Method for administration of Anti-IFN-α / ω antibody

Abstract

To provide methods for administration of an anti-IFN-α / ω antibody by subcutaneous or intravenous administration in a clinically proven safe amount.SOLUTION: Provided is an administeration method that includes administering a pharmaceutical composition comprising an anti-IFN-α / ω antibody and a pharmaceutically acceptable carrier to the subject by subcutaneous or intravenous administration, where a total dosage of the antibody administered is 0.1 mg / kg to 20 mg / kg (body weight of the subject) per administration. Also provided is a method for clinically proven safe treatment of IFN-I mediated diseases, such as systemic lupus erythematosus (SLE), by subcutaneous or intravenous administration of an anti-IFN-α / ω antibody.SELECTED DRAWING: None

Description

[Technical field]

[0001] (Reference to electronically submitted sequence listing) This application is filed on April 4, 2019 under the title "JBI6068WOPCT1Seql The sequence list was sent via EFS-Web in ASCII format with the file name "ist.txt". The sequence listing, which is approximately 43 kb in size, was submitted electronically via EFS-Web. The sequence listing submitted herewith is incorporated by reference in its entirety. Be absorbed.

[0002] FIELD OF THEINVENTION The present invention relates to a method for administering a clinically proven safe amount of an anti-IFN-α / ω antibody, and IFN-α / ω antibodies administered subcutaneously or intravenously in a clinically proven, safe dose The present invention relates to a method for treating I-mediated diseases.

[0003] BACKGROUND OF THEINVENTION Type I IFN (IFN-I) is a ubiquitously expressed heterodimeric receptor IFN Signaling occurs through IFNAR (a heterodimer of IFNAR1 and IFNAR2), resulting in It is a family of cytokines that exert antiviral, antiproliferative, and immunomodulatory effects. In humans, type I IFNs are classified into at least 12 IFN-α protein subtypes and IF One subtype each for IFN-β, IFN-ε, IFN-κ, and IFN-ω The release of IFN-I is mediated by both microbial and sterile ligands. It occurs in response to

[0004] The IFN-I family of cytokines is composed of the ubiquitously expressed heterodimeric IFN-α receptor. Type I IFNs signal through the IFN receptor (IFNAR). (Elkon & Stone, Journal Inter Feron Cytokine Res.,31(11):803-812(2011) ;Finke et al.,Autoimmunity,42(4):349-352 (2009)). IFNs react to infectious agents such as viruses to help control infection. They are rapidly produced in response to microbial factors, endogenous ligands (e.g., necrotic cells), and immune responses. The immune complex activates both Toll-like receptor (TLR)-dependent and TLR-independent pathways. By this, IFN-I production can be induced. The resulting IFN-I is Binds to the AR, resulting in activation of antiviral, antiproliferative, and immunomodulatory genes This so-called IFN-inducible gene signature has been observed in many autoimmune diseases. It is being done.

[0005] Some immune-mediated inflammatory or autoimmune diseases, such as systemic lupus erythematosus Lupus, including cutaneous lupus erythematosus (SLE) and cutaneous lupus erythematosus (CLE), type I diabetes, psoriasis, Egren's disease, systemic sclerosis, rheumatoid arthritis, immune thrombocytopenia (ITP), Aicardi Agni-Gouttierre syndrome (AGS), myositis, common variable immunodeficiency (CVID) and autoimmune diseases Immune thyroid disease is present in whole blood and / or tissues in at least a subset of patients. overexpression of IFN-inducible gene transcripts, commonly referred to as the IFN signature, or It is associated with increased IFN-I.

[0006] SLE is a condition in which pathogenic T cell, B cell, and innate immune responses drive inflammation across multiple organ systems. It is a chronic autoimmune or immune-mediated inflammatory disease that causes inflammation and tissue damage. The disease presents with a wide range of symptoms, including heterogeneous clinical signs, systemic, cutaneous, renal, musculoskeletal, neurological, and SLE can vary widely in severity and can be chronic, remitting, or relapsing. It is active in cycles with periods of improvement or remission that can last for weeks, months, or years. Sexuality flares.

[0007] IFN-α is elevated in SLE patients and promotes loss of tolerance to self-antigens IFN-α is thought to promote sustained dendritic cell activation, thereby enhancing antigen presentation and S It has been shown that IFN-α contributes to the suppression of Treg function, which may contribute to LE. , induces BLyS expression, which is the target of the commercially available SLE drug BENLYSTA™. A number of polymorphisms have been identified that are associated with IFN-I production or response to IFN-I, They account for more than half of the identified SLE-associated polymorphisms (Ghodke-Puranik & Niewold,International journal of clin ical rheumatology 8,doi:10.2217 / ijr.13.5 8 (2013)). Antibodies that neutralize various IFN-α subtypes (pan-IFN-α antibodies) , which have been evaluated in clinical trials for SLE (see, e.g., WO 02 / 066649 , No. 05 / 059106, No. 06 / 086586, No. 09 / 135861 reference).

[0008] In addition to IFN-α, IFN-ω is a key type 1 IFN that is overexpressed in SLE patients. SLE patients produce autoantibodies against IFN, which may be an additional important subclass. In two studies, the highest levels of nascent autoantibodies were found to be directed against IFN-ω. This is in contrast to the fact that IFN-ω may be a potent inhibitor of other classes of IFNs in some SLE patients. This suggests that there may be more of them than previously thought (McBride et al. .,Arthritis Rheum.,64(11):3666-3676(2012 );Petri et al.,Arthritis Rheum.,65(4):10 11-1021(2013)). The anti-IFN-α antibody (sifalimumab ( MEDI-545), rontalizumab, and AGS-009) do not neutralize IFN-ω. Clinical trial data with these antibodies have shown that patients following treatment with anti-IFN-α antibodies showed a partial reduction in the type I IFN signature in n Rheum Dis 70:1905-1913,2011;Yao et al. ,Arthritis Rheum 60:1785-1796,2009), Rontali Phase 2 data from a study using izumab (a pan-anti-IFN-α antibody) showed that the interferon signature A pre-specified biomarker study was performed for patients with low-moderate to severe active lupus according to the International Society for Mental Disorders (ISM) criteria. Signs and symptoms of SLE, incidence rate, and steroid load at 24 weeks in the follow-up group The results showed that ISM improves the expression of IFN-inducible genes, which was previously defined as high levels. No benefit was observed in patients with ACR / ARHP Annual Meeting;Abstract #2622,2 012).

[0009] The current standard treatment for SLE includes corticosteroids, antimalarials, and immunosuppression. These treatments include chemotherapy, chemotherapy-induced inflammatory bowel disease, chemotherapy-induced leukemia ... may not be suitable for treating all lupus patients. Thus, there is a need for additional therapeutic treatments for SLE and other IFN-I mediated diseases. There are.

[0010] BRIEF SUMMARY OF THEINVENTION The present invention relates to a method for treating IFN-I mediated diseases in subjects with systemic lupus erythematosus (SLE). Clinically proven and safe treatment of anti-IFN-α / ω antibodies in patients with Regarding safe administration as specified.

[0011] In one general aspect, the present invention provides an anti-IFN-α / ω antibody to a human subject in need thereof. 4. A method for providing a clinically proven and safe administration of said antibody and a pharma- ceutical administering to the subject a pharmaceutical composition comprising a carrier for administering to the subject subcutaneously or intravenously, The antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region being represented by SEQ ID NO:3 Heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, and H and the light chain variable region comprises the CDR3 amino acid sequences of SEQ ID NOs: 30, 31, and 32 light chain complementarity determining regions (LCDRs) LCDR1, LCDR2, and LCDR3 amino acids The antibody contains an α-amino acid sequence, and the total dose of the antibody administered is 0.1 mg / kg to 2 0 mg / kg (body weight of the subject).

[0012] In one embodiment, the anti-IFN-α / ω antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO:28. A variable region (VH) and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO:29. .

