.), and polyvinylpyrrolidone. Preferably, the hydrophilic polymer for modifying the antibodies of the present invention has a molecular weight of about 800 to about 150,000 daltons as an individual molecule. For example, PEG and PEG can be used, and the subscript is the average molecular weight (daltons) of the polymer. The hydrophilic polymer group can be substituted with 1 to about 6 alkyl groups, fatty acid groups, or fatty acid ester groups. Hydrophilic polymers substituted with fatty acid or fatty acid ester groups can be prepared by utilizing suitable methods. For example, a polymer containing an amine group can be linked to a carboxylate of a fatty acid or fatty acid ester, and an activated carboxylate on the fatty acid or fatty acid ester (e.g., activated with N,N-carbonyldiimidazole) can be used. 5000 20,00 0 ​​​​​​​​​​​​​​​​​can be linked to a hydroxyl group on the polymer.

[0112] Suitable fatty acids and fatty acid esters for modifying the antibodies of the present invention may be saturated or may contain one or more unsaturated units. Suitable lipids for modifying the antibodies of the present invention As fatty acids, for example, n-dodecanoate (C 12 , laurate), n-tetradecanoate ate (C 14 , myristate), n-octadecanoate (C 18 , stearate), n-eicosanoate (C 20 , arachidate), n-docosanoate (C 22 , behenic acid ), n-triacontanoate (C 30 ), n-tetracosanoate (C 40 ), cis-Δ 9-octadecenoate (C 18 , oleate), all cis-Δ5,8,11,14- eicosatetraenoate (C 20 , arachidonate), octanedioic acid, tetradecane dioic acid, octadecanedioic acid, docosanedioic acid, etc. are mentioned. Suitable fatty acid esters Sterols include monoesters of dicarboxylic acids containing a straight-chain or branched-chain lower alkyl group . The lower alkyl group may contain 1 to about 12, preferably 1 to about 6 carbon atoms.

[0113] Modified human antibodies and antigen-binding fragments can be prepared using suitable methods such as reacting with one or more modifiers. As used herein, the term "modifier" means a suitable organic group containing an activating group (e.g., a hydrophilic polymer, a fatty acid, a fatty acid ester) . "Activating group" means a group that reacts with a second chemical group under appropriate conditions, thereby causing the modifier It is a chemical moiety or functional group capable of forming a covalent bond with a second chemical group. For example, amine-reactive activating groups include electrophilic groups such as tosylate, mesylate, halo (chloro, bromo, fluoro, iodo), N-hydroxysuccinimidyl ester (NHS), etc. Activating groups reactive with thiols include, for example, maleimide, iodoacetate, acryloyl, pyridyldisulfide, 5-thiol-2-nitrobenzoic acid thiol (TNB-thiol), etc. Aldehyde functional groups can be linked to amine- or hydrazide-containing molecules, and azide groups can react with trivalent phosphorus groups to form phosphoramidate or phosphorimide bonds. Suitable methods for introducing activating groups into molecules are known in the art (see, for example, Hermanson, G.T., Bioconjugate Techniques, Academic Press: San Diego, CA (1996)). Activating groups can be attached directly to organic groups (e.g., hydrophilic polymers, fatty acids, fatty acid esters) or via a linker moiety, e.g., a divalent C 1 ~C group where one or more carbon atoms can be substituted with heteroatoms such as oxygen, nitrogen, or sulfur (see, for example, Hermanson, G.T., Bioconjugate Techniques, Academic Press: San Diego, CA (1996)). Suitable linker moieties include, for example, tetraethylene glycol, -(CH 2) 1 ~C 12 group (where one or more carbon atoms can be substituted with heteroatoms such as oxygen, nitrogen, or sulfur). Activating groups can be attached directly to organic groups (e.g., hydrophilic polymers, fatty acids, fatty acid esters) or via a linker moiety, e.g., a divalent C ~C 2 2 3 group, -NH-(CH 2 2 6 2 2 2 -NH- and -CH 2 2 2 -O-CH 2 2 2 -C H2 The linker moiety-containing modifying agent includes, for example, 1-ethyl-3- In the presence of (3-dimethylaminopropyl)carbodiimide (EDC), mono-Boc- Alkyl diamines (e.g., mono-Boc-ethylenediamine, mono-Boc-diamino By reacting hexane with fatty acids, free amines and fatty acid carboxylates are produced. The Boc protecting group can be converted to a trifluoro The product was removed by treatment with acetic acid (TFA) and converted to the other carboxylate salts as described. This exposes a primary amine which can be coupled or reacted with maleic anhydride. and cyclizing the resulting product to produce an activated maleimide derivative of the fatty acid. (See, e.g., Thompson, 2002, the teachings of which are incorporated herein by reference in their entirety. (See WO 92 / 16221 to G. et al.).

[0114] The modified antibodies of the present invention can be prepared by reacting a human antibody or antigen-binding fragment with a modifying agent. For example, the organic moiety can be generated by an amine-reactive modifying agent, e.g., PEG. NHS esters of the compounds can be used to conjugate to antibodies in a non-site-specific manner. Disulfide bonds (e.g., intrachain disulfide bonds) of antibodies or antigen-binding fragments can be (a) preparing a modified human antibody or antigen-binding fragment thereof; In this case, the reduced antibody or antigen-binding fragment can be subjected to thiol-reactive modification. The antibody of the present invention can be reacted with a decorating agent to produce a modified antibody of the present invention. Modified human antibodies and antigen-binding fragments containing organic moieties attached to specific sites of the antibody are known as reverse transcription antibodies. Proteolysis (Fisch et al., Bioconjugate Chem., 3 :147-153(1992), Werlen et al., Bioconjugat e Chem., 5:411-417(1994), Kumaran et al., P rotein Sci. 6(10):2233-2241(1997), Itoh et al., Bioorg.Chem., 24(1):59-68(1996), Cape llas et al., Biotechnol.Bioeng., 56(4):456 -463(1997)) and Hermanson, G.T., Bioconjugate Techniques, Academic Press: San Diego, CA( 1996) and other suitable methods such as those described therein can be used for preparation.

[0115] Anti-idiotype antibody against the anti-Tnf antibody composition. In addition to monoclonal or chimeric anti-TN F antibodies, the present invention also relates to anti-idiotype (anti-Id) antibodies specific for such antibodies of the present invention. Anti-Id antibodies are generally antibodies that recognize unique determinants related to the antigen-binding region of another antibody. Anti-Id can be prepared by immunizing an animal of the same species and genotype as the Id antibody source (e.g., a mouse strain) with the antibody or its CDR-containing region. The immunized animal recognizes and responds to the idiotype determinant of the immunizing antibody and generates anti-I d antibodies. Anti-Id antibodies can also be used as an "immunogen" to induce an immune response in yet another animal, generating so-called anti-anti-Id antibodies.

[0116] Anti-Tnf antibody composition. The present invention also provides the antibodies described herein and / or those in the art ​​As known in the art, at least one non-naturally occurring composition, mixture, or form is provided. 1, at least 2, at least 3, at least 4, at least 5, at least At least one anti-TNF antibody composition comprising six or more of said anti-TNF antibodies is also provided. Such compositions include those comprising the contiguous amino acids of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8. Selected from the group consisting of 70-100%, or a specified fragment, domain, or variant thereof At least one or two full-length, C and / or C-terminal amino acid sequences of the anti-TNF antibody to be used non-naturally occurring compositions, including N-terminal deletion variants, domains, fragments, or variants thereof, as specified. A preferred anti-TNF antibody composition comprises a compound selected from the group consisting of 70 to 1 of SEQ ID NOs: 1, 2, 3, 4, 5, and 6. 00% of an anti-TNF antibody, or a specified fragment, domain or variant thereof, At least one or two full-length, fragment, domain, or fragments as CDR or LBR-containing portions. Further preferred compositions include the 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, 0-100%, or at least one of the specified fragments, domains, or variants thereof The percentages of such compositions are known in the art. As used herein, weight, volume, concentration, molarity, or Molar mass as a liquid or dry solution, mixture, suspension, emulsion, or colloid It depends on the concentration.

[0117] The anti-TNF antibody compositions of the present invention further comprise a compound that is capable of inhibiting the proliferation, proliferation, and / or proliferation of cells in need of such modulation, treatment or therapy. , a tissue, an organ, an animal or a patient, and optionally at least one anti-TNF antibody. , at least one TNF antagonist (e.g., a TNF antibody or fragment, a soluble TNF receptor such as a body or fragment, their fusion protein, or a small molecule TNF antagonist, etc., but not limited to these ), antirheumatic drugs (for example, methotrexate, auranofin, aurothioglucose, azathioprine, etanercept, sodium aurothiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), muscle relaxants, narcotics , non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, anesthetics, sedatives , local anesthetics, neuromuscular blockers, antibacterial agents (for example, aminoglycosides, antifungal agents, anthelmintics, antiviral agents, carbapenems, cephalosporins, fluoroquinolones, macrolides , penicillins, sulfonamides, tetracyclines, and other antibacterial agents), anti-psoriatic agents, corticosteroids, anabolic steroids, diabetes-related drugs, minerals, nutritional agents, thyroid drugs , vitamins, calcium-related hormones, antidiarrheal agents, antitussives, antiemetics, antiulcer agents, laxatives, anticoagulants, erythropoietin (for example, epoetin alpha), filgrastim (for example G-C SF, Neupogen), sargramostim (GM-CSF, Leukine), immunomodulators, immunoglobulins, immunosuppressive agents (for example, basiliximab, cyclosporine, dacli zumab), growth hormones, hormone replacement agents, estrogen receptor modulators, mydriatics, ciliary muscle regulators, alkylating agents, antimetabolites, mitotic inhibitors, radiopharmaceuticals, antidepressants, antimanic drugs, antipsychotics, anxiolytics, hypnotics, sympathomimetics, stimulants, donepezil, tacrine, laxatives, beta-agonists, inhaled steroids, leukotriene inhibitors, methylxanthines, chromolyn, epinephrine or similar drugs, dornase alpha (Pulmozyme), cytokines Optionally further comprising at least one selected from cytokine antagonists, any suitable and effective amount of at least one of a composition or a pharmaceutical composition. Such cytokines Non-limiting examples of include any of IL-1 to IL-23, but are not limited thereto. Suitable dosages are well known in the art. For example, Wells et al., eds., Pharmacotherapy Handbook, 2 nd Edition, Appleton and Lange, Stamford, CT ( 2000), PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarasc on Publishing, Loma Linda, CA (2000) are hereby incorporated by reference in their entirety herein.

[0118] Such anti-cancer agents or anti-infective agents may also include toxin molecules associated with, bound to, co-prescribed with, or combined with at least one antibody of the present invention. The toxin can optionally act to selectively kill diseased cells or tissues. Diseased cells can be cancer cells or other cells. Such toxins include, but are not limited to, for example, at least one selected from ricin, diphtheria toxin, snake venom, or bacterial toxins, and can be a purified or recombinant toxin or toxin fragment comprising at least one functional cytotoxic domain of the toxin. The term toxin also includes any naturally occurring, mutated or recombinant bacterium or which can cause any condition, including toxic shock that can lead to death, in humans and other mammals. contains both endotoxins and exotoxins produced by viruses. Such toxins include enterotoxigenic Escherichia coli heat-labile enterotoxin (LT), heat-stable enterotoxin (ST) , Shigella cell toxin, Aeromonas enterotoxin, toxic shock syndrome toxin-1 ( TSST-1), Staphylococcus enterotoxin A (SEA), B (SEB), or C (S EC), streptococcal enterotoxin, and the like, but are not limited thereto . Such bacteria include enterotoxigenic Escherichia coli (ETEC), enterohemorrhagic Escherichia coli (e.g., serotype 0 157 strains: H7), Staphylococcus species (e.g., Staphylococcus aureus, Staphylococcus - pi ogenes), Shigella species (e.g., Shigella dysenteriae, Shigella flexneri, Shigella boydii, and S onnei), Salmonella species (e.g., Salmonella typhi, Salmonella cholerae - suis, Salmon ella enteritidis), Clostridium species (e.g., Clostridium - perfringens, Clostridium - difficile, Clostridium - botulinum), Can pylobacter species (e.g., Campylobacter - jejuni, Campylobacter - fetus sus), Helicobacter species (e.g., Helicobacter - pylori), Aeromonas species (e.g. Aeromonas - sobria, Aeromonas - hydrophila, Aeromonas - caviae) , Plesiomonas - shigelloides, Yersinia enterocolitica, Vibrio species (e.g., Vibrio cholerae, V ibrio - parahaemolyticus), Klebsiella species, Pseudomonas aeruginosa, and strains of Streptococcus species are included, but are not limited thereto. For example, Stein, ed., INTERNAL MEDI CINE, 3rd ed., pp 1 - 13, Little, Brown and Co ., Boston, (1990), Evans et al., eds., Bacter ​ ial Infections of Humans:Epidemiology an d Control,2d.Ed.,pp 239-254,Plenum Medicine al Book Co., New York (1991), Mandell et al. ,Principles and Practice of Infectious D iseases,3d.Ed.,Churchill Livingstone,New York (1990), Berkow et al, eds., The Merck Manual,16th edition,Merck and Co.,Rahway ,NJ,1992,Wood et al,FEMS Microbiology Immunology,76:121-134(1991), Marrack et a. See, for example, J. Med., Science, 248:705-711 (1990) (these references (the contents of which are incorporated herein by reference in their entirety).

