Anti-TNF antibody compositions, and methods for treatment of psoriatic arthritis

Abstract

To provide a method for treating a patient having active psoriatic arthritis (PsA).SOLUTION: The present invention relates to compositions and methods utilizing anti-TNF antibodies or antigen binding fragments thereof in the treatment of active psoriatic arthritis (PsA), for example, a treatment utilizing an 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 is filed on May 1, 2020, entitled "JBI6103WOPCT1Seq The sequence list in ASCII format with the file name "Listing.txt" is stored in EFS-W. The sequence listing, which has a size of 25 kb, was submitted electronically via EFS-W. The Sequence Listing submitted via ibm.com is incorporated herein by reference in its entirety. be incorporated into the book.

[0002] FIELD OF THE INVENTION The present invention relates to the use of anti-T lymphocytes in the treatment of active psoriatic arthritis (PsA). Compositions and methods utilizing NF antibodies or antigen-binding fragments thereof, e.g., the amino acid sequence of SEQ ID NO: 36 a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 37 and a light chain comprising the amino acid sequence of SEQ ID NO: 37 The present invention relates to a treatment using anti-TNF antibodies having a light chain (LC). [Background technology]

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

[0004] Cells other than monocytes or macrophages also produce TNFα. For example, human non-monocytic tumor cells The cell line produces TNFα and CD4+ and CD8+ peripheral blood T lymphocytes, and several cultures Selected T and B cell lines also produce TNFα.

[0005] TNFα induces cartilage and bone degradation, adhesion molecule induction, and procoagulant activity in vascular endothelial cells Increases adhesion of neutrophils and lymphocytes, and promotes adhesion of macrophages, neutrophils and blood vessels Pro-inflammatory effects, such as stimulating the release of platelet-activating factor from endothelial cells, leading to tissue damage Causes use.

[0006] TNFα is involved in infections, immune disorders, neoplastic, autoimmune, and graft-versus-host pathologies. The association of TNFα with cancer and infectious pathologies is related to the catabolic state of the host. Cancer patients often suffer from weight loss, which is usually associated with loss of appetite.

[0007] The severe wasting associated with cancer and other diseases is known as "cachexia." Progressive weight loss, anorexia, and persistent loss of lean body mass in response to malignant tumor growth Cachexia is a major cause of morbidity and mortality in many cancers. TNFα is a There is evidence that it is involved in cachexia in infectious conditions and other catabolic states.

[0008] TNFα contributes to the development of gram-negative sepsis and endotoxin, including fever, fatigue, anorexia, and cachexia. Endotoxin is thought to play a central role in acute shock. Strongly activates phage production and secretion of TNFα and other cytokines. and other monocyte-derived cytokines mediate metabolic and neurohormonal responses to endotoxin Endotoxin administration to human volunteers produces fever, tachycardia, increased metabolic rate, and stress. This leads to acute illness with flu-like symptoms, including the release of TNFα. Circulating levels of β-lactamase are increased in patients with gram-negative sepsis.

[0009] Therefore, TNFα plays a key role in the treatment of inflammatory diseases, autoimmune diseases, viral, bacterial and parasitic infections. , malignancies, and / or neurodegenerative diseases, and has been associated with rheumatoid arthritis and crow's feet. These are useful targets for specific biological treatments in diseases such as Crohn's disease. The beneficial effects of successful retreatment after relapse in rheumatoid arthritis and Crohn's disease are related to TNFα This has been reported in an open-label study using a monoclonal antibody against inflammatory bowel disease. Beneficial results in rheumatoid arthritis have also been reported in randomized, double-blind, placebo-controlled trials.

[0010] Neutralizing antisera or mAbs against TNF have been shown to inhibit experimental endotoxin production in mammals other than humans. To prevent adverse physiological changes and death after lethal challenge in hemodialysis and bacteremia. This effect has been demonstrated, for example, in rodent lethality assays and primate pathology models. It is shown in the system.

[0011] The putative receptor binding site for hTNF has been disclosed, and amino acids 11-13 and 37 of TNF are The receptor binding locus of TNFα consisting of 42, 49, 57, and 155, 157 is disclosed. There are.

[0012] Non-human mammals, chimeric, polyclonal (e.g., antisera), and / or monoclonal Monoclonal antibodies (Mabs) as well as fragments (e.g., proteolytic digests or fusion protein fragments thereof) These compounds are active ingredients that are being investigated in some cases in an attempt to treat certain diseases. However, such antibodies or fragments may cause immune reactions when administered to humans. Such an immune response may elicit an immune complex of antibodies or fragments from the blood circulation. This can result in mediated clearance, making repeated administration unsuitable for therapy, thereby increasing patient This reduces the therapeutic benefit to the patient and limits re-administration of the antibody or fragment. Repeated administration of antibodies or fragments containing the antibody may result in serum sickness and / or anaphylaxis. To avoid these and other problems, chimerization and Many approaches have been taken to reduce the immunogenicity of such antibodies and portions thereof, including antibody synthesis and humanization. However, these and other approaches still have some immunogenicity. , low affinity, low binding activity, or cell culture, scale-up, production and / or This can result in antibodies or fragments with problems in low yield. Fragments may not be ideally suited for production or use as therapeutic proteins. be.

[0013] There is a need to provide a TNF inhibitor that overcomes one or more of these problems. Currently available anti-TNF antibodies and other TNF inhibitors, such as REMICAD E® (infliximab), HUMIRA® (adalimumab), and Other TNF inhibitors include cyclosporine and cyclosporine. are, for example, CIMZIA® (certolizumab pegol), PEGylated antibody fragments, and ENBREL® (etanercept), a soluble TNF receptor fusion protein For a review of TNF inhibitors, see, for example, Lis et al., "Arch M ed Sci. (December 22, 2014) Vol. 10, No. 6, pp. 1175-1185.

[0014] Psoriatic arthritis (PsA) is a chronic inflammatory, usually rheumatoid arthritis (RFA)-associated condition associated with psoriasis. The prevalence of psoriasis in the general Caucasian population is approximately Approximately 6% to 39% of people with psoriasis develop PsA. Psoriatic arthritis is a condition that affects 30 It peaks between the ages of 55 and 60, affecting men and women equally. involves peripheral joints, axial skeleton, sacroiliac joints, nails, and tendon insertions and is associated with psoriatic skin lesions More than half of PsA patients may have signs of erosion on x-ray, and up to 40% of patients have severe erosion. Psoriatic arthritis leads to erosive arthropathy. It is associated with disability, reduced quality of life, and increased mortality. resulting in an increase.

[0015] Interactions between T cells and monocytes / macrophages, the major source of inflammatory cytokines The interaction plays a role in the pathogenesis of PsA. Increased levels of TNFα are secreted into the joint fluid and It has been detected in skin and tissues, and in psoriatic skin lesions in PsA patients. Infliximab, subcutaneous (SC) golimumab, adalimumab, and certo TNF-targeted biologic therapies, including lizumab pegol, have an acceptable safety profile. Rapid and significant improvement of arthritis and psoriasis in subjects with active PsA while maintaining inflammatory bowel disease Considering the safety and efficacy of SC golimumab, IV golimumab has an acceptable safety profile consistent with other anti-TNFα agents It was assumed that it could be proven to be effective. Summary of the Invention [Means for solving the problem]

[0016] For brevity, the independent and dependent patent applications attached hereto are incorporated herein by reference. The generic and preferred embodiments are defined by the appended claims. Embodiments, features, and advantages will become apparent from the following detailed description taken in conjunction with the accompanying drawings. It will become clear.

[0017] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis (PsA). The present invention provides a method for treating a tumor necrosis factor (TNF) antibody comprising administering an intravenous (IV) dose of an anti-TNF antibody. the anti-TNF antibody comprises a polypeptide 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, 52 weeks after treatment. After a period of time, patients were assessed for Disease Activity in PsA (DAPSA) scores. Patients achieve low disease activity from PsA-based remission or a PsA activity score (PsA Acti Patients achieve inactive disease activity based on the PASDAS or experience clinical disease Achieved remission based on Clinical Disease Activity Index (CDAI) score or the patient achieves a Minimal Disease Activity (MDA) score or the patient has a Very Low Disease Activity (VLDA) score Achieve this.

[0018] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis (PsA). The present invention provides a method for treating TNF-α, which comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the anti-TNF antibody comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and After 52 weeks of treatment, 4 of the patients More than 5% achieved remission to low disease activity based on DAPSA score, or 45% of patients > 25% of patients achieve inactive disease activity based on PASDAS or > 25% achieve CDAI Achieving score-based remission, or >40% of patients achieving MDA score, or Over 12% of patients achieve a VLDA score.

[0019] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis (PsA). The present invention provides a method for treating TNF-α, which comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the anti-TNF antibody comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37, and after 52 weeks of treatment, the patient Achieving remission to low disease activity based on the Disease Activity in sA (DAPSA) score or patients achieve inactive disease activity based on the PsA Activity Score (PASDAS). or the patient achieves remission based on the Clinical Disease Activity Index (CDAI) score, or the patient A minimal disease activity (MDA) score is achieved or the patient is diagnosed with very low disease activity (VL The anti-TNF antibody achieved a DA score of 0 and 4 weeks, then 8 weeks thereafter. It is administered at a dose of 2 mg / kg every 8 weeks (q8w).

[0020] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis (PsA). The present invention provides a method for treating TNF-α, which comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the anti-TNF antibody comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37, and after 52 weeks of treatment, the patient Achieving remission to low disease activity based on the Disease Activity in sA (DAPSA) score or patients achieve inactive disease activity based on the PsA Activity Score (PASDAS). or the patient achieves remission based on the Clinical Disease Activity Index (CDAI) score, or the patient A minimal disease activity (MDA) score is achieved or the patient is diagnosed with very low disease activity (VL Achieve a DA score and these patients are 18 years of age or older.

[0021] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis (PsA). The present invention provides a method for treating TNF-α, which comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the anti-TNF antibody comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37, and after 52 weeks of treatment, the patient Achieving remission to low disease activity based on the Disease Activity in sA (DAPSA) score or patients achieve inactive disease activity based on the PsA Activity Score (PASDAS). or the patient achieves remission based on the Clinical Disease Activity Index (CDAI) score, or the patient A minimal disease activity (MDA) score is achieved or the patient is diagnosed with very low disease activity (VL The treatment achieved a DA score and consisted of the treatment of this anti-TNF antibody with methotrexate. , MTX) or without MTX.

[0022] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis (PsA). The present invention provides a method for treating TNF-α, which comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the anti-TNF antibody comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37, and after 52 weeks of treatment, the patient Achieving remission to low disease activity based on the Disease Activity in sA (DAPSA) score or patients achieve inactive disease activity based on the PsA Activity Score (PASDAS). or the patient achieves remission based on the Clinical Disease Activity Index (CDAI) score, or the patient A minimal disease activity (MDA) score is achieved or the patient is diagnosed with very low disease activity (VL and the anti-TNF antibody is administered as a pharmaceutical composition comprising the anti-TNF antibody. will be done.

[0023] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis (PsA). The present invention provides a method for treating TNF-α, which comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the anti-TNF antibody comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37, and after 52 weeks of treatment, the patient Achieving remission to low disease activity based on the Disease Activity in sA (DAPSA) score or patients achieve inactive disease activity based on the PsA Activity Score (PASDAS). or the patient achieves remission based on the Clinical Disease Activity Index (CDAI) score, or the patient A minimal disease activity (MDA) score is achieved or the patient is diagnosed with very low disease activity (VL and the anti-TNF antibody is administered as a pharmaceutical composition comprising the anti-TNF antibody. The composition contains 2 mg / kg of anti-TNF antibody administered to patients at week 0, week 4, and thereafter. Thereafter, the drug is administered every 8 weeks.

[0024] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis (PsA). The present invention provides a method for treating TNF-α, which comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the anti-TNF antibody comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37, and after 52 weeks of treatment, the patient Achieving remission to low disease activity based on the Disease Activity in sA (DAPSA) score or patients achieve inactive disease activity based on the PsA Activity Score (PASDAS). or the patient achieves remission based on the Clinical Disease Activity Index (CDAI) score, or the patient A minimal disease activity (MDA) score is achieved or the patient is diagnosed with very low disease activity (VL and the anti-TNF antibody is administered as a pharmaceutical composition comprising the anti-TNF antibody. These patients were aged 18 years or older.

[0025] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis (PsA). The present invention provides a method for treating TNF-α, which comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the anti-TNF antibody comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37, and after 52 weeks of treatment, the patient Achieving remission to low disease activity based on the Disease Activity in sA (DAPSA) score or patients achieve inactive disease activity based on the PsA Activity Score (PASDAS). or the patient achieves remission based on the Clinical Disease Activity Index (CDAI) score, or the patient A minimal disease activity (MDA) score is achieved or the patient is diagnosed with very low disease activity (VL and the anti-TNF antibody is administered as a pharmaceutical composition comprising the anti-TNF antibody. The composition may be administered with or without methotrexate (MTX). Further includes:

[0026] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The method comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the 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: 3 After 52 weeks of treatment, patients showed a significant improvement in psoriasis area and 75% improvement in the Patient Acute Anxiety and Severity Index (PASI) score (PASI75), 90% improvement in PASI score (PASI90) or 100% improvement in PASI score Achieve (PASI100).

[0027] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The method comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the 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: 3 After 52 weeks of treatment, patients showed a significant improvement in psoriasis area and 75% improvement in the Patient Acute Anxiety and Severity Index (PASI) score (PASI75), 90% improvement in PASI score (PASI90) or 100% improvement in PASI score Patients achieved PASI100 and had a baseline body surface area (BSA) score of 3% or greater. ce area, BSA) with psoriasis involvement.

[0028] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The method comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the 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: 3 After 52 weeks of treatment, more than 70% of patients had P Achieving ASI75, or >55% of patients achieving PASI90, or 25% of patients achieving PASI90 Over % achieve PASI 100.

[0029] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The method comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the 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: 3 After 52 weeks of treatment, patients showed a significant improvement in psoriasis area and 75% improvement in the Patient Acute Anxiety and Severity Index (PASI) score (PASI75), 90% improvement in PASI score (PASI90) or 100% improvement in PASI score Patients achieved a PASI100 score and the Dermatology Life Quality Index (Dermatology Life Quality Index) Achieve a 5-point or greater improvement in DLQI (Dementia and Quality Index) score.

[0030] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The method comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the 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: 3 After 52 weeks of treatment, more than 60% of patients had P Achieving a 5-point or greater improvement in ASI75 and DLQI scores or achieving a 50% improvement in patients More than % achieved a 5-point or greater improvement in PASI75 and DLQI scores, or More than 20% of patients achieved a 5-point or greater improvement in PASI100 and DLQI scores. Achieve.

[0031] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The method comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the 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: 3 After 52 weeks of treatment, patients showed a significant improvement in psoriasis area and 75% improvement in the Patient Acute Anxiety and Severity Index (PASI) score (PASI75), 90% improvement in PASI score (PASI90) or 100% improvement in PASI score (PASI100), and the patient achieved a 20% improvement in the American College of Rheumatology classification criteria ( Achieve the American College of Rheumatology (ACR20).

[0032] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The method comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the 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: 3 After 52 weeks of treatment, more than 55% of patients had P Achieve ASI75 and ACR20 response or PASI90 and ACR in more than 45% of patients Achieve 20 responses or >20% of patients achieve PASI100 and ACR20 responses do.

[0033] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The method comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the 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: 3 After 52 weeks of treatment, patients reported a significant improvement in psoriasis area and 75% improvement in the Patient Acute Anxiety and Severity Index (PASI) score (PASI75), 90% improvement in PASI score (PASI90) or 100% improvement in PASI score The anti-TNF antibody achieved a PASI score of 100 at weeks 0 and 4, and then The subsequent dose is 2 mg / kg every 8 weeks (q8w).

[0034] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The method comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the 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: 3 After 52 weeks of treatment, patients showed a significant improvement in psoriasis area and 75% improvement in the Patient Acute Anxiety and Severity Index (PASI) score (PASI75), 90% improvement in PASI score (PASI90) or 100% improvement in PASI score (PASI 100) and these patients were aged 18 years or older.

[0035] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The method comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the 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: 3 After 52 weeks of treatment, patients showed a significant improvement in psoriasis area and 75% improvement in the Patient Acute Anxiety and Severity Index (PASI) score (PASI75), 90% improvement in PASI score (PASI90) or 100% improvement in PASI score The patient achieved a PASI score of 100, and treatment consisted of combining this anti-TNF antibody with methotrexate (MTX). with or without MTX.

[0036] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The method comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the 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: 3 After 52 weeks of treatment, patients showed a significant improvement in psoriasis area and 75% improvement in the Patient Acute Anxiety and Severity Index (PASI) score (PASI75), 90% improvement in PASI score (PASI90) or 100% improvement in PASI score This anti-TNF antibody achieved a PASI 100 score, and the anti-TNF antibody was used as a pharmaceutical composition containing the anti-TNF antibody. It is administered as follows.

[0037] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The method comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the 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: 3 After 52 weeks of treatment, patients showed a significant improvement in psoriasis area and 75% improvement in the Patient Acute Anxiety and Severity Index (PASI) score (PASI75), 90% improvement in PASI score (PASI90) or 100% improvement in PASI score This anti-TNF antibody achieved a PASI 100 score, and the anti-TNF antibody was used as a pharmaceutical composition containing the anti-TNF antibody. The composition is administered at 2 mg / kg of anti-TNF antibody to the patient at week 0, week 4, It is then administered every 8 weeks thereafter.

[0038] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The method comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the 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: 3 After 52 weeks of treatment, patients showed a significant improvement in psoriasis area and 75% improvement in the Patient Acute Anxiety and Severity Index (PASI) score (PASI75), 90% improvement in PASI score (PASI90) or 100% improvement in PASI score This anti-TNF antibody achieved a PASI 100 score, and the anti-TNF antibody was used as a pharmaceutical composition containing the anti-TNF antibody. These patients are aged 18 years or older.

[0039] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The method comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the 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: 3 After 52 weeks of treatment, patients showed a significant improvement in psoriasis area and 75% improvement in the Patient Acute Anxiety and Severity Index (PASI) score (PASI75), 90% improvement in PASI score (PASI90) or 100% improvement in PASI score This anti-TNF antibody achieved a PASI 100 score, and the anti-TNF antibody was used as a pharmaceutical composition containing the anti-TNF antibody. The treatment may be administered with or without methotrexate (MTX). It further includes providing.

[0040] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The method comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the 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: 3 7 amino acid sequence, corrected at baseline after 52 weeks of treatment. Modified Nail Psoriasis Severity Index (mNAPSI) score Patients with a score above 0 had a 100% improvement in mNAPSI score and dermatological quality of life Achieve a 5-point or greater improvement in the DLQI score.

[0041] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The method comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the 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: 3 7 amino acid sequence, corrected at baseline after 52 weeks of treatment. Patients with a mNAPSI score >0 had a higher mNAPSI score than those with a lower mNAPSI score. 100% improvement in Dermatological Life Quality Index (DLQI) score and 5 points improvement in DLQI score Patients must achieve an improvement of ≥3% body surface area (BSA) psoriasis involvement at baseline. It has.

[0042] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The method comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the 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: 3 After 52 weeks of treatment, more than 30% of patients had a light chain (LC) containing the amino acid sequence 100% improvement in mNAPSI score and ≥5 points improvement in DLQI score Achieve the above improvements.

[0043] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The method comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the 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: 3 7 amino acid sequence, corrected at baseline after 52 weeks of treatment. Patients with a mNAPSI score >0 had a higher mNAPSI score than those with a lower mNAPSI score. 100% improvement in Dermatological Life Quality Index (DLQI) score and 5 points improvement in DLQI score This anti-TNF antibody achieved the above improvement at weeks 0 and 4, and then at week 8. It is administered at a dose of 2 mg / kg every 8 weeks (q8w).

[0044] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The method comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the 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: 3 7 amino acid sequence, corrected at baseline after 52 weeks of treatment. Patients with a mNAPSI score >0 had a higher mNAPSI score than those with a lower mNAPSI score. 100% improvement in Dermatological Life Quality Index (DLQI) score and 5 points improvement in DLQI score These patients were 18 years of age or older and achieved improvement of 18 years or older.

[0045] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The method comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the 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: 3 7 amino acid sequence, corrected at baseline after 52 weeks of treatment. Patients with a mNAPSI score >0 had a higher mNAPSI score than those with a lower mNAPSI score. 100% improvement in Dermatological Life Quality Index (DLQI) score and 5 points improvement in DLQI score The above improvement was achieved, and treatment consisted of this anti-TNF antibody in combination with methotrexate (MTX). Alternatively, it may be administered without MTX.

[0046] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The method comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the 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: 3 7 amino acid sequence, corrected at baseline after 52 weeks of treatment. Patients with a mNAPSI score >0 had a higher mNAPSI score than those with a lower mNAPSI score. 100% improvement in Dermatological Life Quality Index (DLQI) score and 5 points improvement in DLQI score The above improvements have been achieved, and the anti-TNF antibody is administered as a pharmaceutical composition comprising the anti-TNF antibody. can be.

[0047] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The method comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the 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: 3 7 amino acid sequence, corrected at baseline after 52 weeks of treatment. Patients with a mNAPSI score >0 had a higher mNAPSI score than those with a lower mNAPSI score. 100% improvement in Dermatological Life Quality Index (DLQI) score and 5 points improvement in DLQI score The above improvements have been achieved, and the anti-TNF antibody is administered as a pharmaceutical composition comprising the anti-TNF antibody. The composition contains 2 mg / kg of anti-TNF antibody at week 0, week 4, and then It is administered to patients every eight weeks.

[0048] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The method comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the 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: 3 7 amino acid sequence, corrected at baseline after 52 weeks of treatment. Patients with a mNAPSI score >0 had a higher mNAPSI score than those with a lower mNAPSI score. 100% improvement in Dermatological Life Quality Index (DLQI) score and 5 points improvement in DLQI score The above improvements have been achieved, and the anti-TNF antibody is administered as a pharmaceutical composition comprising the anti-TNF antibody. These patients were aged 18 years or older.

[0049] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The method comprises administering to a patient an intravenous (IV) dose of an anti-TNF antibody. the 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: 3 7 amino acid sequence, corrected at baseline after 52 weeks of treatment. Patients with a mNAPSI score >0 had a higher mNAPSI score than those with a lower mNAPSI score. 100% improvement in Dermatological Life Quality Index (DLQI) score and 5 points improvement in DLQI score The above improvements have been achieved, and the anti-TNF antibody is administered as a pharmaceutical composition comprising the anti-TNF antibody. The treatment may be administered with or without methotrexate (MTX). It further includes:

[0050] In certain embodiments, the present invention provides a safety and efficacy study for patients with active psoriatic arthritis. and providing a composition for use in a clinically proven and clinically effective treatment. The composition comprises at least one pharmaceutically acceptable carrier or diluent and a compound selected from the group consisting of SEQ ID NO: A heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a light chain (L) comprising the amino acid sequence of SEQ ID NO: 37. C) at least one isolated mammalian anti-TNF antibody, and administering the composition to the patient by IV infusion, and at 52 weeks of this treatment, Patients treated with NF antibodies experience a decline in disease activity in PsA (DAPSA) from remission Patients identified as having active disease, those with moderate disease activity on DAPSA Patients identified as having PsA activity score (PASDAS) inactive Patients identified as having active disease, moderate disease activity in PASDAS Patients identified as having minimal disease activity (MDA) patients with MDA, patients identified as not having MDA, and patients with very low disease activity (VLDA) Patients identified as having VLDA, patients identified as not having VLDA, and patients with clinical disease Patients identified as having remission on the CDAI and a patient selected from the group consisting of patients identified as having low disease activity in Total modified van der Heijde-Sharpe (vdH-S) score at baseline have significant mean changes.

[0051] In certain embodiments, the present invention provides a safety and efficacy study for patients with active psoriatic arthritis. and providing a composition for use in a clinically proven and clinically effective treatment. The composition comprises at least one pharmaceutically acceptable carrier or diluent and a compound selected from the group consisting of SEQ ID NO: A heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a light chain (L) comprising the amino acid sequence of SEQ ID NO: 37. C) at least one isolated mammalian anti-TNF antibody having and administering to the patient by IV infusion the composition of formula (I), wherein at 52 weeks of this treatment, the anti-TN Patients treated with F antibody showed a progression from remission to low disease activity in PsA (DAPSA). Patients identified as having active disease, those with moderate disease activity on DAPSA Patients identified as having PsA activity, inactive on the PsA activity score (PASDAS) Patients identified as having active disease, moderate disease activity in PASDAS Patients identified as having minimal disease activity (MDA) patients with MDA, patients identified as not having MDA, and patients with very low disease activity (VLDA) Patients identified as having VLDA, patients identified as not having VLDA, and patients with clinical disease Patients identified as having remission on the CDAI and a patient selected from the group consisting of patients identified as having low disease activity in Total modified van der Heijde-Sharpe (vdH-S) score at baseline There were significant mean changes from baseline in the total modified vdH-S score. Significant mean changes were identified as those with remission to low disease activity on DAPSA. vdH-S = -0.88 ± 2.3 (SD) in patients with moderate DAPSA vdH-S = -0.48 ± 1.82 in patients identified as having active disease (SD), for patients identified as having inactive disease activity in PASDAS vdH-S = -1.01 ± 2.384 (SD) in the PASDAS. vdH-S = -0.20 ± 1.965 in patients identified as having active disease (SD), vdH-S = -1.16 ± 2 in patients identified as having MDA .46 (SD), vdH-S = 0.0 in patients identified as not having MDA 3 ± 2.44 (SD), vdH-S in patients identified as having VLDA = -1.49 ± 2.22 (SD), v in patients identified as not having VLDA dH-S=-0.30±2.52(SD), identified as having remission in CDAI vdH-S = -1.06 ± 2.41 (SD) in patients with schizophrenia, and CDAI vdH-S=-0.81±2 in patients identified as having low disease activity. 12(SD).

[0052] In certain embodiments, the present invention provides a method for treating psoriatic arthritis in patients with clinically proven psoriatic arthritis. and providing a composition for use in a safe, clinically proven, and effective treatment, which comprises: The composition comprises at least one pharmaceutically acceptable carrier or diluent and an amino acid sequence of SEQ ID NO: 36. and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37. and at least one isolated mammalian anti-TNF antibody, wherein the treatment comprises administering the composition to a mammal. In the 52nd week of this treatment, Patients who received the treatment had remission to low disease activity in PsA (DAPSA). Patients identified as having moderate disease activity on DAPSA Patients with inactive disease activity according to 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 having no disease, very low disease activity (VLDA) Patients identified as having VLDA, patients identified as not having VLDA, and patients with clinical disease activity index (C Patients identified as having remission on the DAI and low disease on the CDAI Total correction in patients selected from the group consisting of patients identified as having active disease Significant mean change from baseline in positive van der Heijde-Sharpe (vdH-S) scores The mean change from baseline in the total modified vdH-S score was v in patients identified as having remission to low disease activity on the DAPSA dH-S=-0.88±2.3(SD), DAPSA showed moderate disease activity vdH-S = -0.48 ± 1.82 (SD) in patients identified as having PAS vdH-S in patients identified as having inactive disease activity on the DAS =-1.01±2.384(SD), with moderate disease activity in PASDAS vdH-S = -0.20 ± 1.965 (SD) in patients identified as MDA vdH-S = -1.16 ± 2.46 (SD) in patients identified as having vdH-S = 0.03 ± 2.44 (S D), vdH-S=-1.49±2 in patients identified as having VLDA. 22(SD), vdH-S=-0 in patients identified as not having VLDA. 30±2.52 (SD), in patients identified as having remission in the CDAI The vdH-S score was -1.06 ± 2.41 (SD) and the CDAI showed low disease activity. vdH-S = -0.81 ± 2.12 (SD) in patients identified as having and the composition is selected from the group consisting of: It is administered at a dose of 2 mg / kg every 8 weeks (q8w).

[0053] In certain embodiments, the present invention provides a method for the treatment of psoriatic arthritis, the safety of which is clinically demonstrated in patients with active psoriatic arthritis. providing compositions for use in therapeutic treatments that are experimentally proven and clinically proven to be effective; The composition comprises at least one pharmaceutically acceptable carrier or diluent and a compound of SEQ ID NO: 36. A heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 37 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37 and at least one isolated mammalian anti-TNF antibody having a TNF-α or TNF-β receptor agonist activity, The treatment involves administering to the patient via IV infusion, and at 52 weeks of this treatment, the patient is treated with an anti-TNF antibody. Treated patients achieved remission to low disease activity in PsA (DAPSA) Patients identified as having moderate disease activity on DAPSA Patients identified as having inactive disease activity according to 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 DA, those with very low disease activity (VLDA) patients identified as having VLDA, patients identified as not having VLDA, patients with clinical disease activity index Patients identified as having remission on the CDAI and those with low CDAI The overall number of patients selected from the group consisting of patients identified as having low disease activity Significant improvement in the overall modified van der Heijde-Sharpe (vdH-S) score from baseline Mean change from baseline in total modified vdH-S score. The progression was observed in patients identified as having remission to low disease activity on the DAPSA. vdH-S = -0.88 ± 2.3 (SD), and DAPSA showed moderate disease activity. vdH-S = -0.48 ± 1.82 (SD) in patients identified as having vd in patients identified as having inactive disease activity in PASDAS HS=-1.01±2.384(SD), PASDAS showed moderate disease activity vdH-S = -0.20 ± 1.965 (SD) in patients identified as having vdH-S = -1.16 ± 2.46 (S D) vdH-S = 0.03 ± 2.4 in patients identified as not having MDA 4 (SD), vdH-S = -1.49 in patients identified as having VLDA ±2.22 (SD), vdH-S in patients identified as not having VLDA = -0.30 ± 2.52 (SD), patients identified as having remission in CDAI vdH-S = -1.06 ± 2.41 (SD) in the 2016-2017 study, and low disease activity in the CDAI. vdH-S = -0.81 ± 2.12 (SD) in patients identified as having hyperactivity ), and the composition is selected from the group consisting of: Thereafter, the drug was administered at a dose of 2 mg / kg every 8 weeks (q8w). The composition is administered over a period of 30±10 minutes.