[0013] In one embodiment, the pharmaceutical composition is administered intravenously. The total dose of anti-IFN-α / ω antibody administered was 0.1 mg / kg, 0.3 mg / kg, and g, 1 mg / kg, 3 mg / kg, 10 mg / kg, 15 mg / kg, or 20 mg / kg (body weight of subject), or any dose therebetween.

[0014] In one embodiment, the pharmaceutical composition is administered subcutaneously. The total dose of anti-IFN-α / ω antibody administered to , 0.5mg / kg, 0.7mg / kg, 1mg / kg, 1.2mg / kg, 1.5mg / kg, 1.7mg / kg, 2mg / kg, 2.3mg / kg, or 2.5mg / kg g (body weight of subject), or any dose therebetween.

[0015] In one embodiment, administration of the pharmaceutical composition results in: (i) about 50 μg Area under the concentration-time curve (AUC) from .day / mL to approximately 7000μg.day / mL (0-t) and (ii) The maximum observed concentration (C max ) are selected At least one parameter is achieved.

[0016] In one embodiment, administration of an anti-IFN-α / ω antibody does not result in an increase in the level of anti-IFN-α / ω in a subject. Antibodies against antibodies are not produced.

[0017] In another general aspect, the present invention provides a method for treating IFN-I mediated inflammatory bowel disease in a human subject in need thereof. A method for providing a clinically proven and safe treatment of a disease comprising administering to said patient an antibody and a pharmacologic agent approved for use in said treatment. The pharmaceutical composition includes administering to the subject subcutaneously or intravenously a pharmaceutical composition comprising an acceptable carrier, The antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region being represented by SEQ ID NO: 33, 34, and 35 heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, and and the light chain variable region comprises an HCDR3 amino acid sequence represented by SEQ ID NO: 30, 31, and and 32 light chain complementarity determining regions (LCDRs) LCDR1, LCDR2, and LCDR3. The antibody contains a 5'-amino acid sequence, and the total dose of the antibody administered is 0.1 mg / kg or more per administration. 20 mg / kg (body weight of the subject).

[0018] In one embodiment, the IFN-I mediated disease is systemic lupus erythematosus (SLE), type I. Diabetes, psoriasis, primary Sjogren's disease, systemic sclerosis, rheumatoid arthritis, transplant rejection, dermatomyopathy inflammation, polymyositis, Aicardi-Goutière syndrome, infantile-onset Sting-related vasculitis ( SAVI), or chronic atypical neutrophilic dermatosis syndrome with lipodystrophy and fever (C Preferably, the disease is systemic lupus erythematosus (SLE). and more preferably mild to moderate SLE.

[0019] In one embodiment, the anti-IFN-α / ω antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO:28. A variable region (VH) and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO:29. .

[0020] In one embodiment, the anti-IFN-α / ω antibody is of the IgG1 isotype. Several polymorphisms (e.g., known allotypes) exist within the constant domain,214,3 Positions 56, 358, 422, 431, 435, or 436 (residue numbering according to EU numbering) (e.g., IMGT Web Resources; IMGT Repertoire (IG and TR);Proteins and alleles;alloty pes). Anti-IFN-α / ω antibodies were G1m17, G1m3, G1m1, It may be any IgG1 allotype, such as G1m2, G1m27, or G1m28.

[0021] In one embodiment, the pharmaceutical composition is administered at 10 mg / kg of subject's body weight per dose. The total dose of anti-IFN-α / ω antibody administered intravenously to human subjects over 30 minutes Preferably, the pharmaceutical composition is administered to a human subject repeatedly, more preferably once every two weeks. It is given intravenously.

[0022] In one embodiment, administration of the pharmaceutical composition results in: (i) about 1000 Area under the concentration time curve (AUC) from μg.day / mL to approximately 3500μg.day / mL (0-14 d) and (ii) the maximum observed concentration (C max ) At least one parameter selected from the following is achieved.

[0023] In one embodiment, the human subject is administered the pharmaceutical composition and, by 100 days after administration, has: i) systemic erythropoietin syndrome; Systemic Lupus Erythematosus Responder Index (SR i) Decline in the number of cases; ii) New British Isles Lupus Assessment Group ment Group, BILAG) no shift to A or 2B, iii) systemic lupus erythematosus Systemic Lupus Erythematosus Disease Activity Index 20 00, SLEDAI-2K) decline from baseline, iv) systemic lupus erythematosus 2 Systemic Lupus Erythematosus 2000 Responder Index-50 , S2K RI-50), and v) physician-reported disease activity. Physician's Global Assessment of Disease Activity (PGA) baseline and / or a reduction in the severity of the disease.

[0024] In one embodiment, the human subject achieves antibody steady state within 40-50 days after administration.

[0025] In one embodiment, administration of an anti-IFN-α / ω antibody does not result in a malignant or anaplastic disease in a subject. Treatment emergent adverse events related to phylaxis or serum sickness-type reactions No adverse events (TEAEs) occurred.

[0026] In another general aspect, the method of the invention comprises: a. one or more of the genes DHX58, EIF2AK2 in a biological sample from a human subject; HERC5, IFI44, IFI44L, IFI6, IRF7, PARP9, PLSCR 1, and assaying gene expression of SAMD9L; b. Prior to administering a pharmaceutical composition comprising an antibody and a pharma- ceutical acceptable carrier to a human subject, and identifying the subject as responding to treatment with the antibody.

[0027] The details of one or more embodiments of the invention are set forth in the description below. Other Features and Advantages These points will become apparent from the following detailed description and the appended claims. [Brief description of the drawings]

[0028] The above "Summary of the Invention" and the following "Description of the Preferred Embodiments" should be read in conjunction with the accompanying drawings. The invention will be better understood by reading the following detailed description of the preferred embodiments shown in the drawings. It should be understood that this is not a limitation. [Figure 1] 1 shows a schematic representation of the study design for a clinical trial using an anti-IFN-α / ω antibody (Antibody A) according to an embodiment of the present application. [Diagram 2] 1 shows the disposition of subjects in Part A of the study. [Diagram 3] 1 shows the disposition of subjects in Part B of the study. [Figure 4] 1 shows the mean (SD) serum concentration-time profiles of antibody A following a single intravenous infusion of antibody A at doses ranging from 0.3 to 15 mg / kg (cohorts 1-5) in healthy subjects. [Diagram 5] 1 shows the mean (SD) serum concentration-time profiles of antibody A following a single intravenous infusion of 1.0 mg / kg antibody A (cohort 2) or a single subcutaneous injection of 1.0 mg / kg antibody A (cohort 6) in healthy subjects. [Figure 6] 1 shows the mean (SD) serum concentration-time profiles of Antibody A following multiple intravenous infusions of 10 mg / kg of Antibody A in subjects with mild-moderate systemic lupus erythematosus.

[0029] DETAILED DESCRIPTION OF THE PRESENT EMBODIMENT Various publications, articles and patents are cited or referenced in the Background and throughout this specification. Each of these references is incorporated herein by reference in its entirety. Any discussion of documents, operations, materials, devices, articles or the like which has been included in the specification is in accordance with the context of the present invention. Such discussion is intended to provide a basis for discussion of any or all of these matters. Admitted to constitute prior art to any invention shown or claimed in the present application. It's not something like that.

[0030] Unless otherwise defined, all technical and scientific terms used herein refer to the It has the same meaning as commonly understood by one of ordinary skill in the art to which it pertains. Certain terms used herein have the meanings set forth herein. All patents, published patent applications and publications cited herein are hereby incorporated by reference. No. 6,393,633, filed on Oct. 23, 2003, and is incorporated in its entirety as if set forth herein.

[0031] As used in this specification and the appended claims, the singular forms "a," "an," and " It is important to note that "the" includes multiple referents unless the context makes clear otherwise. There is.