[0119] The anti-TNF antibody compounds, compositions or mixtures of the present invention may further comprise a diluent, binder, stabilizer, buffer, etc. Any additives, such as, but not limited to, buffers, salts, lipophilic solvents, preservatives, adjuvants, etc. The composition may comprise at least one of the following suitable auxiliary agents: Pharmaceutically acceptable auxiliary agents are preferred. Non-limiting examples of and methods for preparing such sterile solutions are well known in the art. For example, see Gennaro, Ed., Remington's Pharmaceut. Physical Sciences, 18 th Edition, Mack Publication Examples of commercially available products include, but are not limited to, 1990. Well-known in the art, or as described herein, pharmaceutically acceptable carriers suitable for the administration method, solubility, and / or stability of anti-TNF antibodies, fragments, or mutant compositions can be routinely selected.

[0120] Pharmaceutical excipients and additives useful in the present composition include, but are not limited to, proteins, peptides, amino acids, lipids, and carbohydrates (e.g., saccharides including monosaccharides, disaccharides, trisaccharides, tetrasaccharides, and oligosaccharides, alditols, aldonic acids, derivatized sugars such as esterified sugars, as well as polysaccharides or sugar polymers), which may be present alone or in combination and are included in an amount of 1 to 99.99% by weight or volume, alone or in combination. Representative protein excipients include serum albumins such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Representative amino acid / antibody components that can also function in buffering capacity include alanine, glycine, arginine, betaine, histidine , glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine , methionine, phenylalanine, aspartame, and the like. One of the preferred amino acids is glycine.

[0121] Suitable carbohydrate excipients for use in the present invention include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, etc., disaccharides such as lactose, sucrose, trehalose, cellobiose, etc., polysaccharides such as raffinose, melezitose, maltodextrin, dextran, starches, etc., and alditols such as mannitol, xylitol, lactitol, lactitol, xylitol, sorbitol (glucitol), Alditols such as myo-inositol can be mentioned. Preferred carbohydrates used in the present invention as excipients are mannitol, trehalose, and

[0122] The anti-TNF antibody composition may also contain a buffer or a pH adjuster. Typically, the buffer is a salt prepared from an organic acid or a base. Representative buffers include organic acid salts such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, tromethamine hydrochloride, or phosphate buffers. Preferred buffers for use in the present

[0123] In addition, the anti-TNF antibody composition of the present invention may contain polyvinylpyrrolidone, ficoll (polysaccharide), dextrates (e.g., 2-hydroxypropyl-β-cyclodextrin and other cyclodextrins), polyethylene glycol, flavoring agents, antibacterial agents, sweeteners, antioxidants, antistatic agents, surfactants (e.g., polysorbates such as "TWEEN 20" and "TWEEN 80"), lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol), and chelating agents (e.g., EDTA) and other polymer excipients / additives. may be included.

[0124] These and additional known pharmaceutical excipients and / or additives suitable for use in the anti-TNF antibody, fragment or variant composition according to the present invention are known in the art, for example, "Remington: The Science & Practice of P th harmacy", 19 995), and "Physician’s Desk Reference", 52 nd ed, Medical Economics, Montvale, NJ (1998) are listed, and these disclosures are incorporated herein by reference in their entirety. Preferred carrier or excipient materials are carbohydrates (e.g., monosaccharides and alditols) and buffers (e.g., citric acid) or polymeric agents.

[0125] Formulations. As described above, the present invention preferably provides a stable formulation that is physiological saline or a phosphate buffer containing a selected salt, as well as a storage solution and formulation containing a preservative, and a pharmaceutical or veterinary use suitable for a multi-purpose storage formulation containing at least one anti-TNF antibody in a pharmaceutically acceptable formulation. The storage formulation contains, in an aqueous diluent, at least one known i.e., at least one of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrate, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkyl parabens (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride benzethonium chloride, sodium dehydroacetate, and thimerosal, or a mixture thereof optionally selected from the group consisting of preservatives. As is known in the art 0.001 to 5%, or 0.001, 0.003, 0.005, 0.00 9, 0.01, 0.02, 0.03, 0.05, 0.09, 0.1, 0.2, 0.3, 0 .4., 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, selected. As is known in the art, 0.001 to 5%, or 0.001, 0.003, 0.005, 0.00 9, 0.01, 0.02, 0.03, 0.05, 0.09, 0.1, 0.2, 0.3, 0 .4., 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.3, 4.5, 4.6, 4.7, 4.8, 4.9, or any range or value therein, etc., but not limited thereto, any suitable concentration or mixture of any range or value therein may be used Thereof. As non-limiting examples, preservative-free, 0.1 - 2% m-cresol (e.g., 0. 2, 0.3, 0.4, 0.5, 0.9, 1.0%), about 0.1 - 3% benzyl alcohol (e.g., 0.5, 0.9, 1.1, 1.5, 1.9, 2.0, 2.5%), 0.00 1 - 0.5% thimerosal (e.g., 0.005, 0.01), 0.001 - 2.0% phenol (e.g., 0.05, 0.25, 0.28, 0.5, 0.9, 1.0%), 0.0005 - 1.0% alkyl parabens (plural available) (e.g., 0.00075, 0. 0009, 0.001, 0.002, 0.005, 0.0075, 0.009, 0.01 , 0.02, 0.05, 0.075, 0.09, 0.1, 0.2, 0.3, 0.5, 0. 75, 0.9, 1.0%), etc. can be mentioned.

[0126] As described above, the present invention provides a product comprising a packaging material and at least one vial containing a solution of at least one anti-TNF antibody with a buffer and / or a preservative formulated in an aqueous diluent if desired, and this packaging material includes a label stating that it can hold such a solution for 1, 2, 3, 4, 5, 6, 9, 12, 18, 20, 24, 30, 36, 40, 48, 54, 60, 66, 72 hours or more. The present invention also provides a packaging material and a lyophilized ​ a first vial containing at least one anti-TNF antibody that has been produced, and a second vial containing an aqueous diluent of a formulated buffer or preservative, and the packaging further includes a product, and the packaging material has a label that instructs the patient to reconstitute at least one anti-TNF antibody with the aqueous diluent to form a solution that can be retained for over 24 hours. A product comprising a second vial containing an aqueous diluent of a formulated buffer or preservative, and the packaging further includes a product, and the packaging material has a label that instructs the patient to reconstitute at least one anti-TNF antibody with the aqueous diluent to form a solution that can be retained for over 24 hours. At least one anti-TNF antibody is reconstituted with an aqueous diluent to form a solution that can be retained for over 24 hours. The solution can be retained for over 24 hours.

[0127] At least one anti-TNF antibody used in the present invention may be produced by recombinant means including those produced from mammalian cells or transgenic preparations as described herein or known in the art, or may be purified from other biological sources. At least one anti-TNF antibody used in the present invention may be produced by recombinant means including those produced from mammalian cells or transgenic preparations as described herein or known in the art, or may be purified from other biological sources. At least one anti-TNF antibody used in the present invention may be produced by recombinant means including those produced from mammalian cells or transgenic preparations as described herein or known in the art, or may be purified from other biological sources.

[0128] The range of at least one anti-TNF antibody contained in the product of the present invention, in the case of a wet / dry system, is an amount that gives a concentration in the range of about 1.0 μg / mL to about 1000 mg / mL upon reconstitution, but lower and higher concentrations are also workable, and these concentrations are determined by the intended delivery vehicle, for example, in a solution formulation, it is different from a transdermal patch, lung, transmucosal, or osmotic or micropump method. The range of at least one anti-TNF antibody contained in the product of the present invention, in the case of a wet / dry system, is an amount that gives a concentration in the range of about 1.0 μg / mL to about 1000 mg / mL upon reconstitution, but lower and higher concentrations are also workable, and these concentrations are determined by the intended delivery vehicle, for example, in a solution formulation, it is different from a transdermal patch, lung, transmucosal, or osmotic or micropump method. The range of at least one anti-TNF antibody contained in the product of the present invention, in the case of a wet / dry system, is an amount that gives a concentration in the range of about 1.0 μg / mL to about 1000 mg / mL upon reconstitution, but lower and higher concentrations are also workable, and these concentrations are determined by the intended delivery vehicle, for example, in a solution formulation, it is different from a transdermal patch, lung, transmucosal, or osmotic or micropump method. Preferably, the aqueous diluent optionally further includes a pharmaceutically acceptable preservative. Preferred preservatives include those selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl parabens (such as methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal or mixtures thereof. The concentration of the preservative used in the formulation is a concentration sufficient to produce an antibacterial effect. Such a concentration is selected. Preferably, the aqueous diluent optionally further includes a pharmaceutically acceptable preservative. Preferred preservatives include those selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl parabens (such as methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal or mixtures thereof. The concentration of the preservative used in the formulation is a concentration sufficient to produce an antibacterial effect. Such a concentration is selected.

[0129] Preferably, the aqueous diluent optionally further includes a pharmaceutically acceptable preservative. Preferred preservatives include those selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl parabens (such as methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal or mixtures thereof. The concentration of the preservative used in the formulation is a concentration sufficient to produce an antibacterial effect. Such a concentration is selected. Preferably, the aqueous diluent optionally further includes a pharmaceutically acceptable preservative. Preferred preservatives include those selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl parabens (such as methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal or mixtures thereof. The concentration of the preservative used in the formulation is a concentration sufficient to produce an antibacterial effect. Such a concentration is selected. Preferably, the aqueous diluent optionally further includes a pharmaceutically acceptable preservative. Preferred preservatives include those selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl parabens (such as methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal or mixtures thereof. The concentration of the preservative used in the formulation is a concentration sufficient to produce an antibacterial effect. Such a concentration is selected. Preferably, the aqueous diluent optionally further includes a pharmaceutically acceptable preservative. Preferred preservatives include those selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl parabens (such as methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal or mixtures thereof. The concentration of the preservative used in the formulation is a concentration sufficient to produce an antibacterial effect. Such a concentration is selected. Preferably, the aqueous diluent optionally further includes a pharmaceutically acceptable preservative. Preferred preservatives include those selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl parabens (such as methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal or mixtures thereof. The concentration of the preservative used in the formulation is a concentration sufficient to produce an antibacterial effect. Such a concentration is selected. Preferably, the aqueous diluent optionally further includes a pharmaceutically acceptable preservative. Preferred preservatives include those selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl parabens (such as methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal or mixtures thereof. The concentration of the preservative used in the formulation is a concentration sufficient to produce an antibacterial effect. Such a concentration is selected. It varies depending on the preservative used and can be easily determined by those skilled in the art.

[0130] Other excipients, such as isotonic agents, buffers, antioxidants, and preservative enhancers, can be added to the diluent if desired and preferably. Isotonic agents such as glycerin are commonly used at known concentrations. Preferably, a physiologically tolerated buffer is added to provide improved pH control. The formulation can be targeted at a wide range of pH ranges, such as from about pH 4 to about pH 10, and preferably from about pH 5 to about pH 9, and most preferably from about 6.0 to about 8.0. Preferably, the formulation of the present invention has a pH of from about 6.8 to about 7.8. Suitable buffers include phosphate buffers, and most preferably sodium phosphate, especially phosphate buffered saline (PBS).