[0054] In certain embodiments, the present invention provides a method for the treatment of psoriatic arthritis, the safety of which is clinically demonstrated in patients with active psoriatic arthritis. providing compositions for use in therapeutic treatments that are experimentally proven and clinically proven to be effective; The composition comprises at least one pharmaceutically acceptable carrier or diluent and a compound of SEQ ID NO: 36. A heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 37 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37 and at least one isolated mammalian anti-TNF antibody having the and administering the composition to the patient by IV infusion, and at 52 weeks of this treatment, Patients treated with steroids showed a decline in disease activity in PsA (DAPSA) from remission to low disease activity. Patients identified as having moderate disease activity on DAPSA Patients identified as having inactive disease activity according to 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 with very low disease activity (VLDA) Patients identified as having VLDA, patients identified as not having VLDA, and clinical disease activity Patients identified as having remission in the Clinical and Clinical Assessment Index (CDAI) and those in the In patients selected from the group consisting of patients identified as having low disease activity The total modified van der Heijde-Sharpe (vdH-S) score from baseline Significant mean change from baseline in total modified vdH-S score Mean change is defined as patients who are in remission to have low disease activity on DAPSA. vdH-S = -0.88 ± 2.3 (SD) in the 24-month follow-up period, and moderate disease activity in the 24-month follow-up period. vdH-S = -0.48 ± 1.82 (SD) in patients identified as having hyperactivity ), 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 a ), vdH-S=-1.16±2.46 in patients identified as having MDA (SD), vdH-S = 0.03 ± 2 in patients identified as not having MDA .44 (SD), vdH-S=-1 in patients identified as having VLDA. 49 ± 2.22 (SD), vdH- in patients identified as not having VLDA S = -0.30 ± 2.52 (SD), identified as having remission on CDAI vdH-S in patients = -1.06 ± 2.41 (SD), and CDAI was low. vdH-S = -0.81 ± 2.12 ( SD), and the composition is selected from the group consisting of: Thereafter, the drug is administered at a dose of 2 mg / kg every 8 weeks (q8w). These patients were adults aged 18 years or older.

[0055] In certain embodiments, the present invention provides a method for the treatment of psoriatic arthritis, the safety of which is clinically demonstrated in patients with active psoriatic arthritis. providing compositions for use in therapeutic treatments that are experimentally proven and clinically proven to be effective; The composition comprises at least one pharmaceutically acceptable carrier or diluent and a compound of SEQ ID NO: 36. A heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 37 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37 and at least one isolated mammalian anti-TNF antibody having a TNF-α or TNF-β receptor agonist activity, The treatment involves administering to the patient via IV infusion, and at 52 weeks of this treatment, the patient is treated with an anti-TNF antibody. Treated patients achieved remission to low disease activity in PsA (DAPSA) Patients identified as having moderate disease activity on DAPSA Patients identified as having inactive disease activity according to 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 DA, those with very low disease activity (VLDA) patients identified as having VLDA, patients identified as not having VLDA, patients with clinical disease activity index Patients identified as having remission on the CDAI and those with low CDAI The overall number of patients selected from the group consisting of patients identified as having low disease activity Significant improvement in the overall modified van der Heijde-Sharpe (vdH-S) score from baseline Mean change from baseline in total modified vdH-S score. The progression was observed in patients identified as having remission to low disease activity on the DAPSA. vdH-S = -0.88 ± 2.3 (SD), and DAPSA showed moderate disease activity. vdH-S = -0.48 ± 1.82 (SD) in patients identified as having vd in patients identified as having inactive disease activity in PASDAS HS=-1.01±2.384(SD), PASDAS showed moderate disease activity vdH-S = -0.20 ± 1.965 (SD) in patients identified as having vdH-S = -1.16 ± 2.46 (S D) vdH-S = 0.03 ± 2.4 in patients identified as not having MDA 4 (SD), vdH-S = -1.49 in patients identified as having VLDA ±2.22 (SD), vdH-S in patients identified as not having VLDA = -0.30 ± 2.52 (SD), patients identified as having remission in CDAI vdH-S = -1.06 ± 2.41 (SD) in the 2016-2017 study, and low disease activity in the CDAI. vdH-S = -0.81 ± 2.12 (SD) in patients identified as having hyperactivity ), and the composition is selected from the group consisting of: Thereafter, the drug was administered at a dose of 2 mg / kg every 8 weeks (q8w). The treatment may involve administering the composition with or without methotrexate (MTX). Further includes:

[0056] In certain embodiments, the present invention provides a method for treating a TNF-associated condition in a patient. The method further comprises administering to the patient a TNF-associated condition, the TNF-associated condition being active psoriatic arthritis, prior to treating the patient. Determining the patient's total modified van der Heijde-Sharpe (vdH-S) score and a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a Anti-TN antibody with light chain (LC) in a clinically proven, effective dose with clinically proven safety. Treating patients by administering a composition comprising F antibody via intravenous (IV) infusion and determining the patient's total modified vdH-S score at 52 weeks of this treatment. A composition containing an anti-TNF antibody in an amount that has been clinically proven to be safe and clinically proven to be effective. These patients treated with the compound showed a significant improvement in disease activity in PsA (DAPSA) from remission to Patients identified as having low disease activity, moderate disease activity on DAPSA Patients identified as having PsA activity, inactive on the PsA activity score (PASDAS) Patients identified as having active disease activity, those with moderate disease activity in the PASDAS Patients identified as having minimal disease activity (MDA) patients identified as having no MDA, patients with very low disease activity (VLD) A) patients identified as having VLDA, patients identified as not having VLDA, Patients identified as having remission on the CDAI and CD patients identified as having low disease activity on an AI Achieving a significant mean change from baseline in the total modified vdH-S score in patients do.

[0057] In certain embodiments, the present invention provides a method for treating a TNF-associated condition in a patient. The method further comprises administering to the patient a TNF-associated condition, the TNF-associated condition being active psoriatic arthritis, prior to treating the patient. Determining the patient's total modified van der Heijde-Sharpe (vdH-S) score and a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a Anti-TN antibody with light chain (LC) in a clinically proven, effective dose with clinically proven safety. Treating patients by administering a composition comprising F antibody via intravenous (IV) infusion and determining the patient's total modified vdH-S score at 52 weeks of this treatment. A composition containing an anti-TNF antibody in an amount that has been clinically proven to be safe and clinically proven to be effective. These patients treated with the compound showed a significant improvement in disease activity in PsA (DAPSA) from remission to Patients identified as having low disease activity, moderate disease activity on DAPSA Patients identified as having PsA activity, inactive on the PsA activity score (PASDAS) Patients identified as having active disease activity, those with moderate disease activity in the PASDAS Patients identified as having minimal disease activity (MDA) patients identified as having no MDA, patients with very low disease activity (VLD) A) patients identified as having VLDA, patients identified as not having VLDA, Patients identified as having remission on the CDAI and CD patients identified as having low disease activity on an AI Baseline total modified van der Heijde-Sharpe (vdH-S) score in patients Achieved a significant mean change from baseline in total modified vdH-S score These significant mean changes were particularly pronounced in patients with remission to low disease activity on the DAPSA. vdH-S in patients with pulmonary embolism was -0.88±2.3 (SD), and in patients with pulmonary embolism, ... 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), intermediate in PASDAS vdH-S = -0.20 ± 1 in patients identified as having high disease activity. 965(SD), vdH-S=-1.1 in patients identified as having MDA 6 ± 2.46 (SD), vdH-S in patients identified as not having MDA = 0.03 ± 2.44 (SD), vdH in patients identified as having VLDA -S = -1.49 ± 2.22 (SD) in patients identified as not having VLDA vdH-S = -0.30 ± 2.52 (SD) for those with remission in CDAI. vdH-S = -1.06 ± 2.41 (SD) in patients identified by vdH-S=-0.81 in patients identified as having low disease activity in ±2.12 (SD).

[0058] In certain embodiments, the present invention provides a method for treating a TNF-associated condition in a patient. The method further comprises administering to the patient a TNF-associated condition, the TNF-associated condition being active psoriatic arthritis, prior to treating the patient. Determining the patient's total modified van der Heijde-Sharpe (vdH-S) score and a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a Anti-TN antibody with light chain (LC) in a clinically proven, effective dose with clinically proven safety. Treating patients by administering a composition comprising F antibody via intravenous (IV) infusion and determining the patient's total modified vdH-S score at 52 weeks of this treatment. A composition containing an anti-TNF antibody in an amount that has been clinically proven to be safe and clinically proven to be effective. These patients treated with the compound showed a significant improvement in disease activity in PsA (DAPSA) from remission to Patients identified as having low disease activity, moderate disease activity on DAPSA Patients identified as having PsA activity, inactive on the PsA activity score (PASDAS) Patients identified as having active disease activity, those with moderate disease activity in the PASDAS Patients identified as having minimal disease activity (MDA) patients identified as having no MDA, patients with very low disease activity (VLD) A) patients identified as having VLDA, patients identified as not having VLDA, Patients identified as having remission on the CDAI and CD patients identified as having low disease activity on an AI Baseline total modified van der Heijde-Sharpe (vdH-S) score in patients Achieved a significant mean change from baseline in total modified vdH-S score These significant mean changes were particularly pronounced in patients with remission to low disease activity on the DAPSA. vdH-S in patients with pulmonary embolism was -0.88±2.3 (SD), and in patients with pulmonary embolism, ... 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), intermediate in PASDAS vdH-S = -0.20 ± 1 in patients identified as having high disease activity. 965(SD), vdH-S=-1.1 in patients identified as having MDA 6 ± 2.46 (SD), vdH-S in patients identified as not having MDA = 0.03 ± 2.44 (SD), vdH in patients identified as having VLDA -S = -1.49 ± 2.22 (SD) in patients identified as not having VLDA vdH-S = -0.30 ± 2.52 (SD) for those with remission in CDAI. vdH-S = -1.06 ± 2.41 (SD) in patients identified by vdH-S=-0.81 in patients identified as having low disease activity in ±2.12 (SD), wherein the anti-TNF antibody is selected from the group consisting of Administered at a dose of 2 mg / kg on the first and fourth weeks, then every 8 weeks (q8w) thereafter. It is administered so that

[0059] In certain embodiments, the present invention provides a method for treating a TNF-associated condition in a patient. The method further comprises administering to the patient a TNF-associated condition, the TNF-associated condition being active psoriatic arthritis, prior to treating the patient. Determining the patient's total modified van der Heijde-Sharpe (vdH-S) score and a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a Anti-TN antibody with light chain (LC) in a clinically proven, effective dose with clinically proven safety. Treating patients by administering a composition comprising F antibody via intravenous (IV) infusion and determining the patient's total modified vdH-S score at 52 weeks of this treatment. A composition containing an anti-TNF antibody in an amount that has been clinically proven to be safe and clinically proven to be effective. These patients treated with the compound showed a significant improvement in disease activity in PsA (DAPSA) from remission to Patients identified as having low disease activity, moderate disease activity on DAPSA Patients identified as having PsA activity, inactive on the PsA activity score (PASDAS) Patients identified as having active disease activity, those with moderate disease activity in the PASDAS Patients identified as having minimal disease activity (MDA) patients identified as having no MDA, patients with very low disease activity (VLD) A) patients identified as having VLDA, patients identified as not having VLDA, Patients identified as having remission on the CDAI and CD patients identified as having low disease activity on an AI Baseline total modified van der Heijde-Sharpe (vdH-S) score in patients Achieved a significant mean change from baseline in total modified vdH-S score These significant mean changes were particularly pronounced in patients with remission to low disease activity on the DAPSA. vdH-S in patients with pulmonary embolism was -0.88±2.3 (SD), and in patients with pulmonary embolism, ... 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), intermediate in PASDAS vdH-S = -0.20 ± 1 in patients identified as having high disease activity. 965(SD), vdH-S=-1.1 in patients identified as having MDA 6 ± 2.46 (SD), vdH-S in patients identified as not having MDA = 0.03 ± 2.44 (SD), vdH in patients identified as having VLDA -S = -1.49 ± 2.22 (SD) in patients identified as not having VLDA vdH-S = -0.30 ± 2.52 (SD) for those with remission in CDAI. vdH-S = -1.06 ± 2.41 (SD) in patients identified by vdH-S=-0.81 in patients identified as having low disease activity in ±2.12 (SD), wherein the anti-TNF antibody is selected from the group consisting of Administered at a dose of 2 mg / kg on the first and fourth weeks, then every 8 weeks (q8w) thereafter. The composition is administered over a period of 30±10 minutes.

[0060] In certain embodiments, the present invention provides a method for treating a TNF-associated condition in a patient. The method further comprises administering to the patient a TNF-associated condition, the TNF-associated condition being active psoriatic arthritis, prior to treating the patient. Determining the patient's total modified van der Heijde-Sharpe (vdH-S) score and a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a Anti-TN antibody with light chain (LC) in a clinically proven, effective dose with clinically proven safety. Treating patients by administering a composition comprising F antibody via intravenous (IV) infusion and determining the patient's total modified vdH-S score at 52 weeks of this treatment. A composition containing an anti-TNF antibody in an amount that has been clinically proven to be safe and clinically proven to be effective. These patients treated with the compound showed a significant improvement in disease activity in PsA (DAPSA) from remission to Patients identified as having low disease activity, moderate disease activity on DAPSA Patients identified as having PsA activity, inactive on the PsA activity score (PASDAS) Patients identified as having active disease activity, those with moderate disease activity in the PASDAS Patients identified as having minimal disease activity (MDA) patients identified as having no MDA, patients with very low disease activity (VLD) A) patients identified as having VLDA, patients identified as not having VLDA, Patients identified as having remission on the CDAI and CD patients identified as having low disease activity on an AI Baseline total modified van der Heijde-Sharpe (vdH-S) score in patients Achieved a significant mean change from baseline in total modified vdH-S score These significant mean changes were particularly pronounced in patients with remission to low disease activity on the DAPSA. vdH-S in patients with pulmonary embolism was -0.88±2.3 (SD), and in patients with pulmonary embolism, ... 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), intermediate in PASDAS vdH-S = -0.20 ± 1 in patients identified as having high disease activity. 965(SD), vdH-S=-1.1 in patients identified as having MDA 6 ± 2.46 (SD), vdH-S in patients identified as not having MDA = 0.03 ± 2.44 (SD), vdH in patients identified as having VLDA -S = -1.49 ± 2.22 (SD) in patients identified as not having VLDA vdH-S = -0.30 ± 2.52 (SD) for those with remission in CDAI. vdH-S = -1.06 ± 2.41 (SD) in patients identified by vdH-S=-0.81 in patients identified as having low disease activity in ±2.12 (SD), wherein the anti-TNF antibody is selected from the group consisting of Administered at a dose of 2 mg / kg on the first and fourth weeks, then every 8 weeks (q8w) thereafter. These patients are adults aged 18 years or older.

[0061] In certain embodiments, the present invention provides a method for treating a TNF-associated condition in a patient. The method further comprises administering to the patient a TNF-associated condition, the TNF-associated condition being active psoriatic arthritis, prior to treating the patient. Determining the patient's total modified van der Heijde-Sharpe (vdH-S) score and a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a Anti-TN antibody with light chain (LC) in a clinically proven, effective dose with clinically proven safety. Treating patients by administering a composition comprising F antibody via intravenous (IV) infusion and determining the patient's total modified vdH-S score at 52 weeks of this treatment. A composition containing an anti-TNF antibody in an amount that has been clinically proven to be safe and clinically proven to be effective. These patients treated with the compound showed a significant improvement in disease activity in PsA (DAPSA) from remission to Patients identified as having low disease activity, moderate disease activity on DAPSA Patients identified as having PsA activity, inactive on the PsA activity score (PASDAS) Patients identified as having active disease activity, those with moderate disease activity in the PASDAS Patients identified as having minimal disease activity (MDA) patients identified as having no MDA, patients with very low disease activity (VLD) A) patients identified as having VLDA, patients identified as not having VLDA, Patients identified as having remission on the CDAI and CD patients identified as having low disease activity on an AI Baseline total modified van der Heijde-Sharpe (vdH-S) score in patients Achieved a significant mean change from baseline in total modified vdH-S score These significant mean changes were particularly pronounced in patients with remission to low disease activity on the DAPSA. vdH-S in patients with pulmonary embolism was -0.88±2.3 (SD), and in patients with pulmonary embolism, ... 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), intermediate in PASDAS vdH-S = -0.20 ± 1 in patients identified as having high disease activity. 965(SD), vdH-S=-1.1 in patients identified as having MDA 6 ± 2.46 (SD), vdH-S in patients identified as not having MDA = 0.03 ± 2.44 (SD), vdH in patients identified as having VLDA -S = -1.49 ± 2.22 (SD) in patients identified as not having VLDA vdH-S = -0.30 ± 2.52 (SD) for those with remission in CDAI. vdH-S = -1.06 ± 2.41 (SD) in patients identified by vdH-S=-0.81 in patients identified as having low disease activity in ±2.12 (SD), and the antibody is selected from the group consisting of to be administered at a dose of 2 mg / kg on week 14, then every 8 weeks (q8w) thereafter The method further comprises administering the anti-TNF composition in combination with methotrexate (MTX) or MTX. Further including administration without TX.

[0062] In certain embodiments, the present invention provides a method for treating a TNF-associated condition in a patient. The method further comprises administering to the patient a TNF-associated condition, the TNF-associated condition being active psoriatic arthritis, prior to treating the patient. Determining the patient's total modified van der Heijde-Sharpe (vdH-S) score and a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a Anti-TN antibody with light chain (LC) in a clinically proven, effective dose with clinically proven safety. Treating patients by administering a composition comprising F antibody via intravenous (IV) infusion and determining the patient's total modified vdH-S score at 52 weeks of this treatment. A composition containing an anti-TNF antibody in an amount that has been clinically proven to be safe and clinically proven to be effective. These patients treated with the compound showed a significant improvement in disease activity in PsA (DAPSA) from remission to Patients identified as having low disease activity, moderate disease activity on DAPSA Patients identified as having PsA activity, inactive on the PsA activity score (PASDAS) Patients identified as having active disease activity, those with moderate disease activity in the PASDAS Patients identified as having minimal disease activity (MDA) patients identified as having no MDA, patients with very low disease activity (VLD) A) patients identified as having VLDA, patients identified as not having VLDA, Patients identified as having remission on the CDAI and CD patients identified as having low disease activity on an AI Baseline total modified van der Heijde-Sharpe (vdH-S) score in patients Achieved a significant mean change from baseline in total modified vdH-S score These significant mean changes were particularly pronounced in patients with remission to low disease activity on the DAPSA. vdH-S in patients with pulmonary embolism was -0.88±2.3 (SD), and in patients with pulmonary embolism, ... 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), intermediate in PASDAS vdH-S = -0.20 ± 1 in patients identified as having high disease activity. 965(SD), vdH-S=-1.1 in patients identified as having MDA 6 ± 2.46 (SD), vdH-S in patients identified as not having MDA = 0.03 ± 2.44 (SD), vdH in patients identified as having VLDA -S = -1.49 ± 2.22 (SD) in patients identified as not having VLDA vdH-S = -0.30 ± 2.52 (SD) for those with remission in CDAI. vdH-S = -1.06 ± 2.41 (SD) in patients identified by vdH-S=-0.81 in patients identified as having low disease activity in ±2.12 (SD), wherein the anti-TNF antibody is selected from the group consisting of Administered at a dose of 2 mg / kg on the first and fourth weeks, then every 8 weeks (q8w) thereafter. and the method includes administering a detectable antibody before, simultaneously with, or after this administration. Labels or reporters, TNF antagonists, antirheumatic drugs, muscle relaxants, narcotics, nonsteroidal anti-inflammatory drugs Anti-inflammatory drugs (NSAIDs), analgesics, anesthetics, sedatives, local anesthetics, neuromuscular blockers, antibacterial agents, Antipsoriatic agents, corticosteroids, anabolic steroids, erythropoietin, vaccinations , immunoglobulins, immunosuppressants, growth hormones, hormone replacement drugs drugs), radiopharmaceuticals, antidepressants, antipsychotics, stimulants, asthma medications, beta-agonists, inhaled steroids at least one of the following: steroids, epinephrine or similar drugs, cytokines or cytokine antagonists at least one compound or protein selected from the group consisting of: The method further comprises administering one composition to a subject.

[0063] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. A small number of studies have been conducted to determine if a drug is safe and effective for use in a clinically proven treatment. At least one isolated mammalian anti-TNF antibody is provided, and at least one isolated The mammalian anti-TNF antibody comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a The therapeutic comprises at least one isolated light chain (LC) comprising a 37 amino acid sequence. and administering to the patient by IV infusion a mammalian anti-TNF composition containing the compound. At week 1, patients treated with anti-TNF antibodies had a significantly lower disease activity in PsA (DAPSA) Patients identified as having remission to low disease activity, intermediate DAPSA scores Patients identified as having active disease, based on the PsA Activity Score (PASDAS) Patients identified as having inactive disease activity in the PASDAS Patients identified as having 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, identified as having remission on the Clinical Disease Activity Index (CDAI); and patients identified as having low disease activity on the CDAI. The baseline total modified van der Heijde-Sharpe (vdH-S) score in selected patients have a significant mean change from baseline.

[0064] In certain embodiments, the present invention provides a method for the treatment of psoriatic arthritis, the safety of which is clinically demonstrated in patients with active psoriatic arthritis. at least one isolated compound for use in a therapeutic treatment that has been experimentally proven and clinically proven to be effective and providing at least one isolated mammalian anti-TNF antibody. The antibody comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a HC comprising the amino acid sequence of SEQ ID NO: 37. and the treatment comprises at least one isolated mammalian anti-TNF receptor. The patient received an anti-TNF antibody by IV infusion at week 52 of this treatment. Patients treated with steroids showed a decline in disease activity in PsA (DAPSA) from remission to low disease activity. Patients identified as having moderate disease activity on DAPSA Patients identified as having inactive disease activity according to 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 with very low disease activity (VLDA) Patients identified as having VLDA, patients identified as not having VLDA, and clinical disease activity Patients identified as having remission in the Clinical and Clinical Assessment Index (CDAI) and those in the In patients selected from the group consisting of patients identified as having low disease activity The total modified van der Heijde-Sharpe (vdH-S) score from baseline Significant mean change from baseline in total modified vdH-S score Mean change is defined as patients who are in remission to have low disease activity on DAPSA. vdH-S = -0.88 ± 2.3 (SD) in the 24-month follow-up period, and moderate disease activity in the 24-month follow-up period. vdH-S = -0.48 ± 1.82 (SD) in patients identified as having hyperactivity ), 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 a ), vdH-S=-1.16±2.46 in patients identified as having MDA (SD), vdH-S = 0.03 ± 2 in patients identified as not having MDA .44 (SD), vdH-S=-1 in patients identified as having VLDA. 49 ± 2.22 (SD), vdH- in patients identified as not having VLDA S = -0.30 ± 2.52 (SD), identified as having remission on CDAI vdH-S in patients = -1.06 ± 2.41 (SD), and CDAI was low. vdH-S = -0.81 ± 2.12 ( SD).

[0065] In certain embodiments, the present invention provides a method for the treatment of psoriatic arthritis, the safety of which is clinically demonstrated in patients with active psoriatic arthritis. at least one isolated compound for use in a therapeutic treatment that has been experimentally proven and clinically proven to be effective and providing at least one isolated mammalian anti-TNF antibody. A heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and an amino acid sequence of SEQ ID NO: 37 and the treatment comprises at least one isolated mammalian anti-TNF antibody. The treatment involves administering the compound to the patient via IV infusion, and at 52 weeks of this treatment, the patient is treated with an anti-TNF antibody. Treated patients achieved remission to low disease activity in PsA (DAPSA) Patients identified as having moderate disease activity on DAPSA Patients identified as having inactive disease activity according to 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 DA, those with very low disease activity (VLDA) patients identified as having VLDA, patients identified as not having VLDA, patients with clinical disease activity index Patients identified as having remission on the CDAI and those with low CDAI The overall number of patients selected from the group consisting of patients identified as having low disease activity Significant improvement in the overall modified van der Heijde-Sharpe (vdH-S) score from baseline Mean change from baseline in total modified vdH-S score. The progression was observed in patients identified as having remission to low disease activity on the DAPSA. vdH-S = -0.88 ± 2.3 (SD), and DAPSA showed moderate disease activity. vdH-S = -0.48 ± 1.82 (SD) in patients identified as having vd in patients identified as having inactive disease activity in PASDAS HS=-1.01±2.384(SD), PASDAS showed moderate disease activity vdH-S = -0.20 ± 1.965 (SD) in patients identified as having vdH-S = -1.16 ± 2.46 (S D) vdH-S = 0.03 ± 2.4 in patients identified as not having MDA 4 (SD), vdH-S = -1.49 in patients identified as having VLDA ±2.22 (SD), vdH-S in patients identified as not having VLDA = -0.30 ± 2.52 (SD), patients identified as having remission in CDAI vdH-S = -1.06 ± 2.41 (SD) in the 2016-2017 study, and low disease activity in the CDAI. vdH-S = -0.81 ± 2.12 (SD) in patients identified as having hyperactivity ), wherein at least one isolated mammalian anti-TNF antibody is selected from the group consisting of: Administered at a dose of 2 mg / kg on the first and fourth weeks, then every 8 weeks (q8w) thereafter. do.

[0066] In certain embodiments, the present invention provides a method for the treatment of psoriatic arthritis, the safety of which is clinically demonstrated in patients with active psoriatic arthritis. at least one isolated compound for use in a therapeutic treatment that has been experimentally proven and clinically proven to be effective and providing at least one isolated mammalian anti-TNF antibody. A heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and an amino acid sequence of SEQ ID NO: 37 and the treatment comprises at least one isolated mammalian anti-TNF antibody. and administering to the patient by IV infusion an anti-TNF composition, wherein at 52 weeks of treatment, Patients treated with the antibody showed a significant improvement in disease activity in PsA (DAPSA) from remission to low disease activity. Patients identified as having active disease, with moderate disease activity on DAPSA Patients identified as having inactive disease according to the PsA Activity Score (PASDAS) Patients identified as having active disease, those with moderate disease activity in PASDAS Patients identified as having minimal disease activity (MDA) patients identified as having very low disease activity (VLDA), those without MDA, and those with very low disease activity (VLDA). Patients identified as having VLDA, patients identified as not having VLDA, and patients with clinical disease activity Patients identified as having remission in the Clinical Dynamics Index (CDAI) and those with In a patient selected from the group consisting of patients identified as having low disease activity in Total modified van der Heijde-Sharpe (vdH-S) score from baseline with a significant mean change from baseline in the total modified vdH-S score The mean change was the number of patients identified as having remission to low disease activity on the DAPSA. vdH-S = -0.88 ± 2.3 (SD) in patients with moderate disease in DAPSA vdH-S = -0.48 ± 1.82 (S D) In ​​patients identified as having inactive disease activity in PASDAS vdH-S = -1.01 ± 2.384 (SD), and moderate disease activity in PASDAS. vdH-S = -0.20 ± 1.965 (S D) vdH-S = -1.16 ± 2.4 in patients identified as having MDA 6 (SD), vdH-S = 0.03 ± 0.05 in patients identified as not having MDA 2.44 (SD), vdH-S = -1 in patients identified as having VLDA 0.49 ± 2.22 (SD), vdH in patients identified as not having VLDA -S = -0.30 ± 2.52 (SD), identified as having remission in CDAI vdH-S = -1.06 ± 2.41 (SD) in patients with schizophrenia, and low CDAI vdH-S = -0.81 ± 2.12 in patients identified as having active disease (SD), wherein at least one isolated mammalian anti-TNF antibody is selected from the group consisting of: , at a dose of 2 mg / kg at weeks 0 and 4, then every 8 weeks (q8w) thereafter. and the at least one isolated mammalian anti-TNF antibody is administered for a period of 30±10 minutes. It is administered over a period of time.

[0067] In certain embodiments, the present invention provides a method for the treatment of psoriatic arthritis, the safety of which is clinically demonstrated in patients with active psoriatic arthritis. at least one isolated compound for use in a therapeutic treatment that has been experimentally proven and clinically proven to be effective and providing at least one isolated mammalian anti-TNF antibody. The composition 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: 37. and a light chain (LC) comprising the sequence, and the treatment comprises at least one isolated mammalian anti-T and administering to the patient an IV infusion of an NF antibody composition, and at 52 weeks of this treatment, Patients treated with TNF antibodies showed a significant improvement in disease activity in PsA (DAPSA) from remission to low. Patients identified as having low disease activity, moderate disease activity on DAPSA Patients identified as having PsA activity score (PASDAS) inactive Patients identified as having active disease, moderate disease activity on PASDAS Patients identified as having minimal disease activity (MDA) patients identified as having no MDA, patients with very low disease activity (VLDA) ), patients identified as not having VLDA, clinical Patients identified as having remission on the Disease Activity Index (CDAI) and CDA patients selected from the group consisting of patients identified as having low disease activity in I Baseline total modified van der Heijde-Sharpe (vdH-S) score in subjects with a significant mean change from baseline in total modified vdH-S score Significant mean changes were identified as those with remission to low disease activity on the DAPSA. vdH-S = -0.88 ± 2.3 (SD) in patients with vasoconstriction, and moderate in DAPSA vdH-S=-0.48±1.8 in patients identified as having disease activity of 2(SD), patients identified as having inactive disease activity in PASDAS vdH-S=-1.01±2.384(SD) in the 2010 study, and moderate in the PASDAS study. vdH-S = -0.20 ± 1.96 in patients identified as having active disease 5 (SD), vdH-S = −1.16 ± 5 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 in patients identified as having VLDA = -1.49 ± 2.22 (SD) in patients identified as not having VLDA vdH-S=-0.30±2.52(SD), which was particularly significant for those with remission in CDAI. vdH-S = -1.06 ± 2.41 (SD) in patients with pulmonary embolism, and vdH-S = -0.81 ± 2 in patients identified as having low disease activity .12(SD) and at least one isolated mammalian anti-TNF The antibody was administered at a dose of 2 mg / kg at weeks 0 and 4, then every 8 weeks (q8w) thereafter. The dose is administered in an amount suitable for the treatment of adult patients aged 18 years or older.