[0032] Unless otherwise noted, the term "at least" preceding a series of elements refers to every element in the series. It should be understood that the present invention refers to elements of the It will be appreciated that the present invention is not limited to the above embodiment, and that many equivalents to the specific embodiments described herein may be recognized. Such equivalents are intended to be encompassed by this invention. can be.

[0033] Throughout this specification and the following claims, unless the context otherwise requires, the term "comprises" or "includes" will be used interchangeably. "comprises" and variations such as "comprises" and "comprising" are used herein as examples. Including the specified integer or step or group of integers or steps, but including any other integer or step number. is not meant to exclude any whole number or step or group of steps. It will be understood that, as used herein, the term "comprise" can be used interchangeably with the term "contain" or "Including" may be substituted or, as sometimes used herein, It can also be replaced with the term "having."

[0034] As used herein, "consisting of" refers to any element of a claim that is specified in the claim. As used herein, "excludes any element, step, or ingredient not included in the present invention." "Qualitative" means material that does not materially affect the basic and novel characteristics of the claim. As used herein in relation to an aspect or embodiment of the invention, When used herein, the terms "comprising," "containing," and "including" are used to vary the scope of the disclosure. Any of the above terms "including" and "having" may be replaced with the term "consisting of" or can be replaced with "consisting essentially of."

[0035] As used herein, the conjunctive term "and / or" between multiple listed elements means Both individual and combined options are understood to be encompassing. For example, When elements are connected by "and / or," the first option may be used without the second option. The first element is applicable. The second option is that the second element can be applied without the first element. The third option refers to the first and second elements being applicable together. Any one of these options is within the meaning and therefore the As used in the specification, it is understood that the requirement of the term "and / or" is met. The simultaneous applicability of two or more of the following is also included within the meaning, and thus the term "and / or" It is understood that the above requirements are met.

[0036] As used herein, the term "subject" refers to a person who is receiving an anti-IFN-α / ω antibody in accordance with the methods of the present invention. The patient is diagnosed with an IFN-I mediated disease for which the patient is scheduled to receive or has received IFN-I. A mammalian subject, preferably a human, diagnosed or suspected of having an IFN-I mediated disease. The diagnosis may be made by a clinical diagnostic test, a physical examination of a subject, or by a method for diagnosing a subject with a particular disease. Any other accepted method can be followed by the clinician.

[0037] As used herein, a "subject suspected of having an IFN-I mediated disease" refers to a subject who is suspected of having an IFN-I mediated disease by a clinician. and / or the subject exhibits a discernible sign or symptom indicative of an IFN-I mediated disorder, The suspected diagnosis may be based on clinical diagnostic tests, physical examination of the subject, or a suspected IFN-I mediated disorder. The subject has not been identified by other accepted methods for diagnosing a subject with .

[0038] Examples of IFN-I-mediated diseases include systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), and inflammatory bowel disease (ICD). CLE, type I diabetes, psoriasis, Sjogren's disease, systemic sclerosis, rheumatoid arthritis Arthritis, immune thrombocytopenia (ITP), Aicardi-Goutières syndrome (AGS), myositis, unclassifiable immunodeficiency (CVID), autoimmune thyroid disease, transplant rejection, dermatomyositis, Polymyositis, Sting-associated vasculitis in infancy (SAVI), and lipodystrophy and fever Chronic atypical neutrophilic dermatosis syndrome (CANDLE) is one of the most common skin disorders. Not limited.

[0039] The term "type I interferon" or "IFN-I" refers to a type I interferon that binds to the common interferon receptor. All native subtypes of human interferon-α that bind to IFNAR, as well as Interferon-β, interferon-ε, interferon-ω, and interferon-β This refers to one of the subtypes of feron-κ.

[0040] The term "interferon-α" (IFN-α) as used herein refers to a human alveolar Refers to all native subtypes of fine interferon. Native IFN-α is At least 12 closely related genes are encoded by distinct genes with a high degree of structural homology. Consists of related protein subtypes (Weissmann and Weber, rog Nucl Acid Res Mol Biol.,33:251,1986; Roberts et al.,J Interferon Cytokine Res .18:805-816,1998). The nomenclature of human interferons is available at http: / / www. / www_genenames_org / genefamilies / _IFN Table 1 below lists the IFN-α subtypes used herein, in addition to other type I IFNs. The sequence of the loop is shown.

[0041] The term IFN-ω, as used herein, refers to the amino acid sequence shown in SEQ ID NO:1 and Un It refers to human IFN with iProt accession number P05000. Human IFN-ω Also, SEQ ID NO: 1 in which at position 80 (T80) threonine is replaced by glutamic acid This also includes variants of 2.

[0042] IFN-α subtypes and IFN-ω were recombinantly expressed using standard methods. Exemplary signals that can be used to induce secretion include The sequences are shown in SEQ ID NOs:21-25.

[0043] As used herein, the term "INFAR" refers to the IFNAR1 and IFNAR2 genes. Refers to the well-known interferon receptors, which are heterodimers: IFNAR1 and IFNAR2. The protein sequences of the mature extracellular domain of INFAR1 are shown in SEQ ID NOs: 26 and 27, respectively. The main portion spans residues 28 to 436 of SEQ ID NO:26 and is the mature extracellular domain of INFAR2. spans residues 27 to 243 of SEQ ID NO:27.

[0044] [Table 1]

[0045] As used herein, an "anti-IFN-α / ω antibody" refers to a antibody having a concentration of 1×10 -10 Affinity below M Binds to at least 10 human interferon alpha (IFN-α) subtypes It also binds with high affinity to human interferon omega (IFN-ω) and neutralizes it. A genetically engineered fully human monoclonal antibody (mAb ) or an antigen-binding fragment thereof. Preferably, the anti-IFN-α / ω antibody is an interferon The anti-IFN-α / ω antibodies or Examples of antigen-binding fragments thereof include those described in US Pat. No. 6,313,990, the entire contents of which are incorporated herein by reference. IFWM3405, IFWM3442, and IFW described in Japanese Patent No. 10,208,113 M3525, IFWM3423, IFWM3444, IFWM3421, or other anti-IF Examples of the antibody include, but are not limited to, N-α / ω antibodies or fragments thereof. In one embodiment, the anti-IFN-α / ω antibody is capable of inhibiting at least 11 of the 12 IFN alphas. In another preferred embodiment, the anti-IFN-α / ω antibody comprises a heavy chain variable region and a light chain variable region. The heavy chain variable regions are the heavy chain variable regions of SEQ ID NOs: 33, 34, and 35, respectively. Complementarity determining region (HCDR) containing HCDR1, HCDR2, and HCDR3 amino acid sequences. The light chain variable regions are represented by the light chain complementarity determining regions of SEQ ID NOs: 30, 31, and 32, respectively. (LCDR) comprises LCDR1, LCDR2, and LCDR3 amino acid sequences. In the present invention, the anti-IFN-α / ω antibody comprises a heavy chain variable region (V A preferred embodiment of the present invention comprises a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 29. In embodiments, the anti-IFN-α / ω antibody is a humanized or fully human immunoglobulin.

[0046] Anti-IFN-α / ω antibodies can be produced using a variety of methods, including, but not limited to, hybridoma production. Any method known in the art in light of the present disclosure for preparing a monoclonal antibody. For example, anti-IFN-α / ω antibodies can be prepared by recombinant DNA techniques. in mammalian cell lines (e.g., Chinese hamster ovary (CHO) cell lines) using In particular, methods for producing anti-IFN-α / ω antibodies useful in the present invention include See, for example, U.S. Pat. No. 10,208,113, which is incorporated herein by reference. It is described in.