[0131] Other additives, such as Tween 20 (polyoxyethylene (20) sorbitan monolaurate), Tween 40 (polyoxyethylene (20) sorbitan monopalmitate), Tween 80 (polyoxyethylene (20) sorbitan monooleate), P luronic F68 (polyoxyethylene polyoxypropylene block copolymer ), and PEG (polyethylene glycol), pharmaceutically acceptable solubilizing agents, or polysorbate 20 or 80 or poloxamer 184 or 188, Pluron ic (registered trademark) polyols and other nonionic surfactants, other block copolymers , and chelating agents such as EDTA and EGTA can be optionally added to the formulation or composition to reduce aggregation. These additives can be used with a pump for administering the formulation or It is particularly useful when a plastic container is used. A pharmaceutically acceptable surfactant The presence of reduces the tendency of the protein to aggregate.

[0132] The formulation of the present invention comprises at least one anti-TNF antibody and phenol, m-cresol, p -cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl para ben (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium nium, sodium dehydroacetate, and thimerosal or a mixture thereof, and a preservative selected from the group consisting of It can be prepared by a process comprising mixing in an aqueous diluent. Mixing at least one anti-TNF antibody and a preservative in an aqueous diluent is a conventional It is carried out using dissolution and mixing procedures. To prepare a suitable formulation, for example, a certain amount of at least one anti-TNF antibody in a buffer solution is combined with a desired preservative in a buffer solution in an amount sufficient to provide the desired concentration of protein and preservative. Variations of this process will be recognized by those skilled in the art. For example, the order of addition of components, the use or non-use of additional additives, the temperature and pH during formulation preparation are all factors that can be optimized with respect to the administration concentration and administration means to be used. For example, a certain amount of at least one anti-TNF antibody in a buffer solution is combined with a desired preservative in a buffer solution in an amount sufficient to provide the desired concentration of protein and preservative. This process can be varied. Forms will be recognized by those skilled in the art. For example, the order of addition of components, the use or non-use of additional additives, the temperature and pH during formulation preparation are all factors that can be optimized with respect to the administration concentration and administration means to be used. For example, the order of addition of components, the use or non-use of additional additives, the temperature and pH during formulation preparation are all factors that can be optimized with respect to the administration concentration and administration means to be used. It is a factor that can be optimized.

[0133] The claimed formulation can be provided to a patient as a dual vial containing a vial of lyophilized at least one anti-TNF antibody that is reconstituted in a second vial containing water, a preservative and / or an excipient, preferably a phosphate buffer and / or saline, and a selected salt in an aqueous diluent, as a transparent solution. It can be provided to the patient as a dual vial containing a vial of lyophilized at least one anti-TNF antibody that is reconstituted in a second vial containing water, a preservative and / or an excipient, preferably a phosphate buffer and / or saline, and a selected salt in an aqueous diluent, as a transparent solution. Both single-solution vials or dual vials that require reconstitution can be reused multiple times, can meet single or multiple patient treatment cycles, and thus can provide a more convenient treatment regimen than is currently available.

[0134] The claimed product is useful for administration over a period of from immediately up to 24 hours or more. Thus, the product claimed by the present invention provides a great benefit to patients. The formulations of the present invention can be stored safely, optionally, at temperatures from about 2 to about 40 °C, maintaining the biological activity of the protein over a long period of time, and thus the packaging label can indicate that the solution can be held and / or used over a period of 6, 12, 18, 24, 36, 48, 72, or 96 hours or more. When using a stored diluent, such a label can include use up

[0135] to 1 to 12 months, six months, one and a half years and / or two years. Solutions of at least one anti-TNF antibody of the present invention can be prepared by a process that includes mixing at least one antibody in an aqueous diluent. Mixing is performed using conventional dissolution and mixing procedures. To prepare a suitable diluent, for example, a certain amount of at least one antibody in water or buffer is combined in an amount sufficient to provide the desired concentration of protein and, optionally, a preservative or buffer. Variations of this process will be recognized by those skilled in the art. For example, the order of addition of components, the use or

[0136] The claimed product can be provided to patients as a dual vial containing a lyophilized vial of at least one anti-TNF antibody, which is returned as a clear solution or in a second vial containing an aqueous diluent. As a dual vial, it can be provided to patients. Single solution vials or dual vials that require reconstitution can all be reused multiple times and can satisfy single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than is currently available. As a dual vial, it can be provided to patients. Single solution vials or dual vials that require reconstitution can all be reused multiple times and can satisfy single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than is currently available. As a dual vial, it can be provided to patients. Single solution vials or dual vials that require reconstitution can all be reused multiple times and can satisfy single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than is currently available. As a dual vial, it can be provided to patients. Single solution vials or dual vials that require reconstitution can all be reused multiple times and can satisfy single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than is currently available. As a dual vial, it can be provided to patients. Single solution vials or dual vials that require reconstitution can all be reused multiple times and can satisfy single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than is currently available.

[0137] The claimed product can be indirectly provided to patients by providing a dual vial containing a lyophilized vial of at least one anti-TNF antibody, which is returned as a clear solution or in a second vial containing an aqueous diluent, to pharmacies, clinics, or other such institutions and facilities. The clear solution in this case can have a volume of up to 1 liter or even more, and a smaller amount of at least one antibody solution can be taken out from this large container one or more times and transferred to smaller vials, and can be provided to customers and / or patients by pharmacies or clinics. As a dual vial, it can be provided to patients. Single solution vials or dual vials that require reconstitution can all be reused multiple times and can satisfy single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than is currently available. As a dual vial, it can be provided to patients. Single solution vials or dual vials that require reconstitution can all be reused multiple times and can satisfy single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than is currently available. As a dual vial, it can be provided to patients. Single solution vials or dual vials that require reconstitution can all be reused multiple times and can satisfy single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than is currently available. As a dual vial, it can be provided to patients. Single solution vials or dual vials that require reconstitution can all be reused multiple times and can satisfy single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than is currently available. As a dual vial, it can be provided to patients. Single solution vials or dual vials that require reconstitution can all be reused multiple times and can satisfy single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than is currently available. As a dual vial, it can be provided to patients. Single solution vials or dual vials that require reconstitution can all be reused multiple times and can satisfy single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than is currently available.

[0138] Approved devices including these single vial systems include BD Pens, BD Autojector (registered trademark), Humaject (registered trademark), NovoPen (registered trademark), B-D (registered trademark) Pen, AutoPen (registered trademark), and OptiPen (registered trademark), GenotropinPen (registered trademark), GenotronormPen (registered trademark), Humatro Pen (registered trademark), Reco-Pen (registered trademark), Roferon Pen (registered trademark), Biojector (registered trademark), ije utojector(registered trademark), Humaject(registered trademark), NovoPen(registered trademark), B-D(registered trademark)Pen, AutoPen(registered trademark), and OptiPen(registered trademark), GenotropinPen(registered trademark), Genotronorm Pen(registered trademark), Humatro Pen(registered trademark), Reco-Pen(registered trademark), Roferon Pen(registered trademark), Biojector(registered trademark), ije n(registered trademark), GenotropinPen(registered trademark), Genotronorm Pen(registered trademark), Humatro Pen(registered trademark), Reco-Pen(registered trademark), Roferon Pen(registered trademark), Biojector(registered trademark), ije trademark), Roferon Pen(registered trademark), Biojector(registered trademark), ije ct (Registered Trademark), J-tip Needle-Free Injector (Registered Trademark ), Intraject (Registered Trademark), Medi-Ject (Registered Trademark), etc. for solution delivery include pen-type injector devices. For example, Becton Dickensen (Franklin Lakes, NJ, www. bectondickenson.com), Disetronic (Burgdorf, Switzerland, www.dis etronic.com; Bioject, Portland, Oregon (www.bioject.com ); Weston Medical (Peterborough, UK, www.west on-medical.com), Medi-Ject Corp (Minneapolis, MN, www.medij ect.com) have been manufactured or developed.

[0139] Approved devices including dual vial systems include HumatroPen (Registered Trademark ), etc., pen-type injector systems for redissolving freeze-dried drugs in a cartridge for delivering the redissolved solution .

[0140] The product claimed herein includes a packaging material. The packaging material provides the conditions under which the product can be used in addition to the information required by the regulatory authorities. The packaging material of the present invention forms a solution by redissolving at least one anti-TNF antibody in an aqueous diluent and provides instructions to the patient to use this solution for wet / dry two-vial products over a period of 2 to 24 hours or more. In the case of a single vial solution product, the label states that this solution is for 2 to 24 hours or more​​​ It shows that it can be used over a longer period. The product claimed herein is useful for pharmaceutical product applications for humans.

[0141] The formulation of the present invention can be prepared by a process comprising mixing at least one anti-TNF antibody and a selected buffer, preferably a phosphate buffer containing physiological saline or a selected salt. The mixing of at least one antibody and the buffer in an aqueous diluent is carried out using conventional dissolution and mixing procedures. To prepare a suitable formulation, for example, a certain amount of at least one antibody in water or buffer is combined with the desired buffer in an amount of water sufficient to provide the desired concentration of protein and buffer. Variations of this process will be recognized by those skilled in the art. For example, the order of addition of the components, the use or non-use of additional additives, the temperature and pH during formulation preparation are all factors that can be optimized with respect to the dosage concentration and means of administration used.

[0142] The claimed stable or preservative formulation can be provided to the patient as a clear solution or as a dual vial containing a vial of lyophilized at least one anti-TNF antibody that is reconstituted in an aqueous diluent or returned to a second vial containing a preservative or buffer and excipient. Either a single solution vial or a dual vial that requires reconstitution can be reused multiple times and can satisfy single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than currently available.

[0143] At least one anti- As is well known in the art, TNF antibodies can be administered to a subject according to the present invention via various delivery methods such as SC or IM injection, transdermal, transtracheal , transmucosal, implantation, osmotic pump, cartridge, micropump or other means well known in the art and understood by those skilled in the art.

[0144] Therapeutic applications. The present invention also provides a method for modulating or treating at least one TNF-related disease in cells, tissues, organs, animals or patients using at least one dual integrin antibody of the present invention, which is known in the art or described herein .

[0145] The present invention also provides a method for modulating or treating at least one TNF-related disease in cells, tissues, organs, animals or patients, including but not limited to at least one of obesity, immune-related diseases, cardiovascular diseases, infectious diseases, malignant diseases or neurological diseases .