[0068] In certain embodiments, the present invention provides a method for the treatment of psoriatic arthritis, the safety of which is clinically demonstrated in patients with active psoriatic arthritis. at least one isolated compound for use in a therapeutic treatment that has been experimentally proven and clinically proven to be effective and providing at least one isolated mammalian anti-TNF antibody. The composition 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: 37. and a light chain (LC) comprising the sequence, and the treatment comprises at least one isolated mammalian anti-T The study included administering an anti-TNF antibody to patients via IV infusion, and at week 52 of this treatment, Patients treated with the antibody showed a significant improvement in disease activity in PsA (DAPSA) from remission to low disease activity. Patients identified as having active disease, with moderate disease activity on DAPSA Patients identified as having inactive disease according to the PsA Activity Score (PASDAS) Patients identified as having active disease, those with moderate disease activity in PASDAS Patients identified as having minimal disease activity (MDA) patients identified as having very low disease activity (VLDA), those without MDA, and those with very low disease activity (VLDA). Patients identified as having VLDA, patients identified as not having VLDA, and patients with clinical disease activity Patients identified as having remission in the Clinical Dynamics Index (CDAI) and those with In a patient selected from the group consisting of patients identified as having low disease activity in Total modified van der Heijde-Sharpe (vdH-S) score from baseline with a significant mean change from baseline in the total modified vdH-S score The mean change was the number of patients identified as having remission to low disease activity on the DAPSA. vdH-S = -0.88 ± 2.3 (SD) in patients with moderate disease in DAPSA vdH-S = -0.48 ± 1.82 (S D) In ​​patients identified as having inactive disease activity in PASDAS vdH-S = -1.01 ± 2.384 (SD), and moderate disease activity in PASDAS. vdH-S = -0.20 ± 1.965 (S D) vdH-S = -1.16 ± 2.4 in patients identified as having MDA 6 (SD), vdH-S = 0.03 ± 0.05 in patients identified as not having MDA 2.44 (SD), vdH-S = -1 in patients identified as having VLDA 0.49 ± 2.22 (SD), vdH in patients identified as not having VLDA -S = -0.30 ± 2.52 (SD), identified as having remission in CDAI vdH-S = -1.06 ± 2.41 (SD) in patients with schizophrenia, and low CDAI vdH-S = -0.81 ± 2.12 in patients identified as having active disease (SD), wherein at least one isolated mammalian anti-TNF antibody is selected from the group consisting of: , at a dose of 2 mg / kg at weeks 0 and 4, then every 8 weeks (q8w) thereafter. The treatment involves administering this anti-TNF antibody in combination with methotrexate (MTX) or MTX. Further including administration without TX.

[0069] In certain embodiments, the present invention provides a method for treating active psoriatic arthritis in a patient. The method comprises administering a composition comprising an anti-TNF antibody or an antigen-binding fragment thereof to a subject in need of safety testing. to a patient in an amount that has been clinically proven to be effective, The F antibody has 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. The light chain (LC) containing the sequence was included, and the patient was a responder to treatment and was treated with placebo. There was a statistically significant improvement in disease activity by 24 weeks of treatment compared with patients Improvement was identified and maintained or improved through 52 weeks of treatment, and this disease activity was assessed by a health assessment. Health Assessment Questionnaire-Disability Index (HAQ-DI) ) and the mean change from baseline in the 36-item Short-Form Physical Health Scale (Short-Form-36 Phys Mean change from baseline in the SF-36 Physical Component Summary (SF-36 PCS), 36 items Short-Form-36 Mental Component Summary (SF-36 MC) Mean change from baseline in S, Functional Assessment of Chronic Disease Therapy of Chronic Illness Therapy (FACIT) - Mean change from baseline in fatigue, Eu EuroQol-5D visual analog scale (EQ-VAS) ) and baseline change in Dermatological Life Quality Index (DLQI) The response is determined by a response selected from the group consisting of the mean change from baseline.

[0070] In certain embodiments, the present invention provides a method for treating active psoriatic arthritis in a patient. The method comprises administering a composition comprising an anti-TNF antibody or an antigen-binding fragment thereof to a subject in need of safety testing. to a patient in an amount that has been clinically proven to be effective, The F antibody has 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. The light chain (LC) containing the sequence was included, and the patient was a responder to treatment and was treated with placebo. There was a statistically significant improvement in disease activity by 24 weeks of treatment compared with patients Improvement was identified and maintained or improved through 52 weeks of treatment, with disease activity measured through 24 weeks of treatment. This statistically significant improvement in sexuality was due to HAQ-DI = -0.63 ± 0.5 standard deviations ( Mean change from baseline in standard deviation (SD) of the SF-36 PCS Mean change from baseline in SF-36 MCS = 5.4 ± 8.1 SD Mean change from baseline in 0.3 ± 10.2 SD, FACIT-Fatigue = 9.2 Mean change from baseline in ±9.8 SD, EQ-VAS=20.2±24. Mean change from baseline in 2 SD, and DLQI = -8.1 ± 7.7 SD The mean change from baseline in

[0071] In certain embodiments, the present invention provides a method for treating active psoriatic arthritis in a patient. The method comprises administering a composition comprising an anti-TNF antibody or an antigen-binding fragment thereof to a subject in need of safety testing. to a patient in an amount that has been clinically proven to be effective, The F antibody has 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. The light chain (LC) containing the sequence was included, and the patient was a responder to treatment and was treated with placebo. There was a statistically significant improvement in disease activity by 24 weeks of treatment compared with patients Improvement was identified and maintained or improved through 52 weeks of treatment, and this disease activity was assessed by a health assessment. Mean change from baseline in the HAQ-DI, a 36-item short form Mean change from baseline in physical health status (SF-36 PCS), 36-item short form Mean change from baseline in mental health status (SF-36 MCS), as a function of chronic disease therapy Fatigue Assessment (FACIT)-mean change from baseline, EuroQol-5D visual assessment Mean change from baseline in the EQ-VAS analog scale and the dermatological quality of life index The response was determined by a group consisting of the mean change from baseline in the DLQI (Diagnosis and Life-Long Scale). The composition is designed to administer the anti-TNF antibody or antigen-binding fragment thereof at weeks 0 and 4, Then every 8 weeks (q8w) thereafter at a dose of 2 mg / kg IV It is administered by injection.

[0072] In certain embodiments, the present invention provides a method for treating active psoriatic arthritis in a patient. The method comprises administering a composition comprising an anti-TNF antibody or an antigen-binding fragment thereof to a subject in need of safety testing. to a patient in an amount that has been clinically proven to be effective, The F antibody has 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. The patient is a responder to treatment and has a placebo-treated light chain (LC) containing the sequence There was a statistically significant improvement in disease activity by 24 weeks of treatment compared with patients who were not treated with and the improvement is maintained or improved through 52 weeks of treatment, and this disease activity is Mean change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI), 36 items Mean change from baseline in the Short Form Physical Health Scale (SF-36 PCS), 36 items Mean change from baseline in the Short Form Mental Health Scale (SF-36 MCS), chronic disease treatment Functional Assessment of Intracranial Tract (FACIT)-Mean Change from Baseline in Fatigue, EuroQol-5 Mean change from baseline in the EQ-VAS visual analog scale (EQ-VAS) and dermatological biomarkers The response was selected from the group consisting of the mean change from baseline in the DLQI. The composition is determined by the above, and the anti-TNF antibody or antigen-binding fragment thereof is It is to be administered at a dose of 2 mg / kg in the fourth week and then every eight weeks (q8w) thereafter. via IV infusion, the composition being administered over a period of 30±10 minutes. .

[0073] In certain embodiments, the present invention provides a method for treating active psoriatic arthritis in a patient. The method comprises administering a composition comprising an anti-TNF antibody or an antigen-binding fragment thereof to a subject in need of safety testing. to a patient in an amount that has been clinically proven to be effective, The F antibody has 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. The light chain (LC) containing the sequence was included, and the patient was a responder to treatment and was treated with placebo. There was a statistically significant improvement in disease activity by 24 weeks of treatment compared with patients Improvement was identified and maintained or improved through 52 weeks of treatment, and this disease activity was assessed by a health assessment. Mean change from baseline in the HAQ-DI, a 36-item short form Mean change from baseline in physical health status (SF-36 PCS), 36-item short form Mean change from baseline in mental health status (SF-36 MCS), as a function of chronic disease therapy Fatigue Assessment (FACIT)-mean change from baseline, EuroQol-5D visual assessment Mean change from baseline in the EQ-VAS analog scale and the dermatological quality of life index The response was determined by a group consisting of the mean change from baseline in the DLQI (Diagnosis and Life-Long Scale). The composition is designed to administer the anti-TNF antibody or antigen-binding fragment thereof at weeks 0 and 4, Then every 8 weeks (q8w) thereafter at a dose of 2 mg / kg IV It is administered by infusion and these patients are adults aged 18 years or older.

[0074] In certain embodiments, the present invention provides a method for treating active psoriatic arthritis in a patient. The method comprises administering a composition comprising an anti-TNF antibody or an antigen-binding fragment thereof to a subject in need of safety testing. to a patient in an amount that has been clinically proven to be effective, The F antibody has 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. The light chain (LC) containing the sequence was included, and the patient was a responder to treatment and was treated with placebo. There was a statistically significant improvement in disease activity by 24 weeks of treatment compared with patients Improvement was identified and maintained or improved through 52 weeks of treatment, and this disease activity was assessed by a health assessment. Mean change from baseline in the HAQ-DI, a 36-item short form Mean change from baseline in physical health status (SF-36 PCS), 36-item short form Mean change from baseline in mental health status (SF-36 MCS), as a function of chronic disease therapy Fatigue Assessment (FACIT)-mean change from baseline, EuroQol-5D visual assessment Mean change from baseline in the EQ-VAS analog scale and the dermatological quality of life index The response was determined by a group consisting of the mean change from baseline in the DLQI (Diagnosis and Life-Long Scale). The composition is designed to administer the anti-TNF antibody or antigen-binding fragment thereof at weeks 0 and 4, Then every 8 weeks (q8w) thereafter at a dose of 2 mg / kg IV Infusion of the compound is administered by injection, and the compound is administered in combination with methotrexate (MTX) or Including administering without X.

[0075] In certain embodiments, the present invention provides a method for treating active psoriatic arthritis in a patient. The method comprises administering a composition comprising an anti-TNF antibody or an antigen-binding fragment thereof to a subject in need of safety testing. to a patient in an amount that has been clinically proven to be effective, The F antibody has 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. The light chain (LC) containing the sequence was included, and the patient was a responder to treatment and was treated with placebo. There was a statistically significant improvement in disease activity by 24 weeks of treatment compared with patients Improvement was identified and maintained or improved through 52 weeks of treatment, and this disease activity was assessed by a health assessment. Mean change from baseline in the HAQ-DI, a 36-item short form Mean change from baseline in physical health status (SF-36 PCS), 36-item short form Mean change from baseline in mental health status (SF-36 MCS), as a function of chronic disease therapy Fatigue Assessment (FACIT)-mean change from baseline, EuroQol-5D visual assessment Mean change from baseline in the EQ-VAS analog scale and the dermatological quality of life index The response was determined by a group consisting of the mean change from baseline in the DLQI (Diagnosis and Life-Long Scale). The composition is designed to administer the anti-TNF antibody or antigen-binding fragment thereof at weeks 0 and 4, Then every 8 weeks (q8w) thereafter at a dose of 2 mg / kg IV The method may involve administering a detectable label or label before, simultaneously with, or after administration. Portas, TNF antagonists, antirheumatic drugs, muscle relaxants, narcotics, nonsteroidal anti-inflammatory drugs (NS AIDs), analgesics, anesthetics, sedatives, local anesthetics, neuromuscular blockers, antibacterial agents, antipsoriatic agents, Corticosteroids, anabolic steroids, erythropoietin, vaccinations, immunoglobulins Brine, immunosuppressants, growth hormones, hormone replacement drugs, radiopharmaceuticals, antidepressants, antipsychotics Anti-inflammatory drugs, stimulants, asthma medications, beta-agonists, inhaled steroids, epinephrine or similar drugs, cytokines an effective amount of at least one of a steroid hormone or a cytokine antagonist; and administering at least one composition containing another compound or protein. nothing.

[0076] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The present invention provides a composition for use in the method of the present invention, the method comprising administering to a subject an anti-TNF antibody or antigen-binding fragment thereof. to a patient in an amount that has been clinically proven to be safe and clinically proven to be effective. the anti-TNF antibody comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and the patient is a responder to treatment and the patient comprises a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37. , a statistically significant decrease in disease activity by 24 weeks of treatment compared with placebo-treated patients was identified as having a significant improvement, which was maintained or improved through 52 weeks of treatment. Disease activity was measured as the mean change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI). mean change from baseline in the 36-item Short Form Physical Health Scale (SF-36 PCS) mean change from baseline in the 36-item Short Form Mental Health Scale (SF-36 MCS) Functional Assessment of Chronic Illness Therapy (FACIT)-Mean Change from Baseline in Fatigue, Eu Mean change from baseline in the EQol-5D visual analog scale (EQ-VAS), and and mean change from baseline in Dermatological Life Quality Index (DLQI). This is determined by the response chosen.

[0077] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The present invention provides a composition for use in the method of the present invention, the method comprising administering to a subject an anti-TNF antibody or antigen-binding fragment thereof. to a patient in an amount that has been clinically proven to be safe and clinically proven to be effective. the anti-TNF antibody comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and the patient is a responder to treatment and the patient comprises a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37. , a statistically significant decrease in disease activity by 24 weeks of treatment compared with placebo-treated patients were identified as having significant improvements, and the improvements were maintained or improved through 52 weeks of treatment. This statistically significant improvement in disease activity by 24 weeks was associated with a HAQ-DI of -0. Mean change from baseline in SF-36 PC score was 63 ± 0.5 standard deviations (SD). Mean change from baseline in SF-36 MCS = 9.4 ± 8.1 SD Mean change from baseline in 5.3 ± 10.2 SD, FACIT fatigue score = 9. Mean change from baseline in 2 ± 9.8 SD, EQ-VAS = 20.2 ± 24 Mean change from baseline in 0.2 SD, and DLQI = -8.1 ± 7.7 S The mean change from baseline in D is selected from the group consisting of:

[0078] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The present invention provides a composition for use in the method of the present invention, the method comprising administering to a subject an anti-TNF antibody or antigen-binding fragment thereof. to a patient in an amount that has been clinically proven to be safe and clinically proven to be effective. the anti-TNF antibody comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and the patient is a responder to treatment and the patient comprises a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37. , a statistically significant decrease in disease activity by 24 weeks of treatment compared with placebo-treated patients was identified as having a significant improvement, which was maintained or improved through 52 weeks of treatment. Disease activity was measured as the mean change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI). mean change from baseline in the 36-item Short Form Physical Health Scale (SF-36 PCS) mean change from baseline in the 36-item Short Form Mental Health Scale (SF-36 MCS) Functional Assessment of Chronic Illness Therapy (FACIT)-Mean Change from Baseline in Fatigue, Eu Mean change from baseline in the EQol-5D visual analog scale (EQ-VAS), and and mean change from baseline in Dermatological Life Quality Index (DLQI). The composition comprises the anti-TNF antibody or antigen-binding fragment thereof, and the response is determined by the response selected. at a dose of 2 mg / kg at weeks 0 and 4, then every 8 weeks (q8w) thereafter. It is administered by IV infusion, as in

[0079] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The present invention provides a composition for use in the method of the present invention, the method comprising administering to a subject an anti-TNF antibody or antigen-binding fragment thereof. to a patient in an amount that has been clinically proven to be safe and clinically proven to be effective. the anti-TNF antibody comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and the patient is a responder to treatment and the patient comprises a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37. , a statistically significant decrease in disease activity by 24 weeks of treatment compared with placebo-treated patients was identified as having a significant improvement, which was maintained or improved through 52 weeks of treatment. Disease activity was measured as the mean change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI). mean change from baseline in the 36-item Short Form Physical Health Scale (SF-36 PCS) mean change from baseline in the 36-item Short Form Mental Health Scale (SF-36 MCS) Functional Assessment of Chronic Illness Therapy (FACIT)-Mean Change from Baseline in Fatigue, Eu Mean change from baseline in the EQol-5D visual analog scale (EQ-VAS), and and mean change from baseline in Dermatological Life Quality Index (DLQI). The composition comprises the anti-TNF antibody or antigen-binding fragment thereof, and the response is determined by the response selected. at a dose of 2 mg / kg at weeks 0 and 4, then every 8 weeks (q8w) thereafter. The composition is administered by IV infusion over a period of 30±10 minutes. It is administered as follows.

[0080] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The present invention provides a composition for use in the method of the present invention, the method comprising administering to a subject an anti-TNF antibody or antigen-binding fragment thereof. to a patient in an amount that has been clinically proven to be safe and clinically proven to be effective. the anti-TNF antibody comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and the patient is a responder to treatment and the patient comprises a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37. , a statistically significant decrease in disease activity by 24 weeks of treatment compared with placebo-treated patients was identified as having a significant improvement, which was maintained or improved through 52 weeks of treatment. Disease activity was measured as the mean change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI). mean change from baseline in the 36-item Short Form Physical Health Scale (SF-36 PCS) mean change from baseline in the 36-item Short Form Mental Health Scale (SF-36 MCS) Functional Assessment of Chronic Illness Therapy (FACIT)-Mean Change from Baseline in Fatigue, Eu Mean change from baseline in the EQol-5D visual analog scale (EQ-VAS), and and mean change from baseline in Dermatological Life Quality Index (DLQI). The composition comprises the anti-TNF antibody or antigen-binding fragment thereof, and the response is determined by the response selected. at a dose of 2 mg / kg at weeks 0 and 4, then every 8 weeks (q8w) thereafter. It is administered by IV infusion as directed, and these patients are adult patients aged 18 years or older. be.

[0081] In certain embodiments, the present invention provides a method for treating patients with active psoriatic arthritis. The present invention provides a composition for use in the method of the present invention, the method comprising administering to a subject an anti-TNF antibody or antigen-binding fragment thereof. to a patient in an amount that has been clinically proven to be safe and clinically proven to be effective. the anti-TNF antibody comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and the patient is a responder to treatment and the patient comprises a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 37. , a statistically significant decrease in disease activity by 24 weeks of treatment compared with placebo-treated patients was identified as having a significant improvement, which was maintained or improved through 52 weeks of treatment. Disease activity was measured as the mean change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI). mean change from baseline in the 36-item Short Form Physical Health Scale (SF-36 PCS) mean change from baseline in the 36-item Short Form Mental Health Scale (SF-36 MCS) Functional Assessment of Chronic Illness Therapy (FACIT)-Mean Change from Baseline in Fatigue, Eu Mean change from baseline in the EQol-5D visual analog scale (EQ-VAS), and and mean change from baseline in Dermatological Life Quality Index (DLQI). The composition comprises the anti-TNF antibody or antigen-binding fragment thereof, and the response is determined by the response selected. at a dose of 2 mg / kg at weeks 0 and 4, then every 8 weeks (q8w) thereafter. The composition is administered by IV infusion as described above, and further comprises methotrexate (M This includes administering vasopressin with or without MTX.

[0082] In certain embodiments, the present invention provides a method for treating active psoriatic arthritis in a patient. The method comprises administering an anti-TNF antibody or an antigen-binding fragment thereof to a subject whose safety has been clinically proven. The anti-TNF antibody is administered to a patient in an amount that has been identified and clinically proven to be effective, A heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a light chain comprising the amino acid sequence of SEQ ID NO: 37 The patients were responders to treatment compared with placebo-treated patients. were identified as having a statistically significant improvement in disease activity by 24 weeks of treatment, Improvement was maintained or improved through 52 weeks of treatment, and this disease activity was measured using the Health Assessment Questionnaire-Disability Score. The mean change from baseline in the HAQ-DI index, the 36-item short form physical health index ( Mean change from baseline in SF-36 PCS, 36-item short form mental health score ( mean change from baseline in SF-36 MCS, Functional Assessment of Chronic Illness Therapy (FAC) IT)-mean change from baseline in fatigue, EuroQol-5D visual analogue scale ( Mean change from baseline in EQ-VAS and Dermatological Life Quality Index (DLQI) The response is determined by a response selected from the group consisting of the mean change from baseline in

[0083] In certain embodiments, the present invention provides a method for treating active psoriatic arthritis in a patient. The method comprises administering an anti-TNF antibody or an antigen-binding fragment thereof to a subject whose safety has been clinically proven. The anti-TNF antibody is administered to a patient in an amount that has been identified and clinically proven to be effective, A heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a light chain comprising the amino acid sequence of SEQ ID NO: 37 The patients were responders to treatment compared with placebo-treated patients. were identified as having a statistically significant improvement in disease activity by 24 weeks of treatment, Improvement was maintained or improved through 52 weeks of treatment, with no significant improvement in disease activity through 24 weeks of treatment. A statistically significant improvement in HAQ-DI was observed in the HAQ-DI = -0.63 ± 0.5 standard deviations (SD). mean change from baseline in SF-36 PCS = 9.4 ± 8.1 SD Mean change from baseline in SF-36 MCS = 5.3 ± 10.2 SD Mean change from baseline in FACIT fatigue score = 9.2 ± 9.8 SD Mean change from baseline in EQ-VAS = 20.2 ± 24.2 SD mean change from baseline in DLQI = -8.1 ± 7.7 SD is selected from the group consisting of

[0084] In certain embodiments, the present invention provides a method for treating active psoriatic arthritis in a patient. The method comprises administering an anti-TNF antibody or an antigen-binding fragment thereof to a subject whose safety has been clinically proven. The anti-TNF antibody is administered to a patient in an amount that has been identified and clinically proven to be effective, A heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a light chain comprising the amino acid sequence of SEQ ID NO: 37 The patients were responders to treatment compared with placebo-treated patients. were identified as having a statistically significant improvement in disease activity by 24 weeks of treatment, Improvement was maintained or improved through 52 weeks of treatment, and this disease activity was measured using the Health Assessment Questionnaire-Disability Score. The mean change from baseline in the HAQ-DI index, the 36-item short form physical health index ( Mean change from baseline in SF-36 PCS, 36-item short form mental health score ( mean change from baseline in SF-36 MCS, Functional Assessment of Chronic Illness Therapy (FAC) IT)-mean change from baseline in fatigue, EuroQol-5D visual analogue scale ( Mean change from baseline in EQ-VAS and Dermatological Life Quality Index (DLQI) ) determined by a response selected from the group consisting of the mean change from baseline in Anti-TNF antibody or antigen-binding fragment thereof is administered at weeks 0 and 4, then every 8 weeks thereafter ( q8w) at a dose of 2 mg / kg administered by IV infusion.

[0085] In certain embodiments, the present invention provides a method for treating active psoriatic arthritis in a patient. The method comprises administering a composition comprising an anti-TNF antibody or an antigen-binding fragment thereof to a subject in need of safety testing. to a patient in an amount that has been clinically proven to be effective, The F antibody has 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. The light chain (LC) containing the sequence was included, and the patient was a responder to treatment and was treated with placebo. There was a statistically significant improvement in disease activity by 24 weeks of treatment compared with patients Improvement was identified and maintained or improved through 52 weeks of treatment, and this disease activity was assessed by a health assessment. Mean change from baseline in the HAQ-DI, a 36-item short form Mean change from baseline in physical health status (SF-36 PCS), 36-item short form Mean change from baseline in mental health status (SF-36 MCS), as a function of chronic disease therapy Fatigue Assessment (FACIT)-mean change from baseline, EuroQol-5D visual assessment Mean change from baseline in the EQ-VAS analog scale and the dermatological quality of life index The response was determined by a group consisting of the mean change from baseline in the DLQI (Diagnosis and Life-Long Scale). The anti-TNF antibody or antigen-binding fragment thereof is administered at week 0 and week 4, and then thereafter. administered by IV infusion at a dose of 2 mg / kg every 8 weeks (q8w) and the anti-TNF antibody is administered over a period of 30±10 minutes.

[0086] In certain embodiments, the present invention provides a method for treating active psoriatic arthritis in a patient. The method comprises administering a composition comprising an anti-TNF antibody or an antigen-binding fragment thereof to a subject in need of safety testing. to a patient in an amount that has been clinically proven to be effective, The F antibody has 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. The patient is a responder to treatment and has a placebo-treated light chain (LC) containing the sequence There was a statistically significant improvement in disease activity by 24 weeks of treatment compared with patients who were not treated with and the improvement is maintained or improved through 52 weeks of treatment, and this disease activity is Mean change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI), 36 items Mean change from baseline in the Short Form Physical Health Scale (SF-36 PCS), 36 items Mean change from baseline in the Short Form Mental Health Scale (SF-36 MCS), chronic disease treatment Functional Assessment of Intracranial Tract (FACIT)-Mean Change from Baseline in Fatigue, EuroQol-5 Mean change from baseline in the EQ-VAS visual analog scale (EQ-VAS) and dermatological biomarkers The response was selected from the group consisting of the mean change from baseline in the DLQI. The anti-TNF antibody or antigen-binding fragment thereof was administered at week 0 and week 4, and then Thereafter, the dose will be increased by IV infusion to 2 mg / kg every 8 weeks (q8w). These patients are adult patients aged 18 years or older.

[0087] In certain embodiments, the present invention provides a method for treating active psoriatic arthritis in a patient. The method comprises administering a composition comprising an anti-TNF antibody or an antigen-binding fragment thereof to a subject in need of safety testing. to a patient in an amount that has been clinically proven to be effective, The F antibody has 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. The light chain (LC) containing the sequence was included, and the patient was a responder to treatment and was treated with placebo. There was a statistically significant improvement in disease activity by 24 weeks of treatment compared with patients Improvement was identified and maintained or improved through 52 weeks of treatment, and this disease activity was assessed by a health assessment. Mean change from baseline in the HAQ-DI, a 36-item short form Mean change from baseline in physical health status (SF-36 PCS), 36-item short form Mean change from baseline in mental health status (SF-36 MCS), as a function of chronic disease therapy Fatigue Assessment (FACIT)-mean change from baseline, EuroQol-5D visual assessment Mean change from baseline in the EQ-VAS analog scale and the dermatological quality of life index The response was determined by a group consisting of the mean change from baseline in the DLQI (Diagnosis and Life-Long Scale). The anti-TNF antibody or antigen-binding fragment thereof is administered at week 0 and week 4, and then thereafter. administered by IV infusion at a dose of 2 mg / kg every 8 weeks (q8w) Furthermore, this anti-TNF antibody was administered with or without methotrexate (MTX). This includes administering.

[0088] In certain embodiments, the present invention provides a method for treating active psoriatic arthritis in a patient. The method comprises administering an anti-TNF antibody or an antigen-binding fragment thereof to a subject whose safety has been clinically proven. The anti-TNF antibody is administered to a patient in an amount that has been identified and clinically proven to be effective, A heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a light chain comprising the amino acid sequence of SEQ ID NO: 37 The patients were responders to treatment compared with placebo-treated patients. were identified as having a statistically significant improvement in disease activity by 24 weeks of treatment, Improvement was maintained or improved through 52 weeks of treatment, and this disease activity was measured using the Health Assessment Questionnaire-Disability Score. The mean change from baseline in the HAQ-DI index, the 36-item short form physical health index ( Mean change from baseline in SF-36 PCS, 36-item short form mental health score ( mean change from baseline in SF-36 MCS, Functional Assessment of Chronic Illness Therapy (FAC) IT)-mean change from baseline in fatigue, EuroQol-5D visual analogue scale ( Mean change from baseline in EQ-VAS and Dermatological Life Quality Index (DLQI) ) determined by a response selected from the group consisting of the mean change from baseline in Anti-TNF antibody or antigen-binding fragment thereof is administered at weeks 0 and 4, then every 8 weeks thereafter ( q8w) at a dose of 2 mg / kg by IV infusion, The present invention relates to a method for treating a tumor, comprising administering to a subject a detectable label or reporter, a TNF antagonist, an anti-inflammatory drug, or a combination thereof, before, during, or after administration of the present invention. Arthritis medications, muscle relaxants, anesthetics, nonsteroidal anti-inflammatory drugs (NSAIDs), painkillers, narcotics, Sedatives, local anesthetics, neuromuscular blockers, antibacterials, antipsoriatics, corticosteroids, anabolic steroids steroids, erythropoietin, vaccinations, immunoglobulins, immunosuppressants, growth hormone Drugs, hormone replacement drugs, radiopharmaceuticals, antidepressants, antipsychotics, stimulants, asthma medications, beta-agonists Antidote, inhaled steroids, epinephrine or similar drugs, cytokines or cytokine antagonists an effective amount of at least one compound or protein selected from at least one of The method further comprises administering at least one composition comprising a compound.

[0089] In certain embodiments, the present invention provides a method for treating active psoriatic arthritis in a patient. The method comprises administering a composition comprising an anti-TNF antibody or an antigen-binding fragment thereof to a subject in need of safety testing. to a patient in an amount that has been clinically proven to be effective, The F antibody has 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. The light chain (LC) containing the sequence was included, and the patient was a responder to treatment and was treated with placebo. There was a statistically significant improvement in disease activity by 24 weeks of treatment compared with patients Improvement was identified and maintained or improved through approximately 52 weeks of treatment, and this disease activity was assessed by health assessment. Mean change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI), 36-item short form Mean change from baseline in physical health status (SF-36 PCS), 36-item short form Mean change from baseline in mental health status (SF-36 MCS), effect of chronic disease therapy Mean change from baseline in FACIT-fatigue, EuroQol-5D visual acuity Mean change from baseline in analogue scale (EQ-VAS) and dermatological quality of life by a response selected from the group consisting of mean change from baseline in the DLQI index It is decided.