[0047] The term "antibody" includes antibody mimetics, such as single chain antibodies and fragments thereof. A portion of an antibody that mimics the structure and / or function of the antibody, or a specific fragment or fragment thereof The present invention includes antibodies, digest fragments, specified portions, and variants thereof, including portions thereof. Further contemplated functional fragments include antigen-binding fragments that bind to mammalian IFN-α / ω. For example, Fab (e.g., by papain digestion), Fab' (e.g., by pepyketone digestion), by psulin 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), by digestion with sumin), Fd (e.g., by digestion with pepsin, partial reduction, and reassembly), These include, but are not limited to, Fv or scFv (e.g., by molecular biology techniques) fragments. The present invention provides an antibody fragment capable of binding to IFN-α / ω or a portion thereof that is not (See, e.g., Colligan, Immunology, supra) .

[0048] Such fragments may be used as known in the art and / or as described herein. The antibody can be produced by enzymatic cleavage, synthetic or recombinant techniques, as described in The present invention also provides methods for producing antibody genes in which one or more stop codons have been introduced upstream of the natural stop site. For example, F(ab')2 heavy chain portions can be produced in various truncated forms using The combination of genes to be loaded includes genes encoding the CH1 domain and / or hinge region of the heavy chain. The various portions of the antibody can be engineered to contain a DNA sequence that encodes the It can be chemically linked to a contiguous protein by genetic engineering techniques. It can be prepared as follows.

[0049] As used herein, the term "human antibody" refers to an antibody in which substantially all portions of the protein (e.g., For example, CDR, framework, CL, CH domains (e.g., CH1, CH2, and C H3), hinge (VL, VH) are substantially non-immunogenic in humans, and sequence variations "Human antibody" also refers to an antibody that has only slight mutations in the human germline It may be an antibody derived from the immunoglobulin sequences or it may be an exact match antibody. Human antibodies contain amino acid residues that are not encoded in the germline immunoglobulin sequence (e.g. For example, by the introduction of random or site-specific mutations in vitro or by in vivo Mutations introduced by somatic mutation in vivo. Often, this includes Human antibodies are essentially non-immunogenic in humans. They are classified into groups based on the similarity of their amino acid sequences. Using the search, antibodies with similar linear sequences are identified as templates for generating human antibodies. Similarly, the name can be selected as a primate (monkey, baboon, chimpanzee, etc.). , rodents (mouse, rats, rabbits, guinea pigs, hamsters, etc.) and other mammals. Antibodies containing the same designate such species, subgenus, genus, subfamily, and family specific antibodies. The body may contain any combination of the above. Such changes or mutations are optional and preferred. or retain immunogenicity in humans or other species compared to the unmodified antibody. Thus, a human antibody is distinct from a chimeric antibody or a humanized antibody.

[0050] A human antibody is a functionally rearranged human immunoglobulin (e.g., a heavy and / or light chain ) produced by a non-human animal, or a prokaryotic or eukaryotic cell, capable of expressing a gene Moreover, when the human antibody is a single chain antibody, it is possible to obtain a single chain antibody that is similar to a natural human antibody. For example, Fv can contain a linker peptide not found in the heavy chain variable region and a light chain variable region. A linker peptide such as 2 to about 8 glycine or other amino acid residues that connects the variable region Such linker peptides are considered to be of human origin.

[0051] The term "safety" refers to any dose, administration regimen, treatment, or method of an anti-IFN-α / ω antibody. When a patient is diagnosed with a disease, the standard of care or the revised Federal Food, Drug, and Cosmetic Act is applied. Treatment-emergent adverse events (AEs or A favorable risk profile in which adverse events (termed TEAEs) are of acceptable frequency and / or severity This refers to the benefit-to-cost ratio (Secs. 201-902, 52 Stat. 1040 e t seq., as amended;21 USC§§ 321-392). Special In particular, safety may be related to the dose, administration regimen, or treatment of the anti-IFN-α / ω antibody of the present invention. and the cause is possibly, likely, or possible due to the use of anti-IFN-α / ω antibodies. If the risk is considered to be very high, the acceptable frequency and / or frequency of adverse events associated with antibody administration should be considered. Safety often refers to the time required to achieve a desired effect. The necessary maximum tolerated dose or optimal dose of the active pharmaceutical ingredient is determined by toxicity testing. Safety studies are used to assess any potential adverse events that may result from exposure to a drug. It also seeks to identify adverse effects.

[0052] As used herein, unless otherwise specified, the term "clinically proven" or to modify the term "safe") is evidence that a drug has been proven safe by clinical trials in human subjects. The clinical trials have been approved by the U.S. Food and Drug Administration, the European Medicines Agency (EMEA), or the corresponding national regulatory approval criteria. In one embodiment of the present application, the clinical trial is a Phase 1 study of an anti-IFN-α / ω antibody in healthy human subjects. A randomized, double-blind, placebo-controlled, single ascending dose study. Preferably, the clinical trial is Multiple anti-IFN-α / ω antibodies in human subjects with moderate systemic lupus erythematosus Further included are multiple dose studies.

[0053] As used herein, the terms "adverse event," "treatment-emergent adverse event," and "treatment-emergent adverse event" are used interchangeably herein. "Adverse Reaction" means any adverse event associated with or resulting from the administration of a pharmaceutical composition or therapeutic agent. Means an adverse, undesirable, unintended, or undesirable symptom or manifestation. However, abnormal values ​​or observations were not deemed clinically significant by the investigator. As used herein, adverse events are not reported unless In this case, "clinically evident" means a medical condition that is clearly evident to a physician or investigator using criteria acceptable to those of skill in the art. Means clinically significant as determined by the physician. When adverse outcomes reach this severity, regulatory authorities may impose restrictions on the use of pharmaceutical compositions or therapeutic agents. The proposed use of anti-IFN-α / ω antibodies may be considered unacceptable. Examples of adverse events or reactions when used in the intravenous setting include, but are not limited to, the following: , including but not limited to: infections and infestations such as rhinitis, shingles, and bullous myrrhitis; coughs, Respiratory, thoracic, and mediastinal disorders, such as pharyngeal irritation and sore throat; gastrointestinal disorders, such as diarrhea and flatulence disorders of the nervous system, such as headaches and dizziness; disorders of the blood and lymphatic system, such as anemia and lymphadenopathy Disorders; back pain, premature labor, infusion reactions, local injection site reactivity, malignancy, and anaphylaxis or serum sickness-type reactions.

[0054] As used herein, "treatment" or "treating" refers to therapeutic treatment. Individuals in need of such treatment include those who have been diagnosed with a disorder or symptoms of a disorder. Subjects who can be treated include those with disorders in which disorders should be prevented. Also included are those prone to or suspected of having a disorder. The effects of these drugs include alleviation of symptoms, lessening the severity of disease, whether detectable or undetectable. reduction, stable (i.e., not worsening) disease state, delay or slowing of disease progression, disease state These include improvement or alleviation of symptoms, and remission (whether partial or total). Beneficial clinical outcomes include, for example, increased proliferation of B cells or dendritic cells in treated subjects. Reduced proliferation, inflammatory cytokines, adhesion molecules, proteases, immunoglobulins, Combination reduction, increased production of anti-inflammatory proteins, reduced number of autoreactive cells, immune Increased tolerance, inhibition of survival of autoreactive cells, and / or IFN-I mediated Clinical response may include a reduction in one or more symptoms. Scanning, X-ray imaging, computed tomography (CT) scanning, flow cytometry or fluorescence-activated cell sorting (FACS) analysis, histology, macroscopic findings, and ELI These include changes that can be detected by SA, RIA, chromatography, etc. can be assessed using screening techniques such as, but not limited to, blood chemistry tests .