[0146] The present invention also provides rheumatoid arthritis, juvenile, systemic-onset juvenile rheumatoid arthritis, ankylosing spondylitis , ankylosing spondylitis, gastric ulcer, seronegative arthropathy, osteoarthritis, inflammatory bowel disease, ulcerative colitis , systemic lupus erythematosus, antiphospholipid syndrome, iridocyclitis / uveitis / optic neuritis , idiopathic pulmonary fibrosis, systemic vasculitis / Wegener's granulomatosis, sarcoidosis, orchitis / vasectomy repair, allergic / atopic diseases, asthma, allergic rhinitis, dermatitis, a llergic contact dermatitis, allergic conjunctivitis, hypersensitivity pneumonitis, transplantation, organ transplant rejection , graft-versus-host disease, systemic inflammatory response syndrome, septic shock syndrome, gram-positive bacteremia, gram-negative ​Septicemia, culture-negative septicemia, fungal septicemia, neutropenic fever, urosepsis, meningococcemia Trauma / hemorrhage, burns, ionizing radiation exposure, acute pancreatitis, adult respiratory distress syndrome, alcoholic hepatitis, chronic inflammatory lesions, sarcoidosis, Crohn's disease, sickle cell anemia, diabetes mellitus, nephrosis, atopic diseases, allergic reactions, allergic rhinitis, hay fever, perennial rhinitis, conjunctivitis, endometriosis, asthma, urticaria, systemic anaphylaxis, dermatitis, pernicious anemia, hemolytic diseases, thrombocytopenia, graft rejection of any organ or tissue, kidney transplant rejection, heart transplant rejection, liver transplant rejection, pancreas transplant rejection, lung transplant rejection, bone marrow transplant (BMT ) rejection, skin allograft rejection, cartilage transplant rejection, bone graft rejection, small intestine transplant rejection , fetal thymus transplant rejection, parathyroid transplant rejection, xenograft rejection of any organ or tissue, allograft rejection, antireceptor overreaction, Graves' disease, Raynaud's disease, type B insulin-resistant diabetes mellitus, asthma, myasthenia gravis, antibody-mediated cytotoxicity, type III hypersensitivity reaction, systemic lupus erythematosus, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin manifestations syndrome), polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin manifestations syndrome, antiphospholipid syndrome, pemphigus, scleroderma, mixed connective tissue disease, idiopathic Addison's disease, true diabetes mellitus, chronic active hepatitis, primary biliary cirrhosis, vitiligo, vasculitis, post-MI cardiotomy syndrome, type IV hypersensitivity, contact dermatitis, hypersensitivity pneumonitis, allograft rejection, granuloma due to intracellular organisms, drug allergy, metabolic / idiopathic Wilson's disease, hemochromatosis, α-1-antitrypsin deficiency, diabetic retinopathy, Hashimoto's thyroiditis, osteoporosis, primary biliary cirrhosis, thyroiditis, encephalomyelitis, cachexia, cysts ​ Pulmonary fibrosis, neonatal chronic lung disease, chronic obstructive pulmonary disease (COPD), lymph of familial blood eating tissue Histiocytosis, dermatological conditions, psoriasis, alopecia, nephrotic syndrome, nephritis, glomerulonephritis , acute renal failure, hemodialysis, uremia, toxicity, preeclampsia, okt3 therapy, anti - cd3 therapy, cytokine therapy, chemotherapy, radiotherapy (for example, including but not limited to weakness, anemia, cachexia, etc.) at least one such as chronic salicylate poisoning, etc., but not limited to them, at least one immune in cells, tissues, organs, animals or patients related diseases are also provided for regulating or treating. For example, Merck Manual , 12th - 17th Editions, Merck & Company, Rahw ay, NJ (1972, 1977, 1982, 1987, 1992, 1999), Pharmacotherapy Handbook, Wells et al., eds., Second Edition, Appleton and Lange, Stamfo rd, Conn. (1998, 2000) are hereby incorporated by reference in their entirety. This invention relates to cardiac stun syndrome, myocardial infarction, congestive heart failure , stroke, ischemic attack, hemorrhage, arteriosclerosis, atherosclerotic arteriosclerosis, restenosis, diabetic arteriosclerotic diseases, hypertension, arterial hypertension, renovascular hypertension, syncope, shock, cardiovascular syphilis

[0147] , heart failure, cor pulmonale, primary pulmonary hypertension, arrhythmia, atrial ectopic beats, atrial fibrillation, atrial flutter (persistent or paroxysmal), post - reperfusion syndrome, cardiopulmonary bypass inflammatory response, chaotic or multifocal atrial tachycardia , etc. are hereby incorporated by reference in their entirety. , etc. are hereby incorporated by reference in their entirety. , heart failure, cor pulmonale, primary pulmonary hypertension, arrhythmia, atrial ectopic beats, atrial fibrillation, atrial flutter (persistent or paroxysmal), post - reperfusion syndrome, cardiopulmonary bypass inflammatory response, chaotic or multifocal atrial tachycardia (persistent or paroxysmal), post - reperfusion syndrome, cardiopulmonary bypass inflammatory response, chaotic or multifocal atrial tachycardia , regular narrow QRS tachycardia, specific arrhythmias, ventricular fibrillation, His bundle arrhythmias, atrioventricular block, bundle branch block, myocardial ischemic diseases, coronary artery diseases, angina pectoris, myocardial infarction, cardiomyopathy, dilated congestive cardiomyopathy, restrictive cardiomyopathy, valvular heart disease, endocarditis, pericardial diseases, cardiac tumors, aortic aneurysm and peripheral artery aneurysm, aortic dissection, aortic inflammation, occlusion of the abdominal aorta and its branches, peripheral vascular disorders, obstructive arterial disorders, peripheral atherosclerotic arterial disease, thromboangiitis obliterans, functional peripheral arterial disorders, Raynaud's phenomenon and diseases, acrocyanosis, erythromelalgia, venous disorders, deep vein thrombosis, venous aneurysm, arteriovenous fistula, lymphedema, lipedema, unstable angina, reperfusion injury, post pump syndrome, ischemic reperfusion injury, etc., including but not limited to at least one of these, a method for regulating or treating cardiovascular diseases in cells, tissues, organs, animals or patients is also provided. Such a method may optionally include administering to the cells, tissues, organs, animals or patients in need of such regulation, treatment or therapy an effective amount of a composition or pharmaceutical composition comprising at least one anti-TNF antibody. hythmias), ventricular fibrillation, His bundle arrhythmias, atrioventricular block, bundle branch block, myocardial ischemic diseases, coronary artery diseases, angina pectoris, myocardial infarction, cardiomyopathy, dilated congestive cardiomyopathy, restrictive cardiomyopathy, valvular heart disease, endocarditis, pericardial diseases, cardiac tumors, aortic aneurysm and peripheral artery aneurysm, aortic dissection, aortic inflammation, occlusion of the abdominal aorta and its branches, peripheral vascular disorders, obstructive arterial disorders, peripheral atherosclerotic arterial disease, thromboangiitis obliterans, functional peripheral arterial disorders, Raynaud's phenomenon and diseases, acrocyanosis, erythromelalgia, venous disorders, deep vein thrombosis, venous aneurysm, arteriovenous fistula, lymphedema, lipedema, unstable angina, reperfusion injury, post pump syndrome, ischemic reperfusion injury, etc., including but not limited to at least one of these. Myocardial infarction, cardiomyopathy, dilated congestive cardiomyopathy, restrictive cardiomyopathy, valvular heart disease, endocarditis, pericardial diseases, cardiac tumors, aortic aneurysm and peripheral artery aneurysm, aortic dissection, aortic inflammation, occlusion of the abdominal aorta and its branches, peripheral vascular disorders, obstructive arterial disorders, peripheral atherosclerotic arterial disease, thromboangiitis obliterans, functional peripheral arterial disorders, Raynaud's phenomenon and diseases, acrocyanosis, erythromelalgia, venous disorders, deep vein thrombosis, venous aneurysm, arteriovenous fistula, lymphedema, lipedema, unstable angina, reperfusion injury, post pump syndrome, ischemic reperfusion injury, etc., including but not limited to at least one of these. Dilated congestive cardiomyopathy, restrictive cardiomyopathy, valvular heart disease, endocarditis, pericardial diseases, cardiac tumors, aortic aneurysm and peripheral artery aneurysm, aortic dissection, aortic inflammation, occlusion of the abdominal aorta and its branches, peripheral vascular disorders, obstructive arterial disorders, peripheral atherosclerotic arterial disease, thromboangiitis obliterans, functional peripheral arterial disorders, Raynaud's phenomenon and diseases, acrocyanosis, erythromelalgia, venous disorders, deep vein thrombosis, venous aneurysm, arteriovenous fistula, lymphedema, lipedema, unstable angina, reperfusion injury, post pump syndrome, ischemic reperfusion injury, etc., including but not limited to at least one of these. Aortic aneurysm and peripheral artery aneurysm, aortic dissection, aortic inflammation, occlusion of the abdominal aorta and its branches, peripheral vascular disorders, obstructive arterial disorders, peripheral atherosclerotic arterial disease, thromboangiitis obliterans, functional peripheral arterial disorders, Raynaud's phenomenon and diseases, acrocyanosis, erythromelalgia, venous disorders, deep vein thrombosis, venous aneurysm, arteriovenous fistula, lymphedema, lipedema, unstable angina, reperfusion injury, post pump syndrome, ischemic reperfusion injury, etc., including but not limited to at least one of these. Peripheral atherosclerotic arterial disease, thromboangiitis obliterans, functional peripheral arterial disorders, Raynaud's phenomenon and diseases, acrocyanosis, erythromelalgia, venous disorders, deep vein thrombosis, venous aneurysm, arteriovenous fistula, lymphedema, lipedema, unstable angina, reperfusion injury, post pump syndrome, ischemic reperfusion injury, etc., including but not limited to at least one of these. Raynaud's phenomenon and diseases, acrocyanosis, erythromelalgia, venous disorders, deep vein thrombosis, venous aneurysm, arteriovenous fistula, lymphedema, lipedema, unstable angina, reperfusion injury, post pump syndrome, ischemic reperfusion injury, etc., including but not limited to at least one of these. Venous disorders, deep vein thrombosis, venous aneurysm, arteriovenous fistula, lymphedema, lipedema, unstable angina, reperfusion injury, post pump syndrome, ischemic reperfusion injury, etc., including but not limited to at least one of these. Post pump syndrome, ischemic reperfusion injury, etc., including but not limited to at least one of these, a method for regulating or treating cardiovascular diseases in cells, tissues, organs, animals or patients is also provided. Such a method may optionally include administering to the cells, tissues, organs, animals or patients in need of such regulation, treatment or therapy an effective amount of a composition or pharmaceutical composition comprising at least one anti-TNF antibody. A method for regulating or treating cardiovascular diseases in cells, tissues, organs, animals or patients is also provided. Such a method may optionally include administering to the cells, tissues, organs, animals or patients in need of such regulation, treatment or therapy an effective amount of a composition or pharmaceutical composition comprising at least one anti-TNF antibody. A method for regulating or treating cardiovascular diseases in cells, tissues, organs, animals or patients is also provided. Such a method may optionally include administering to the cells, tissues, organs, animals or patients in need of such regulation, treatment or therapy an effective amount of a composition or pharmaceutical composition comprising at least one anti-TNF antibody. A composition or pharmaceutical composition comprising at least one anti-TNF antibody is administered to the cells, tissues, organs, animals or patients in need of such regulation, treatment or therapy. Such a method may optionally include administering to the cells, tissues, organs, animals or patients in need of such regulation, treatment or therapy an effective amount of a composition or pharmaceutical composition comprising at least one anti-TNF antibody.

[0148] The present invention also relates to acute or chronic bacterial infections, acute and chronic parasitic or infectious processes including bacterial, viral and fungal infections, HIV infection / HIV neuropathy, meningitis, hepatitis (A, B or C), septic arthritis, peritonitis, pneumonia, epiglottitis, Escherichia coli 0157:h7, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura, malaria, dengue hemorrhagic fever, leishmaniasis, Hansen's disease, toxic shock syndrome, streptococcal myositis, gas gangrene, Mycobacterium tuberculosis, Mycobacterium bovis, etc. HIV infection / HIV neuropathy, meningitis, hepatitis (A, B or C), septic arthritis, peritonitis, pneumonia, epiglottitis, Escherichia coli 0157:h7, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura, malaria, dengue hemorrhagic fever, leishmaniasis, Hansen's disease, toxic shock syndrome, streptococcal myositis, gas gangrene, Mycobacterium tuberculosis, Mycobacterium bovis, etc. Septic arthritis, peritonitis, pneumonia, epiglottitis, Escherichia coli 0157:h7, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura, malaria, dengue hemorrhagic fever, leishmaniasis, Hansen's disease, toxic shock syndrome, streptococcal myositis, gas gangrene, Mycobacterium tuberculosis, Mycobacterium bovis, etc. Hemolytic uremic syndrome / thrombotic thrombocytopenic purpura, malaria, dengue hemorrhagic fever, leishmaniasis, Hansen's disease, toxic shock syndrome, streptococcal myositis, gas gangrene, Mycobacterium tuberculosis, Mycobacterium bovis, etc. Hansen's disease, toxic shock syndrome, streptococcal myositis, gas gangrene, Mycobacterium tuberculosis, Mycobacterium bovis, etc. Mycobacterium intracellulare, Pneumocystis carinii pneumonia, pelvic inflammatory disease , orchitis / epididymitis, Legionella, Lyme disease, influenza A, Epstein-Barr virus, virus-associated hemophagocytic syndrome, viral encephalitis / aseptic meningitis, etc., of which at least one is included but not limited to these, and a method for regulating or treating at least one infectious disease in cells, tissues, organs, animals or patients is also provided.