[0090] In certain embodiments, the present invention provides a method for treating active psoriatic arthritis in a patient. The method comprises administering a composition comprising an anti-TNF antibody or an antigen-binding fragment thereof to a subject in need of safety testing. to a patient in an amount that has been clinically proven to be effective, The F antibody has 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. The light chain (LC) containing the sequence was included, and the patient was a responder to treatment and was treated with placebo. There was a statistically significant improvement in disease activity by 24 weeks of treatment compared with patients Improvement was identified and maintained or improved through 52 weeks of treatment, and this disease activity was assessed by a health assessment. Mean change from baseline in the HAQ-DI, a 36-item short form Mean change from baseline in physical health status (SF-36 PCS), 36-item short form Mean change from baseline in mental health status (SF-36 MCS), as a function of chronic disease therapy Fatigue Assessment (FACIT)-mean change from baseline, EuroQol-5D visual assessment Mean change from baseline in the EQ-VAS analog scale and the dermatological quality of life index The response was determined by one or more of the following measures: mean change from baseline in the DLQI (Diagnosis and Life-Long Scale). It is determined.

[0091] In certain embodiments, the present invention provides a method for treating active psoriatic arthritis in a patient. The method comprises administering a composition comprising an anti-TNF antibody or an antigen-binding fragment thereof to a subject in need of safety testing. to a patient in an amount that has been clinically proven to be effective, The F antibody has 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. The patient is a responder to treatment and has a placebo-treated light chain (LC) containing the sequence There was a statistically significant improvement in disease activity by 24 weeks of treatment compared with patients who were not treated with and the improvement is maintained or improved through 52 weeks of treatment, and this disease activity is Mean change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI), 36 items Mean change from baseline in the Short Form Physical Health Scale (SF-36 PCS), 36 items Mean change from baseline in the Short Form Mental Health Scale (SF-36 MCS), chronic disease treatment Functional Assessment of Intracranial Tract (FACIT)-Mean Change from Baseline in Fatigue, EuroQol-5 Mean change from baseline in the EQ-VAS visual analog scale (EQ-VAS) and dermatological biomarkers Mean change from baseline in the DLQI, or one of its equivalents Determined by responses containing two or more.

[0092] In certain embodiments, the present invention provides a method for treating active psoriatic arthritis in a patient. The method provides a method for administering TNF to a subject having clinically proven safety and clinically proven efficacy. the anti-TNF antibody comprises administering to the patient a composition comprising a means for contacting the patient with an amount of the anti-TNF antibody a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a light chain (LC) and patients were responders to treatment compared with placebo-treated patients were identified as having a statistically significant improvement in disease activity by 24 weeks of treatment. The improvement was maintained or improved through 52 weeks of treatment, and this disease activity was measured using the Health Assessment Questionnaire-Disability Scale. Mean change from baseline in the Harm Index (HAQ-DI), a 36-item short-form physical health index Mean change from baseline in the SF-36 PCS, 36-item short form mental health scale mean change from baseline in the SF-36 MCS (Functional Assessment of Chronic Illness Therapy (FA) CIT)-Mean change from baseline in fatigue, EuroQol-5D visual analogue scale Mean change from baseline in the EQ-VAS (Equation-Response Scale), and the Dermatological Life Quality Index (DLQ) I) the mean change from baseline in the response to the serotonin receptor agonist (SPR) or the serotonin receptor agonist (SPR).

[0093] In certain embodiments, the present invention provides a method for treating active psoriatic arthritis in a patient. The method provides a method for administering TNF to a subject having clinically proven safety and clinically proven efficacy. administering to a patient a pharmaceutical composition comprising a means for contacting the patient with an anti-TNF antibody. A heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and an amino acid sequence of SEQ ID NO: 37 The patients were treated with placebo and were compared to placebo-treated patients. identified as having a statistically significant improvement in disease activity by 24 weeks of treatment compared with The improvement was maintained or improved up to approximately 52 weeks of treatment, and this disease activity was measured using a health assessment questionnaire. Mean change from baseline in the 36-item short form of the Physical Assessment Questionnaire-Disability Index (HAQ-DI) Mean change from baseline in health status (SF-36 PCS), 36-item short form mental Mean change from baseline in health status (SF-36 MCS), functional assessment of chronic disease therapy (FACIT)-mean change from baseline in fatigue, EuroQol-5D visual analogue The mean change from baseline in the EQ-VAS and the Dermatological Quality of Life Index ( The response was determined by a group consisting of the mean change from baseline in the DLQI (Diabetes Mellitus Quality Index) and the mean change from baseline in the DLQI (Diabetes Mellitus Quality Index). can be.

[0094] In certain embodiments, the present invention provides a method for treating a TNF-associated condition in a patient. The present invention provides a method for treating a TNF-associated condition, the TNF-associated condition being active psoriatic arthritis, the method comprising: a.) treating a patient; Determine the patient's total modified van der Heijde-Sharpe (vdH-S) score prior to b.) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and an amino acid sequence of SEQ ID NO: 37 It has a light chain (LC) containing the 2-amino acid sequence, and its safety has been clinically proven. A composition comprising an amount of an anti-TNF antibody, or an antigen-binding fragment thereof, is administered by intravenous (IV) infusion. and c.) treating patients by administering the same to a patient at approximately week 52 of this treatment. and determining the total modified vdH-S score, and the safety of anti-TNF antibodies in clinical trials. These patients treated with a clinically proven and effective amount of the composition have Ps Patients with remission to low disease activity on the Disease Activity in Patients with Advanced Perforation Score (DAPSA) were identified as those with remission to low disease activity. patients identified as having moderate disease activity on DAPSA; Patients identified as having inactive disease activity on the PASDAS patients identified as having moderate disease activity in PASDAS; Patients identified as having minimal disease activity (MDA) and those without MDA Patients identified as having very low disease activity (VLDA), Patients identified as not having VLDA, in the Clinical Disease Activity Index (CDAI) Patients identified as having remission and those with low disease activity on the CDAI Total modified vdH-S score in patients selected from the group consisting of patients identified as Achieve a significant mean change from baseline in serotonin.

[0095] In certain embodiments, the present invention provides a method for treating a TNF-associated condition in a patient. The present invention provides a method for treating a TNF-associated condition, the TNF-associated condition being active psoriatic arthritis, the method comprising: a.) treating a patient; Determine the patient's total modified van der Heijde-Sharpe (vdH-S) score prior to b.) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and an amino acid sequence of SEQ ID NO: 37 It has a light chain (LC) containing the 2-amino acid sequence, and its safety has been clinically proven. A composition comprising an amount of an anti-TNF antibody, or an antigen-binding fragment thereof, is administered by intravenous (IV) infusion. and c.) at week 52 of this treatment, the patient's total and determining a modified vdH-S score for the anti-TNF antibody. These patients treated with a clinically proven amount of the composition demonstrated to be effective in reducing PsA identified as having remission to low disease activity on the Disease Activity Assessment of Patients (DAPSA) Patients with one or more of the following disease types, characterized as having moderate disease activity on DAPSA: Patients with inactive disease activity according to 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 having no disease, very low disease activity (VLDA) Patients identified as having VLDA, patients identified as not having VLDA, and patients with clinical disease activity index (C Patients identified as having remission on the DAI and low disease on the CDAI Total modified vdH in patients with one identified as active - Achieve a significant mean change from baseline in S score.

[0096] In certain embodiments, the present invention provides a method for treating a TNF-associated condition in a patient. The present invention provides a method for treating a TNF-associated condition, the TNF-associated condition being active psoriatic arthritis, the method comprising: a.) treating a patient; Determine the patient's total modified van der Heijde-Sharpe (vdH-S) score prior to b.) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and an amino acid sequence of SEQ ID NO: 37 It has a light chain (LC) containing the 2-amino acid sequence, and its safety has been clinically proven. A composition comprising an amount of an anti-TNF antibody, or an antigen-binding fragment thereof, is administered by intravenous (IV) infusion. and c.) at week 52 of this treatment, the patient's total and determining a modified vdH-S score for the anti-TNF antibody. These patients treated with a clinically proven amount of the composition demonstrated to be effective in reducing PsA identified as having remission to low disease activity on the Disease Activity Assessment of Patients (DAPSA) Patients with one or more of the following disease types, characterized as having moderate disease activity on DAPSA: Patients with inactive disease activity according to 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 having no disease, very low disease activity (VLDA) Patients identified as having VLDA, patients identified as not having VLDA, and patients with clinical disease activity index (C Patients identified as having remission on the DAI and low disease on the CDAI Patients identified as having active disease or one of the following: Achieve a significant mean change from baseline in the total modified vdH-S score.

[0097] In certain embodiments, the present invention provides a method for treating a TNF-associated condition in a patient. The present invention provides a method for treating a TNF-associated condition, the TNF-associated condition being active psoriatic arthritis, the method comprising: a.) treating a patient; Determine the patient's total modified van der Heijde-Sharpe (vdH-S) score prior to and b.) TNF-α in amounts clinically proven to be safe and clinically proven to be effective. by administering by intravenous (IV) infusion a composition comprising a means for contacting the and c.) improving the patient's total modified vdH-S score at week 52 of this treatment. and determining a dose that has been clinically proven to be safe and clinically proven to be effective. These patients treated with a composition comprising a means for contacting TNF-α, Patients with remission to low disease activity on the Disease Activity in Patients with Advanced Perforation Score (DAPSA) were identified as those with remission to low disease activity. patients identified as having moderate disease activity on DAPSA; Patients identified as having inactive disease activity on the PASDAS patients identified as having moderate disease activity in PASDAS; Patients identified as having minimal disease activity (MDA) and those without MDA Patients identified as having very low disease activity (VLDA), Patients identified as not having VLDA, in the Clinical Disease Activity Index (CDAI) Patients identified as having remission and those with low disease activity on the CDAI Total modified vdH-S score in patients selected from the group consisting of patients identified as Achieve a significant mean change from baseline in serotonin.

[0098] In certain embodiments, the present invention provides a method for treating a TNF-associated condition in a patient. The present invention provides a method for treating a TNF-associated condition, the TNF-associated condition being active psoriatic arthritis, the method comprising: a.) treating a patient; Determine the patient's total modified van der Heijde-Sharpe (vdH-S) score prior to and b.) TNF-α in amounts clinically proven to be safe and clinically proven to be effective. by administering a pharmaceutical composition comprising a means for contacting the and c.) treating the patient with a total modified vdH- and determining an S score, and These patients were treated with a composition comprising a means for contacting TNF in an amount , as those with remission to low disease activity in PsA disease activity (DAPSA) Patients identified as having moderate disease activity on DAPSA and those with inactive disease activity according to the PsA Activity Score (PASDAS). Patients identified as having moderate disease activity in PASDAS patients, those identified as having minimal disease activity (MDA), and those without MDA Patients identified as having very low disease activity (VLDA) Patients, those identified as not having VLDA, and those with a Clinical Disease Activity Index (CDAI) Patients identified as having remission on the CDAI and those with low disease activity on the CDAI total modified vdH- in a patient selected from the group consisting of patients identified as Achieve a significant mean change from baseline in S score. [Brief explanation of the drawings]

[0099] [Figure 1] A graphical representation of the assay of the ability of TNV mAbs in hybridoma cell supernatants to inhibit TNFα binding to recombinant TNF receptors is shown. Various amounts of hybridoma cell supernatant containing known amounts of TNV mAb were preincubated with a fixed concentration (5 ng / ml) of 125I-labeled TNFα. The mixture was transferred to a 96-well Optiplate precoated with the recombinant TNF receptor / IgG fusion protein p55-sf2. The amount of TNFα bound to the p55 receptor in the presence of mAb was determined after washing away unbound material and counting using a gamma counter. Eight TNV ​​mAb samples were tested in these experiments; however, for brevity, three of the mAbs shown by DNA sequence analysis to be identical to one of the other TNV mAbs are not shown here. Each sample was tested in duplicate. Results shown are representative of two independent experiments. [Figure 2A]The DNA sequence of the TNV mAb heavy chain variable region is shown. The germline gene shown is the DP-46 gene. "TNVs" indicates that the sequence shown is that of TNV14, TNV15, TNV148, and TNV196. The first three nucleotides of the TNV sequence define the translation initiation Met codon. A dotted line in the TNV mAb gene sequence indicates that the nucleotide is the same as in the germline sequence. The first 19 nucleotides (underlined) of the TNV sequence correspond to the oligonucleotides used to PCR amplify the variable region. The amino acid translation (single-letter code) beginning with the mature mAb is shown only for the germline gene. The three CDR domains in the germline amino acid translation are shown in bold and underlined. The line labeled TNV148(B) indicates that the sequence shown is for both TNV148 and TNV148B. Gaps in the germline DNA sequence (CDR3) result from sequences that were unknown at the time or not present in the germline gene. The TNV mAb heavy chain uses the J6 binding region. [Figure 2B] The DNA sequence of the TNV mAb heavy chain variable region is shown. The germline gene shown is the DP-46 gene. "TNVs" indicates that the sequence shown is that of TNV14, TNV15, TNV148, and TNV196. The first three nucleotides of the TNV sequence define the translation initiation Met codon. A dotted line in the TNV mAb gene sequence indicates that the nucleotide is the same as in the germline sequence. The first 19 nucleotides (underlined) of the TNV sequence correspond to the oligonucleotides used to PCR amplify the variable region. The amino acid translation (single-letter code) beginning with the mature mAb is shown only for the germline gene. The three CDR domains in the germline amino acid translation are shown in bold and underlined. The line labeled TNV148(B) indicates that the sequence shown is for both TNV148 and TNV148B. Gaps in the germline DNA sequence (CDR3) result from sequences that were unknown at the time or not present in the germline gene. The TNV mAb heavy chain uses the J6 binding region. [Figure 3]The DNA sequence of the TNV mAb light chain variable region is shown. The germline gene shown is a representative member of the Vg / 38K family of human kappa germline variable region genes. Dotted lines in the TNV mAb gene sequence indicate nucleotides that are identical to those in the germline sequence. The first 16 nucleotides (underlined) of the TNV sequence correspond to the oligonucleotides used to PCR amplify the variable region. The amino acid translation (single-letter code) of the mature mAb is shown for the germline gene only. The three CDR domains in the germline amino acid translation are shown in bold and underlined. The line labeled TNV148(B) indicates that the sequence shown is for both TNV148 and TNV148B. Gaps in the germline DNA sequence (CDR3) are due to sequences that are unknown or not present in the germline gene. The TNV mAb light chain uses the J3 joining region. [Figure 4] The deduced amino acid sequences of the TNV mAb heavy chain variable regions are shown. The amino acid sequences (single-letter code) shown were deduced from DNA sequences determined from both uncloned and cloned PCR products. The amino acid sequences are divided into secretory signal sequence (signal), framework (FW), and complementarity-determining region (CDR) domains. The amino acid sequence of the DP-46 germline gene is shown in the line above each domain. Dotted lines indicate that the amino acid in the TNV mAb is identical to the germline gene. TNV148(B) indicates that the sequence shown relates to both TNV148 and TNV148B. "TNV" indicates that the sequence shown relates to all TNV mAbs unless a different sequence is indicated. A dashed line in the germline sequence (CDR3) indicates that the sequence is unknown or not present in the germline gene. [Figure 5]The deduced amino acid sequence of the TNV mAb light chain variable region is shown. The amino acid sequence (single-letter code) shown was deduced from DNA sequences determined from both uncloned and cloned PCR products. The amino acid sequence is divided into the secretory signal sequence (signal), framework (FW), and complementarity-determining region (CDR) domains. The amino acid sequence of the Vg / 38K-type light chain germline gene is shown in the line above each domain. Dotted lines indicate that the amino acid in the TNV mAb is identical to the germline gene. TNV148(B) indicates that the sequence shown relates to both TNV148 and TNV148B. "All" indicates that the sequence shown relates to TNV14, TNV15, TNV148, TNV148B, and TNV186. [Figure 6] Figure 1 shows a schematic diagram of the heavy and light chain expression plasmids used to generate rTNV148B-expressing C466 cells. p1783 is the heavy chain plasmid, and p1776 is the light chain plasmid. The rTNV148B variable and constant region coding domains are indicated by black boxes. The immunoglobulin enhancer in the JC intron is indicated by a gray box. Relevant restriction sites are indicated. The plasmids are shown oriented so that transcription of the Ab gene proceeds clockwise. Plasmid p1783 is 19.53 kb in length, and plasmid p1776 is 15.06 kb in length. The complete nucleotide sequences of both plasmids are known. The variable region coding sequence of p1783 can be easily replaced with alternative heavy chain variable region sequences by replacing the BsiWI / BstBI restriction fragment. The variable region coding sequence of p1776 can be replaced with alternative variable region sequences by replacing the SalI / AflII restriction fragment. [Figure 7]A graphical representation of the growth curve analysis of five rTNV148B-producing cell lines is shown. Cultures were initiated on day 0 by seeding cells in I5Q+MHX medium in T75 flasks to a viable cell density of 1.0 x 10 cells / ml in a volume of 30 ml. The cell cultures used in these studies were continuous cultures due to the transfection and subcloning procedures. Cells in the T-flasks were then thoroughly resuspended, and 0.3 ml aliquots of the culture were removed. Growth curve studies were terminated when the cell count dropped below 1.5 x 10 cells / ml. The number of viable cells in the aliquots was determined by trypan blue exclusion, and the remaining aliquot was saved for later mAb concentration determination. A human IgG ELISA was performed on all sample aliquots at the same time. [Figure 8] A graphical representation of a comparison of cell growth rates in the presence of various MHX selection concentrations is shown. Cell subclones C466A and C466B were thawed into MHX-free medium (IMDM, 5% FBS, 2 mM glutamine) and cultured for an additional two days. Both cell cultures were then split into three cultures containing either no MHX, 0.2x MHX, or 1x MHX. One day later, new T75 flasks were seeded with the cultures at a starting density of 1x10 cells / ml, and cells were counted at 24-hour intervals for one week. The doubling time for the first five days was calculated using the formula in SOP PD32.025 and is shown above the bars. [Figure 9] A graphical representation of the stability of mAb production over time from two rTNV148B-producing cell lines is shown. After transfection and subcloning, subclones of cells from the continuous culture were used to initiate long-term continuous culture in 24-well culture dishes. Cells were cultured in I5Q medium with or without MHX selection. Cells were serially passaged by splitting the culture every 4–6 days to maintain new viable cultures while simultaneously exhausting the previous cultures. Aliquots of exhausted cell supernatants were collected immediately after the cultures were exhausted and stored until the mAb concentrations were determined. ELISA for human IgG was performed on all sample aliquots at the same time. [Figure 10]Figure 1 shows the weight change of Tg197 arthritis mouse model mice in response to an anti-TNF antibody of the present invention compared to the control in Example 4. Approximately 4-week-old Tg197 research mice were assigned to one of nine treatment groups based on sex and weight and treated with a single intraperitoneal bolus of Dulbecco's PBS (D-PBS) or an anti-TNF antibody of the present invention (TNV14, TNV148, or TNV196) at either 1 mg / kg or 10 mg / kg. When body weight was analyzed as the change from pre-treatment, animals treated with 10 mg / kg cA2 consistently showed higher weight gain than animals treated with D-PBS throughout the study. This weight gain was significant from weeks 3 to 7. Animals treated with 10 mg / kg TNV148 also achieved significant weight gain by week 7 of the study. [Figure 11A] The progression of disease severity based on the arthritis index shown in Example 4 is shown. The arthritis index for the 10 mg / kg cA2 treatment group was lower than that of the D-PBS control group starting at week 3 and continuing throughout the remainder of the study (week 7). Animals treated with 1 mg / kg TNV14 and 1 mg / kg cA2 failed to demonstrate a significant decrease in AI after week 3 when compared to the D-PBS treatment group. When each was compared with others at similar doses (10 mg / kg cA2 compared to 10 mg / kg TNV14, 148, and 196), there were no significant differences between the 10 mg / kg treatment groups. When comparing the 1 mg / kg treatment groups, 1 mg / kg TNV148 demonstrated significantly lower AIs than 1 mg / kg cA2 at weeks 3, 4, and 7. 1 mg / kg TNV148 was also significantly lower than the 1 mg / kg TNV14 treatment group at weeks 3 and 4. While TNV196 showed a significant reduction in AI by week 6 of the study (when compared to the D-PBS-treated group), TNV148 was the only 1 mg / kg treatment group that remained significant at the end of the study. [Figure 11B]The progression of disease severity based on the arthritis index shown in Example 4 is shown. The arthritis index for the 10 mg / kg cA2 treatment group was lower than that of the D-PBS control group starting at week 3 and continuing throughout the remainder of the study (week 7). Animals treated with 1 mg / kg TNV14 and 1 mg / kg cA2 failed to demonstrate a significant decrease in AI after week 3 when compared to the D-PBS treatment group. When each was compared with others at similar doses (10 mg / kg cA2 compared to 10 mg / kg TNV14, 148, and 196), there were no significant differences between the 10 mg / kg treatment groups. When comparing the 1 mg / kg treatment groups, 1 mg / kg TNV148 demonstrated significantly lower AIs than 1 mg / kg cA2 at weeks 3, 4, and 7. 1 mg / kg TNV148 was also significantly lower than the 1 mg / kg TNV14 treatment group at weeks 3 and 4. While TNV196 showed a significant reduction in AI by week 6 of the study (when compared to the D-PBS-treated group), TNV148 was the only 1 mg / kg treatment group that remained significant at the end of the study. [Figure 11C] The progression of disease severity based on the arthritis index shown in Example 4 is shown. The arthritis index for the 10 mg / kg cA2 treatment group was lower than that of the D-PBS control group starting at week 3 and continuing throughout the remainder of the study (week 7). Animals treated with 1 mg / kg TNV14 and 1 mg / kg cA2 failed to demonstrate a significant decrease in AI after week 3 when compared to the D-PBS treatment group. When each was compared with others at similar doses (10 mg / kg cA2 compared to 10 mg / kg TNV14, 148, and 196), there were no significant differences between the 10 mg / kg treatment groups. When comparing the 1 mg / kg treatment groups, 1 mg / kg TNV148 demonstrated significantly lower AIs than 1 mg / kg cA2 at weeks 3, 4, and 7. 1 mg / kg TNV148 was also significantly lower than the 1 mg / kg TNV14 treatment group at weeks 3 and 4. While TNV196 showed a significant reduction in AI by week 6 of the study (when compared to the D-PBS-treated group), TNV148 was the only 1 mg / kg treatment group that remained significant at the end of the study. [Figure 12]Figure 1 shows the weight change of Tg197, an arthritic mouse model, in response to an anti-TNF antibody of the present invention compared to the control in Example 5. Approximately 4-week-old Tg197 research mice were assigned to one of eight treatment groups based on body weight and treated with an intraperitoneal bolus of either a control article (D-PBS) or 3 mg / kg of antibody (TNV14, TNV148) (week 0). Injections were repeated in all animals at weeks 1, 2, 3, and 4. Groups 1-6 were evaluated for efficacy of the test article. Serum samples obtained from animals in groups 7 and 8 were evaluated for immune response induction and pharmacokinetic clearance of TNV14 or TNV148 at weeks 2, 3, and 4. [Figure 13A] 1 is a graph depicting the progression of disease severity based on the arthritic index in Example 5. The arthritic index for the group treated with 10 mg / kg cA2 was significantly lower than the D-PBS control group, beginning at week 2 and continuing throughout the remainder of the study (week 5). Animals treated with 1 mg / kg or 3 mg / kg cA2 and animals treated with 3 mg / kg TNV14 failed to achieve any significant reduction in AI at any time point throughout the study when compared to the d-PBS control group. Animals treated with 3 mg / kg TNV148 showed a significant reduction starting at week 3 and continuing through week 5 when compared to the d-PBS-treated group. Animals treated with 10 mg / kg cA2 showed a significant reduction in AI when compared to both lower doses of cA2 (1 mg / kg and 3 mg / kg) at weeks 4 and 5 of the study, and were also significantly lower than animals treated with TNV14 at weeks 3-5. Although there appeared to be no significant differences between any of the 3 mg / kg treatment groups, the AI ​​for animals treated with 3 mg / kg TNV14 was significantly higher than 10 mg / kg at some time points, whereas animals treated with TNV148 were not significantly different from animals treated with 10 mg / kg cA2. [Figure 13B]1 is a graph depicting the progression of disease severity based on the arthritic index in Example 5. The arthritic index for the group treated with 10 mg / kg cA2 was significantly lower than the D-PBS control group, beginning at week 2 and continuing throughout the remainder of the study (week 5). Animals treated with 1 mg / kg or 3 mg / kg cA2 and animals treated with 3 mg / kg TNV14 failed to achieve any significant reduction in AI at any time point throughout the study when compared to the d-PBS control group. Animals treated with 3 mg / kg TNV148 showed a significant reduction starting at week 3 and continuing through week 5 when compared to the d-PBS-treated group. Animals treated with 10 mg / kg cA2 showed a significant reduction in AI when compared to both lower doses of cA2 (1 mg / kg and 3 mg / kg) at weeks 4 and 5 of the study, and were also significantly lower than animals treated with TNV14 at weeks 3-5. Although there appeared to be no significant differences between any of the 3 mg / kg treatment groups, the AI ​​for animals treated with 3 mg / kg TNV14 was significantly higher than 10 mg / kg at some time points, whereas animals treated with TNV148 were not significantly different from animals treated with 10 mg / kg cA2. [Figure 13C]1 is a graph depicting the progression of disease severity based on the arthritic index in Example 5. The arthritic index for the group treated with 10 mg / kg cA2 was significantly lower than the D-PBS control group, beginning at week 2 and continuing throughout the remainder of the study (week 5). Animals treated with 1 mg / kg or 3 mg / kg cA2 and animals treated with 3 mg / kg TNV14 failed to achieve any significant reduction in AI at any time point throughout the study when compared to the d-PBS control group. Animals treated with 3 mg / kg TNV148 showed a significant reduction starting at week 3 and continuing through week 5 when compared to the d-PBS-treated group. Animals treated with 10 mg / kg cA2 showed a significant reduction in AI when compared to both lower doses of cA2 (1 mg / kg and 3 mg / kg) at weeks 4 and 5 of the study, and were also significantly lower than animals treated with TNV14 at weeks 3-5. Although there appeared to be no significant differences between any of the 3 mg / kg treatment groups, the AI ​​for animals treated with 3 mg / kg TNV14 was significantly higher than 10 mg / kg at some time points, whereas animals treated with TNV148 were not significantly different from animals treated with 10 mg / kg cA2. [Figure 14] Figure 1 shows the weight change of Tg197 arthritis mouse model mice in response to anti-TNF antibodies of the present invention compared to the control in Example 6. Approximately 4-week-old Tg197 study mice were assigned to one of six treatment groups based on sex and weight and treated with a single intraperitoneal bolus of either 3 mg / kg or 5 mg / kg of antibody (cA2 or TNV148). The study utilized D-PBS and a 10 mg / kg cA2 control group. [Figure 15]The progression of disease severity based on the arthritis index shown in Example 6 is shown. All treatment groups showed some protection at early time points, with 5 mg / kg cA2 and 5 mg / kg TNV148 showing significant reductions in AI at weeks 1-3, and all treatment groups showing significant reductions at week 2. Later in the experiment, animals treated with 5 mg / kg cA2 showed some protection, with significant reductions at weeks 4, 6, and 7. Both low-dose (3 mg / kg) cA2 and TNV148 showed significant reductions at week 6, and all treatment groups showed significant reductions at week 7. None of the treatment groups were able to maintain significant reductions at the end of the study (week 8). There were no significant differences between any of the treatment groups (except the saline control group) at any time point. [Figure 16] Figure 1 shows the weight change of Tg197, an arthritic mouse model, in response to an anti-TNF antibody of the present invention, compared to the control in Example 7. To compare the efficacy of a single intraperitoneal administration of TNV148 (derived from hybridoma cells) and rTNV148B (derived from transfected cells), approximately 4-week-old Tg197 research mice were assigned to one of nine treatment groups based on sex and weight and treated with Dulbecco's PBS (D-PBS) or a single intraperitoneal bolus of 1 mg / kg antibody (TNV148, rTNV148B). [Figure 17]Figure 1 depicts the progression of disease severity based on the arthritis index as shown in Example 7. The arthritis index for the 10 mg / kg cA2 treatment group was lower than the D-PBS control group starting at week 4 and continuing throughout the remainder of the study (week 8). Both the TNV148-treated group and the 1 mg / kg cA2-treated group showed a significant reduction in AI at week 4. While a previous study (P-099-017) showed that TNV148 was slightly more effective in reducing the arthritis index after a single 1 mg / kg intraperitoneal bolus, this study showed slightly higher AIs from groups treated with both versions of the TNV antibody. The group treated with 1 mg / kg cA2 (except at week 6) did not have a significant increase when compared with the 10 mg / kg cA2 group, and the group treated with TNV148 was significantly higher at weeks 7 and 8, but there were no significant differences in AI between 1 mg / kg cA2, 1 mg / kg TNV148, and 1 mg / kg TNV148B at any time point in the study. [Figure 18] FIG. 1 shows a diagram of the study design for a trial of intravenously administered Simponi® (golimumab) in subjects with active psoriatic arthritis (PsA). [Figure 19A] The proportion of patients with ≥3% BSA psoriatic skin involvement at baseline who achieved PASI75, PASI90, and PASI100 responses is shown for the overall (Figure 19A), patients who used methotrexate (Figure 19B), and patients who did not use baseline methotrexate (Figure 19C). *p<0.0001, **p=0.0020, ***p=0.0098. P values ​​are based on a Cochran-Mantel-Haenszel test with baseline methotrexate use (yes / no) as the stratification variable for all patients and a chi-square test with baseline methotrexate use (yes / no). (BSA = body surface area, IV = intravenous, n = number of patients, PASI = psoriasis area and severity index.) [Figure 19B]The proportion of patients with ≥3% BSA psoriatic skin involvement at baseline who achieved PASI75, PASI90, and PASI100 responses is shown for the overall (Figure 19A), patients who used methotrexate (Figure 19B), and patients who did not use baseline methotrexate (Figure 19C). *p<0.0001, **p=0.0020, ***p=0.0098. P values ​​are based on a Cochran-Mantel-Haenszel test with baseline methotrexate use (yes / no) as the stratification variable for all patients and a chi-square test with baseline methotrexate use (yes / no). (BSA = body surface area, IV = intravenous, n = number of patients, PASI = psoriasis area and severity index.) [Figure 19C] The proportion of patients with ≥3% BSA psoriatic skin involvement at baseline who achieved PASI75, PASI90, and PASI100 responses is shown for the overall (Figure 19A), patients who used methotrexate (Figure 19B), and patients who did not use baseline methotrexate (Figure 19C). *p<0.0001, **p=0.0020, ***p=0.0098. P values ​​are based on a Cochran-Mantel-Haenszel test with baseline methotrexate use (yes / no) as the stratification variable for all patients and a chi-square test with baseline methotrexate use (yes / no). (BSA = body surface area, IV = intravenous, n = number of patients, PASI = psoriasis area and severity index.) [Figure 20A]Figure 20A shows the mean change from baseline in (Figure 20A) mNAPSIa score and (Figure 20B) DLQIb score overall and in patients with and without baseline methotrexate use, and (Figure 20C) the simultaneous achievement of clinically important improvements from baseline in mNAPSI (≥50% / ≥75% / ≥100%) and DLQI (≥5-point improvement). For Figure 20A, *p<0.0001, **p=0.0006; P values ​​are based on ANCOVA with baseline methotrexate use (yes / no) and mNAPSI score as covariates for all patients, and baseline mNAPSI only with methotrexate use (yes / no). For Figure 20B, *p<0.0001; P values ​​are based on ANOVA with baseline methotrexate use (yes / no) and ANCOVA with methotrexate use (yes / no) as covariates for all patients. In Figure 20C, *p≦0.0002, P value based on the Cochran-Mantel-Haenszel test controlling for baseline methotrexate use (yes / no) for all patients. (amNAPSI was assessed in all randomized patients with mNAPSI >0 at baseline. bDLQI was assessed in all randomized patients with BSA psoriatic skin involvement ≥3% at baseline and a DLQI score >1 at baseline. cAssessed in all randomized patients with BSA psoriatic skin involvement ≥3% and an mNAPSI >0 and a DLQI score >1 at baseline. ANCOVA = analysis of covariance, ANOVA = analysis of variance, BL = baseline, BSA = body surface area, DLQI = Dermatological Life Quality Index, IV = intravenous, mNAPSI = Modified Nail Psoriasis Severity Index, n = number of patients.) [Figure 20B]Figure 20A shows the mean change from baseline in (Figure 20A) mNAPSIa score and (Figure 20B) DLQIb score overall and in patients with and without baseline methotrexate use, and (Figure 20C) the simultaneous achievement of clinically important improvements from baseline in mNAPSI (≥50% / ≥75% / ≥100%) and DLQI (≥5-point improvement). For Figure 20A, *p<0.0001, **p=0.0006; P values ​​are based on ANCOVA with baseline methotrexate use (yes / no) and mNAPSI score as covariates for all patients, and baseline mNAPSI only with methotrexate use (yes / no). For Figure 20B, *p<0.0001; P values ​​are based on ANOVA with baseline methotrexate use (yes / no) and ANCOVA with methotrexate use (yes / no) as covariates for all patients. In Figure 20C, *p≦0.0002, P value based on the Cochran-Mantel-Haenszel test controlling for baseline methotrexate use (yes / no) for all patients. (amNAPSI was assessed in all randomized patients with mNAPSI >0 at baseline. bDLQI was assessed in all randomized patients with BSA psoriatic skin involvement ≥3% at baseline and a DLQI score >1 at baseline. cAssessed in all randomized patients with BSA psoriatic skin involvement ≥3% and an mNAPSI >0 and a DLQI score >1 at baseline. ANCOVA = analysis of covariance, ANOVA = analysis of variance, BL = baseline, BSA = body surface area, DLQI = Dermatological Life Quality Index, IV = intravenous, mNAPSI = Modified Nail Psoriasis Severity Index, n = number of patients.) [Figure 20C]Figure 20A shows the mean change from baseline in (Figure 20A) mNAPSIa score and (Figure 20B) DLQIb score overall and in patients with and without baseline methotrexate use, and (Figure 20C) the simultaneous achievement of clinically important improvements from baseline in mNAPSI (≥50% / ≥75% / ≥100%) and DLQI (≥5-point improvement). For Figure 20A, *p<0.0001, **p=0.0006; P values ​​are based on ANCOVA with baseline methotrexate use (yes / no) and mNAPSI score as covariates for all patients, and baseline mNAPSI only with methotrexate use (yes / no). For Figure 20B, *p<0.0001; P values ​​are based on ANOVA with baseline methotrexate use (yes / no) and ANCOVA with methotrexate use (yes / no) as covariates for all patients. In Figure 20C, *p≦0.0002, P value based on the Cochran-Mantel-Haenszel test controlling for baseline methotrexate use (yes / no) for all patients. (amNAPSI was assessed in all randomized patients with mNAPSI >0 at baseline. bDLQI was assessed in all randomized patients with BSA psoriatic skin involvement ≥3% at baseline and a DLQI score >1 at baseline. cAssessed in all randomized patients with BSA psoriatic skin involvement ≥3% and an mNAPSI >0 and a DLQI score >1 at baseline. ANCOVA = analysis of covariance, ANOVA = analysis of variance, BL = baseline, BSA = body surface area, DLQI = Dermatological Life Quality Index, IV = intravenous, mNAPSI = Modified Nail Psoriasis Severity Index, n = number of patients.) [Figure 21A]The proportion of patients who achieved a PASI50 / 75 / 90 / 100 response and a 5-point or greater improvement in (Figure 21A) DLQI score a, or (Figure 21B) ACR20 response b, is shown. In Figure 21A, *p<0.0001, P value is based on the Cochran-Mantel-Haenszel test controlling for baseline methotrexate use (yes / no) for all patients. In Figure 21B, *p<0.0001, P value is based on the Cochran-Mantel-Haenszel test controlling for baseline methotrexate use (yes / no) for all patients. (a Randomized patients had ≥3% BSA involvement and DLQI score >1 at baseline. b Randomized patients had ≥3% BSA involvement at baseline. ACR20 = 20% improvement on the American College of Rheumatology scale, BSA = body surface area, DLQI = Dermatology Life Quality Index, IV = intravenous, n = number of patients, PASI = Psoriasis Area and Severity Index.) [Figure 21B] The proportion of patients who achieved a PASI50 / 75 / 90 / 100 response and a 5-point or greater improvement in (Figure 21A) DLQI score a, or (Figure 21B) ACR20 response b, is shown. In Figure 21A, *p<0.0001, P value is based on the Cochran-Mantel-Haenszel test controlling for baseline methotrexate use (yes / no) for all patients. In Figure 21B, *p<0.0001, P value is based on the Cochran-Mantel-Haenszel test controlling for baseline methotrexate use (yes / no) for all patients. (a Randomized patients had ≥3% BSA involvement and DLQI score >1 at baseline. b Randomized patients had ≥3% BSA involvement at baseline. ACR20 = 20% improvement on the American College of Rheumatology scale, BSA = body surface area, DLQI = Dermatology Life Quality Index, IV = intravenous, n = number of patients, PASI = Psoriasis Area and Severity Index.) [Figure 22A]The proportions of patients with and without methotrexate use at baseline who achieved a 50% or greater / 75% or greater / 100% improvement in mNAPSI and a 5-point or greater improvement in DLQI score a (Figures 22A-22B), a PASI 50 / 75 / 90 / 100 response and a 5-point or greater improvement in DLQI score b (Figures 22C-22D), or an ACR20 response c (Figures 22E-22F) are shown. In Figure 22A, *p<0.0001, **p=0.0024; P values ​​are based on a chi-square test. In Figure 22B, *p<0.03, **p>0.05; P values ​​are based on a chi-square test. In Figure 22C, *p<0.0001, **p=0.0011; P values ​​are based on a chi-square test. In Figure 22D, *p<0.0001, **p≦0.02, P values ​​are based on chi-squared test. In Figure 22E, *p<0.0001, P values ​​are based on chi-squared test. In Figure 22F, *p<0.0001, **p<0.04, P values ​​are based on chi-squared test. (a Randomized patients had ≥3% BSA involvement, mNAPSI score >0, and DLQI score >1 at baseline. b Randomized patients had ≥3% BSA involvement and DLQI score >1 at baseline. c Randomized patients had ≥3% BSA involvement at baseline. mNAPSI and DLQI are based on imputed data using LOCF for missing data. ACR20 = 20% improvement on the American College of Rheumatology scale, BSA = body surface area, DLQI = Dermatology Quality of Life Index, IV = intravenous, LOCF = last observation carried forward, mNAPSI = modified Nail Psoriasis Severity Index, n = number of patients, PASI = Psoriasis Area and Severity Index.) [Figure 22B]The proportions of patients with and without methotrexate use at baseline who achieved a 50% or greater / 75% or greater / 100% improvement in mNAPSI and a 5-point or greater improvement in DLQI score a (Figures 22A-22B), a PASI 50 / 75 / 90 / 100 response and a 5-point or greater improvement in DLQI score b (Figures 22C-22D), or an ACR20 response c (Figures 22E-22F) are shown. In Figure 22A, *p<0.0001, **p=0.0024; P values ​​are based on a chi-square test. In Figure 22B, *p<0.03, **p>0.05; P values ​​are based on a chi-square test. In Figure 22C, *p<0.0001, **p=0.0011; P values ​​are based on a chi-square test. In Figure 22D, *p<0.0001, **p≦0.02, P values ​​are based on chi-squared test. In Figure 22E, *p<0.0001, P values ​​are based on chi-squared test. In Figure 22F, *p<0.0001, **p<0.04, P values ​​are based on chi-squared test. (a Randomized patients had ≥3% BSA involvement, mNAPSI score >0, and DLQI score >1 at baseline. b Randomized patients had ≥3% BSA involvement and DLQI score >1 at baseline. c Randomized patients had ≥3% BSA involvement at baseline. mNAPSI and DLQI are based on imputed data using LOCF for missing data. ACR20 = 20% improvement on the American College of Rheumatology scale, BSA = body surface area, DLQI = Dermatology Quality of Life Index, IV = intravenous, LOCF = last observation carried forward, mNAPSI = modified Nail Psoriasis Severity Index, n = number of patients, PASI = Psoriasis Area and Severity Index.) [Figure 22C]The proportions of patients with and without methotrexate use at baseline who achieved a 50% or greater / 75% or greater / 100% improvement in mNAPSI and a 5-point or greater improvement in DLQI score a (Figures 22A-22B), a PASI 50 / 75 / 90 / 100 response and a 5-point or greater improvement in DLQI score b (Figures 22C-22D), or an ACR20 response c (Figures 22E-22F) are shown. In Figure 22A, *p<0.0001, **p=0.0024; P values ​​are based on a chi-square test. In Figure 22B, *p<0.03, **p>0.05; P values ​​are based on a chi-square test. In Figure 22C, *p<0.0001, **p=0.0011; P values ​​are based on a chi-square test. In Figure 22D, *p<0.0001, **p≦0.02, P values ​​are based on chi-squared test. In Figure 22E, *p<0.0001, P values ​​are based on chi-squared test. In Figure 22F, *p<0.0001, **p<0.04, P values ​​are based on chi-squared test. (a Randomized patients had ≥3% BSA involvement, mNAPSI score >0, and DLQI score >1 at baseline. b Randomized patients had ≥3% BSA involvement and DLQI score >1 at baseline. c Randomized patients had ≥3% BSA involvement at baseline. mNAPSI and DLQI are based on imputed data using LOCF for missing data. ACR20 = 20% improvement on the American College of Rheumatology scale, BSA = body surface area, DLQI = Dermatology Quality of Life Index, IV = intravenous, LOCF = last observation carried forward, mNAPSI = modified Nail Psoriasis Severity Index, n = number of patients, PASI = Psoriasis Area and Severity Index.) [Figure 22D]The proportions of patients with and without methotrexate use at baseline who achieved a 50% or greater / 75% or greater / 100% improvement in mNAPSI and a 5-point or greater improvement in DLQI score a (Figures 22A-22B), a PASI 50 / 75 / 90 / 100 response and a 5-point or greater improvement in DLQI score b (Figures 22C-22D), or an ACR20 response c (Figures 22E-22F) are shown. In Figure 22A, *p<0.0001, **p=0.0024; P values ​​are based on a chi-square test. In Figure 22B, *p<0.03, **p>0.05; P values ​​are based on a chi-square test. In Figure 22C, *p<0.0001, **p=0.0011; P values ​​are based on a chi-square test. In Figure 22D, *p<0.0001, **p≦0.02, P values ​​are based on chi-squared test. In Figure 22E, *p<0.0001, P values ​​are based on chi-squared test. In Figure 22F, *p<0.0001, **p<0.04, P values ​​are based on chi-squared test. (a Randomized patients had ≥3% BSA involvement, mNAPSI score >0, and DLQI score >1 at baseline. b Randomized patients had ≥3% BSA involvement and DLQI score >1 at baseline. c Randomized patients had ≥3% BSA involvement at baseline. mNAPSI and DLQI are based on imputed data using LOCF for missing data. ACR20 = 20% improvement on the American College of Rheumatology scale, BSA = body surface area, DLQI = Dermatology Quality of Life Index, IV = intravenous, LOCF = last observation carried forward, mNAPSI = modified Nail Psoriasis Severity Index, n = number of patients, PASI = Psoriasis Area and Severity Index.) [Figure 22E]The proportions of patients with and without methotrexate use at baseline who achieved a 50% or greater / 75% or greater / 100% improvement in mNAPSI and a 5-point or greater improvement in DLQI score a (Figures 22A-22B), a PASI 50 / 75 / 90 / 100 response and a 5-point or greater improvement in DLQI score b (Figures 22C-22D), or an ACR20 response c (Figures 22E-22F) are shown. In Figure 22A, *p<0.0001, **p=0.0024; P values ​​are based on a chi-square test. In Figure 22B, *p<0.03, **p>0.05; P values ​​are based on a chi-square test. In Figure 22C, *p<0.0001, **p=0.0011; P values ​​are based on a chi-square test. In Figure 22D, *p<0.0001, **p≦0.02, P values ​​are based on chi-squared test. In Figure 22E, *p<0.0001, P values ​​are based on chi-squared test. In Figure 22F, *p<0.0001, **p<0.04, P values ​​are based on chi-squared test. (a Randomized patients had ≥3% BSA involvement, mNAPSI score >0, and DLQI score >1 at baseline. b Randomized patients had ≥3% BSA involvement and DLQI score >1 at baseline. c Randomized patients had ≥3% BSA involvement at baseline. mNAPSI and DLQI are based on imputed data using LOCF for missing data. ACR20 = 20% improvement on the American College of Rheumatology scale, BSA = body surface area, DLQI = Dermatology Quality of Life Index, IV = intravenous, LOCF = last observation carried forward, mNAPSI = modified Nail Psoriasis Severity Index, n = number of patients, PASI = Psoriasis Area and Severity Index.) [Figure 22F]The proportions of patients with and without methotrexate use at baseline who achieved a 50% or greater / 75% or greater / 100% improvement in mNAPSI and a 5-point or greater improvement in DLQI score a (Figures 22A-22B), a PASI 50 / 75 / 90 / 100 response and a 5-point or greater improvement in DLQI score b (Figures 22C-22D), or an ACR20 response c (Figures 22E-22F) are shown. In Figure 22A, *p<0.0001, **p=0.0024; P values ​​are based on a chi-square test. In Figure 22B, *p<0.03, **p>0.05; P values ​​are based on a chi-square test. In Figure 22C, *p<0.0001, **p=0.0011; P values ​​are based on a chi-square test. In Figure 22D, *p<0.0001, **p≦0.02, P values ​​are based on chi-squared test. In Figure 22E, *p<0.0001, P values ​​are based on chi-squared test. In Figure 22F, *p<0.0001, **p<0.04, P values ​​are based on chi-squared test. (a Randomized patients had ≥3% BSA involvement, mNAPSI score >0, and DLQI score >1 at baseline. b Randomized patients had ≥3% BSA involvement and DLQI score >1 at baseline. c Randomized patients had ≥3% BSA involvement at baseline. mNAPSI and DLQI are based on imputed data using LOCF for missing data. ACR20 = 20% improvement on the American College of Rheumatology scale, BSA = body surface area, DLQI = Dermatology Quality of Life Index, IV = intravenous, LOCF = last observation carried forward, mNAPSI = modified Nail Psoriasis Severity Index, n = number of patients, PASI = Psoriasis Area and Severity Index.) DETAILED DESCRIPTION OF THE INVENTION