[0055] The terms "efficacious" and "effective" are used in the context of a dose, administration regimen, treatment, or method. As used herein, the term refers to the efficacy of a particular dosage, administration, or treatment regimen. Efficacy can be measured based on changes in the course of a disease in response to an agent of the invention. For example, anti-IFN-α / ω antibodies useful in the present invention may be used with at least one antibody that is reflective of the severity of the disorder being treated. in an amount sufficient to induce improvement, preferably sustained improvement, in at least one indicator; and In order to determine whether the amount and duration of the treatment is sufficient, In addition, various indicators that reflect the severity of the subject's disease, disorder or condition can be evaluated. For example, clinical evaluation of disease severity, symptoms, or manifestations of the disorder of interest may be performed. Improvement is assessed overall by the physician, who then evaluates the outcome based on the outcome. can be based on signs, symptoms, biopsy, or other test results, and can be administered to a subject. Adopt questionnaires that provide quality of life information, such as those developed for a given disease. For example, the anti-IFN-α / ω antibodies of the invention can be used to treat a condition in a subject associated with SLE. may be administered to achieve improvement.

[0056] Improvement in SLE should be assessed by at least one of the following clinical response assessments: i) Systemic lupus erythematosus responder index (SRI) score of 1 or 2, a decrease of 3, 4, 5, or 6 points; ii) British Isles Lupus Assessment Group (BILAG) Shift in the systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K) ) decrease from baseline in the Systemic Lupus Erythematosus 2000 Responder Index; and iv) v) decrease from baseline in S2K RI-50 (S2K RI-50); vi) decrease from baseline in the Patient General Assessment (PGA); vi) decrease in cutaneous lupus erythematosus disease area and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CL) vii) Change and percent change from baseline in ASI (Abdominal Spine Injury Score) activity and injury scores; ) Norm-based SF-36, SF-36 Physical and Mental Component Summary Scores Change and percent change from baseline in scores, and viii) EuroQol -Changes from baseline and change patterns on the 5 Dimensions-5 Levels (EQ-5D-5L) scale -cent.

[0057] In addition, joint assessments can be used to assess clinical responses, e.g., joint function with signs of pain and inflammation in a subject. The change from baseline in the number of joints over time was assessed. Each joint was assessed by the assessor for all fingers. At regular visits, subjects are assessed for tenderness and swelling (excluding the buttocks for swelling).

[0058] In some embodiments, the patient has mild to moderate rheumatoid arthritis prior to receiving treatment with an embodiment of the present application. A human subject with SLE is defined by: 1) Systemic Lupus International Collaborating Clinics (SLICC) criteria for diagnosing lupus and treating it Systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K) score within 3 months prior to treatment ) with non-serological clinical activity of at least 1, and 2) Positive serological test within the past 2 months: a) Positive antinuclear antibody (ANA) titer of ≥ 1:80; or b) A positive anti-double-stranded deoxyribonucleic acid test (Note: anti-dsDNA is an enzyme-linked immunosorbent assay). When performed by adsorption assay, the upper limit of normal must be exceeded by 2 to be considered clearly positive. (Twice the test value is needed) positive serology within the last 2 months, or c) Positive anti-Smith antibody and / or anti-ribonucleoprotein (RNP) antibody and / or anti-Ro antibody positive, and in addition to at least one of the above , d) A positive Lupus IFN Profile Score during screening.

[0059] The subject's response to treatment can be assessed by measuring indices of disease activity, clinical symptoms, or any measure of disease activity. As used herein, "response to treatment" can be measured by other measures. "Non- or poorly responding patients" are patients who do not improve or only improve minimally after treatment. Refers to a person.

[0060] As used herein, the dosage of an anti-IFN-α / ω antibody in "mg / kg" is The amount of anti-IFN-α / ω antibody in milligrams per kilogram of body weight of the subject to whom the antibody is to be administered Refers to the mass of the body.

[0061] In one general aspect, the present invention provides a clinically proven and safe skin-repellent formulation of anti-IFN-α / ω antibodies. The present invention also relates to a method for providing intravenous and / or intravenous administration of the same to a human subject in need thereof. Or, the subject is diagnosed with an IFN-I mediated disease in which IFN-I levels are elevated. Elevated levels of type I interferon (IFN-I) and Several conditions, such as systemic sclerosis, Sjögren's syndrome, type I diabetes, and autoimmune thyroid disease, There is an association between several human autoimmune diseases, most notably systemic lupus erythematosus (SLE). According to the methods of the invention, an anti-IFN-α / ω antibody or antigen-binding fragment thereof is administered. Examples of IFN-mediated diseases that a subject may be diagnosed with or suspected of having include systemic erythrocyte sepsis (SLE). erythematosus (SLE), type I diabetes, psoriasis, primary Sjogren's disease, systemic sclerosis, Rheumatoid arthritis, transplant rejection, dermatomyositis, polymyositis, Aicardi-Goutières syndrome (A GS), Sting-associated vasculitis in infancy (SAVI), or lipodystrophy and fever Chronic Atypical Neutrophilic Skin Disease and Lesions (CANDLE) do not have.

[0062] In a preferred embodiment, the subject has been diagnosed with or is suspected of having SLE. SLE can target many organs and tissues, including the skin, blood vessels, muscles, kidneys, and lungs. Preclinical and clinical data support the role of IFN-α and IFN-ω in the initiation and progression of SLE. This confirms the above.

[0063] In one embodiment, a clinically proven and safe administration of an anti-IFN-α / ω antibody is provided to a subject. and / or provide a safe treatment for IFN-mediated diseases, preferably SLE, in human subjects. The method includes administering to the subject a pharmaceutical composition comprising an anti-IFN-α / ω antibody and a pharma- ceutical acceptable carrier. administering the anti-IFN-α / ω antibody subcutaneously or intravenously to the subject. The total dose is 0.1 mg / kg to 20 mg / kg (subject's body weight) per administration. .

[0064] In one embodiment, the pharmaceutical composition is administered subcutaneously. Subcutaneous administration refers to administration under the skin; The drug or therapeutic agent is injected into the tissue layer between the skin and muscle. Drugs administered intravenously are usually absorbed more slowly than those administered intravenously. If administration of the ω antibody is via subcutaneous injection, the amount of anti-IFN-α administered to a subject per administration The total dose of the / ω antibody may be administered as a single subcutaneous injection or multiple cutaneous injections, e.g., 1, 2, 3, 4, 5 The dose may be administered as a single or multiple subcutaneous injections.

[0065] In another embodiment, the pharmaceutical composition is administered intravenously. Intravenous administration includes administration directly into a vein. Intravenous administration refers to administering a substance by injection (e.g., using a syringe under higher pressure) or by injection (e.g., using gravity pressure). Typically, the drug or therapeutic agent is delivered through the blood circulation, allowing the drug or therapeutic agent to be distributed throughout the body. It is the fastest method of drug delivery. Anti-IFN-α / ω antibodies are administered intravenously. When administered via intravenous infusion or injection, it is preferably administered via infusion. For example, the total dose of anti-IFN-α / ω antibody administered to a subject per administration is For example, about 30 minutes to 180 minutes, preferably 60 minutes to 120 minutes, for example, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, or 180 minutes, or any period in between The drug can be administered by intravenous infusion.

[0066] The total dose of anti-IFN-α / ω antibody per administration was determined in clinical trials. Selected to provide safe administration and / or safe treatment by subcutaneous or intravenous administration. According to an embodiment of the present invention, when the pharmaceutical composition is administered intravenously, The total dose of the anti-IFN-α / ω antibody to be administered is, for example, 0.1 mg / kg, 0.3 mg / kg, / kg, 0.5mg / kg, 1mg / kg, 2mg / kg, 3mg / kg, 4mg / kg , 5mg / kg, 6mg / kg, 7mg / kg, 8mg / kg, 9mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, or any dose therebetween. When the composition is administered subcutaneously, the total dose of anti-IFN-α / ω antibody administered per administration The amount can be, for example, 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, kg, 1mg / kg, 1.2mg / kg, 1.5mg / kg, 1.7mg / kg, 2mg / kg, 2.3mg / kg, 2.5mg / kg, or any dose therebetween.