[0149] The present invention also relates to leukemia, acute leukemia, acute lymphoblastic leukemia (ALL), B cells, T cells or FAB ALL, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, myelodysplastic syndrome (MDS), lymphoma , Hodgkin's disease, malignant lymphoma, non-Hodgkin's lymphoma, Burkitt lymphoma, multiple myeloma , Kaposi's sarcoma, colorectal cancer, pancreatic cancer, nasopharyngeal cancer, malignant histiocytosis, malignant tumor-associated symptoms / hypercalcemia, solid tumors, adenocarcinoma, sarcoma, malignant melanoma, hemangioma, metastatic diseases, cancer -related bone resorption, cancer-related bone pain, etc., of which at least one is included but not limited to these, and a method for regulating or treating at least one malignant disease in cells, tissues, organs, animals or patients is also provided.

[0150] The present invention also relates to neurodegenerative diseases, multiple sclerosis, migraine, AIDS dementia complex, demyelinating diseases, for example, multiple sclerosis and acute transverse myelitis, extrapyramidal and cerebellar disorders, for example, corticospinal system lesions, basal ganglia disorders or cerebellar disorders, hyperkinetic movement disorders, for example, Huntington's chorea and senile chorea, drug-induced movement disorders, for example, blocking CNS dopamine receptors induced by a drug, hypokinetic movement disorder, for example, Parkinson's disease, progressive supranuclear palsy, cerebellar structural lesions, spinocerebellar degeneration, for example, spinal ataxia, Friedreich 's ataxia, cerebellar cortical degeneration, multisystem degeneration (Mencel, Dejerine-Thom as, Shi-Drager and Machado-Joseph), systemic diseases (Reeves m's disease, abetalipoproteinemia, ataxia, telangiectasia, and mitochondrial multisystem disorders), demyelinating core disorders, for example, multiple sclerosis, acute transverse myelitis and disorders of the motor unit, for example, neurogenic muscular atrophy (anterior horn cell degeneration, for example amyotrophic lateral sclerosis, infantile spinal muscular atrophy and juvenile spinal muscular atrophy), Alzheimer's disease, middle-aged Down syndrome, diffuse Lewy body disease, Lewy body type senile dementia disease, Wernicke-Korsakoff syndrome, chronic alcoholism, Creutzfeldt-Jakob disease subacute sclerosing panencephalitis, Hallervorden-Spatz disease, and boxer dementia, etc. including but not limited to at least one of these, a method for modulating or treating at least one neurological disease in cells, tissues, organs, animals or patients is also provided. Optionally more, administering an effective amount of a composition or pharmaceutical composition comprising at least one TNF antibody or a specified portion or variant to cells, tissues, organs, animals or patients in need of such modulation, treatment or therapy can be included. For example, Merck Manua l, 16 Edition, Merck & Company, Rahway, NJ th (1992). See (1992).

[0151] Any method of the present invention involves administering to cells, tissues, organs, animals or patients in need of such regulation, treatment, or therapy, an effective amount of a composition or pharmaceutical composition comprising at least one anti-TNF antibody. Such methods may optionally further include co-administration or combination therapy for the treatment of such immune diseases, and the administration of this at least one anti-TNF antibody, the identified portion or variants thereof, is at least one TNF antagonist (e.g., TNF antibody or fragment, soluble TNF receptor or fragment, its fusion protein, or small molecule TN F antagonist, etc., but not limited thereto), anti-rheumatic drugs (e.g., methotrexate ate, auranofin, aurothioglucose, azathioprine, etanercept, gold thi sodium orotate, hydroxychloroquine sulfate, leflunomide, sulfasalazine) , muscle relaxants, narcotics, non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, anesthetics , sedatives, local anesthetics, neuromuscular blockers, antibacterial drugs (e.g., amino glycosides, antifungal drugs, anthelmintics, antiviral drugs, carbapenems, cephalosporins, flu oroquinolones, macrolides, penicillins, sulfonamides, tetracyclines, other anti bacterial drugs), anti-psoriatic agents, corticosteroids, anabolic steroids, diabetes-related drugs, mino ral, nutritional agents, thyroid drugs, vitamins, calcium-related hormones, antidiarrheal drugs, antitussives, antiemetics , anti-ulcer agents, laxatives, anticoagulants, erythropoietin (e.g., epoetin α), filg rastim (e.g., G-CSF, Neupogen), sargramostim (GM-CSF , Leukine), immunizing agents, immunoglobulins, immunosuppressive drugs (e.g., basiliximab , Cyclosporine, Daclizumab), Growth Hormone, Hormone Replacement Therapy, Estrogen Receptor Agents for regulating physical condition, mydriatics, ciliary muscle paralytic agents, alkylating agents, antimetabolites, mitotic inhibitors, radioactive medicines, antidepressants, antimanic drugs, antipsychotics, anxiolytics, hypnotics, sympathomimetic agents, stimulants, Donepezil, Tacrolimus, asthma medications, beta-agonists, inhaled steroids, leukotriene inhibitors, Methylxanthine, Cromolyn, Epinephrine or analogs, Dornase alfa (Pulmo zyme), at least one selected from cytokines or cytokine antagonists Further includes administering before, simultaneously, and / or after. Suitable dosages are well-known in the art . For example, Wells et al., eds., Pharmaco therapy Handbook, 2 nd Edition, Appleton an d Lange, Stamford, CT (2000), PDR Pharmacopo eia, Tarascon Pocket Pharmacopoeia 2000, D eluxe Edition, Tarascon Publishing, Loma L inda, CA (2000) are hereby incorporated by reference in their entirety into this specification .

[0152] Suitable TNF antagonists for the compositions, combination therapies, simultaneous administrations, devices and / or methods of the present invention (further comprising at least one antibody, its identified portion and its variants of the present invention) are anti-TNF antibodies, their antigen-binding fragments, and receptor molecules that specifically bind to TNF, TNF synthesis , TNF release, or compounds that block and / or inhibit its action on target cells, for example, thalidomide, tenidap, phosphodiesterase inhibitors (e.g., pentoxify irin and loperamide), A2b adenosine receptor agonists and A2b adenosine receptor enhancers, compounds that block and / or inhibit TNF receptor signaling, such as mitogen-activated protein (MAP) kinase inhibitors, compounds that block and / or inhibit membrane TNF cleavage, such as metalloproteinase inhibitors, compounds that block and / or inhibit TNF activity, such as angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril), and compounds that block and / or inhibit TNF production and / or synthesis, such as MAP kinase inhibitors, including but not limited to these. When used herein, "tumor necrosis factor antibody", "TNF antibody", "TNFα antibody" or "fragment", etc., reduce, block, inhibit, suppress or interfere with TNFα activity in vitro, in situ, and / or preferably in vivo. For example, a preferred TNF human antibody of the present invention can bind to TNFα and includes anti-TNF antibodies, antigen-binding fragments thereof, and identified mutants or domains thereof that specifically bind to TNFα. Preferred TNF antibodies or fragments can also reduce, block, suppress, interfere with, prevent and / or inhibit TNF RNA, DNA, or protein synthesis, TNF release, TNF receptor signaling, membrane TNF cleavage, TNF activity, TNF production and / or synthesis. The chimeric antibody cA2 consists of the antigen-binding variable region of a high-affinity neutralizing mouse anti-human TNFα IgG1 antibody called A2 and the constant region of human IgG1 κ immunoglobulin. The human IgG1 Fc region improves the effector function of the homologous antibody and increases the circulating serum half-life. When used herein, "tumor necrosis factor antibody", "TNF antibody", "TNFα antibody" or "fragment", etc., reduce, block, inhibit, suppress or interfere with TNFα activity in vitro, in situ, and / or preferably in vivo. For example, a preferred TNF human antibody of the present invention can bind to TNFα and includes anti-TNF antibodies, antigen-binding fragments thereof, and identified mutants or domains thereof that specifically bind to TNFα. Preferred TNF antibodies or fragments can also reduce, block, suppress, interfere with, prevent and / or inhibit TNF RNA, DNA, or protein synthesis, TNF release, TNF receptor signaling, membrane TNF cleavage, TNF activity, TNF production and / or synthesis. The chimeric antibody cA2 consists of the antigen-binding variable region of a high-affinity neutralizing mouse anti-human TNFα IgG1 antibody called A2 and the constant region of human IgG1 κ immunoglobulin. The human IgG1 Fc region improves the effector function of the homologous antibody and increases the circulating serum half-life. When used herein, "tumor necrosis factor antibody", "TNF antibody", "TNFα antibody" or "fragment", etc., reduce, block, inhibit, suppress or interfere with TNFα activity in vitro, in situ, and / or preferably in vivo. For example, a preferred TNF human antibody of the present invention can bind to TNFα and includes anti-TNF antibodies, antigen-binding fragments thereof, and identified mutants or domains thereof that specifically bind to TNFα. Preferred TNF antibodies or fragments can also reduce, block, suppress, interfere with, prevent and / or inhibit TNF RNA, DNA, or protein synthesis, TNF release, TNF receptor signaling, membrane TNF cleavage, TNF activity, TNF production and / or synthesis. The chimeric antibody cA2 consists of the antigen-binding variable region of a high-affinity neutralizing mouse anti-human TNFα IgG1 antibody called A2 and the constant region of human IgG1 κ immunoglobulin. The human IgG1 Fc region improves the effector function of the homologous antibody and increases the circulating serum half-life.

[0153] When used herein, "tumor necrosis factor antibody", "TNF antibody", "TNFα antibody" or "fragment", etc., reduce, block, inhibit, suppress or interfere with TNFα activity in vitro, in situ, and / or preferably in vivo. For example, a preferred TNF human antibody of the present invention can bind to TNFα and includes anti-TNF antibodies, antigen-binding fragments thereof, and identified mutants or domains thereof that specifically bind to TNFα. Preferred TNF antibodies or fragments can also reduce, block, suppress, interfere with, prevent and / or inhibit TNF RNA, DNA, or protein synthesis, TNF release, TNF receptor signaling, membrane TNF cleavage, TNF activity, TNF production and / or synthesis. The chimeric antibody cA2 consists of the antigen-binding variable region of a high-affinity neutralizing mouse anti-human TNFα IgG1 antibody called A2 and the constant region of human IgG1 κ immunoglobulin. The human IgG1 Fc region improves the effector function of the homologous antibody and increases the circulating serum half-life. When used herein, "tumor necrosis factor antibody", "TNF antibody", "TNFα antibody" or "fragment", etc., reduce, block, inhibit, suppress or interfere with TNFα activity in vitro, in situ, and / or preferably in vivo. For example, a preferred TNF human antibody of the present invention can bind to TNFα and includes anti-TNF antibodies, antigen-binding fragments thereof, and identified mutants or domains thereof that specifically bind to TNFα. Preferred TNF antibodies or fragments can also reduce, block, suppress, interfere with, prevent and / or inhibit TNF RNA, DNA, or protein synthesis, TNF release, TNF receptor signaling, membrane TNF cleavage, TNF activity, TNF production and / or synthesis. The chimeric antibody cA2 consists of the antigen-binding variable region of a high-affinity neutralizing mouse anti-human TNFα IgG1 antibody called A2 and the constant region of human IgG1 κ immunoglobulin. The human IgG1 Fc region improves the effector function of the homologous antibody and increases the circulating serum half-life. When used herein, "tumor necrosis factor antibody", "TNF antibody", "TNFα antibody" or "fragment", etc., reduce, block, inhibit, suppress or interfere with TNFα activity in vitro, in situ, and / or preferably in vivo. For example, a preferred TNF human antibody of the present invention can bind to TNFα and includes anti-TNF antibodies, antigen-binding fragments thereof, and identified mutants or domains thereof that specifically bind to TNFα. Preferred TNF antibodies or fragments can also reduce, block, suppress, interfere with, prevent and / or inhibit TNF RNA, DNA, or protein synthesis, TNF release, TNF receptor signaling, membrane TNF cleavage, TNF activity, TNF production and / or synthesis. The chimeric antibody cA2 consists of the antigen-binding variable region of a high-affinity neutralizing mouse anti-human TNFα IgG1 antibody called A2 and the constant region of human IgG1 κ immunoglobulin. The human IgG1 Fc region improves the effector function of the homologous antibody and increases the circulating serum half-life. When used herein, "tumor necrosis factor antibody", "TNF antibody", "TNFα antibody" or "fragment", etc., reduce, block, inhibit, suppress or interfere with TNFα activity in vitro, in situ, and / or preferably in vivo. For example, a preferred TNF human antibody of the present invention can bind to TNFα and includes anti-TNF antibodies, antigen-binding fragments thereof, and identified mutants or domains thereof that specifically bind to TNFα. Preferred TNF antibodies or fragments can also reduce, block, suppress, interfere with, prevent and / or inhibit TNF RNA, DNA, or protein synthesis, TNF release, TNF receptor signaling, membrane TNF cleavage, TNF activity, TNF production and / or synthesis. The chimeric antibody cA2 consists of the antigen-binding variable region of a high-affinity neutralizing mouse anti-human TNFα IgG1 antibody called A2 and the constant region of human IgG1 κ immunoglobulin. The human IgG1 Fc region improves the effector function of the homologous antibody and increases the circulating serum half-life.