[0100] The present invention relates to a heavy chain (HC) comprising SEQ ID NO: 36, a light chain (LC) comprising SEQ ID NO: 37, Compositions comprising anti-TNF antibodies having the formula: Provide Seth.

[0101] As used herein, "anti-tumor necrosis factor alpha antibody," "anti-TNF antibody," "anti-TNF "antibody portion" or "anti-TNF antibody fragment" and / or "anti-TNF antibody variant" etc. Complementarity of at least one of the heavy or light chains that can be incorporated into the antibodies of the present invention CDRs or their ligand-binding portions, heavy or light chain variable regions, heavy or light chain or light chain constant region, framework region, or any part thereof, or TNF receptor immunoglobulins, such as, but not limited to, at least one portion of a receptor or binding protein Any protein or peptide containing molecule containing at least a portion of a globulin molecule. Such antibodies include, but are not limited to, molecules that are capable of being isolated from, or detected by, in vitro at least one TNF activity or binding in situ and / or in vivo; or modulate, decrease, increase, antagonize, agonize, attenuate, mitigate, or block TNF receptor activity or binding. Further affecting a particular ligand, such as blocking, inhibiting, suppressing, and / or interfering with it. By way of example, a preferred anti-TNF antibody, specified portion or variant of the invention comprises at least capable of binding to one TNF or a specified part, variant or domain thereof Suitable anti-TNF antibodies, specified portions or variants may be expressed as RNA, DNA, or other suitable vectors, as desired. or protein synthesis, TNF release, TNF receptor signaling, membrane TNF cleavage, TNF TNF activity or TNF synthesis, including, but not limited to, TNF activity, TNF production, and / or synthesis. The term "antibody" may also refer to a molecule that can affect at least one of the functions of the antibody. , antibodies, fragments, specified portions and variants thereof, including antibody mimetics. or portions of antibodies or their derivatives that mimic the structure and / or function of antibodies. The functional fragments include specific fragments or parts of the above, and include single chain antibodies and fragments thereof. Examples of antigen-binding fragments that bind to mammalian TNF include Fab (e.g., PAT). Fab' (e.g., by pepsin digestion and partial reduction) and F( ab')2 (e.g., by pepsin digestion), facb (e.g., by plasmin digestion) ), pFc' (e.g., by pepsin or plasmin digestion), Fd (e.g., by pepsin by digestion, partial reduction and reassembly), Fv or scFv (e.g., by molecular biology techniques and fragments thereof that are capable of binding to TNF or portions thereof, including, but not limited to, fragments thereof Antibody fragments capable of producing the antibody fragments are encompassed by the present invention (see, e.g., Colligan, Immunol., supra). (See ology).

[0102] Such fragments may be used in any manner known in the art and / or as described herein. Antibodies can be produced by enzymatic cleavage, synthetically, or recombinantly, such as by the natural end Using an antibody gene in which one or more stop codons have been introduced upstream of the stop site, various For example, the gene encoding the F(ab')2 heavy chain portion can be recombined. The combination may include a DNA sequence encoding the CH1 domain and / or hinge region of the heavy chain. The various portions of the antibody can be chemically coupled by conventional techniques, or They can be prepared as contiguous proteins using genetic engineering techniques.

[0103] As used herein, the term "human antibody" refers to a human antibody in which substantially all parts of the protein are humanized. minutes (e.g., CDR, framework, C L , C H Domain (e.g., C H 1. C H 2. and CH3), hinge (V L , V H )) is substantially non-immunogenic in humans and has Similarly, antibodies derived from primates (monkeys, baboons) have only minor changes or mutations in their sequences. , chimpanzees, etc.), rodents (mice, rats, rabbits, guinea pigs, hamsters, etc.) ), and other mammalian designated antibodies are specific for such species, subgenus, genus, subfamily, family Furthermore, chimeric antibodies include any combination of the above. The differences optionally and preferably result in increased activity in humans or other species compared to the unmodified antibody. Thus, human antibodies are not chimeric or human antibodies. Human antibodies are distinct from recombinant antibodies. Human antibodies are functionally rearranged human immunoglobulins (e.g., recombinant human antibodies). non-human animals, or prokaryotic or It is noted that human antibodies can be produced by eukaryotic cells. Furthermore, when the human antibody is a single-chain antibody, It may contain a linker peptide not found in naturally occurring human antibodies. For example, an Fv may contain a linker peptide that is not found in the variable region of the heavy chain. A linker such as 2 to about 8 glycine or other amino acid residues connecting the variable region of the light chain and the variable region of the light chain Such linker peptides are considered to be of human origin.

[0104] Monoclonal antibodies with binding specificities for at least two different antigens, preferably Human or humanized antibodies, bispecific (e.g., DuoBody®), xenogeneic Specific, heterologous, or similar antibodies may be used. one directed against at least one TNF protein and the other against any other Methods for making bispecific antibodies are known in the art. Traditionally, recombinant production of bispecific antibodies relies on the co-expression of two immunoglobulin heavy-light chain pairs. Based on the nucleotide sequence of the ribosomal RNA, where the two heavy chains have different specificities (Milstein and Cuell o, Nature, Vol. 305, p. 537 (1983). Immunoglobulin heavy chains and Due to the random assortment of light chains, these hybridomas (quadromas) are This produces a possible mixture of different antibody molecules, of which only one has the correct bispecific structure. The purification of the correct molecule, which is usually done by affinity chromatography steps, Due to the low product yield and laborious nature of the product, different methods to facilitate bispecific antibody production are needed. Methods have been developed.

[0105] Full-length bispecific antibodies can be synthesized, for example, in a cell-free environment in vitro or by co-expression. to favor heterodimer formation of two antibody half molecules with different specificities. By introducing substitutions into the heavy chain CH3 interface in each half molecule, two monospecific bivalent Fab arms can be generated using Fab arm exchange (or half molecule exchange) between antibodies. The exchange reaction is the result of disulfide bond isomerization and dissociation-association of the CH3 domain. The heavy chain disulfide bonds in the hinge region of the parent monospecific antibody are reduced. The resulting free cysteine ​​of one of the parent monospecific antibodies is then linked to a cysteine ​​of a second parent monospecific antibody molecule. The parent antibody CH3 domain dissociates and forms an intra-heavy chain disulfide bond with the α-amino acid residue. The CH3 domain of the Fab arm is released and reformed upon association. The resulting products may be engineered to favor heterodimer formation. A bispecific antibody having two Fab arms or half molecules capable of binding to a target antigen. It is the body.

[0106] As used herein, "homodimerization" refers to the formation of a homodimer having identical CH3 amino acid sequences. As used herein, "homodimer" refers to the interaction of two heavy chains in the same It refers to an antibody having two heavy chains with the same CH3 amino acid sequence.

[0107] As used herein, "heterodimerization" refers to heterodimerization of heterodimers with non-identical CH3 amino acid sequences. As used herein, "heterodimer" refers to the interaction of two heavy chains having " refers to an antibody having two heavy chains with non-identical CH3 amino acid sequences.

[0108] "Knob-in-hole" strategies (e.g., WO 2006 / 02893 6) can be used to generate full-length bispecific antibodies. The selected amino acids that form the interface of the CH3 domain in human IgG are heterodimers. To promote merization, the ribosomal domains were mutated at positions that affect CH3 domain interactions. The amino acid with a small side chain (hole) can be used to generate an antibody that specifically binds to the first antigen. The heavy chain of the antibody is introduced with an amino acid (knob) with a large side chain that specifically binds to the second antigen. After co-expression of the two antibodies, the heterodimer is called a "hole It is formed as a result of preferential interaction between a heavy chain bearing the "knob" and a heavy chain bearing the "knob". Exemplary CH3 substitution pairs that form knobs and holes are T366Y / F405A, T36 6W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y 407A, T366W / T394S, F405W / T394S, and T366W / T36 6S_L368A_Y407V (modification in the first CH3 domain of the first heavy chain (expressed as modified position / modified position in the second CH3 domain of the second heavy chain).

[0109] Other strategies, such as using positively charged residues on one CH3 surface and a second CH3 surface Heavy chain heterodimers using electrostatic interactions by replacing negatively charged residues in The promotion of merization is described in U.S. Patent Application Publication Nos. 2010 / 0015133 and 2009 / 0 No. 182127, No. 2010 / 028637 or No. 2011 / 0123532 In another strategy, heterodimerization may be used as described in U.S. Pat. As described in Publication No. 2012 / 0149876 or Publication No. 2013 / 0195849 Replaces: 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 (modified position in the first CH3 domain of the first heavy chain / modified position in the second heavy chain) This can be enhanced by the addition of a modified position in the second CH3 domain of the chain (represented as a modified position in the second CH3 domain of the chain). Cut.

[0110] In addition to the methods described above, bispecific antibodies can also be prepared using methods described in WO 2011 / 131746. According to the described method, two monospecific homodimers were isolated in a cell-free environment in vitro. Asymmetric mutations are introduced into the CH3 region of a dimeric antibody to isomerize disulfide bonds. Under reducing conditions, two parent monospecific homodimeric antibodies are converted into bispecific heterodimeric antibodies. In this method, a first monospecific bivalent antibody and The second monospecific bivalent antibody has a CH3 domain that promotes heterodimer stability. Although engineered to have certain substitutions, these antibodies have cis- or trans-activation sites in the hinge region. The two compounds were incubated together under reducing conditions sufficient to isomerize the disulfide bond. The antibodies are then incubated, thereby generating bispecific antibodies through Fab arm exchange. Incubation conditions can optimally be returned to non-reducing conditions. Exemplary reducing agents that can be used The compounds are 2-mercaptoethylamine (2-MEA), dithiothreitol (DTT), and dithiothreitol. DTE, glutathione, tris(2-carboxyethyl)phosphine tetrachloroethylene (TCEP), L-cysteine, and beta-mercaptoethanol, preferably The compounds were 2-mercaptoethylamine, dithiothreitol, and tris(2-carboxyethyl)amine. For example, a reducing agent selected from the group consisting of methyl phosphine and methyl phosphine. At room temperature, in the presence of at least 25 mM 2-MEA or at least 0.5 mM di In the presence of thiothreitol, at pH 5 to 8, for example, pH 7.0 or pH 7.4 An incubation of at least 90 minutes may be used.

[0111] Anti-TNF Antibodies (also referred to as TNF Antibodies) Useful in the Methods and Compositions of the Invention The antibody is selected to have high affinity binding to TNF, and optionally and preferably low toxicity. Specifically, individual regions such as variable regions, constant regions, and framework regions can be characterized as desired. The components, individually and / or collectively, optionally and preferably have low immunogenicity. Antibodies of the present invention, specified fragments or variants thereof, having the following structure are useful in the present invention. The antibodies that can be used in the present invention have measurable alleviation of symptoms and low and / or tolerable Optionally, it may be characterized by its ability to treat patients for long periods of time with possible toxicity. Low or acceptable immunogenicity and / or high affinity, as well as other favorable properties, may be obtained. "Low immunogenicity" as used herein can contribute to the therapeutic results achieved by the treatment. Significant HAHA, HACA or HACA incidence in less than about 75%, or preferably less than about 50%, of patients or increased HAMA response and / or low titers (double antigen) in treated patients. an increase of less than about 300, preferably less than about 100, as measured by enzyme immunoassay (Elliott et al., Lancet, Vol. 344, No. 1125-1129) 127 (1994), which is incorporated herein by reference in its entirety).

[0112] Utility: The isolated nucleic acids of the present invention can be used in cells, tissues, organs, or animals (including mammals and humans). ) to measure or act on immune disorders or diseases, cardiovascular disorders or diseases, infectious diseases, malignant, and / or neurological disorders or diseases, but and / or a combination of a TNF-α receptor and a TNF-α receptor. at least one anti-TNF antibody, which may be used to aid in the prevention of, or reduce the symptoms of, TNF-α. or can be used to generate identified variants thereof.

[0113] Such methods include those for modulating, treating, alleviating, preventing, or reducing symptoms, effects, or mechanisms. and administering at least one anti-TNF antibody to a cell, tissue, organ, animal, or patient in need thereof. The effective amount may include administering an effective amount of a composition or pharmaceutical composition comprising the compound of formula (I) or (II) described herein. The method may be performed and determined using known methods, such as those described in the literature or known in the relevant art, and may be used in a single (e.g. For example, approximately 0.001 to 500 mg / kg per bolus, multiple dose, or continuous infusion. Amount, or serum concentration of 0.01 to 5000 μg / ml per single, multiple, or continuous administration The present specification may include an amount to achieve a desired level of efficacy, or any range or value therein. All publications or patents cited herein are incorporated by reference in their entirety. It represents the state of the art at the time of the invention and / or provides an explanation and enablement of the invention. A publication is any material in any form of media, including anything recorded in electronic or printed form. Refers to any scientific publications or patents or any other information available. "Current Trends in Medical Science," edited by Ausubel et al., which is incorporated herein by reference in its entirety. "Protocols in Molecular Biology", John Wi ley&Sons, Inc., NY, NY (1987~2001), Sambrook et al., “Molecular Cloning: A Laboratory Manual ”, 2nd edition, Cold Spring Harbor, NY (1989), Harlo W and Lane, "antibodies," a Laboratory Manual ,Cold Spring Harbor, NY (1989), Colligan et al., eds. , “Current Protocols in Immunology”, John Wiley & Sons, Inc., NY (1994~2001), Colligan et al. , “Current Protocols in Protein Science”, John Wiley & Sons, NY, NY, (1997~2001).