[0067] The total dose of anti-IFN-α / ω antibody is administered daily, weekly, monthly, six months, one year, two years, or Over a longer period, once a day, once a week, once every two weeks, once a month, For example, the administration can be substantially simultaneous, i.e., 0 to 1 minutes. Time period, e.g. 5 min, 10 min, 15 min, 20 min, 25 min, 30 min, 35 min, 40 min , 45 min, 50 min, 55 min, or 1 h, as a single subcutaneous injection or multiple subcutaneous injections ( For example, 2 to 5 injections) with a dose of 0.1 mg / kg to 2.5 mg / kg per injection. A total dose of 100 mg of anti-IFN-α / ω antibody may be administered (e.g., over at least one day) or once a day for a period of about 30 minutes to 3 hours, preferably 60 minutes to 120 minutes. The anti-IFN-γ antibody was administered intravenously at a dose of 0.3 mg / kg to 20 mg / kg per dose. -A total dose of α / ω antibody may be administered (e.g., once daily for at least one day) Anti-IFN-α / ω antibodies were administered at a total dose of 0.3 mg / kg to 20 mg / kg, as necessary. Multiple doses may be administered to a subject in need.

[0068] Pharmaceutical compositions suitable for use in the methods of the invention are formulated for subcutaneous or intravenous administration. Examples of formulations suitable for subcutaneous and / or intravenous administration include solutions, suspensions, emulsions, and and dry products that can be dissolved or suspended in a pharma- ceutical acceptable carrier for injection or infusion. In a preferred embodiment, the method for use in the present invention includes, but is not limited to, The pharmaceutical composition comprising the anti-IFN-α / ω antibody is formulated as a liquid.

[0069] The concentration of anti-IFN-α / ω antibody contained in the pharmaceutical composition used in the present invention may vary. Typically, the concentration of the anti-IFN-α / ω antibody is between 1 mg / mL and 100 mg / mL. , e.g., 1 mg / mL, 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50mg / mL, 60mg / mL, 70mg / mL, 80mg / mL, 90mg / mL, or 100 mg / mL, or any concentration therebetween. The concentration of the anti-IFN-α / ω antibody is 40 mg / mL to 60 mg / mL, for example, 50 mg / mL. mL.

[0070] Pharmaceutical compositions for use in the present invention may be comprised of one or more pharma- ceutical acceptable carriers, e.g. It further includes those that are widely used in the field of pharmaceutical production, particularly in the field of antibody pharmaceutical production. As used herein, the term "carrier" refers to any excipient, diluent, buffer, stabilizer, or pharmaceutical Other materials well known in the art for formulation. In particular, pharma- ceutically acceptable carriers are non-toxic. and must not interfere with the efficacy of the active ingredient. Examples of suitable excipients and / or agents for use in pharmaceutical compositions include those known in the art. Examples of additives include those described in "Re minton:The Science&Practice of Pharmacy " 19th ed., Williams & Williams, (1995) and "Phys. sician's Desk Reference" 52nd ed.,Medical Listed in Economics, Montvale, NJ (1998).

[0071] According to an embodiment of the invention, the pharmaceutical composition for use in the invention comprises an anti-IFN-α / ω In some embodiments, the antibody is a pharma- ceutically acceptable carrier. The carrier may be one or more carbohydrates, e.g., lactose, maltose, sucrose, one or more surfactants, such as polysorbate 20, polysorbate 80, and one or more acids and / or salts such as lactic acid, sodium lactate, acetic acid, sodium acetate. The pharmaceutical composition may be used at a pH of 5 to 6, for example, 5.0, 5.1, 5.2, 5.3, 5.4, 5 A pH of .5, 5.6, 5.7, 5.8, 5.9, or 6.0, or any value between these has.

[0072] In some embodiments, pharmaceutical compositions for use in the present invention comprise from 1% weight / volume to 1 0% by weight / volume (w / v), e.g. sucrose at a concentration of 5% to 10% (w / v), lactose For example, sucrose, lactose, and / or maltose. The concentrations of taurate were 1% (w / v), 1.5% (w / v), 2% (w / v), and 2.5% (w / v), 3%(w / v), 3.5%(w / v), 4%(w / v), 4.5%(w / v), 5%(w / v), 5.5%(w / v), 6%(w / v), 6.5%(w / v), 7%(w / v), 7.5%(w / v), 8%(w / v), 8.5%(w / v), 9%(w / v), It may be 9.5% (w / v), or 10% (w / v), or any concentration therebetween. .

[0073] In some embodiments, the pharmaceutical compositions for use in the present invention contain 0.01% (w / v ) to 0.1% (w / v) or 0.02% (w / v) to 0.08% (w / v) Polysorbate 20 (PS20) and / or Polysorbate 80 (PS80). For example: , the concentration of polysorbate 20 and / or polysorbate 80 is 0.01% (w / v); 0.02%(w / v), 0.03%(w / v), 0.04%(w / v), 0.05%(w / v), 0.06%(w / v), 0.07%(w / v), 0.08%(w / v), 0.0 It may be 9% (w / v), or 0.1% (w / v), or any concentration therebetween.

[0074] In some embodiments, the pharmaceutical compositions for use in the present invention comprise lactic acid, sodium lactate, 10 mM to 10 mM sodium lactate, acetic acid, or sodium acetate based on the amount of lactate or acetate, respectively. For example, the lactate or acetate concentrations are 10 mM, 11 mM, 12 mM, mM, 13mM, 14mM, 15mM, 16mM, 17mM, 18mM, 19mM, 20 It may be in mM, or any concentration therebetween.

[0075] Pharmaceutical compositions comprising anti-IFN-α / ω antibodies for use in the present invention may be used in light of the present disclosure. It can be prepared by any method known in the art. For example, anti-IFN The -α / ω antibody can be mixed with one or more pharma- ceutical acceptable carriers to obtain a solution. The solution is kept at a controlled temperature between -40°C ± 10°C and -70°C ± 20°C until it is administered to the subject. It should be stored as a frozen liquid in suitable vials, protected from light, at the specified temperature. can.

[0076] According to embodiments of the present invention, various factors may be analyzed to determine clinical outcomes, such as those described herein. Studies have demonstrated that specific doses of anti-IFN-α / ω antibodies can be safely administered subcutaneously and / or intravenously. For example, a specific dose of subcutaneous administration and and / or the safety of intravenously administered anti-IFN-α / ω antibodies is evaluated using immunogenicity studies (e.g., anti-IFN-α / ω antibodies). pharmacokinetic studies (e.g., concentration-time curves) Area under the line (AUC) and maximum observed concentration (C max ) can be evaluated by subcutaneous The safety of intravenously and / or intravenously administered anti-IFN-α / ω antibodies was also evaluated by physical examination of the subjects. findings of local injection site reactions, systemic injection-related reactions, and other allergic reactions; electrocardiograms, clinical Monitor for clinical examinations, vital signs, and other adverse events, such as thromboembolic events. You can also search for it.

[0077] In some embodiments, the clinically proven safe administration of anti-IFN-α / ω antibodies and and / or a clinically proven, safe treatment for an autoimmune disease is determined by administering to the subject a sample obtained from the subject. The amount of antibody against the anti-IFN-α / ω antibody detected is determined by measuring the amount of antibody against the anti-IFN-α / ω antibody. The amount of antibody to the FN-α / ω antibody may be any amount known in the art in light of this disclosure. The level of the antibody can be measured by a method such as ELISA.