[0154] The chimeric antibody cA2 consists of the antigen-binding variable region of a high-affinity neutralizing mouse anti-human TNFα IgG1 antibody called A2 and the constant region of human IgG1 κ immunoglobulin. The human IgG1 Fc region improves the effector function of the homologous antibody and increases the circulating serum half-life. The chimeric antibody cA2 consists of the antigen-binding variable region of a high-affinity neutralizing mouse anti-human TNFα IgG1 antibody called A2 and the constant region of human IgG1 κ immunoglobulin. The human IgG1 Fc region improves the effector function of the homologous antibody and increases the circulating serum half-life. The chimeric antibody cA2 consists of the antigen-binding variable region of a high-affinity neutralizing mouse anti-human TNFα IgG1 antibody called A2 and the constant region of human IgG1 κ immunoglobulin. The human IgG1 Fc region improves the effector function of the homologous antibody and increases the circulating serum half-life. , reduce the immunogenicity of the antibody. The binding activity and epitope specificity of the chimeric antibody cA2 are , derived from the variable region of the mouse antibody A2. In certain embodiments, the preferred source of the nucleic acid encoding the variable region of the mouse antibody A2 is the A2 hybridoma cell line.

[0155] Chimeric A2 (cA2) dose-dependently neutralizes the cytotoxic effects of both native and recombinant human TNFα. From the binding assay of the chimeric antibody cA2 with recombinant human TNFα, the affinity constant of the chimeric antibody cA2 was calculated to be 1.04×l0 M 10 -1 . The preferred methods for determining the specificity and affinity of monoclonal antibodies by competitive inhibition are described in Harlow, et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1988, Colligan et al., eds., Current Protocols in Immunology, Greene Publishing Assoc. and Wiley Interscience, New York, (1992 - 2000), Kozbor et al., Immunol. Today, 4:72 - 79 (1983), Ausubel et al., eds. Current Protocols in Molecular Biology, Wiley Interscience, New York (1987 - 2000), and Muller, Meth. Enzymol., 92:58 9 - 601 (1983), and these references are hereby incorporated by reference in their entirety into this specification. (1987 - 2000), and Muller, Meth. Enzymol., 92:58 ​​​​​​​​​​​​It is incorporated into the detailed description.

[0156] In certain embodiments, the murine monoclonal antibody A2 is produced by a cell line designated c134A. The chimeric antibody cA2 is produced by a cell line designated c168A.

[0157] Further examples of monoclonal anti-TNF antibodies that can be used in the present invention are described in the art (e.g., U.S. Patent No. 5,231,024, Moll er, A. et al., Cytokine 2(3):162 - 169(1990), U.S. Application No. 07 / 943,852 (filed September 11, 1992), Rathjen e t al., International Publication No. 91 / 02078 (published February 21, 1991), Rubin et al., EPO Patent Publication No. 0 218 868 (published April 22, 1987) Yone et al., EPO Patent Publication No. 0 288 088 (October 26, 1988), Liang, et al., Biochem. Biophys. Res. Co mmunol. 137:847 - 854(1986), Meager, et al., Hybri doma 6:305 - 311(1987), Fendly et al., Hybri doma 6:359 - 369(1987), Bringman, et al., Hyb ridoma 6:489 - 507(1987) and Hirai, et al., J. I mmunol. Meth. 96:57 - 62(1987). See these reference ences, which are hereby incorporated by reference in their entirety.

[0158] TNF receptor molecules. Preferred TNF receptor molecules useful in the present invention have a high affinity for TNFα. linked (e.g., Feldmann et al., WO 92 / 07076 (published April 30, 1992), Schall et al., Cell 61:361-370 ( 1990), and Loetscher et al., Cell 61:351-359 ( 1990); see these references, which are incorporated herein by reference in their entirety), and have low immunogenicity if desired. In particular, the TNF cell surface receptors of 55 kDa (p55 TNF-R) and 75 kDa (p75 TNF-R) are useful in the present invention. Cleaved forms of these receptors that include the extracellular domain (ECD) of the receptor or a functional portion thereof (see, e.g., Corcoran et al., Eur. J. Biochem. 223:831-840 (1994)) are also useful in the present invention. Cleaved forms of the TNF receptor that include the ECD have been detected in urine and serum as 30 kDa and 40 kDa TNFα inhibitory binding proteins (Engelmann, H. et al., J. Biol. Chem. 265:1531-1536 (1990)). TNF receptor multimeric molecules and TNF immunoreceptor fusion molecules, and their derivatives and fragments or portions thereof, are further examples of TNF receptor molecules useful in the methods and compositions of the present invention. TNF receptor molecules that can be used in the present invention

[0159] are characterized by the ability to provide good to excellent symptom Linked via one or more polypeptide linkers or other non - peptide linkers, such as and includes all or functional portions of the ECDs of two or more TNF receptors. The multimeric molecule may further include a signal peptide of a secreted protein to effect expression of the multimeric molecule. These multimeric molecules and methods for their production are described in U.S. Application No. 08 / 437,533 (filed May 9, 1995), the contents of which are hereby incorporated by reference in their entirety. (filed May 9, 1995), the contents of which are hereby incorporated by reference in their entirety.

[0160] TNF immunoreceptor fusion molecules useful in the methods and compositions of the present invention include at least one portion of one or more immunoglobulin molecules and all or functional portions of one or more TNF receptors. These immunoreceptor fusion molecules can be assembled as monomers or hetero - or homo - multimers. The immunoreceptor fusion molecules can be either monovalent or multivalent. Examples of such TNF immunoreceptor fusion molecules are TNF receptor / IgG fusion proteins. TNF immunoreceptor fusion molecules and methods for their production are described in the art (Lesslauer et al., Eur. J. Immunol. 21:2 883 - 2886 (1991), Ashkenazi et al., Proc. Natl. Acad. Sci. USA 88:10535 - 10539 (1991), Peppel et al., J. Exp. Med. 174:1483 - 1489 (1991), Kolls et al., Proc. Natl. Acad. Sci. USA 91:2 15 - 219 (1994), Butler et al., Cytokine 6(6) :616 - 623 (1994), Baker et al., Eur. J. Immunol (Lesslauer et al., Eur. J. Immunol. 21:2 883 - 2886 (1991), Ashkenazi et al., Proc. Natl. Acad. Sci. USA 88:10535 - 10539 (1991), Peppel et al., J. Exp. Med. 174:1483 - 1489 (1991), Kolls et al., Proc. Natl. Acad. Sci. USA 91:2 15 - 219 (1994), Butler et al., Cytokine 6(6) :616 - 623 (1994), Baker et al., Eur. J. Immunol :616 - 623 (1994), Baker et al., Eur. J. Immunol ​​​​l.24:2040-2048(1994), Beutler et al., U.S. Patent No. 5,447 ,851 and U.S. Application No. 08 / 442,133 (filed May 16, 1995), each of these reference documents is hereby incorporated by reference in its entirety). The method for generating an immunoreceptor fusion molecule can also be found in Capon et al., U.S. Patent No. 5,116,964, Capon et al., U.S. Patent No. 5,225,538 and Capon et al., Nature 337:5 25-531(1989), and these reference documents are hereby incorporated by reference in their entirety. A functional equivalent, derivative, fragment, or region of a TNF receptor molecule is of a size and sequence sufficient to be functionally similar to a TNF receptor molecule that can be used in the present invention ( for example, binds to TNFα with high affinity and has low immunogenicity), a portion of a TNF receptor molecule, or a portion of a TNF receptor molecule sequence encoding a TNF receptor molecule. A functional equivalent of a TNF

[0161] receptor molecule can also be a modified TNF receptor molecule that is functionally similar to a TNF receptor molecule that can be used in the present invention (for example, binds to TNFα with high affinity and has low immunogenicity). For example, a functional equivalent of a TNF receptor molecule may contain a "SILE NT" codon, or one or more amino acid substitutions, deletions, or additions (for example, using one acidic amino acid in place of another acidic amino acid, or using one codon encoding the same or a different hydrophobic amino acid in place of another codon encoding a hydrophobic amino acid). Ausubel et al., Current Protoc ols in Molecular Biology, Greene Publishi ed by reference in its entirety). A functional equivalent of a TNF receptor molecule also includes a modified TNF receptor molecule that is functionally similar to a TNF receptor molecule that can be used in the present invention (for example, binds to TNFα with high affinity and has low immunogenicity). For example, a functional equivalent of a TNF receptor molecule may contain a "SILE NT" codon, or one or more amino acid substitutions, deletions, or additions (for example, using one acidic amino acid in place of another acidic amino acid, or using one codon encoding the same or a different hydrophobic amino acid in place of another codon encoding a hydrophobic amino acid). Ausubel et al., Current Protoc ols in Molecular Biology, Greene Publishi ng Associates, Inc., hereby incorporated by reference in its entirety). ng Assoc. and Wiley-Interscience, New York See (1987-2000).

[0162] Cytokines include any known cytokine. For example, see Copewith Cytokines.com. Cytokine antagonists include any antibody , fragment or mimetic, any soluble receptor, fragment or mimetic, any small molecule antagonist , or any combination thereof, but are not limited thereto.

[0163] Therapeutic treatment. Any method of the present invention provides an effective amount of a composition or pharmaceutical composition comprising at least one anti-TNF antibody to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy, and may include a method for treating a TNF-mediated disorder. Such a method may optionally further include co-administration or combination therapy for the treatment of such immune diseases, and the administration of this at least one anti-TNF antibody, the identified moiety or variant thereof is at least one TNF antagonist (e.g., a TNF antibody or fragment, a soluble TNF receptor or fragment, its fusion protein, or a small molecule TNF antagonist, etc., but not limited thereto), anti-rheumatic drugs (e.g., methotrexate, auranofin, aurothioglucose, azathioprine, etanercept, sodium aurothiomalate, hydroxychloroquine sulfate , leflunomide, sulfasalazine), muscle relaxants, narcotic ic, non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, anesthetic c, sedatives, local anesthetics, neuromuscular blockers, antibacterial drugs (e.g., aminoglycosides, anti ​​Antifungal drugs, anthelmintics, antiviral drugs, carbapenems, cephalosporins, fluoroquinolones, macrolides, penicillins, sulfonamides, tetracyclines, other antibacterial drugs), anti-psoriasis agents, corticosteroids, anabolic steroids, diabetes-related drugs, minerals, nutritional drugs, thyroid drugs, vitamins, calcium-related hormones, antidiarrheal drugs, antitussives, antiemetics, anti-ulcer agents, laxatives, anticoagulants, erythropoietin (e.g., epoetin alpha), filgrastim (e.g., G-CSF, Neupogen), sargramostim (GM-CSF, Leukin e), immunizing agents, immunoglobulins, immunosuppressive drugs (e.g., basiliximab, cyclosporine ne, daclizumab), growth hormones, hormone replacement drugs, estrogen receptor modulators, mydriatic drugs, ciliary muscle paralytic drugs, alkylating agents, antimetabolites, mitotic inhibitors, radiopharmaceuticals, antidepressants drugs, antimanic drugs, antipsychotic drugs, anxiolytics, hypnotics, sympathomimetic drugs, stimulants, donepezil, tacrine, asthma drugs, beta-agonists, inhaled steroids, leukotriene inhibitors, methylxanthines chromolyn, epinephrine or analogs, dornase alpha (Pulmozyme), at least one selected from cytokines or cytokine antagonists, before, simultaneously, and / or after administration.