[0114] Antibodies of the invention: all of the heavy chain variable CDR regions of SEQ ID NOs: 1, 2 and 3, and / or At least one anti-TN antibody of the present invention comprising all of the light chain variable CDR regions of numbers 4, 5 and 6. The F antibody can optionally be derived from a cell line, a mixed cell line, an immortalized cell line, or any other suitable cell line, as is well known in the art. These may be produced by clonal populations of transformed or immortalized cells. , “Current Protocols in Molecular Biology ”, John Wiley & Sons, Inc., NY, NY (1987~2001) , Sambrook et al., “Molecular Cloning: A Laborato ry Manual” 2nd edition, Cold Spring Harbor, NY (1989 Harlow & Lane, "antibodies", a Laborator y Manual, Cold Spring Harbor, NY (1989), Co. Current Protocols in Immunolog, edited by lligan et al. y”, John Wiley & Sons, Inc., NY (1994~2001), C olligan et al., “Current Protocols in Protein S science”, John Wiley&Sons, NY, NY, (1997~2001 ), each of which is incorporated herein by reference in its entirety.

[0115] Human antibodies specific for human TNF protein or fragments thereof are isolated and / or Suitable molecules such as TNF proteins or portions thereof (including synthetic molecules such as synthetic peptides) Other specific or general mammalian antibodies may be raised against any suitable immunogenic antigen. Preparation of immunogenic antigens and generation of monoclonal antibodies can be performed using any suitable technique. This can be done using techniques.

[0116] In one approach, hybridomas are generated using a suitable immortalized cell line (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 Myeloma cells, such as, but not limited to, 44, NAMAIWA, and NEURO 2A strains, or heteromylomas, their fusion products, or any derived therefrom. or any other suitable cell line known in the art. For example, see www.atcc.org, www.lifete See ch.com. Isolated or cloned spleen, peripheral blood, lymphocytes, etc. such as, but not limited to, lymph nodes, tonsils, or other immune or B cell-containing cells. Antibody-producing cells, or recombinant or endogenous, viral, bacterial, algal, prokaryotic, amphibian animals, insects, reptiles, fish, mammals, rodents, horses, sheep, goats, lambs, primates , eukaryotes, genomic DNA, cDNA, rDNA, mitochondrial DNA or RNA , chloroplast DNA or RNA, hnRNA, mRNA, tRNA, single-stranded, double-stranded or endogenous or heterologous, such as triple-stranded, hybridized, etc., or combinations thereof. heavy or light chain constant or variable or framework nucleic acids as any of the species or any other cell that expresses the CDR sequences. See Colligan, Immunology, supra, Chapter 2. Both documents are incorporated herein by reference in their entirety.

[0117] Antibody-producing cells can be obtained from the peripheral blood of humans or other suitable animals immunized with the antigen of interest, or from the Alternatively, the cells may be obtained from the spleen or lymph nodes. Any other suitable host cell may be used. and a heterologous or endogenous nucleic acid encoding an antibody of the invention, a specified fragment, or a variant thereof. The fused cells (hybridomas) or recombinant cells can be grown in a selective medium. The cells are isolated using culture conditions or other suitable known methods, and then subjected to limiting dilution or cell sorting or other methods. It can be cloned by known methods. Cells that are transfected can be selected by a suitable assay (eg, ELISA).

[0118] Examples include methods for selecting recombinant antibodies from peptide or protein libraries. Any suitable method for producing or isolating antibodies with the required specificity, including but not limited to: Other methods can be used (e.g., bacteriophage, ribosome, oligonucleotide Display libraries including, but not limited to, nucleotides, RNA, and cDNA For example, Cambridge Antibody Technologies, mbridgeshire, UK, MorphoSys, Martinsreid / Pl anegg, DE, Biovation, Aberdeen, Scotland, UK, BioInvent, Lund, Sweden, Dyax Corp., Enzon, A ffymax / Biosite, Xoma, Berkeley, CA, from Ixsys. (See, for example, European Patent No. 368,684, International Application No. PCT / GB91 / 01134, International Application No. PCT / GB92 / 01755, International Application No. PCT / GB92 / 002240, International Application No. PCT / GB92 / 00883, International Application No. PCT / GB93 / 00605, U.S. Patent Application No. 08 / 350260 (5 / 12 / 94), International Application P CT / GB94 / 01422, International Application PCT / GB94 / 02662, International Application P CT / GB97 / 01835, (CAT / MRC), International Publication No. 90 / 14443, International Publication No. 90 / 14424, International Publication No. 90 / 14430, International Application No. PCT / US 94 / 1234, WO 92 / 18619, WO 96 / 07754 (Sc ripps), European Patent No. 614 989 (MorphoSys), International Publication No. 95 / 16027 (BioInvent), WO 89 / 06630, WO 90 / 3809 (Dyax), U.S. Patent No. 4,704,692 (Enzon), International Application PCT / US91 / 02989 (Affymax), WO 88 / 06283, European Patent No. 371998, European Patent No. 550400, (Xoma), European Patent No. 22 No. 9046, International Application No. PCT / US91 / 07149 (Ixsys), or probabilistically Generated peptides or proteins - U.S. Patent Nos. 5,723,323 and 5,7631 No. 92, No. 5814476, No. 5817483, No. 5824514, No. 5 976862, International Publication No. 86 / 05803, European Patent No. 590689 (Ixsy s, currently Applied Molecular Evolution (AME), respectively (which are incorporated herein by reference in their entirety) or Generating a repertoire of human antibodies, as known and / or described herein. Rely on the immunization of transgenic animals capable of transfecting the immune system (e.g., SCID mice, Nguyen et al., 2014). n et al., "Microbiol. Immunol.", Vol. 41, pp. 901-907 (199 7), Sandhu et al., "Crit. Rev. Biotechnol." Vol. 16, No. 9 5-118 (1996), Eren et al., Immunol., Vol. 93, No. 154-1 61 (1998), each of which is incorporated by reference in its entirety. ribosomal display (Hanes et al., Proc. Natl. Acad. Sci. US A,” Vol. 94, pp. 4937-4942 (May 1997), Hanes et al., “Proc. Natl. Acad. Sci. USA, Vol. 95, pp. 14130-14135 (1998) (November 2011), single-cell antibody production technologies (e.g., Selected Lymphocyte Antibody Method ("SLAM")) (U.S. Pat. No. 5,627,052; Wen et al., J. Immunol. Vol. 17, No. 88 pp. 7-892 (1987), Babcook et al., “Proc.Natl.Acad.S ci.USA, Vol. 93, pp. 7843-7848 (1996), gel microdroplet Platelet and flow cytometry (Powell et al., Biotechnol. Vol. 8 pp. 333-337 (1990), One Cell Systems (Cambri dge, MA), Gray et al., J. Imm. Meth., Vol. 182, No. 155-163 (1995), Kenny et al., Bio / Technol., Vol. 13, No. 787-7 90 (1995), B cell selection (Steenbakkers et al., "Molec. B Journal of Biomedical Research, Vol. 19, pp. 125-134 (1994), Jonak et al. "Progress Biotech" Vol. 5, In Vitro Immunozat ion in Hybridoma Technology, edited by Borrebaeck. Elsevier Science Publishers BV, Amsterd am, Netherlands (1988) .

[0119] Methods for engineering or humanizing non-human or human antibodies may also be used, and techniques may be used. Generally, humanized or engineered antibodies are derived from, for example, murine, Such mammals include, but are not limited to, rats, rabbits, non-human primates, or other mammals. These human amino acids have one or more amino acid residues from a non-human source. The amino acid residue is often called the "import" residue and is typically the "import" residue of a known human sequence. The "port" may be taken from a variable region, constant region, or other domain.

[0120] Known human Ig sequences are disclosed in numerous publications and websites, e.g., 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.,Kabat et al. “Sequences of Proteins of Immunological Interest" and USDept. Health (1983), each of which is , which is incorporated herein by reference in its entirety.

[0121] Such imported sequences may be used to reduce immunogenicity or to enhance the ability of the polypeptides to be expressed in a manner that is well known in the art. As is known in the art, binding, affinity, association rate constant, dissociation rate constant, avidity, specificity, can be used to reduce, enhance or modify the shear life or any other suitable property Generally, some or all of the non-human or human CDR sequences are present in the non-human variable and constant regions. The sequence is maintained while replacing the amino acids with human or other amino acids. This allows for humanization while retaining high affinity for the antigen and other favorable biological properties. To this end, humanized antibodies can be produced, if desired, by combining the parental sequence and the humanized sequence. By a process of analysis of the parent sequence and various conceptual humanized products using a three-dimensional model of the sequence. Three-dimensional immunoglobulin models are commonly available. , well known to those skilled in the art. Computer programs are available for illustrating and displaying three-dimensional structures. By inspecting the display, the likelihood of the residues being involved in the function of the candidate immunoglobulin sequence can be determined. This allows for the analysis of the residues that affect the antigen-binding ability of immunoglobulin candidates. In this way, desirable antibody properties, such as increased affinity for the target antigen, are achieved. FR residues are selected and combined from the consensus sequence and the import sequence so that In general, the CDR residues directly and most substantially influence antigen binding. The antibodies of the present invention can be humanized or engineered as described in Winter (Jones et al., "Nat. ure,” Vol. 321, p. 522 (1986), Riechmann et al., “Nature 332, 323 (1988), Verhoeyen et al., Science Vol. 239, p. 1534 (1988)), Sims et al., "J. Immunol." No. 15 1, pp. 2296 (1993), Chothia and Lesk, J. Mol. Biol. l." Vol. 196, p. 901 (1987), Carter et al., "Proc. Natl. Acad.SCi.USA, Vol. 89, p. 4285 (1992), Presta et al., J. Immunol., Vol. 151, p. 2623 (1993), U.S. Pat. No. 57 No. 23323, No. 5976862, No. 5824514, No. 5817483, Same No. 5814476, Same No. 5763192, Same No. 5723323, Same No. 5,766 No. 886, No. 5714352, No. 6204023, No. 6180370, No. No. 5693762, No. 5530101, No. 5585089, No. 5225539 No. 4816567, International Application No. PCT / :US98 / 16280, US96 / 1 No. 8978, No. US91 / 09630, No. US91 / 05939, No. US94 / 01234 No., GB89 / 01334, GB91 / 01134, GB92 / 01755, International Publication Nos. 90 / 14443, 90 / 14424, 90 / 14430, European Patent Application No. 229246 (each of which is incorporated by reference in its entirety and cited therein). Any known method, including but not limited to those described in the literature, It can be done using.

[0122] The anti-TNF antibody is optionally any of those described herein and / or known in the art. Certain transgenic animals capable of producing a repertoire of human antibodies (e.g., They can also be produced by immunization of animals such as mice, rats, hamsters, and non-human primates. Cells producing anti-TNF antibodies are isolated from such animals and cultured using methods such as those described herein. The cells may be immortalized using any suitable method.

[0123] Transgenics capable of producing a repertoire of human antibodies that bind to human antigens Mice can be generated by known methods, including but not limited to, U.S. Patent Nos. 5,770,428 and 5,569,828 issued to Lonberg et al. No. 25, No. 5,545,806, No. 5,625,126, No. 5,625,82 Nos. 5, 5,633,425, 5,661,016, and 5,789,6 50, WO 98 / 50433 by Jakobovits et al. WO 98 / 24893 to S. et al., WO 98 / 24884 to Lonberg et al. No. 97 / 13852 to Lonberg et al., International Publication No. 94 / 25585, Kucherlapate et al., International Publication No. 96 / 34096, K European Patent No. 0463151(B1) to Kucherlapate et al. European Patent No. 0710719(A1) to Ate et al., U.S. Patent No. 5,544 to Surani et al. No. 5,807, Bruggemann et al., International Publication No. 90 / 04036, Brugge mann et al., European Patent No. 0438474(B1), Lonberg et al., European Patent No. 08 14259(A2), Lonberg et al., UK Patent No. 2272440(A), L Onberg et al., Nature, vol. 368, pp. 856-859 (1994), Ta ylor et al., Int. Immunol., Vol. 6, No. 4, pp. 579-591 (1994) Green et al., Nature Genetics, Vol. 7, pp. 13-21 (1999) 1994), Mendez et al., Nature Genetics, Vol. 15, No. 146-1 56 (1997), Taylor et al., "Nucleic Acids Research ch,” Vol. 20, No. 23, pp. 6287-6295 (1992), Tuaillon et al. Proc Natl Acad Sci USA, Vol. 90, No. 8, pp. 3720-372 4 (1993), Lonberg et al., Int Rev Immunol, Vol. 13 1, pp. 65-93 (1995), and Fishwald et al., "Nat. Biote chnol,” Vol. 14, No. 7, pp. 845-851 (1996), which are incorporated by reference. (Each of which is incorporated herein in its entirety.) Generally, these mice contain functionally reconstituted or at least one human immunoglobulin gene capable of undergoing functional rearrangement The mouse contains at least one transgene comprising DNA derived from an endogenous locus. The immunoglobulin locus is disrupted or deleted to remove the endogenous genes encoded by the mouse. This can eliminate the ability to produce antibodies that are inhibited by the antibody.

[0124] Screening of antibodies for specific binding to similar proteins or fragments can be performed using peptide This can be successfully achieved using a hand-display library. Screening a large sample collection of peptides for individual members with novel functions or structures Antibody screening of peptide display libraries involves the use of a technique called The length of the displayed peptide sequence is 3,000 or more. amino acids, frequently 5-100 amino acids long, mostly about 8-25 amino acids In addition to direct chemical synthesis methods for generating peptide libraries, several recombinant methods are available. DNA methods have also been described. One type involves the use of DNA fragments on the surface of bacteriophages or cells. Each bacteriophage or cell contains a specific deoxyribonucleotide sequence. The method comprises the step of: , International Application Publication Nos. 91 / 17271, 91 / 18980, and 91 / 19818 and 93 / 08278. Other systems include aspects of both in vitro chemical synthesis and recombinant methods. Publication Nos. 92 / 05258, 92 / 14843, and 96 / 19256 See also U.S. Patent Nos. 5,658,754 and 5,643,768. Peptide display libraries, vectors, and screening kits are available from I Invitrogen (Carlsbad, CA) and Cambridge Antibodies Suppliers such as dy Technologies (Cambridgeshire, UK) See, for example, U.S. Patent No. 4,704,692 assigned to Enzon; Same No. 4939666, Same No. 4946778, Same No. 5260203, Same No. 54550 No. 30, No. 5518889, No. 5534621, No. 5656730, No. 5 Nos. 763733, 5767260, and 5856456 were assigned to Dyax. U.S. Patent Nos. 5,223,409, 5,403,484, 5,571,698, and 58 37500, U.S. Patent Nos. 5,427,908 and 5,580 assigned to Affymax No. 717, assigned to Cambridge antibody Technologies U.S. Patent No. 5,885,793 assigned to Genentech; U.S. Patent No. 5,750 assigned to Genentech; 373, U.S. Patent Nos. 5,618,920 and 5,595,898 assigned to Xoma; Same No. 5576195, Same No. 5698435, Same No. 5693493, Same No. 56984 No. 17, the above Colligan, the above Ausubel, or the above Sambrook. See, e.g., U.S. Pat. No. 6,229,999, each of which is incorporated herein by reference in its entirety. Be absorbed.

[0125] The antibodies of the present invention can be obtained from transgenic animals such as goats, cows, horses, and sheep that produce such antibodies in their milk. To provide a transgenic animal or mammal, nucleic acids encoding at least one antibody Such animals may be prepared using known methods. For example, but not limited to, U.S. Pat. No. 5,827,690 , No. 5,849,992, No. 4,873,316, No. 5,849,992, Nos. 5,994,616, 5,565,362, 5,304,489, etc. See, e.g., (each of which is incorporated herein by reference in its entirety).

[0126] The antibodies of the present invention can be used to detect the specific Transgenic plants and cultured plant cells (e.g., To provide at least Further, the present invention can be prepared using a single anti-TNF antibody-encoding nucleic acid. For example, transgenic plants that express recombinant proteins using inducible promoters are used. Quebec leaves have been successfully used to provide large amounts of recombinant proteins. For example, Cra mer et al., "Curr. Top. Microbol. Immunol.", Vol. 240, No. 9 See pages 5-118 (1999) and the references cited therein. Transgenic corn is a protein produced in other recombinant systems or from natural sources. Mammalian proteins having biological activity equivalent to proteins purified from commercial sources are For example, Hood et al., "Adv. Exp. M ed. Biol., Vol. 464, pp. 127-147 (1999) and references therein. See references in the literature. Antibodies are single chain antibodies (scFv) including tobacco seeds and potato tubers. ) have also been produced in large quantities from transgenic plant seeds containing antibody fragments such as Conrad et al., Plant Mol. Biol., Vol. 38, pp. 101-109 (1998) and the references cited therein. Thus, the antibodies of the present invention , can also be produced using transgenic plants by known methods. ,Fischer et al., "Biotechnol. Appl. Biochem.", Vol. 30 pp. 99-108 (October 1999), Ma et al., “Trends Biotechno 13, pp. 522-7 (1995), Ma et al., “Plant Physiol. 109, pp. 341-346 (1995); Whitelam et al., Biochem Soc.Trans., Vol. 22, pp. 940-944 (1994), and See also the references cited in, generally, Plant Expression of Antibodies. Each of the above documents is incorporated herein by reference in its entirety.

[0127] The antibodies of the present invention have a wide range of affinities (K D ) and can bind to human TNF In a preferred embodiment, at least one human mAb of the invention is optionally human TN For example, human mAbs can bind human TNF with high affinity. - 7 M or less, for example, 0.1 to 9.9 (or any range or value therein) x 10 -7 , 1 0 -8 , 10 -9 , 10 -10 , 10 -11 , 10 -12 , 10 -13 or any of them Ranges or values ​​of K, such as (but not limited to)D can be combined with

[0128] The affinity or avidity of an antibody for an antigen can be determined experimentally using any suitable method. (See, e.g., Berzofsky et al., "Antibody-Antige n Interactions”, In Fundamental Immunolog y, Paul, WE ed., Raven Press: New York, NY (198 4 years), Kuby, Janis, "Immunology", WHFreeman and Company: New York, NY (1992), and as described herein. (See methods described in the literature.) The affinity measured for a particular antibody-antigen interaction may vary depending on the The affinity may differ when measured under different conditions (e.g., salt concentration, pH). and other antigen binding parameters (e.g., K D , K. a , K. d ) is preferably measured by The assay is performed using standard solutions of antibody and antigen, and standard buffers such as those described herein. It can be done.

[0129] Nucleic acid molecule. At least one contiguous amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8 Nucleotide sequences encoding at least 70-100% of the amino acids, specified fragments, variants variants or their consensus sequences, or a sequence containing at least one of these sequences The heavy chains of SEQ ID NOS: 1, 2 and 3 can be prepared using the information provided herein, including the deposited vectors. All of the variable CDR regions and / or all of the light chain variable CDR regions of SEQ ID NOs: 4, 5 and 6 Nucleic acid molecules of the invention encoding at least one anti-TNF antibody comprising the These can be prepared or obtained using methods known in the art.

[0130] The nucleic acid molecules of the present invention may be in the form of mRNA, hnRNA, tRNA or any other form. in the form of RNA, or cDNA obtained by cloning or produced synthetically and genomic DNA, or any of these forms of DNA. The DNA may be triple-stranded, double-stranded, single-stranded, or a combination of these. Any combination of any portion of at least one strand of DNA or RNA The DNA may be the coding strand, also known as the sense strand, or may be called the antisense strand. It may also be the non-coding strand.

[0131] The isolated nucleic acid molecules of the present invention may optionally contain one or more introns. Open reading frame (ORF), including, but not limited to, at least CD of one heavy chain (e.g., SEQ ID NOs: 1 to 3) or light chain (e.g., SEQ ID NOs: 4 to 6) At least one of at least one CDR, such as CDR1, CDR2, and / or CDR3 Nucleic acid molecules containing one specified portion, coding sequences for anti-TNF antibodies or variable regions (e.g., For example, nucleic acid molecules comprising SEQ ID NOs: 7 and 8, as well as nucleic acid molecules that are substantially different from the above-mentioned nucleic acid molecules but contain the same genetic information. Due to the degeneracy of the genetic code, some of the sequences described herein and / or known in the art may be used. The present invention may also include nucleic acid molecules comprising a nucleotide sequence encoding at least one anti-TNF antibody. Of course, the genetic code is well known in the art. It is within the skill of the art to generate such degenerate nucleic acid variants encoding the particular anti-TNF antibodies of the invention. It would be routine to do so. See, e.g., Ausubel et al., supra, for such nucleic acids. Mutants are encompassed by the present invention. Non-limiting examples of isolated nucleic acid molecules of the present invention include: , HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 Non-limiting examples of nucleic acids encoding the LC CDR3, HC variable region, and LC variable region include: Corresponding sequences include SEQ ID NOs: 10, 11, 12, 13, 14, and 15.

[0132] As provided herein, nucleic acid molecules of the invention, including nucleic acids encoding anti-TNF antibodies, , which itself encodes the amino acid sequence of an antibody fragment, a full-length antibody or a portion of an antibody the coding sequence for the antibody, fragment or portion thereof, as well as additional sequences, e.g. non-coding sequences, with or without the additional coding sequences described above, such as at least one intron Coding 5' and 3' sequences, e.g., splicing and polyadenylation signals (e.g., in transcription, mRNA processing, including ribosome binding and stability of mRNA together with additional non-coding sequences, including but not limited to transcribed and non-translated sequences, which play a role in at least one signal leader or fusion peptide coding sequence, additional amino acids including additional coding sequences encoding amino acids, e.g., amino acids that provide additional functions. Therefore, the sequence encoding the antibody can be linked to a marker sequence, but is not limited to these. For example, the marker sequence may include an antibody fragment or portion fused thereto. It is a sequence that encodes a peptide that facilitates the purification of antibodies containing the

[0133] Polynucleotides that selectively hybridize to the polynucleotides described herein The present invention provides a method for selectively hybridizing to the polynucleotides disclosed herein. The present invention provides an isolated nucleic acid that hybridizes under conditions of hybridization. Polynucleotides may 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 Partial or full-length clones in the resulting library can be identified, isolated, or amplified. In some embodiments, the polynucleotides are isolated or otherwise If not, a genomic sequence complementary to a cDNA from a human or mammalian nucleic acid library, or This is a cDNA sequence.

[0134] Preferably, the cDNA library contains at least 80% of the full-length sequences, preferably the complete 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 representation of rare sequences. Low or medium stringency, which uses sequences with low sequence identity to the complementary sequence, can be used. The hybridization conditions of the present invention are typical, but not limited to, those of the present invention. For more highly identical sequences, medium and high stringency conditions are optionally used. Low stringency conditions are selective for sequences with approximately 70% sequence identity. To allow hybridization and identify orthologous or paralogous sequences Available.

[0135] Optionally, the polynucleotide of the present invention is a polynucleotide described herein. The polypeptides of the present invention will encode at least a portion of an antibody encoded by the polypeptide. The nucleotides are selected to hybridize to the polynucleotides encoding the antibodies of the present invention. For example, Ausubel, supra, See Colligan, supra, each of which is incorporated herein by reference in its entirety. can be.

[0136] Construction of Nucleic Acids. The isolated nucleic acids of the present invention can be prepared by (a) recombinant methods, (b) recombinant methods, (c) recombinant methods, (d) recombinant methods, (e) recombinant methods, (f) recombinant methods, (g) recombinant methods, (h) recombinant methods, (i) recombinant methods, (j ... b) synthetic techniques, (c) purification techniques, or a combination thereof. do.

[0137] The nucleic acids can conveniently include sequences in addition to the polynucleotides of the present invention. For example, a multiple cloning sequence containing one or more endonuclease restriction sites may be used. The site can be inserted into a nucleic acid to aid in the isolation of the polynucleotide. A sequence capable of being inserted to aid in the isolation of the translated polynucleotide of the present invention can be used. For example, a hexa-histidine marker sequence may be used for convenient purification of the proteins of the present invention. The nucleic acids of the invention (excluding the coding sequence) can optionally be used to prepare polynucleotides of the invention. vectors, adapters or linkers for cloning and / or expression of polypeptides.

[0138] Additional sequences may be added to such cloning and / or expression sequences to facilitate cloning and expression. and / or optimizing their function in expression, aiding in the isolation of polynucleotides. This can improve the transfer of polynucleotides into cells. The use of adapters, expression vectors, adapters, and linkers is well known in the art. (See, for example, Ausubel, supra, or Sambrook, supra).

[0139] Recombinant methods for constructing nucleic acids, including RNA, cDNA, genomic DNA, or any of these. The isolated nucleic acid compositions of the present invention, such as any combination thereof, may be prepared from any number of clones known to those of skill in the art. In some embodiments, the present invention can be obtained from biological sources using enzyme-linked immunosorbent assays. An oligonucleotide that selectively hybridizes to a polynucleotide under stringent conditions. A oligonucleotide probe is used to identify a desired sequence in a cDNA or genomic DNA library. Isolation of RNA and construction of cDNA and genomic libraries are well within the skill of those in the art. (See, e.g., Ausubel, supra, or Sambrook, supra. (This refers to

[0140] Nucleic acid screening and isolation methods. Probes based on the nucleotide sequence are used to screen cDNA or genomic libraries. Probes can be used to identify fragments of genomic DNA or cDNA sequences. Homologous genes from the same or different organisms can be isolated by hybridization. If so, use varying degrees of hybridization stringency in the assay. and either the hybridization or the wash medium can be stringent. It is clear that the hybridization conditions can be made more stringent. The greater the degree of complementarity between the probe and target when duplex formation occurs, the greater the degree of complementarity between the probe and target. The degree of stringency can be determined by factors such as temperature, ionic strength, pH, and formamide. or the presence of such partially denaturing solvents. For example, the stringency of hybridization may be in the range of 0% to 50%. This was successfully modified by changing the polarity of the reaction solution through manipulation of the formamide concentration at The degree of complementarity (sequence identity) required for detectable binding depends on the hybridization sequence. The degree of complementarity depends on the stringency of the application and / or washing medium. Preferably, it is 100%, or 70 to 100%, or any range or value therein. However, slight differences in the sequences of the probe and primers can affect hybridization and This can be compensated for by reducing the stringency of the wash medium and / or It should be understood that:

[0141] Methods for amplifying RNA or DNA are well known in the art and are well suited to the teachings provided herein. and guidelines that can be used in accordance with the present invention without undue experimentation.

[0142] Known methods for DNA or RNA amplification include polymerase chain reaction (PCR) and related related amplification processes (e.g., Mullis et al., U.S. Pat. No. 4,683,195; ...). No. 4,683,202, No. 4,800,159, No. 4,965,188, Tab U.S. Patent Nos. 4,795,699 and 4,921,794 to Orr et al.; U.S. Patent No. 5,142,033, Wilson et al., U.S. Patent No. 5,122,464, U.S. Patent No. 5,091,310 to Innis and U.S. Patent No. 5,091,310 to Gyllensten et al. ,066,584, Gelfand et al., U.S. Pat. No. 4,889,818, Silve U.S. Patent No. 4,994,370 to R. et al., U.S. Patent No. 4,766,067 to Biswas See U.S. Patent No. 4,656,134 to Ringold), and double-stranded D Using antisense RNA against a target sequence as a template for RNA synthesis NA-mediated amplification (U.S. Patent No. 5,130,238 to Malek et al., trade name NASBA) These include, but are not limited to, the following documents (the entire contents of which are incorporated herein by reference): (See, e.g., Ausubel, supra, or Sambrook, supra.) See .)

[0143] For example, polymerase chain reaction (PCR) techniques can be used to generate genomic DNA or cDNA fragments. Amplifying the sequences of the polynucleotides of the present invention and related genes directly from the library. PCR and other in vitro amplification methods can also be used to, for example, amplify the protein to be expressed. cloning a nucleic acid sequence encoding the desired mRNA; detecting the presence of the desired mRNA in a sample; to generate nucleic acids to be used as probes for nucleic acid sequencing or for other purposes. It may be useful for the in vitro amplification method. Examples of techniques are Berger, supra; Sambrook, supra; and Ausubel, supra. and Mullis et al., U.S. Pat. No. 4,683,202 (1987), and Inni s et al., “PCR Protocols A Guide to Methods and "Applications", edited by Academic Press Inc., San D. See Iego, CA (1990). Commercially available kits for genomic PCR amplification are available in the technical field. For example, Advantage-GC Genomic PCR K See it (Clontech). In addition, see, e.g., T4 gene 32 protein (Boehringer Mannheim) to improve the yield of long PCR products. It is possible.

[0144] Synthetic Methods for Constructing Nucleic Acids. The isolated nucleic acids of the present invention can be prepared by direct chemical synthesis using known methods. They can also be prepared by chemical synthesis (see, for example, Ausubel et al., supra). Generally, by hybridization with a complementary sequence or by using a single strand as a template. single-stranded oligonucleotides that can be converted into double-stranded DNA by polymerization with the DNA polymerase used Those skilled in the art will appreciate that chemical synthesis of DNA produces about 100 or more bases. Although the sequence may be limited, longer sequences can be obtained by ligation of shorter sequences. You will realize that you can.

[0145] Recombinant Expression Cassettes. The present invention further provides recombinant expression cassettes comprising a nucleic acid of the invention. The nucleic acid sequences of the invention, e.g., cDNA or genomic sequences encoding the antibodies of the invention, can be used. and constructing a recombinant expression cassette that can be introduced into at least one desired host cell. The recombinant expression cassette typically expresses a polynucleotide sequence that is expressed in the intended host cell. a polynucleotide of the present invention operably linked to a transcription initiation regulatory sequence that directs transcription of the gene Both heterologous and non-heterologous (i.e., endogenous) promoters can be used to produce the nucleic acids of the present invention. This can lead to the development of acid.