[0078] In some embodiments, the clinically proven safe administration of anti-IFN-α / ω antibodies and and / or A clinically proven and safe treatment for an IFN-mediated disease is the detection of anti-IFN- Pharmacokinetic (PK) parameters of the α / ω antibody, e.g., area under the concentration-time curve (AUC) and The maximum measured concentration (C max ) by analyzing serum samples. In light of the present disclosure, anti-IFN-α / ω antibodies may be isolated by any method known in the art. The concentration is then determined. The pharmacokinetic parameters are then analyzed, for example, by non-compartmental analysis (NCA). Analyze and calculate pharmacokinetic parameters, e.g., AUC, C max , terminal half-life (T 1 / 2 ), Shizuka Total systemic clearance (CL) after intravenous administration, terminal distribution volume (V z ), biological Total systemic clearance over bioavailability (CL / F) and terminal bioavailability Distribution volume in (V z Calculate the formula:

[0079] In some embodiments, the clinically proven and safe administration of anti-IFN-α / ω antibodies Therefore, the AUC ranges from about 50 μg.day / mL to about 7000 μg.day / mL. (0-t) (0 hours? A curve representing the area under the cytosolic endothelial cell wall (AUC vs. time curve) from the time corresponding to the last quantifiable serum concentration is achieved. For example, AUC (0-t) are 50 μg.day / mL, 100 μg.day / mL, and 500 μg. day / mL, 1000μg.day / mL, 2000μg.day / mL, 3000μg.day / mL , 4000μg.day / mL, 5000μg.day / mL, 6000μg.day / mL, 700 0 μg.day / mL, or any number in between.

[0080] In some embodiments, the clinically proven and safe administration of anti-IFN-α / ω antibodies Therefore, the maximum observed concentration (C max ) is achieved. For example, C max is approximately 5μg / mL, 10μg / mL, 50μg / mL, 100μg / mL mL, 200μg / mL, 300μg / mL, 400μg / mL, 500μg / mL, or can be any number between these.

[0081] In some embodiments, the administration of an anti-IFN-α / ω antibody is used to treat an IFN-I mediated disease. Clinically proven and safe treatment ranges from about 1000 μg.day / mL to about 3500 μg. AUC in days / mL (0-t) (from time 0 to the time corresponding to the last quantifiable serum concentration A curve of AUC vs. time is achieved. For example, AUC (0-t) is 1000μg.day / mL, 1500μg.day / mL, 2000μg.day / mL, 2500μg.day / mL, 3 000 μg.day / mL, 3500 μg.day / mL, or any number in between. .

[0082] In some embodiments, administration of an anti-IFN-α / ω antibody improves the clinical outcome of IFN-mediated disease. With a proven and safe treatment, the actual maximum concentration is about 120μg / mL to about 400μg / mL. High concentration (C max ) is achieved. For example, C max is about 120μg / mL, 150μ g / mL, 200μg / mL, 250μg / mL, 300μg / mL, 350μg / mL , 400 μg / mL, or any number in between.

[0083] In another general aspect, the methods of the invention provide a method for treating IFN-α / ω antibody-responsive disease. 1. A method for diagnosing a subject having an NI-mediated disease, comprising: a. one or more of the genes DHX58, EIF2AK2 in a biological sample from a human subject; HERC5, IFI44, IFI44L, IFI6, IRF7, PARP9, PLSCR 1, and assaying gene expression of SAMD9L; b. prior to administering to a human subject a pharmaceutical composition comprising the antibody and a pharma- ceutical acceptable carrier. and identifying the subject as responsive to treatment with the antibody.

[0084] Specifically, this diagnostic method can be performed, for example, by using the method described in This is further described in US Provisional Patent Application No. 62 / 751,019, which is hereby incorporated by reference.

[0085] Embodiment The present invention also provides the following non-limiting embodiments.

[0086] Embodiment 1 is a clinically proven and safe amount of an anti-IFN-α / ω antibody or antigen binding thereof. A method for administering an antibody or a medicament comprising administering to a human subject in need thereof an antibody or a medicament comprising administering to said subject an antibody or a medicament comprising administering to said subject a medicament ... administering to the human subject a pharmaceutical composition comprising a carrier comprising the compound of formula (I) or (II), The total dose of the antibody administered is 0.1 mg / kg to 20 mg / kg (for The weight of an elephant is the method.

[0087] Embodiment 1a is an embodiment in which the anti-IFN-α / ω antibody comprises a heavy chain variable region and a light chain variable region, The heavy chain variable region is a heavy chain complementarity determining region (HCR) of SEQ ID NOs: 33, 34, and 35, respectively. CDR) The light chain variable region includes HCDR1, HCDR2, and HCDR3 amino acid sequences. The light chain complementarity determining region (LCDR) LCDR regions are set forth in SEQ ID NOs: 30, 31, and 32, respectively. 2. The method of embodiment 1, comprising the amino acid sequences R1, LCDR2, and LCDR3. .

[0088] In embodiment 1b, the anti-IFN-α / ω antibody has the amino acid sequence of SEQ ID NO:28. A heavy chain variable region (VH) and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO:29 The method according to embodiment 1 or 1a, comprising:

[0089] Embodiment 1c is a further embodiment of the present invention, wherein the anti-IFN-α / ω antibody is an anti-IFN-α / ω antibody, the entire contents of which are incorporated herein by reference. IFWM3405, IFWM3 as described in incorporated U.S. Pat. No. 10,208,113 442, IFWM3525, IFWM3423, IFWM3444, or IFWM342 2. The method of embodiment 1, wherein

[0090] Embodiment 1d is a method according to any one of embodiments 1 to 1, wherein the anti-IFN-α / ω antibody is a fully human antibody. c) in any one of the above.

[0091] Embodiment 2 is any one of embodiments 1 to 1d, wherein the pharmaceutical composition is administered intravenously. This is the method described.

[0092] In embodiment 2a, the total dose of the anti-IFN-α / ω antibody administered per administration is , 0.1mg / kg, 0.3mg / kg, 1mg / kg, 3mg / kg, 10mg / kg , 15mg / kg, or 20mg / kg (subject body weight), or any dose therebetween. 3. The method of embodiment 2, wherein the amount is

[0093] Embodiment 2b is a method for administering the pharmaceutical composition intravenously to a human subject over a period of 30 minutes or more. The method according to embodiment 2 or 2a,

[0094] Embodiment 3 is a method according to any one of embodiments 1 to 1d, wherein the pharmaceutical composition is administered subcutaneously. This is the method described above.

[0095] In embodiment 3a, the total dose of the anti-IFN-α / ω antibody administered per administration is , 0.1mg / kg, 0.3mg / kg, 0.5mg / kg, 0.7mg / kg, 1mg / kg, 1.2mg / kg, 1.5mg / kg, 1.7mg / kg, 2mg / kg, 2. 3 mg / kg, or 2.5 mg / kg (subject body weight), or any dose in between. 4. The method of embodiment 3, wherein the amount

[0096] In a fourth embodiment, administration of the pharmaceutical composition results in: (i) about 5 Area under the concentration-time curve (AUC) from 0 μg.day / mL to approximately 7000 μg.day / mL (0-t ) and (ii) the maximum observed concentration (C max ) In any one of the embodiments 1 to 3a, at least one parameter selected from the above is achieved. This is the method described.

[0097] In embodiment 4a, administration of the pharmaceutical composition results in a decrease in plasma levels of about 50 μg / mL in the subject. g.day / mL, 100μg.day / mL, 500μg.day / mL, 1000μg.day / mL , 2000μg.day / mL, 3000μg.day / mL, 4000μg.day / mL, 500 0 μg.day / mL, 6000 μg.day / mL, 7000 μg.day / mL, or anything in between Area under the concentration-time curve (AUC) of any number of (0-t) As described in embodiment 4, This is the method.

[0098] In embodiment 4a, the human subject is a healthy subject and the dose is 0.3 mg / kg, 1.0 mg / kg g, 3.0 mg / kg, 10 mg / kg, or 15 mg / kg of the anti-IFN-α / ω antibody A single intravenous dose of 100 mg ... .6), 287(31.9), 1143(245), 3694(610), or 5944 (1036) Area under the concentration-time curve (AUC) of μg.day / mL (0-t) is achieved, 5. The method according to embodiment 4.