[0164] As used herein, the term "safe" refers to the acceptable frequency and / or acceptable severity of adverse events (AE) and serious adverse events (SAE) compared to standard care for a favorable risk or another comparator such as other anti-TNF agents, in relation to a composition, dosage, dosing regimen, treatment or method by an anti-TNF antibody of the present invention (e.g., anti-TNF antibody golimumab). An adverse event is an undesirable Specifically, the compositions, dosages, and administration of the anti-TNF antibodies of the present invention are Safety of a regimen, treatment, or method may include, for example, infusion reactions, abnormal liver and biliary tests, T Acceptable frequency and / or severity of adverse events, including infections, including B, and malignancies Refers to the degree.

[0165] As used herein in the context of a composition, dosage, dosing regimen, treatment or method The terms "effect" and "effective" refer to the use of an anti-TNF antibody of the invention (e.g., an anti-TNF antibody). Effectiveness refers to the effectiveness of a particular composition, dose, administration, treatment or method using golimumab. The efficacy can be measured based on changes in the course of the disease in response to an agent of the invention. For example, The anti-TNF antibodies of the invention have at least one indicator that reflects the severity of the disorder being treated. and administering to the patient in an amount and for a time sufficient to cause improvement, preferably a sustained improvement, in To determine whether the amount and duration of treatment is adequate, the disease, Various indicators that reflect the extent of a disease or condition can be assessed. Such indicators include, for example, A clinically recognized indication of the severity, symptoms, or manifestations of the disorder of interest. The degree of improvement is generally determined by a physician or other appropriately trained individual. They will be provided with evidence of signs, symptoms, biopsy or other test results indicating improvement in clinical symptoms or disease. The activity may be determined based on any other measure. For example, the anti-TNF antibodies of the invention may be used to treat psoriasis. The drug may be administered to achieve improvement in a patient's condition associated with prostate cancer (PsA). Improvement in the patient's condition can be measured, for example, by the Health Assessment Questionnaire-Disability Index score (HAQ-DI). , Tendonitis evaluation, Dactylitis evaluation, 36-item Short Form Health Survey Physical Summary Score ( SF-36 Physical Component Summary (PCS), and / or the 36-Item Short-Form Health Survey Mental Component Summary can be evaluated using one or more criteria including a score (SF-36 MCS). The HAQ-DI is a 20-question instrument that assesses the degree of difficulty a person experiences in performing tasks in eight functional areas (self-care, rising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Tendinitis can be evaluated by assessing the presence of pain by applying local pressure to tendinous insertions including, for example, the left and right lateral epicondyles of the elbow, the left and right medial epicondyles of the elbow, and the left and right Achilles tendon insertions. Finger inflammation can be evaluated for presence and severity in both hands and both feet. The SF-36 is a questionnaire consisting of eight scored multi-item scales, and the SF-36 PCS and SF-36 MCS are summary scores derived from the SF-36 that enable comparison of the relative burdens of different diseases and the relative benefits of different treatments. As used herein, unless otherwise specified, the term "clinically proven" (used alone or used to modify the terms "safety" and / or "efficacy") is meant to be proven by clinical trials that meet the approval criteria of the United States Food and Drug Administration, the EMEA, or the corresponding national regulatory agency. For example, a clinical trial may be a randomized double-blind trial of appropriate size used to clinically prove the effect of a drug.

[0166] Typically, treatment of a condition averages a total of 1 depending on the specific activity of the composition contained therein.

[0167] ​​​​​​​at least about 0.01 to 500 milligrams per kilogram of patient body weight per administration of at least one anti-TNF antibody, preferably at least about 0.1 to 100 milligrams per kilogram of patient body weight per single or multiple administrations is achieved by administering a safe and effective amount or dosage of the at least one anti-TNF antibody composition. Alternatively, an effective serum concentration may include a serum concentration of 0.1 to 5000 μg / mL per single or multiple administrations. Suitable dosages are known to medical practitioners and will, of course, depend on the specific disease state, the specific activity of the composition being administered, and the particular patient being treated. In some cases, repeated administrations, i.e., providing repeated individual administrations of a specified monitored amount or dose, may be necessary to obtain the desired therapeutic amount, in which case the individual administrations are repeated until the desired daily dose or effect is obtained. Preferably, the dosage may be, if desired, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0 .7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 4 0, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53 .

[0168] ​​​​​​​​, 95, 96, 97, 98, 99 and / or 100 - 500 mg / kg / dose, or includes any range, value or fraction thereof, or 0. 1, 0.5, 0.9, 1.0, 1.1, 1.2, 1.5, 1.9, 2.0, 2.5, 2. 9, 3.0, 3.5, 3.9, 4.0, 4.5, 4.9, 5.0, 5.5, 5.9, 6. 0, 6.5, 6.9, 7.0, 7.5, 7.9, 8.0, 8.5, 8.9, 9.0, 9. 5, 9.9, 10, 10.5, 10.9, 11, 11.5, 11.9, 20, 12.5, 12.9, 13.0, 13.5, 13.9, 14.0, 14.5, 15, 15.5, 15 .9, 16, 16.5, 16.9, 17, 17.5, 17.9, 18, 18.5, 18. 9, 19, 19.5, 19.9, 20, 20.5, 20.9, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 7 0, 75, 80, 85, 90, 96, 100, 200, 300, 400, 500, 600 , 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 35 00, 4000, 4500 and / or 5000 μg / mL serum concentration, or any range, value or fraction thereof that may be obtained.

[0169] Alternatively, the dose administered may vary depending on known factors such as the pharmacodynamic characteristics of the particular agent, its method and route of administration , the age, health status and weight of the recipient, the nature and degree of the symptoms, the type of co - treatment, the treatment frequency, and the desired effect. The dosage of the active ingredient may usually be about 0.1 - 100 milligrams per kilogram of body weight. Usually, 1 kilogram per dose is 0.1 - 50, preferably 0.1 - 10 milligrams or in sustained - release form, is effective for obtaining a desirable result.

[0170] As a non-limiting example, the treatment of a human or animal may be carried out once, by injection or repeated administration, on 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, at least 1 day out of the 31st, 32nd, 33rd, 34th, 35th, 36th, 37th, 38th, 39th or 40th day, or alternatively, additionally, on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 , 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 5 1 or at least 1 week out of the 52nd week, or alternatively, additionally, on 1, 2, 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 , or at least 1 year out of the 20th year, or in any combination thereof, per day from 0.1 to 100 mg / kg, for example, 0.5, 0.9, 1.0, 1.1, 1.5, 2 , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 1 , 8, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40 , 45, 50, 60, 70, 80, 90, or 100 mg / kg, and may be provided as a single or periodic dosage of at least one antibody of the present invention.

[0171] A dosage form (composition) suitable for in vivo administration is generally about 0.1 milligrams contains from about 500 milligrams of the active ingredient. In these pharmaceutical compositions, the active ingredient is usually present in an amount of about 0.5 to 99.999 weight percent, based on the total weight of the composition.

[0172] For parenteral administration, the antibody can be formulated as a solution, suspension, emulsion, or lyophilized powder, combined with a pharmaceutically acceptable parenteral vehicle or administered separately thereof. Examples of such vehicles are water, physiological saline, Ringer's solution, dextrose solution, and 1 to 10% human serum albumin. Non-aqueous vehicles such as liposomes and fixed oils can also be used. The vehicle or lyophilized powder can contain additives to maintain isotonicity and chemical stability (e.g., sodium chloride, mannitol for isotonicity; buffers and preservatives for chemical stability). The formulation is sterilized by known or suitable techniques. Suitable pharmaceutical carriers are described in the latest edition of Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in the field.

[0173] Alternative administrations. Many known and developed methods of administration can be used according to the present invention to administer a pharmaceutically effective amount of at least one anti-TNF antibody according to the present invention. Although pulmonary administration is used in the following description, other modes of administration may be used according to the present invention to obtain suitable results.

[0174] The TNF antibody of the present invention can be in the form of a solution, emulsion, colloid, or suspension in a carrier, or as a dry powder, and can be administered by inhalation or by other methods described herein or known in the art

[0175] in the art.​​​​​​​​ Any of a variety of devices and methods suitable for administration by other methods known in the wild can be used to deliver.

[0176] Parenteral formulations and administration. Formulations for parenteral administration include sterile water or physiological saline as common excipients water, polyalkylene glycols such as polyethylene glycol, oils derived from plants, hydrogen ated naphthalene, etc. Aqueous or oily suspensions for injection can be prepared by following known methods using appropriate emulsifiers or wetting agents and suspending agents. Injectables are For example, non-toxic parenterally administrable diluents such as aqueous solutions, sterile injection solutions, or suspensions in solvents may be. Vehicles or solvents that can be used include water, Ringer's solution, isotonic saline etc., and as ordinary solvents or suspending solvents, sterile non-volatile oils can be used For these purposes, natural or synthetic or semi-synthetic, fatty oils or fatty acids, natural or synthetic or semi-synthetic, monoglycerides or diglycerides or triglycerides containing All kinds of non-volatile oils and fatty acids can be used. Parenteral administration is known in the art field, and conventional injection means, gas pressurized needleless injection devices such as those described in U.S. Patent No. 5,851,198, and those described in U.S. Patent No. 5,839,446 as such laser perforator devices, but are not limited thereto, and these are hereby incorporated by reference in their entirety into this specification.

[0177] Alternative delivery. The present invention further provides parenteral, subcutaneous, intramuscular, intravenous, intra-articular, intratracheal, intra-abdominal , intra-pouch, intra-cartilage, intra-cavity, intra-cavity, intra-cerebellar, intraventricular, intra-colonic, endocervical, intra-gastric, intra-hepatic, intramyocardial, Within the bone, within the pelvis, within the pericardium, within the abdominal cavity, within the pleura, within the prostate, within the lung, within the rectum, within the kidney, within the retina, within the spinal cord, within the synovial sac, within the thorax, within the uterus, within the bladder, bolus, within the vagina, rectum, within the oral cavity, sublingually, within the nasal cavity, or relates to the administration of at least one anti-TNF antibody by percutaneous means. At least one anti-TNF antibody composition is parenteral (subcutaneous, intramuscular or intravenous) or any other administration, in particular, for use in the form of a liquid solution or suspension, in particular, in a semi-solid form such as creams and suppositories, etc. but not limited to these, for use in vaginal or rectal administration in the form of tablets or capsules, etc. but not limited to these, for oral or sublingual administration in the form of tablets or capsules, etc. but not limited to these, for nasal administration, or in the form of powders, nasal drops or aerosols, or certain drugs, etc. but not limited to these, into the nasal cavity, or to modify the skin structure, or to increase the drug concentration in the transdermal patch using a chemical enhancer such as dimethyl sulfoxide (Junginger, et al. In "Drug Permeatio n Enhancement"; Hsieh, D.S., Eds., pp. 59-90( Marcel Dekker, Inc. New York 1994, which is hereby incorporated by reference in its entirety into this specification), or using an oxidizing agent that enables the application of a formulation containing proteins and peptides to the skin (International Publication No. WO98 / 53847), or for creating a transient transport pathway such as electroporation or applying an electric field to increase the mobility of charged drugs through the skin such as iontophoresis, or applying ultrasound such as sonophoresis (U.S. Patent Nos. 4,309,989 and 4,767,402), using a gel, ointment, lotion, suspension or patch delivery system, etc., but not limited to these ​​​​​ No, it can be prepared transdermally (the above publications and patents are incorporated herein by reference in their entirety). ).