[0146] In some embodiments, isolated proteins that function as promoters, enhancers, or other elements. The nucleic acid may be used in combination with a polynucleotide of the invention to up- or down-regulate expression of the polynucleotide of the invention. Introducing a non-heterologous form of a nucleotide at the appropriate position (upstream, downstream, or within an intron) For example, by mutation, deletion and / or substitution in vivo or in vitro, The endogenous promoter can be altered.

[0147] Vectors and host cells. The present invention relates to vectors, recombinant vectors, which contain the isolated nucleic acid molecules of the present invention. Genetically engineered host cells and the like, and the ability to produce at least some of the cells by recombinant techniques well known in the art. The present invention also relates to the production of at least one anti-TNF antibody. See, e.g., Sambrook et al., supra; See Ausubel et al., each of which is incorporated herein by reference in its entirety. .

[0148] The polynucleotide optionally comprises a vector containing a selectable marker for propagation in a host. Generally, plasmid vectors are prepared in a manner similar to calcium phosphate precipitates. The vector is introduced into a precipitate such as a virus or into a complex with a charged lipid. , packaging it in vitro using an appropriate packaging cell line, and then transducing it into host cells. It is possible.

[0149] The DNA insert should be operably linked to an appropriate promoter. The target is a transcription start site, a transcription termination site, and, within the transcribed region, a ribosome for translation. The coding portion of the mature transcript expressed by the construct preferably further comprises a nucleotide sequence encoding ... or a sequence that contains a translation initiation site at the beginning and a stop codon (e.g., UAA, UGA, or UAG) will be appropriately positioned. For expression, UAA and UAG are preferred.

[0150] The expression vector preferably contains at least one selectable marker, although this is optional. Such markers include, for example, methotrexate (MTX) for eukaryotic cell culture, dinucleotides (DNTPs), and nucleotides (TNF-α) for eukaryotic cell culture. Hydrofolate reductase (DHFR, U.S. Pat. Nos. 4,399,216 and 4,634 , No. 665, No. 4,656,134, No. 4,956,288, No. 5,149, No. 636, No. 5,179,017, ampicillin, neomycin (G418), mycobacterium erythropoeias Cophenolic acid or glutamine synthetase (GS) (U.S. Pat. No. 5,122,464 , 5,770,359, 5,827,739) resistance genes, and E. coli and tetracycline or ampicillin resistance for cultivation in other bacteria or prokaryotes These include, but are not limited to, sex genes (the above patents are incorporated herein by reference in their entirety). Suitable culture media and conditions for the above host cells are well known in the art. Suitable vectors will be readily apparent to those skilled in the art. The transfection of the activator construct was performed using calcium phosphate transfection, DEAE-Dex transfection, and transfection, cationic lipid-mediated transfection, electrophoresis This can be affected by troporation, transduction, infection or other known methods. Regarding the law, see Sambrook, supra, chapters 1-4 and 16-18; Aus, supra ubel, Chapters 1, 9, 13, 15, 16, etc. in the technical field.

[0151] At least one antibody of the present invention may be expressed in a modified form, such as a fusion protein. The polypeptide may contain not only a secretion signal but also additional heterologous functional regions. For example, a region of additional amino acids. Adding regions, particularly charged amino acids, to the N-terminus of the antibody to prevent fragmentation during purification or subsequent processing and storage The stability and persistence in host cells can be improved. The antibody or at least one fragment thereof may be added to the antibody to facilitate purification. Such regions can be removed prior to final preparation of the sample. ook, Chapters 17.29-17.42 and 18.1-18.74, Ausub above el, Chapters 16, 17, and 18, and many other standard laboratory manuals. .

[0152] Those skilled in the art will appreciate that there are numerous expression vectors available for expressing nucleic acids encoding the proteins of the present invention. I'm familiar with the system.

[0153] Alternatively, the nucleic acids of the invention can be derived from a host cell containing endogenous DNA encoding an antibody of the invention. It can be expressed in the host cell by being switched on (by engineering) in the host cell. Such methods are described in U.S. Patent Nos. 5,580,734, 5,641,670, As described in US Pat. Nos. 5,733,746 and 5,733,761, are well known in the art and are incorporated herein by reference in their entirety.

[0154] An example of a cell culture useful for producing antibodies, specified portions or variants thereof is mammalian cell culture. Mammalian cell lines often take the form of a monolayer of cells, but mammalian cells Suspension or bioreactor systems can also be used. Intact glycosylated proteins can be expressed. Several suitable host cell lines 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. American Type Culture Collection,Manassas Preferred host cells include CHO cells, as well as myeloma and Particularly preferred host cells include cells derived from the lymphatic system, such as lymphoma cells. CHO cells, P3X63Ag8.653 cells (ATCC accession number CRL-1580), and SP2 / 0-Ag14 cells (ATCC accession number CRL-1851).

[0155] Expression vectors for these cells include an origin of replication, a promoter (e.g., late or early SV40 promoter, CMV promoter (U.S. Patent Nos. 5,168,062 and 5,385,8 No. 39), HSV tk promoter, pgk (phosphoglycerate kinase) promoter , EF-1α promoter (U.S. Patent No. 5,266,491), at least one human immune immunoglobulin promoter, enhancer, and / or ribosome binding site, RNA splice a polyadenylation site (e.g., the SV40 large T Ag polyaddition site), and Expression control sequences, including, but not limited to, processing information sites such as transcription termination sequences The sequences may include one or more of the sequences described in, for example, Ausubel et al., supra; See Ambrook et al. Other useful nucleic acid or protein preparations for the production of the invention include: The cells may be any known and / or commercially available from, for example, American Type Culture Collection. Collection of cell lines and hybridomas catalogue or other known Alternatively, it may be available from commercial sources.

[0156] When a eukaryotic host cell is used, a polyadenylation or transcription termination site is typically included in the vector. An example of a termination sequence is the polyadenylation sequence from the bovine growth hormone gene. Sequences for accurate splicing of the transcript may also be included. An example of a splicing sequence is the VP1 intron from SV40 (Sprague et al. , "J. Virol." Vol. 45, pp. 773-781 (1983)). In addition, technical As is known in the art, gene sequences for controlling replication within host cells are included in the vector. can be incorporated into

[0157] Antibody purification. Anti-TNF antibodies were purified using protein A, ammonium sulfate, or ethanol precipitation. precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography hydrophobic interaction chromatography, affinity chromatography, hydroxy Examples of suitable methods include, but are not limited to, leupertite chromatography and lectin chromatography. It can be recovered and purified from recombinant cell culture by any well-known method, including but not limited to. High performance liquid chromatography (HPLC) It can also be used for purification. cols in Immunology or Current Protocols in Protein Science,John Wiley & Sons,NY,NY (1997-2001), see, for example, chapters 1, 4, 6, 8, 9, and 10. are incorporated herein by reference in their entireties.

[0158] Antibodies of the present invention include naturally purified products, products of chemical synthetic procedures, as well as products derived from, e.g., Produced by recombinant techniques from eukaryotic hosts, including yeast, higher plants, insect and mammalian cells Depending upon the host employed in a recombinant production procedure, the antibody of the present invention may be glycosylated or unglycosylated. It may be sylated or non-glycosylated, but is preferably glycosylated. Such methods are described in Sambrook, supra, Sections 17.37-17.42, and Au, supra. subel, Chapters 10, 12, 13, 16, 18, and 20, Colligan, supra. Many standard laboratory manuals, such as Protein Science, Chapters 12-14 and the like, all of which are incorporated herein by reference in their entireties.

[0159] Anti-TNF antibody All of the heavy chain variable CDR regions of SEQ ID NOs: 1, 2 and 3 and / or SEQ ID NOs: 4, 5 and 6 The isolated antibodies of the present invention comprising all of the light chain variable CDR regions of The amino acid sequences of the antibodies disclosed herein encoded by the nucleotides, or any single Preferably, the human antibody or antigen-binding fragment is directed against human TNF. binds to, and thereby partially or substantially inhibits at least one biological activity of, the protein Neutralize at least one biological activity of at least one TNF protein or fragment. an antibody or a specified portion or variant thereof that partially or preferably substantially neutralizes binds to the protein or fragment, thereby inhibiting TNF through binding to the TNF receptor. or can inhibit activity mediated through other TNF-dependent or -mediated mechanisms. As used herein, the term "neutralizing antibody" refers to a neutralizing antibody that is approximately 20-100% neutralizing, depending on the assay. 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 refers to an antibody that can inhibit TNF-dependent activity by 100% or more. The ability of anti-TNF antibodies to inhibit TNF activity is preferably as described herein and / or in the art. by at least one suitable TNF protein or receptor assay known in the art. The human antibodies of the present invention can be used in any class (IgG, IgA, IgM, IgE IgD, etc.) or isotype and may contain kappa or lambda light chains. In embodiments, the human antibody comprises an IgG heavy chain or a defined fragment, e.g., IgG1, Ig The antibody contains at least one of the following isotypes: IgG2, IgG3, or IgG4. The antibody may be any antibody that binds to at least one human antibody described herein and / or known in the art. Transfection of human light chains (e.g., IgG, IgA) and IgM (e.g., γ1, γ2, γ3, γ4) A transgenic mouse or other transgenic non-human mammal containing the gene. In another embodiment, the anti-human TNF human antibody can be prepared by using The body contains an IgG1 heavy chain and an IgG1 light chain.

[0160] As used herein, the term "antibody" or "antibodies" refers to the 2009 The Biologics Price Competition and Innovation Act (BPCI Act) and similar global legislation Under the BPCI Act, antibodies are classified as biosimilar antibodies, including those approved by the BPCI Act and regulations. , and is "very similar" to the reference product despite slight differences in clinically inactive ingredients. , and is "expected" to produce clinical results equivalent to those of the reference product in terms of safety, purity, and potency. If data indicate biosimilarity may be demonstrated (Endocrine Probe). Actice: February 2018, Vol. 24, No. 2, pp. 195-204). Similla antibody molecules offer an abbreviated approval pathway, allowing applicants to seek regulatory approval. We rely on clinical data from innovators' reference products to ensure Biosimilar antibodies compared to the original innovator reference antibody approved by the FDA based on Such molecules are referred to herein as "biosimilars." As provided herein, SIMPONI® (golimumab) approved by FDA based on successful clinical trials Golimumab is the original innovator reference anti-TNF antibody. It is sold in the United States.

[0161] Exemplary Sequences In various embodiments, the TNF inhibitor is the anti-TNF antibody SIMPONI® (golimumab), or an antigen-binding fragment thereof comprising the sequence shown below: Anti-TNF antibody SI For more information about MPONI® (golimumab) and other anti-TNF antibodies, see See, for example, U.S. Patent Nos. 7,250,165, 7,691,378, and 7, No. 521,206, No. 7,815,909, No. 7,820,169, No. 8,2 Nos. 41,899, 8,603,778, 9,321,836, and 9, See No. 828,424.

[0162] Example Sequence of an Exemplary Anti-TNFα Antibody—Simponi® (Golimumab) Each heavy chain CDR (HCDR) and light chain CDR (LCDR) corresponds to the heavy and light chains of golimumab. (defined by Kabat) is underlined.

[0163] Amino acid sequence of the golimumab heavy chain (HC) with CDRs underlined: (SEQ ID NO: 36)

[0164] [ka]

[0165] Amino acid sequence of the golimumab light chain (LC) with CDRs underlined: (SEQ ID NO: 37)

[0166] [ka]

[0167] Amino acid sequence of golimumab variable heavy chain (VH) with CDRs underlined: (SEQ ID NO: 38 )

[0168] [ka]

[0169] Amino acid sequence of the golimumab variable light chain (VL) with CDRs underlined: (SEQ ID NO: 39 )

[0170] [ka]

[0171] Amino acid sequence of complementarity determining region 1 (HCDR1) of golimumab heavy chain: (SEQ ID NO: 40) SYAMH

[0172] Amino acid sequence of complementarity determining region 2 (HCDR2) of the golimumab antibody heavy chain: (SEQ ID NO: 4 1) FMSYDGSNKKYADSVKG

[0173] Amino acid sequence of complementarity determining region 3 (HCDR3) of golimumab heavy chain: (SEQ ID NO: 42) DRGIAAGGNYYYYGMDV

[0174] Amino acid sequence of complementarity determining region 1 (LCDR1) of golimumab light chain: (SEQ ID NO: 43) RASQSVYSYLA

[0175] Amino acid sequence of complementarity determining region 2 (LCDR2) of golimumab light chain: (SEQ ID NO: 44) DASNRAT

[0176] Amino acid sequence of complementarity determining region 3 (LCDRL) of golimumab light chain: (SEQ ID NO: 45) QQRSNWPPFT

[0177] At least one antibody of the present invention may be directed to at least one TNF protein, subunit, or both. at least one specific epitope specific to the polypeptide, fragment, portion, or any combination thereof; The at least one epitope binds to at least a portion of the protein. and the epitope can preferably comprise at least one antibody binding region comprising , at least one extracellular portion of the protein, a soluble portion, a hydrophilic portion, an external portion, At least one identified epitope is present in the sequence. At least 1 to 3 amino acids for the entire specified portion of adjacent amino acids in sequence number 9 It can comprise any combination of at least one amino acid sequence.

[0178] Generally, the human antibodies or antigen-binding fragments of the invention contain at least one human complementarity-determining region. (CDR1, CDR2 and CDR3) or a variant of at least one heavy chain variable region, and At least one human complementarity determining region (CDR1, CDR2 and CDR3) or at least and an antigen-binding region comprising a variant of at least one light chain variable region. The antigen-binding portion or variant may comprise a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 3 and and / or at least one of the light chain CDR3s having the amino acid sequence of SEQ ID NO: 6. In certain embodiments, the antibody or antigen-binding fragment comprises corresponding CDR1, 2 and / or 3. at least one heavy chain having an amino acid sequence of (e.g., SEQ ID NOs: 1, 2 and / or 3) an antibody comprising at least a portion of a CDR (i.e., CDR1, CDR2, and / or CDR3); In another specific embodiment, the antibody or antigen-binding portion may have an original binding region. or variants of the corresponding CDR1, 2 and / or 3 amino acid sequences (e.g., SEQ ID NO: at least one light chain CDR (i.e., CDR1, CDR2, CDR3, CDR4, CDR5, CDR6, CDR7, CDR8, CDR9, CDR10, CDR11, CDR12, CDR13, CDR14, CDR15, CDR16, CDR17, CDR18, CDR19 ...10, CDR111, CDR12, C and an antigen-binding region comprising at least a portion of CDR2 and / or CDR3. In a preferred embodiment, the antibody or antigen-binding fragment has three heavy chain CDRs and three light chain CDRs. The chain CDRs are those of mAbs TNV148, TNV14, TNV15, At least one pair of TNV196, TNV118, TNV32, and TNV86 Such antibodies can be produced using conventional techniques involving recombinant DNA technology, with the amino acid sequences of the CDRs corresponding to the CDRs. The antibody is then subjected to a nucleic acid sequence encoding the antibody. or by using any other suitable method. Various parts of an antibody (e.g., CDRs, framework) are chemically linked together using It can be prepared by

[0179] Anti-TNF antibodies contain at least one heavy or light chain variable region having a defined amino acid sequence. For example, in a preferred embodiment, the anti-TNF antibody may include at least one of: Optionally, a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7 and / or optionally a heavy chain variable region having the amino acid sequence of SEQ ID NO: At least one of the light chain variable regions has the amino acid sequence of SEQ ID NO:8. Antibodies that bind to human TNF and that contain defined heavy or light chain variable regions can be produced by a suitable method, For example, phage dissociation vectors known in the art and / or described herein. Play (Katsube, Y. et al., "Int J Mol. Med" Vol. 1, No. 5, No. 86 3-868 (1998)) or methods employing transgenic animals, For example, functionally rearranged human immunoglobulins can be prepared using methods such as A human immunoglobulin heavy chain transgene and a human immunoglobulin light chain gene capable of undergoing functional rearrangement. and a transgenic mouse containing a transgene containing DNA from the locus, or a fragment thereof to induce the production of antibodies. The cells can be isolated and used as described herein and / or as known in the art. As is known, hybridomas or other immortalized antibody-producing cells can be prepared. Alternatively, the antibody, specified portion or variant can be produced by infecting an encoding nucleic acid in a suitable host cell. or a portion thereof can be expressed.

[0180] The present invention relates to amino acids in sequences that are substantially the same as the amino acid sequences described herein. The present invention also relates to antibodies, antigen-binding fragments, immunoglobulin chains and CDRs comprising the Antibodies or antigen-binding fragments containing such chains or CDRs have high affinity (e.g. , K. D is about 10 -9 M or less) and can bind to human TNF. The amino acid sequence that is substantially the same as the sequence described above includes conservative amino acid substitutions and amino acid substitutions. Conservative amino acid substitutions include sequences containing amino acid deletions and / or insertions. The amino acid is selected from the group consisting of a first amino acid, a second amino acid, a third amino acid, a fourth amino acid, a sixth amino acid, a sixth amino acid, a seventh ... Conservative substitution refers to the substitution of a second amino acid with a different amino acid (e.g., a nucleotide sequence, polarity, or hydrophobicity / hydrophilicity). Substitutions involve replacing one amino acid with another amino acid within the following group: lysine ( K), arginine (R) and histidine (H); aspartate (D) and glutamine Acid salt (E); Asparagine (N), Glutamine (Q), Serine (S), Threonine (T) , tyrosine (Y), K, R, H, D, and E; alanine (A), valine (V), leucine (L), isoleucine (I), proline (P), phenylalanine (F), tryptophan (T) thiamin (W), methionine (M), cysteine ​​(C), and glycine (G); F, W, and Y ;C, S, and T.

[0181] Amino Acid Codes: The amino acids that make up the anti-TNF antibodies of the invention are often abbreviated. The amino acid notation can be its one-letter code, its three-letter code, its name, or three nucleotides. The codons used to represent amino acids can be used to represent amino acids, and are well understood in the art. (Alberts, B. et al., "Molecular Biology of The Cell” 3rd edition, Garland Publishing, Inc., Ne. (See York (1994)).

[0182] [Table 1]

[0183] The anti-TNF antibodies of the invention may be naturally occurring or humanized, as specified herein. may contain one or more amino acid substitutions, deletions, or additions by any of the manipulations .

[0184] Of course, the number of amino acid substitutions that one skilled in the art can make is limited to a large number, including those mentioned above. Generally speaking, for any given anti-TNF antibody, fragment or variant, The number of amino acid substitutions, insertions, or deletions in the 0, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, Not exceeding 5, 4, 3, 2, 1, e.g., 1 to 30, or any range or value therein .

[0185] Amino acids within the anti-TNF antibodies of the invention that are essential for function can be identified by site-directed mutagenesis or are identified by methods known in the art, such as alanine scanning mutagenesis. (See, e.g., Ausubel, supra, Chapters 8 and 15; Cunningham and Wells, Science, 244, 1081-1085 (1989). The latter procedure involves the introduction of single alanine mutations at every residue in the molecule. The resulting mutant molecules may have, for example, at least one TNF-neutralizing activity. These are tested for biological activity including, but not limited to, the following: Key sites will also be identified by structural analysis such as crystallization, nuclear magnetic resonance, or photoaffinity labeling. (Smith et al., J. Mol. Biol., vol. 224, pp. 899-904) (1992) and de Vos et al., Science, vol. 255, pp. 306-312 (1992)).

[0186] 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:

[0187] The anti-TNF antibody may further optionally comprise at least one of the flanking amino acids of SEQ ID NOs: 7 and 8. It may contain at least one polypeptide with 70 to 100% of its amino acids.

[0188] In one embodiment, an immunoglobulin chain or a portion thereof (e.g., a variable region, a CDR) The amino acid sequence of SEQ ID NO: 7, SEQ ID NO: 8 is the amino acid sequence of at least one corresponding chain of SEQ ID NO: 7, SEQ ID NO: 8. and approximately 70–100% 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 of these For example, the amino acid sequence of the light chain variable region may be the sequence of SEQ ID NO: 8. The amino acid sequence of the heavy chain CDR3 can be compared to SEQ ID NO:7. Preferably, the amino acid sequence has 70 to 100% amino acid identity (i.e., 90, 91, 9 2, 93, 94, 95, 96, 97, 98, 99, 100, or any range therein The values ​​(or values) may be calculated using suitable computer algorithms, as known in the art. It is determined using

[0189] Exemplary heavy and light chain variable region sequences are shown in SEQ ID NOs: 7 and 8. The antibody or specified variant thereof may contain any number of contiguous amino acid residues from an antibody of the invention. The number is selected from the group of integers consisting of 10 to 100% of the number of adjacent residues in the anti-TNF antibody. Optionally, this substring of contiguous amino acids is selected from 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. The number of is any number selected from the group consisting of 1 to 20, such as at least 2, 3, 4, or 5. can be an integer.

[0190] As will be apparent to one skilled in the art, the present invention includes a compound having at least one biological activity of the present invention. Biologically active antibodies include natural (non-synthetic), endogenous or related and previously identified antibodies. At least 20%, 30%, or 40%, and preferably at least 5%, of the known antibodies. 0%, 60% or 70%, and most preferably at least 80%, 90% or 95% to 1 The enzyme has a specific activity of 0.000%. The assay and quantification methods for enzyme activity and substrate specificity are , well known to those skilled in the art.

[0191] In another aspect, the present invention provides a method for preparing a compound according to any one of the methods described herein that is modified by the covalent attachment of an organic moiety. Such modifications may result in improved pharmacokinetic properties (e.g., and / or increased serum half-life in vivo. The organic moiety may be a linear or branched hydrophilic polymer group, a fatty acid group, or a fatty acid ester group. In certain embodiments, the hydrophilic polymeric group can have a molecular weight of about 800 to about 1. 20,000 daltons, polyalkane glycol (e.g., polyethylene glycol) polypropylene glycol (PPG), carbohydrate polymers, amino acids polymer or polyvinylpyrrolidone, and the fatty acid group or fatty acid ester group is It may contain from about 8 to about 40 carbon atoms.

[0192] The modified antibodies and antigen-binding fragments of the present invention are covalently bound to the antibody, either directly or indirectly. 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 polymer group, a fatty acid group, or a fatty acid ester group. As used herein, the term "fatty acid" refers to monocarboxylic and dicarboxylic acids. As used herein, the term "hydrophilic polymeric group" refers to a polymeric group such as octane. It refers to an organic polymer that is more soluble in water than in water. For example, polylysine is Therefore, antibodies modified with covalent polylysine bonds have a higher solubility in water than Suitable hydrophilic polymers for modifying the antibodies of the invention include linear or branched polymers. They may be branched, for example, polyalkane glycols (e.g., PEG, monomethoxy-poly ethylene glycol (mPEG, PPG, etc.), carbohydrates (e.g., dextran, sugars, oligosaccharides, polysaccharides, etc.), polymers of hydrophilic amino acids (e.g., polylysine, poly realginine, polyaspartic acid, etc.), polyalkane oxide (e.g., polyethylene Polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylvinyloxide, polypropylene oxide, etc. For example, the hydrophilic polymer that modifies the antibody of the present invention may be about 800 to about 1000 individual molecular entities. It has a molecular weight of 50,000 daltons. For example, PEG 5000 and PEG 20,00 0 can be used, and the subscript is the average molecular weight of the polymer in Daltons. The water-soluble polymer group is 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 are preferred. For example, a polymer containing amine groups can be prepared by It can be linked to the carboxylate salt of a fatty acid or a fatty acid ester, Activated carboxylates on esters (e.g., activated with N,N-carbonyldiimidazole) The hydroxyl groups on the polymer can be linked to the hydroxyl groups on the polymer.

[0193] Fatty acids and fatty acid esters suitable for modifying antibodies of the invention may be saturated. The antibodies of the present invention may contain one or more unsaturated units. Suitable fatty acids include, for example, n-dodecanoate (C 12 , laurate), n-Tet Ladecanoate (C 14 , myristate), n-octadecanoate (C 18 , stearin acid salt), n-eicosanoate (C 20 , arachidate), n-docosanoate (C 22 , behenic acid), n-triacontanoate (C 30 ), n-tetracontanoate (C 40 ), cis-Δ9-octadecanoate (C 18 , oleate), all cis-Δ5,8,11 ,14-eicosatetraenoic acid salt (C 20 , arachidonate), octanedioic acid, tetrahydrofuran Examples of suitable hydroxycarboxylic acids include octadecanedionic acid, docosanedioic acid, and the like. Fatty acid esters are monoesters of dicarboxylic acids containing straight or branched chain lower alkyl groups. The lower alkyl group may contain 1 to about 12, preferably 1 to about 6, carbon atoms. do.

[0194] The modified human antibodies and antigen-binding fragments can be subjected to any suitable treatment, such as by reacting with one or more modifying agents. As used herein, the term "modifying agent" refers to a compound that can be prepared using a method such as the The term refers to a suitable organic group (e.g., hydrophilic polymers, fatty acids, fatty acid esters) containing an activating group. An "activating group" means a group that, under appropriate conditions, reacts with a second chemical group, thereby A chemical moiety or functional group capable of forming a covalent bond between the modifying agent and a second chemical group. For example, amine-reactive activating groups include tosylate, mesylate, halo (chloro, bromo) Electrophilic groups such as mono, fluoro, and iodo, and N-hydroxysuccinimidyl esters (N HS) and the like. Examples of activating groups that can react with thiols include maleimide, iodine, and the like. acetyl, acrylolyl, pyridyl disulfide, 5-thiol-2-nitrobenzoic acid The aldehyde functional group can be an amine or The hydrazide-containing molecule can be linked, and the azide group can react with the trivalent phosphorus group to form A phosphoramidate or phosphorimide bond can be formed. Suitable methods for introducing ##STR00001## are known in the art (e.g., Hermans on, GT, “Bioconjugate Techniques”, Academ (See, e.g., ic Press: San Diego, CA (1996)). The group may be attached directly to an organic group (e.g., a hydrophilic polymer, a fatty acid, a fatty acid ester) or to a linker. Linker moieties, e.g., divalent C1-C 12 a group in which one or more carbon atoms are oxygen The bond can be via a heteroatom (which may be substituted with a heteroatom such as , nitrogen, or sulfur). Suitable linker moieties include, for example, tetraethylene glycol, —(CH 2 ) 3 —, —NH— (CH2)6-NH-, -(CH2)2-NH- and -CH2-O-CH2-CH2-O -CH2-CH2-O-CH-NH-. Modifiers containing a linker moiety include, for example, 1- In the presence of ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), -Boc-alkyldiamines (e.g., mono-Boc-ethylenediamine, mono-Boc -diaminohexane) with fatty acids to produce free amines and fatty acid carboxylates. The Boc protecting group can be removed by forming an amide bond between the The product was removed by trifluoroacetic acid (TFA) treatment and another carboxylate was added as described. This can expose a primary amine that can be coupled to a maleic anhydride. and the resulting product is cyclized to form an activated maleimide derivative of the fatty acid. (See, e.g., Thom, 1999, the teachings of which are incorporated herein by reference in their entirety. See WO 92 / 16221 to Pson et al.

[0195] 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 these compounds can be used to conjugate them to antibodies in a non-site-specific manner. Disulfide bonds (e.g., intrachain disulfide bonds) of antibodies or antigen-binding fragments can be Modified human antibodies or antigen-binding fragments can also be prepared by reduction. In this case, the reduced antibody or antigen-binding fragment is reacted with a thiol-reactive modifying agent to form the antibody or antigen-binding fragment of the present invention. It is possible to produce a variety of modified antibodies. Modified human antibodies and antigen-binding fragments containing an organic moiety are synthesized by reverse proteolysis (Fisc). h et al., "Bioconjugate Chem." Vol. 3, pp. 147-153 (1992) Werlen et al., Bioconjugate Chem., Vol. 5, No. 411-4 17 (1994), Kumaran et al., Protein Sci., Vol. 6, No. 10 No. 2233-2241 (1997), Itoh et al., "Bioorg. Chem." 24, No. 1, pp. 59-68 (1996), Capellas et al., "Biotech 56, No. 4, pp. 456-463 (1997)) and He rmanson, GT, "Bioconjugate Techniques", A Academic Press: San Diego, CA (1996) The compound can be prepared using any suitable method, such as the method described above.

[0196] Anti-idiotypic antibodies to anti-TNF antibody compositions. Monoclonal or chimeric anti-TNF In addition to F antibodies, the present invention also provides anti-idiotypes (anti-Ids) specific for such antibodies of the present invention. Anti-Id antibodies generally contain unique determinants associated with the antigen-binding region of another antibody. Anti-Id is an antibody that recognizes the Id antibody from an animal (e.g., mouse) of the same species and genotype as the source of the Id antibody. can be prepared by immunizing a strain of the host (a strain of the host) with the antibody or a CDR-containing region thereof. The immunized animal recognizes and responds to the idiotypic determinants of the immunizing antibody, producing anti-Id Anti-Id antibodies can also be used as "immunogens" to induce immune responses in other animals. It can be used to generate so-called anti-anti-Id antibodies.

[0197] Anti-TNF antibody compositions. The present invention relates to compositions comprising anti-TNF antibodies described herein and / or known in the art. As known, at least one, or a few, compounds provided in a non-naturally occurring composition, mixture, or form. At least two, at least three, at least four, at least five, at least six or more Also provided is at least one anti-TNF antibody composition comprising the anti-TNF antibody. The composition is 70 to 100% of the adjacent amino acids of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, or an anti-TNF antibody selected from the group consisting of a specified fragment, domain, or variant thereof; At least one or two full-length, C- and / or N-terminal deletion variants of the amino acid sequence of , domains, fragments, or specified variants thereof. The anti-TNF antibody composition contains 70 to 100% of the anti-TNF antibodies of SEQ ID NOs: 1, 2, 3, 4, 5, and 6. at least one CDR or a specified fragment, domain or variant thereof At least one or two full-length, fragment, domain, or variant LBR-containing portions More preferred compositions include 70-100% of SEQ ID NO: 1, 2, 3, 4, 5, 6, or Contains 40-99% of at least one of the specified fragments, domains, or variants thereof Percentages of such compositions may be used as known in the art or as set forth herein. As described, by weight, volume, concentration, molarity, or liquid or dry solution, By molality as a mixture, suspension, emulsion, or colloid.