[0178] Pulmonary / nasal administration. For pulmonary administration, preferably, at least one anti-TNF antibody composition is delivered at a particle size effective to reach the lower airways or sinuses of the lungs. According to the present invention, at least one anti-TNF antibody can be delivered by any of various inhalation or nasal devices known in the art for administering therapeutic agents by inhalation. These devices, which can deposit the aerosolized formulation in the patient's nasal cavity or alveoli, include metered-dose inhalers, nebulizers, dry powder generators, atomizers, and the like. Other devices suitable for the purpose of pulmonary or nasal administration of the antibody are also known in the art. All such devices can use formulations suitable for administration to distribute the antibody in the aerosol. Such aerosols can be composed of either solutions (both aqueous and non-aqueous) or solid particles. Metered-dose inhalers, such as the Ventolin® metered-dose inhaler, typically use a propellant gas and require actuation during inhalation (see, e.g., International Publication No. 94 / 16970, International Publication No. 98 / 35888). Dry powder inhalers, such as the Turbuhaler™ (Astra), Rotahaler® (Glaxo), Diskus® (Glaxo), Spiros™ inhaler (Dura), devices commercially available from Inhale Therapeutics, and the Spinhaler® powder inhaler (Fisons), etc., mix ). (See International Publication No. 94 / 16970, International Publication No. 98 / 35888). haler (trademark) (Astra), Rotahaler (registered trademark) (Glaxo), Diskus (registered trademark) (Glaxo), Spiros (trademark) inhaler (Dura), devices commercially available from Inhale Therapeutics, and Spin haler (registered trademark) powder inhaler (Fisons), etc., dry powder inhalers Using the inspiratory actuation of the powder (U.S. Patent No. 4,668,218 (Astra), European Patent No. 2 37,507 (Astra), International Publication No. 97 / 25086 (Glaxo), International Publication No. 94 / 08552 (Dura), U.S. Patent No. 5,458,135 (Inhale), U.S. International Publication No. 94 / 06498 (Fisons), which are hereby incorporated by reference in their entirety herein). Nebulizers such as AERx (trademark) (Aradigm), Ultravent (registered trademark) nebulizer (Mallinckrodt), and Acorn II (registered trademark) nebulizer ( Marquest Medical Products) (U.S. Patent No. 5,404,871 (Aradigm), International Publication No. 97 / 22376) (the above documents are hereby incorporated by reference in their entirety herein) generate an aerosol from a solution, while metered-dose inhalers, dry powder inhalers, etc. generate small-particle aerosols. These specific examples of commercially available inhalation devices are intended to represent specific devices suitable for the practice of the present invention and are not intended to limit the scope of the present invention. Preferably, a composition comprising at least one anti-TNF antibody is delivered by a dry powder inhaler or a nebulizer . The inhalation devices for administering at least one antibody of the present invention have a plurality of desirable features. For example, delivery by an inhalation device is advantageously highly reliable, reproducible, and accurate. The inhalation device can, if desired, deliver small dry particles that can be breathed in well, e.g., particles smaller than about 10 μm, preferably about 1-5 μm .

[0179] Administration of the TNF antibody composition by spray. A spray containing the TNF antibody composition protein ​​、passing the nozzle under pressure through a suspension or solution of at least one anti-TNF antibody can generate. The size and configuration of the nozzle, the applied pressure, and the liquid supply rate can be selected to achieve the desired output and particle size. For example, electrospray can be produced by an electric field together with a capillary or noz...

Claims

1. 1. A composition for use in treating a patient with active psoriatic arthritis, comprising: At least one pharma- ceutically acceptable carrier or diluent and the amino acid sequence of SEQ ID NO:

36. and a light chain (LC) comprising the amino acid sequence of SEQ ID NO:

37. and an isolated mammalian anti-TNF antibody, the treatment comprising administering the composition to the patient by IV infusion; At week 52 of the treatment, the patient treated with the anti-TNF antibody had Disease Activity (DAPSA) Remission - Patients identified as having low disease activity Patients with moderate disease activity in the DAPSA; Patients identified as having inactive disease activity on the PASDAS score Patients identified as having moderate disease activity in the PASDAS, patients with minimal disease activity Patients identified as having MDA and those identified as not having MDA Patients identified as having very low disease activity (VLDA), patients with VLDA Patients identified as not having ALK, and those with remission on the Clinical Disease Activity Index (CDAI) Patients identified as having low disease activity in the CDAI total modified van der Heide-Schafer expression in a patient selected from the group consisting of A composition having a significant mean change from baseline in vdH-S score.

2. A significant mean change from baseline in the total modified vdH-S score is vdH-S in patients identified as having remission-low disease activity in SA = -0.88 ± 2.3 (SD), and those with moderate disease activity in the DAPSA vdH-S = -0.48 ± 1.82 (SD) in patients identified as PASD vdH-S in patients identified as having inactive disease activity in AS = -1.01±2.384 (SD), with moderate disease activity in the PASDAS vdH-S in patients identified as vdH-S in patients identified as having DA = -1.16 ± 2.46 (SD ), vdH-S in patients identified as not having MDA=0.03±2. 44(SD), vdH-S=-1 in patients identified as having VLDA 49±2.22 (SD), v in patients identified as not having VLDA dH-S = -0.30 ± 2.52 (SD), as a person with remission in the CDAI vdH-S in the identified patients = -1.06 ± 2.41 (SD), and the CDAI vdH-S = -0.8 in patients identified as having low disease activity in 1 ± 2.12 (SD).

3. The composition comprises administering the antibody at weeks 0 and 4, and every 8 weeks (q8w) thereafter. The composition of claim 2, administered at a dose of 2 mg / kg.

4. The composition of claim 3 , wherein the composition is administered over a period of 30±10 minutes.

5. The method of claim 3 , wherein the patient is an adult patient aged 18 years or older.

6. The treatment comprises administering the composition with or without methotrexate (MTX). The composition of claim 3, further comprising:

7. The treatment may comprise administering, prior to, simultaneously with, or after administering (a), a detectable label or reporter, TNF antagonist, antirheumatic, muscle relaxant, narcotic, non Steroidal anti-inflammatory drugs (NSAIDs), painkillers, anesthetics, sedatives, local anesthesia Anesthetics, neuromuscular blockers, antibiotics, psoriasis medications, corticosteroids, anabolic steroids roid, erythropoietin, immunization, immunoglobulin, immunosuppressant , growth hormone, hormone replacement drugs, radiopharmaceuticals, antidepressants, antipsychotics, stimulants, asthma Therapeutic agents, beta-agonists, inhaled steroids, epinephrine or analogs, cytokines or a cytokine antagonist. and further comprising administering at least one composition comprising an effective amount of one of the compounds or proteins. The composition according to any one of claims 1 to 6, comprising

8. A method for treating a TNF-associated condition in a patient, the TNF-associated condition being treated by psoriatic arthritis, the method comprising: (a) measuring the total modified van der Heijde-Schwarz (vSchwarz) of the patient prior to treating the patient; determining a dH-S score; (b) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 37; and a light chain (LC) comprising the TNF sequence. treating said patient by administering (c) determining said patient's total modified vdH-S score at week 52 of said treatment. and The patient treated with the composition comprising the anti-TNF antibody has a decreased disease activity (D Patients identified as having remission-low disease activity in the AAPSA; Patients identified as having moderate disease activity in the PsA activity score (PA Patients identified as having inactive disease activity on the PASDAS Patients identified as having moderate disease activity in the Patients identified as having MDA, patients identified as not having MDA, and patients identified as having very low Patients identified as having very low disease activity (VLDA) and those without VLDA Patients identified as having remission on the Clinical Disease Activity Index (CDAI) From patients who are identified as having low disease activity in the CDAI The present invention relates to a method for evaluating the effect of the total modified vdH-S score on the progression of pulmonary hypertension in patients selected from the group consisting of: A method for achieving arbitrary mean changes.

9. A significant mean change from baseline in the total modified vdH-S score is vdH-S in patients identified as having remission-low disease activity in SA = -0.88 ± 2.3 (SD), and those with moderate disease activity in the DAPSA vdH-S = -0.48 ± 1.82 (SD) in patients identified as PASD vdH-S in patients identified as having inactive disease activity in AS = -1.01±2.384 (SD), with moderate disease activity in the PASDAS vdH-S in patients identified as vdH-S in patients identified as having DA = -1.16 ± 2.46 (SD ), vdH-S in patients identified as not having MDA=0.03±2. 44(SD), vdH-S=-1 in patients identified as having VLDA 49±2.22 (SD), v in patients identified as not having VLDA dH-S = -0.30 ± 2.52 (SD), as a person with remission in the CDAI vdH-S in the identified patients = -1.06 ± 2.41 (SD), and the CDAI vdH-S = -0.8 in patients identified as having low disease activity in 9. The method of claim 8, wherein the mean mean is selected from the group consisting of: 1±2.12 (SD).

10. The composition comprises administering the anti-TNF antibody at weeks 0 and 4, and then every 8 weeks (q8 10. The method of claim 9, wherein said first and second subunits are administered in a dose of 2 mg / kg.

11. 11. The method of claim 10, wherein the composition is administered over a period of 30±10 minutes.

12. 11. The method of claim 10, wherein the patient is an adult patient aged 18 years or older.

13. administering the composition with or without methotrexate (MTX); The method of claim 10 further comprising:

14. a detectable label or reporter, either before, simultaneously with, or after administering (a); TNF antagonists, antirheumatics, muscle relaxants, narcotics, nonsteroidal Anti-inflammatory drugs (NSAIDs), analgesics, anesthetics, sedatives, local anesthetics, neuromuscular Blockers, antibiotics, antipsoriatic drugs, corticosteroids, anabolic steroids, erythropoietin thropoietin, immunization, immunoglobulin, immunosuppressant, growth hormone drugs, hormone replacement drugs, radiopharmaceuticals, antidepressants, antipsychotics, stimulants, asthma medications, β- agonists, inhaled steroids, epinephrine or analogs, cytokines, or cytokines. At least one compound selected from at least one of the following: further comprising administering at least one composition comprising an effective amount of the protein.

14. The method according to any one of 8 to 13.

15. At least one isolated compound for use in treating a patient with active psoriatic arthritis.

1. A mammalian anti-TNF antibody, comprising: The at least one isolated mammalian anti-TNF antibody has the amino acid sequence of SEQ ID NO:

36. and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37, The treatment comprises administering to the patient an IV injection of the at least one isolated mammalian anti-TNF antibody. administering the compound by injection, At week 52 of the treatment, the patient treated with the anti-TNF antibody had Disease Activity (DAPSA) Remission - Patients identified as having low disease activity Patients with moderate disease activity in the DAPSA; Patients identified as having inactive disease activity on the PASDAS score Patients identified as having moderate disease activity in the PASDAS, patients with minimal disease activity Patients identified as having MDA and those identified as not having MDA Patients identified as having very low disease activity (VLDA), patients with VLDA Patients identified as not having ALK, and those with remission on the Clinical Disease Activity Index (CDAI) Patients identified as having low disease activity in the CDAI total modified van der Heide-Schafer expression in a patient selected from the group consisting of At least one patient with a significant mean change from baseline in the vdH-S score 2. An isolated mammalian anti-TNF antibody.

16. A significant mean change from baseline in the total modified vdH-S score is vdH-S in patients identified as having remission-low disease activity in SA = -0.88 ± 2.3 (SD), and those with moderate disease activity in the DAPSA vdH-S = -0.48 ± 1.82 (SD) in patients identified as PASD vdH-S in patients identified as having inactive disease activity in AS = -1.01±2.384 (SD), with moderate disease activity in the PASDAS vdH-S in patients identified as vdH-S in patients identified as having DA = -1.16 ± 2.46 (SD ), vdH-S in patients identified as not having MDA=0.03±2. 44(SD), vdH-S=-1 in patients identified as having VLDA 49±2.22 (SD), v in patients identified as not having VLDA dH-S = -0.30 ± 2.52 (SD), as a person with remission in the CDAI vdH-S in the identified patients = -1.06 ± 2.41 (SD), and the CDAI vdH-S = -0.8 in patients identified as having low disease activity in 16. At least one of the compounds according to claim 15 selected from the group consisting of: 1±2.12 (SD). An isolated mammalian anti-TNF antibody.

17. The at least one isolated mammalian anti-TNF antibody is administered at week 0 and week 4.

17. The medicament of claim 16, wherein the medicament is administered at a dose of 2 mg / kg every 8 weeks (q8w) thereafter. At least one isolated mammalian anti-TNF antibody.

18. The at least one isolated mammalian anti-TNF antibody is administered over a period of 30±10 minutes.

20. At least one isolated mammalian anti-TNF antibody according to claim 17.

19. 18. The method of claim 17, wherein the patient is an adult patient aged 18 years or older. A mammalian anti-TNF antibody.

20. The treatment comprises administering to said subject at least one isolated mammalian anti-TNF antibody in combination with methotrexate.

17. The method of claim 16, further comprising administering the compound with or without methotrexate.

2. At least one isolated mammalian anti-TNF antibody according to claim 1.

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