[0198] The anti-TNF antibody compositions of the present invention further comprise a compound that can be used to treat 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 These include antibodies or fragments thereof, fusion proteins thereof, or small molecule TNF antagonists. antirheumatic drugs (e.g., methotrexate, auranofin, thiazolinone ... Lothioglucose, azathioprine, etanercept, sodium gold thiomalate, sulfuric acid Hydroxychloroquine, Leflunomide, Sulfasalidine), muscle relaxants, narcotics, nonsteroidal antihistamines Nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, anesthetics, sedatives, local anesthetics, neuromuscular blockers , antibacterial agents (e.g., aminoglycosides, antifungals, anthelmintics, antivirals, carbapenems) , cephalosporins, fluoroquinolones, macrolides, penicillins, sulfonamides, Tetracyclines, other antibacterials), antipsoriatics, corticosteroids, anabolics Steroids, diabetes-related drugs, minerals, nutritional drugs, thyroid drugs, vitamins, calcium-related hormones Antidiarrheals, antitussives, antiemetics, antiulcer drugs, laxatives, anticoagulants, erythropoietic drugs (e.g. e.g., epoetin alfa), filgrastim (e.g., G-CSF, Neupogen), Gramostim (GM-CSF, Leukine), vaccination, immunoglobulin, immunosuppression medicines (e.g., basiliximab, cyclosporine, daclizumab), growth hormone, hormone Supplements, estrogen receptor modulators, mydriatics, cyclomodulators, alkylating agents, antimetabolites , mitotic inhibitors, radiopharmaceuticals, antidepressants, antimanic drugs, antipsychotics, anxiolytics, hypnotics , sympathomimetic drugs, stimulants, donepezil, tacrine, asthma medications, beta-agonists, inhaled steroids , leukotriene inhibitors, methylxanthines, cromolyn, epinephrine or similar drugs, lunase alpha (Pulmozyme), cytokines or cytokine antagonists any suitable and effective amount of the composition or pharmaceutical composition further comprising at least one of Non-limiting examples of such cytokines include IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19 ... Suitable dosages include, but are not limited to, any of the following: IL-23. See, for example, Wells et al., "Pharmacotherapy H andbook,” 2nd ed., Appleton and Lange, Stamford, CT (2000), “PDR Pharmacopoeia, Tarascon Po cket Pharmacopoeia 2000'', special edition, Tarascon Pu See Blishing, Loma Linda, CA (2000). each of which is incorporated herein by reference in its entirety.

[0199] Such anti-cancer or anti-infective agents may be associated, bound, or associated with at least one antibody of the invention. The toxin may also contain a toxin molecule that is co-administered or used in combination with the toxin. The toxin selectively kills diseased cells or tissues. The pathological cells may be cancer cells or other cells. Such toxins include, but are not limited to, ricin, diphtheria, At least one of the toxins is selected from at least one of a bacterial toxin, a snake toxin, or a bacterial toxin. It can be a purified or recombinant toxin or toxin fragment containing one functional cytotoxic domain. The term toxin also refers to the potentially fatal toxic shock that occurs in humans and other mammals. Any naturally occurring, mutated, or recombinant bacteria or viruses that can cause any disease state, including These include both endotoxins and exotoxins produced by viruses. Escherichia coli heat-labile enterotoxin (LT), heat-stable enterotoxin (ST), red Diarrhea cytotoxin, Aeromonas enterotoxin, toxic shock syndrome toxin-1 (TS ST-1), Staphylococcal enterotoxin A (SEA), B (SEB), or C (SEC ), streptococcal enterotoxins, etc., but are not limited to these. Such bacteria include enterotoxigenic Escherichia coli (ETEC), enterohemorrhagic Escherichia coli (e.g., serotype 015), 7 strains: H7), Staphylococcus species (e.g., Staphylococcus aureus, Staphylococcus pyogenes), ness), Shigella species (e.g., Shigella dysenteriae, Shigella flexneri, Shigella boydii, and Shigella sonnei Shigella), Salmonella species (e.g., Salmonella typhi, Salmonella cholera-suis, Salmonella enteritidis), Clostridium species (e.g., Clostridium perfringens Clostridium difficile, Clostridium botulinum), Campylo Bacter species (e.g., Campylobacter jujuni, Campylobacter fetus), Helicobacter Helicobacter species (e.g., Helicobacter pylori), Aeromonas species (e.g., Aeromonas -Sobria, Aeromonas hydrophila, Aeromonas caviae), Plesiomona S. shigelloides, Yersinia enterocolitica, Vibrio species (e.g., Vibrio cholerae, Vibrio parahaemolyticus) including, but not limited to, strains of Klebsiella species, Pseudomonas aeruginosa, and Streptococcus species. For example, Stein, ed., "INTERNAL MEDICINE," 3rd ed., 1999 pp. 1-13, Little, Brown and Co., Boston (1990) , Evans et al., eds., Bacterial Infections of Humans :Epidemiology and Control” 2nd edition, pp. 239-254, P. lenum Medical Book Co., New York (1991), M andell et al., “Principles and Practice of Infe ctious Diseases" 3rd edition, Churchill Livingston e, New York (1990), Berkow et al. (eds.), "The Merck Ma 16th edition, Merck and Co., Rahway, NJ (1992 (2003), Wood et al., "FEMS Microbiology Immunology", Vol. Marrack et al., Science, Vol. 76, pp. 121-134 (1991), Vol. 2 48, pp. 705-711 (1990) (the contents of these documents are incorporated by reference). (which is incorporated herein in its entirety).

[0200] The anti-TNF antibody compounds, compositions or mixtures of the present invention may further comprise a diluent, binder, stabilizer, buffer, or the like. any additives, such as, but not limited to, buffers, salts, lipophilic solvents, preservatives, adjuvants, etc. The composition may contain 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, including: For example, Gennaro, ed., "Remington's Pharmaceutical Sciences,” 18th ed., Mack Publishing Co. (East n, PA) (1990), and the like. or a method of administering an anti-TNF antibody, fragment, or variant composition as described herein; It is routine to select a pharmaceutically acceptable carrier suitable for solubility and / or stability. can.

[0201] Pharmaceutical additives and excipients useful in the present compositions include, but are not limited to, tannins, lactic acid bacteria ... Proteins, peptides, amino acids, lipids and carbohydrates (e.g., monosaccharides, disaccharides, trisaccharides, tetrasaccharides, and sugars including oligosaccharides, derivatized sugars such as alditols, aldonic acids, and esterified sugars; and polysaccharides or sugar polymers), which may be present alone or in combination. , alone or in combination, in an amount of 1 to 99.99% by weight or volume. Protein additives include serum albumins such as human serum albumin (HSA), recombinant human albumin (RIA), and Typical examples of buffering agents include rHA, gelatin, and casein. Amino acids / antibody components include alanine, glycine, arginine, betaine, and histidine , glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, Preferred amino acids include amine, methionine, phenylalanine, and aspartame. One of the acids is glycine.

[0202] Suitable carbohydrate additives for use in the present invention include, for example, fructose, maltose, Monosaccharides such as lactose, galactose, glucose, D-mannose, and sorbose, Disaccharides such as sucrose, trehalose, and cellobiose, raffinose, melezitol, Polysaccharides such as maltodextrin, dextran, and starches, mannitol, xylitol, Lactitol, maltitol, lactitol, xylitol, sorbitol (glucitol), Preferred carbohydrates for use in the present invention include alditols such as myo-inositol. The compound additives are mannitol, trehalose, and raffinose.

[0203] The anti-TNF antibody composition may also include a buffer or pH adjusting agent; typically, the buffer is an organic A salt prepared from an acid or base. Typical buffers include citric acid, ascorbic acid, organic acid salts such as salts of acetic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid; Suitable anti-inflammatory agents for use in the present compositions include phosphate buffer, thiamin mononitrate, thrombin hydrochloride, and phosphate buffer. Preferred buffers are organic acid salts such as citrate.

[0204] In addition, the anti-TNF antibody composition of the present invention contains polyvinylpyrrolidone, Ficoll (polymer sugars), dextrates (e.g., 2-hydroxypropyl-β-cyclodextrin, etc. (Cyclodextrin), polyethylene glycol, flavoring, antibacterial agent, sweetener, antioxidant agents, antistatic agents, surfactants (e.g., "TWEEN 20" and "TWEEN 80" polysorbates), lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol polymer additives / additives such as esters, and chelating agents (e.g., EDTA) obtain.

[0205] These and additional compounds suitable for use in anti-TNF antibody, portion or variant compositions according to the invention Additional known pharmaceutical additives and / or excipients are known in the art and include, for example: "Remington: The Science & Practice of Pharm acy," 19th edition, Williams & Williams, (1995), and "Ph Doctor's Desk Reference, 52nd Edition, Medical E These developments are listed in Economics, Montvale, NJ (1998). The disclosure of which is incorporated herein by reference in its entirety. Preferred carrier or additive materials are carbohydrates. compounds (e.g., monosaccharides and alditols) and buffers (e.g., citric acid) or polymers It is a drug.

[0206] Formulations. As noted above, the present invention preferably provides a formulation containing saline or a selected salt. Stable formulations that are phosphate buffers, as well as preservative-containing storage solutions and formulations, and pharmaceutical Pharmaceutical or veterinary uses comprising at least one anti-TNF antibody in a therapeutically acceptable formulation - Patent Application 20070122933 The present invention provides a multi-use preserved formulation suitable for the treatment of various conditions. The preserved formulation comprises at least one pre-existing compound in an aqueous diluent. known preservatives, or at least one of phenol, m-cresol, p-cresol, o- Cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrate, phenoxyethanol ethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate ), alkylparaben (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride Benzethonium chloride, sodium dehydroacetate, and thimerosal, or The preservative is optionally selected from the group consisting of a mixture of As is known, 0.001 to 5%, or 0.001, 0.003, 0.005, 0.0 09, 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. Any suitable concentration or mixture may be used, without limitation, any range or value therein. Non-limiting examples include preservative-free, 0.1-2% m-cresol (e.g., 0 0.2, 0.3, 0.4, 0.5, 0.9, 1.0%), about 0.1 to 3% benzyl alcohol rule (e.g., 0.5, 0.9, 1.1, 1.5, 1.9, 2.0, 2.5%), 0.0 0.1-0.5% 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 to 1.0% alkylparabens (e.g., 0.00075, 0.0009 ,0.001,0.002,0.005,0.0075,0.009,0.01,0.0 2, 0.05, 0.075, 0.09, 0.1, 0.2, 0.3, 0.5, 0.75, 0 0.9, 1.0%).

[0207] As mentioned above, the present invention provides a pharmaceutical composition comprising a packaging material and, optionally, a buffer formulated in an aqueous diluent. and / or at least one vial containing a solution of at least one anti-TNF antibody with a preservative. and the packaging material is configured to contain the solution in the form of 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 relates to a packaging material and a label that indicates that the product can be stored for a long period of time. a first vial containing at least one anti-TNF antibody formulated in a formulation containing a buffer or preservative; and a second vial containing an aqueous diluent of the preservative, and the packaging material further comprises at least At least one anti-TNF antibody is reconstituted in an aqueous diluent and maintained for at least 24 hours. The composition includes a label instructing the patient to form a solution that can be administered intravenously.

[0208] At least one anti-TNF antibody used in accordance with the present invention may be any of those described herein or It can be produced from mammalian cells or transgenic preparations, as known in the art. The polypeptide may be produced by recombinant means, including by recombinant DNA technology, or may be purified from other biological sources.

[0209] The range of at least one anti-TNF antibody included in the product of the present invention is a wet / dry system. In this case, the amount is such that upon reconstitution a concentration ranging from about 1.0 μg / ml to about 1000 mg / ml is obtained. However, lower and higher concentrations are possible and these concentrations are not intended. The delivery vehicle chosen depends on the type of drug, e.g., solution formulations, transdermal patches, pulmonary, transmucosal, or is different from osmotic or micropump methods.

[0210] Preferably, the aqueous diluent optionally further comprises a pharmaceutically acceptable preservative. New preservatives include phenol, m-cresol, p-cresol, o-cresol, and chloroform. Benzyl alcohol, alkylparaben (methyl, ethyl, propyl, butylparaben) Benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and Thimerosal or mixtures thereof. The concentration of preservative used is sufficient to produce an antimicrobial effect. The amount of preservative used will vary and can be easily determined by one skilled in the art.

[0211] Other additives, such as isotonicity agents, buffers, antioxidants, preservative enhancers, may be added as desired. Preferably, an isotonic agent such as glycerin can be added to the diluent at a known concentration. Generally used. Preferably, a physiologically tolerable buffer is added to improve pH control. The formulations provide a pH range of about pH 4 to about pH 10, and preferably about pH 5 to about pH 9. and most preferably in the range of about 6.0 to about 8.0. Preferably, the formulation of the present invention has a pH of about 6.8 to about 7.8. Suitable buffers include phosphate buffers, most preferably sodium phosphate, especially phosphate. phosphate-buffered saline (PBS).

[0212] Other additives, such as Tween 20 (polyoxyethylene (20) sorbitan monolaurate) rate), Tween 40 (Polyoxyethylene (20) sorbitan monopalmitate) , Tween 80 (Polyoxyethylene (20) sorbitan monooleate), Plur onic F68 (polyoxyethylene polyoxypropylene block copolymer), and and PEG (polyethylene glycol), or a pharmaceutically acceptable solubilizer. Poloxamer 20 or 80 or Poloxamer 184 or 188, Pluronic Nonionic surfactants such as Benzyl Alcohols, other block copolymers, and In addition, chelating agents such as EDTA and EGTA can be optionally added to the formulation or composition to improve coagulation. These additives can be used in pumps or pumps to administer the formulation. This is particularly useful when a stick container is used. The presence of a pharmaceutically acceptable surfactant This reduces the tendency of the protein to aggregate.

[0213] The formulations of the present invention comprise at least one anti-TNF antibody and a soluble component selected from the group consisting of phenol, m-cresol, p -cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl para Benzyl (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride from the group consisting of thimerosal, ... and a selected preservative, in an aqueous diluent. The mixture of at least one anti-TNF antibody and a preservative in an aqueous diluent can be used in a variety of ways, including conventional methods. Dissolution and mixing procedures are used to prepare suitable formulations. A quantity of at least one anti-TNF antibody in a solution containing a desired concentration of protein and a preservative is added. The mixture is combined with the desired preservative in a buffer solution sufficient to provide a desired product. The form will be recognized by one of ordinary skill in the art. For example, the order of addition of the components, the additional addition The use of an antiviral agent, the temperature and pH during preparation of the formulation, all relate to the dosage concentration and administration method used. It is a factor that can be optimized.

[0214] The claimed formulations may be prepared as clear solutions or in the presence of water, preservatives and / or excipients, preferably Preferably, phosphate buffer and / or saline, and selected salts in aqueous diluents. and a second vial containing at least one lyophilized anti-TNF antibody. It can be provided to patients as a dual vial containing a vial of the active ingredient. Either the single solution vial or the dual vial requiring reconstitution may be reused multiple times. can satisfy single or multiple patient treatment cycles, and therefore, It may provide a more convenient treatment regimen than is available.

[0215] The claimed product is useful for administration from immediate to over a 24 hour period. Thus, the products claimed by the present invention provide significant benefits to patients. The formulation can optionally be safely stored at a temperature of about 2 to about 40°C, and the protein The biological activity of the solution can be maintained for a long period of time, and therefore, the packaging label recommends that the solution be kept for 6 to 1 Can be retained and / or used for 2, 18, 24, 36, 48, 72, or 96 hours or more If a stored diluent is used, such label may indicate a maximum of 1 to 10 mg of This can include use up to 12 months, six months, one and a half years, and / or two years.

[0216] Solutions of at least one anti-TNF antibody of the present invention comprise dissolving at least one antibody in an aqueous diluent. The mixture can be prepared by a process comprising mixing in a conventional dissolving and To prepare a suitable diluent, for example, water or a buffer a desired concentration of protein, and optionally a preservative, or in an amount sufficient to provide a buffer. Variations of this process are known to those skilled in the art. For example, the order of addition of components, whether additional additives are used, etc. The temperature and pH of the formulation are all optimized for the dosage concentration and means of administration used. This is a factor that can be used.

[0217] The claimed product is available as a clear solution or in a second vial containing an aqueous diluent. A dual vial containing at least one lyophilized anti-TNF antibody vial reconstituted with It can be provided to patients as a single solution vial or as a reconstitution-requiring vial. Both dual vials can be reused multiple times for single or multiple patient treatment cycles. This could potentially satisfy the needs of patients with HIV / AIDS, thus providing a more convenient treatment regimen than is currently available. do.

[0218] The claimed product is reconstituted in a second vial containing a clear solution or aqueous diluent. Dual vials containing at least one lyophilized vial of anti-TNF antibody, to pharmacies, clinics, or other such institutions and facilities. In this case, the clear solution can be delivered indirectly up to 1 liter or even more. or more, and a smaller volume of at least one antibody solution is dispensed from this larger container. One or more withdrawals are transferred to smaller vials and distributed to customers and clinics by the pharmacy or clinic. and / or can be provided to patients.

[0219] Recognized devices that include these single vial systems include the BD® ( Pen-type injector device), NOVOPEN (registered trademark) (pen-type injector device), AUTOPEN (registered trademark) (pen-type injector device), OPTIPEN (registered trademark) (Pen-type injector device), GENOTROPIN PEN (registered trademark) (Pen-type injector device) -HUMATROPEN (registered trademark) (pen-type injector device), B IOJECTOR (registered trademark) (pen-type injector device), Reco-Pen, Hum aject, J-tip Needle-Free Injector, Intraje Examples include pen-type injector devices for delivering solutions such as CT and Medi-Ject. and are manufactured or developed, for example, by Becton Dickens ( Franklin Lakes, NJ, www.bectondickenson.co m), Disetronic (Burgdorf, Switzerland, www.d isetronic.com, Bioject, Portland, Oregon (ww w.bioject.com), National Medical Products , Weston Medical (Peterborough, UK, www.west on-medical.com), Medi-Ject Corp (Minneapol is, MN, www.mediject.com). Approved devices, including combination vials Examples include the HUMATROPEN (registered trademark) (pen-type injector device) and reconstituting the lyophilized drug in a cartridge for delivery of the reconstituted solution. Examples include pen-type injector systems.

[0220] The products claimed herein include packaging. The packaging may be required by a regulatory agency. In addition to the information about the product, the packaging material of the present invention also provides the conditions under which the product can be used. At least one anti-TNF antibody is reconstituted with an aqueous diluent to form a solution, and the solution is left to stand for at least 2-24 hours. The instructions stated that this solution should be used for two vials of wet / dry product over a period of time. For single-vial solution products, the label should state that the solution is The products claimed herein can be used for human pharmaceutical applications. It is useful for

[0221] The formulations of the present invention comprise at least one anti-TNF antibody and a selected buffer, preferably a biocompatible buffer. by a process that includes mixing saline or a phosphate buffer containing the selected salt. The mixture of at least one antibody and a buffer in an aqueous diluent can be prepared by: Conventional dissolution and mixing procedures are used to prepare suitable formulations, e.g. A quantity of at least one antibody in water or buffer is added to the desired concentration of protein and buffer. and a desired buffer in a sufficient amount of water to provide a solution of the compound. For example, the order of addition of the components, the amount of additional additives, etc., will be recognized by those skilled in the art. Whether or not it is used, the temperature and pH during preparation of the formulation, and the dosage concentration and administration method used It is a factor that can be optimized.

[0222] The claimed stable or preserved formulations are available as clear solutions or in aqueous diluents containing preservatives or or a lyophilized small vial that is reconstituted in a second vial containing buffer and additives. Provide patients with dual vials containing at least one vial of anti-TNF antibody. Both single solution vials or dual vials requiring reconstitution can be used in multiple It can be reused multiple times to satisfy single or multiple patient treatment cycles. This provides a more convenient treatment regimen than is currently available.

[0223] At least one of the stable or preserved formulations or solutions described herein TNF antibodies can be administered by SC or IM injection, transdermal, pulmonary, or intravenous route, as is well known in the art. Mucosal membranes, implants, osmotic pumps, cartridges, micropumps or The present invention provides a method for the delivery of a pharmaceutical composition to a patient via a variety of delivery methods, including other means known and understood by those skilled in the art. It can be administered to a subject.

[0224] Therapeutic Applications. The present invention relates to therapeutic applications of compounds known in the art or as described herein. and the like. Also provided are methods for modulating or treating at least one TNF-related disorder in a patient. do.

[0225] The present invention relates to a method for treating obesity, immune-related diseases, cardiovascular diseases, infectious diseases, malignant diseases or neurological diseases. In a cell, tissue, organ, animal or patient, including but not limited to at least one of Also provided are methods for modulating or treating at least one TNF-related disorder in a subject.

[0226] The present invention relates to rheumatoid arthritis, juvenile and systemic onset juvenile rheumatoid arthritis, ankylosing spondylitis, and rheumatoid arthritis. Orthodontic 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 / vas deferens Excision and repair, allergic / atopic diseases, asthma, allergic rhinitis, dermatitis, allergies Allergic contact dermatitis, allergic conjunctivitis, hypersensitivity pneumonitis, transplantation, organ transplant rejection, transplantation Gram-versus-host disease, systemic inflammatory response syndrome, sepsis syndrome, gram-positive sepsis, gram-negative sepsis sepsis, culture-negative sepsis, fungal sepsis, neutropenic fever, urinary sepsis, 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, NEPH Rose, atopic diseases, hypersensitivity reactions, allergic rhinitis, hay fever, perennial rhinitis, conjunctivitis , endometriosis, asthma, urticaria, systemic anaphylaxis, dermatitis, pernicious anemia, hemolytic disease , thrombocytopenia, any organ or tissue transplant rejection, kidney transplant rejection, heart transplant rejection Reaction, liver transplant rejection, pancreas transplant rejection, lung transplant rejection, bone marrow transplant (BMT) rejection Reaction, skin allograft rejection, cartilage graft rejection, bone graft rejection, small intestine transplant rejection , fetal thymus transplant rejection, parathyroid transplant rejection, any organ or tissue xenograft rejection response, allograft rejection, antireceptor hyperreaction, Graves' disease, Raynaud's disease, type B insulin Resistant diabetes, asthma, myasthenia gravis, antibody-mediated cytotoxicity, type III hypersensitivity reaction, systemic Lupus erythematosus, POEMS syndrome (polyneuropathy, organomegaly, endocrine disorders, monoclonal gammopathy, and cutaneous syndrome), polyneuropathy, organomegaly, endocrine Disorders, monoclonal gammopathy, skin symptom syndrome, antiphospholipid syndrome, pemphigus, Scleroderma, mixed connective tissue disease, idiopathic Addison's disease, diabetes mellitus, chronic active hepatitis, primary biliary tract infection Hemolytic cirrhosis, vitiligo, vasculitis, post-MI cardiotomy syndrome, type IV hypersensitivity, contact dermatitis, hypersensitivity Sensitivity pneumonitis, allograft rejection, granulomas caused by intracellular organisms, drug hypersensitivity, metabolic / idiopathic virus Luson's disease, hemacromatosis, alpha-1-antitrypsin deficiency, diabetic retinopathy, pontine Thyroiditis, osteoporosis, primary biliary cirrhosis, thyroiditis, encephalomyelitis, cachexia, cystic fibrosis Neonatal chronic lung disease, chronic obstructive pulmonary disease (COPD), familial hemophagocytic lymphohistiocytosis Hypertension, dermatological conditions, psoriasis, alopecia, nephrotic syndrome, nephritis, glomerulonephritis, acute Renal failure, hemodialysis, uremia, toxicity, pre-eclampsia, OKT3 therapy, anti-CD3 therapy, cytotoxicity Radiation therapy, chemotherapy, and radiation therapy (e.g., asthenia, anemia, cachexia, etc.) and chronic salicylate intoxication, among others. at least one immune-related disease in a cell, tissue, organ, animal, or patient, including but not limited to Also provided are methods for regulating or treating diseases. 12th to 17th editions, Merck & Company, Rahway, NJ (1972, 1 977, 1982, 1987, 1992, 1999), “Pharmacoth "Erapy Handbook," edited by Wells et al., 2nd ed., Appleton and See Lange, Stamford, and Conn. (1998, 2000). , each of which is incorporated by reference in its entirety.

[0227] The present invention provides a method for treating cardiac stun syndrome, myocardial infarction, congestive heart failure, and other conditions. , stroke, ischemic attack, hemorrhage, arteriosclerosis, atherosclerosis, restenosis, diabetic arteries Sclerotic diseases, hypertension, arterial hypertension, renovascular hypertension, syncope, shock, syphilis of the cardiovascular system , heart failure, cor pulmonale, primary pulmonary hypertension, arrhythmia, atrial ectopic beats, atrial flutter, atrial fibrillation (chronic persistent or paroxysmal), post-reflow syndrome, cardiopulmonary bypass inflammatory response, chaotic or multifocal atrial tachycardia , regular narrow QRS tachycardia, specific arrhythmia ventricular fibrillation, His bundle arrhythmias, atrioventricular block, bundle branch block Lock, myocardial ischemic disease, coronary artery disease, angina pectoris, myo...

Claims

1. A method for treating patients with active psoriatic arthritis (PsA) comprising administering intravenously ( IV) administering to said patient a dose of an anti-TNF antibody, said anti-TNF antibody having the sequence A heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 36 and a light chain comprising the amino acid sequence of SEQ ID NO:

37. (LC), and after 52 weeks of treatment, the patient has a disease activity in PsA (DAPS) A) Achieve score-based remission to low disease activity or the patient achieves a PsA activity score and achieving inactive disease activity based on the PASDAS or the patient achieving clinical disease activity. and the patient achieves remission based on the CDAI score or minimal disease activity (MDA). A) achieves a score or the patient achieves a very low disease activity (VLDA) score. The method.

2. More than 45% of the patients achieve remission to low disease activity based on the DAPSA score. or more than 45% of the patients achieve inactive disease activity based on the PASDAS more than 25% of said patients achieve remission based on said CDAI score or 40% of said patients More than 12% of the patients achieve the MDA score or more than 12% of the patients achieve the VLDA score. The method of claim 1 .

3. A method for treating a patient with active psoriatic arthritis, comprising administering an intravenous (IV) dose to said patient, wherein said anti-TNF antibody is of the formula: A heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 37 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO:

37. and after 52 weeks of treatment, the patient has a Psoriasis Area and Severity Index (PASI) score of 75% improvement in PASI score (PASI 75), 90% improvement in PASI score (PASI 90), or achieve a 100% improvement in PASI score (PASI 100), How to write.

4. The patient has 3% or more body surface area (BSA) psoriasis involvement at baseline. Item 3. The method according to item 3.

5. More than 70% of the patients achieve the PASI 75 or more than 55% of the patients achieve the PASI 75. Achieving SI90 or having more than 25% of the patients achieve PASI100. Item 3. The method according to item 3.

6. The patient has a 5-point or greater improvement in Dermatological Life Quality Index (DLQI) score. The method of claim 3, wherein the method achieves the desired effect.

7. More than 60% of the patients have a 5-point improvement in the PASI75 and DLQI scores or more than 50% of the patients achieve an improvement of at least 10% in the PASI 75 and DLQI scores. Achieve a 5-point or greater improvement in core or more than 20% of the patients achieve the 5-point or greater improvement in core. Achieving the 5 or more point improvement in ASI100 and the DLQI score. The method according to claim 6.

8. The patient achieves an American College of Rheumatology 20% improvement (ACR20) response. The method of claim 3 comprising:

9. More than 55% of the patients achieve the PASI 75 and ACR 20 response or More than 45% of patients achieve the PASI90 and ACR20 response, or 9. The method of claim 8, wherein more than 20% achieve the PASI 100 and ACR 20 response. Law.

10. A method for treating a patient with active psoriatic arthritis, comprising administering an intravenous (IV) dose to said patient, wherein said anti-TNF antibody is of the formula: A heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 37 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO:

37. and modified Nail Psoriasis Severity Index (mNAPSI) scores at baseline and after 52 weeks of treatment. The patient with a mNAPSI score greater than 0 will have a 100% improvement in mNAPSI score and dermatological The method achieves a 5-point or greater improvement in the DLQI score.

11. The patient has 3% or more body surface area (BSA) psoriasis involvement at baseline. Item 11. The method according to item 10.

12. More than 30% of the patients have the 100% improvement in the mNAPSI score and the D 11. The method of claim 10, wherein said 5 or more point improvement in LQI score is achieved.

13. the anti-TNF antibody is administered at weeks 0 and 4, and then every 8 weeks (q8w) thereafter; 11. The method of claim 1, 3, or 10, administered at a dose of 2 mg / kg.

14. 14. The method of claim 13, wherein the patient is 18 years of age or older.

15. The treatment comprises administering the anti-TNF antibody with or without methotrexate (MTX).

14. The method of claim 13, further comprising administering

16. 10. The method of claim 1, wherein the anti-TNF antibody is administered as a pharmaceutical composition comprising the anti-TNF antibody.

10. The method according to claim 1, 3, or 10.

17. The composition comprises administering 2 mg / kg of the anti-TNF antibody to the patient at week 0, week 4, and 17. The method of claim 16, wherein the medicament is administered every 8 weeks thereafter.

18. 17. The method of claim 16, wherein the patient is 18 years of age or older.

19. The treatment comprises administering the composition with or without methotrexate (MTX).

17. The method of claim 16, further comprising:

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