[0099] In embodiment 4b, the human subject is a healthy subject and the dose is 0.3 mg / kg, 1.0 mg / kg g, 3.0 mg / kg, 10 mg / kg, or 15 mg / kg of the anti-IFN-α / ω antibody A single intravenous dose of 100 mg ... 961), 22.5 (2.21), 76.5 (9.30), 230 (22.4), or 4 The maximum measured concentration (C max ) is achieved in embodiment 4 or 4a.

[0100] Embodiment 4c is a further embodiment in which the human subject is a healthy subject and the human subject is administered 1.0 mg / kg of the anti-IFN- A single dose of the α / ω antibody administered subcutaneously resulted in a 226 (69.5 ) Area under the concentration-time curve (AUC) in μg.day / mL (0-t) In embodiment 4, This is a method according to the present invention.

[0101] Embodiment 4d is a method for treating a human subject, the method comprising administering 1.0 mg / kg of the anti-IFN- Subcutaneous administration of the α / ω antibody resulted in a 7.96 (2.48) μg / mL The highest measured concentration in mL (C max The method according to embodiment 4 or 4c, wherein .

[0102] In a fifth embodiment, administration of the anti-IFN-α / ω antibody does not result in a decrease in the level of the anti-IFN-α / ω antibody in the subject. According to any one of the embodiments 1 to 4d, no antibodies against N-α / ω antibodies are produced This is the method.

[0103] Embodiment 6 is a method for treating a human subject having an IFN-I mediated disease, such as systemic lupus erythematosus. Systemic lupus erythematosus (SLE), type I diabetes, psoriasis, primary Sjogren's disease, systemic sclerosis, rheumatoid arthritis Transplant rejection, dermatomyositis, polymyositis, Aicardi-Goutières syndrome, infantile onset S ting-associated vasculitis (SAVI), or chronic atypical neutrophilic leukemia with lipodystrophy and fever Any of embodiments 1 to 5, in which the patient is in need of treatment for chronic cutaneous and cutaneous lesions syndrome (CANDLE). This is a method according to the present invention.

[0104] In embodiment 7, the human subject has mild to moderate systemic lupus erythematosus (SLE). 7. The method of embodiment 6, wherein the patient is in need of treatment.

[0105] Embodiment 8 is a method according to any one of embodiments 6 to 7, in which the pharmaceutical composition is administered intravenously to the human subject. The method according to any one of the above.

[0106] In embodiment 8a, the total dose of the anti-IFN-α / ω antibody administered is 9. The method of embodiment 8, wherein the dose is 10 mg / kg (body weight of the subject).

[0107] Embodiment 8b is an embodiment in which the pharmaceutical composition is administered to the human subject once every two weeks. The method according to embodiment 8 or 8a.

[0108] Embodiment 9 is the method of any one of embodiments 6 to 7, wherein the pharmaceutical composition is administered subcutaneously to the human subject. The method is any one of the above.

[0109] In embodiment 9a, the total dose of the anti-IFN-α / ω antibody administered is 1 mg / kg (body weight of subject), in embodiment 9.

[0110] Embodiment 10 relates to a method for producing, in the plasma of a subject, (i) about Area under the concentration-time curve (AUC) from 800 μg.day / mL to approximately 3500 μg.day / mL (0 -14d) and (ii) the maximum observed concentration (C m ax Any of the embodiments 7 to 9a, in which at least one parameter selected from the following is achieved: The method is any one of the above.

[0111] In embodiment 10a, the pharmaceutical composition contains 10 mg / kg of the anti-IFN antibody per dose. - an α / ω antibody administered intravenously to the human subject once every two weeks, and after the first administration, The dose-interval concentration in the plasma of the subject was 1387 (354) μg.day / mL. Area under the degree time curve (AUC) (0-14d) 11. The method according to claim 10, wherein be.

[0112] In embodiment 10b, the pharmaceutical composition contains 10 mg / kg of the anti-IFN antibody per dose. - an α / ω antibody administered intravenously to the human subject once every 2 weeks, and after the sixth administration, The plasma concentration of 2340 (690) μg.day / mL was obtained during the dosing interval. Area under the degree time curve (AUC) (0-14d) In the embodiment 10 or 10a, This is the method described above.

[0113] Embodiment 10c includes administering a first intravenous dose of 10 mg / kg of the anti-IFN-α / ω antibody. The maximum observed concentration (C max )but This is achieved by the method according to any one of embodiments 10 to 10b.

[0114] Embodiment 10d includes administering a sixth intravenous dose of 10 mg / kg of the anti-IFN-α / ω antibody. The maximum observed concentration (C max )but and each administration of the pharmaceutical composition is administered to the human subject once every two weeks. The method according to any one of modes 10 to 10c.

[0115] Embodiment 11 is a method for treating a patient with a chronic rheumatoid arthritis (CR) syndrome by 100 days after administration of the pharmaceutical composition in a human subject. A decrease in the Systemic Lupus Erythematosus Responder Index (SRI), preferably a decrease of 4 points, more preferably In any one of embodiments 7 to 10d, the decrease is preferably 5 points, and most preferably 6 points. This is the method described.

[0116] Embodiment 12 is a method for determining whether a new inflammatory bowel disease occurs in a human subject by 100 days after administration of the pharmaceutical composition. Not shifting to British Isles Lupus Assessment Group (BILAG) A or 2B, implementation form The method according to any one of modes 7 to 11.

[0117] Embodiment 13 is a method for treating a pulmonary artery disease in a human subject by day 100 after administration of the pharmaceutical composition. Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) was used as a baseline score. 13. The method according to any one of embodiments 7 to 12, wherein the concentration of

[0118] Embodiment 14 is a method for treating a patient with a chronic rheumatoid arthritis (CR) syndrome by 100 days after administration of the pharmaceutical composition in a human subject. Systemic lupus erythematosus 2000 Responder Index 50 (S2K RI-50) was baseline 14. The method according to any one of embodiments 7 to 13, wherein the amount of the serotonin produced is reduced from the in-

[0119] Embodiment 15 is a method for treating a patient with a pulmonary edema by administering the pharmaceutical composition to a human subject within 100 days after administration of the pharmaceutical composition. The nurse's global assessment of disease activity (PGA) is reduced from baseline, in embodiments 7-1 4. The method according to claim 3,

[0120] In embodiment 16, the human subject achieves a steady state of the antibody within 40 to 50 days after administration. The method according to any one of embodiments 6 to 15,

[0121] Embodiment 17 is a method for treating a malignant disease in a subject, comprising administering the anti-IFN-α / ω antibody to the subject. or treatment-emergent adverse events (TEAEs) related to anaphylaxis or serum sickness-type reactions. 17. The method according to any one of embodiments 6 to 16, wherein said step (a) does not occur.

[0122] Embodiment 18 relates to a method for treating clinically-proven IFN-I mediated disease in a human subject in need thereof. The present invention relates to a method for providing a safe treatment comprising administering to a subject an anti-IFN-α / ω antibody and a pharma- ceutical acceptable salt thereof. The method comprises administering to the subject a pharmaceutical composition comprising a carrier comprising the compound comprising: The total dose of IFN-α / ω antibody is 0.1 mg / kg to 20 mg / kg ( The method is as follows:

[0123] Embodiment 18a is a further embodiment in which the anti-IFN-α / ω antibody comprises a heavy chain variable region and a light chain variable region. , wherein the heavy chain variable region is a heavy chain complementarity determining region ( HCDR) comprising HCDR1, HCDR2, and HCDR3 amino acid sequences, The light chain complementarity determining region (LCDR) LC of SEQ ID NOs: 30, 31, and 32, respectively. 19. The method of embodiment 18, comprising the DR1, LCDR2, and LCDR3 amino acid sequences. be.

[0124] Embodiment 18b is a method for treating IFN-α / ω antibody comprising administering to a subject an antibody having the amino acid sequence of SEQ ID NO:28. and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 29. The method according to embodiment 18 or 18a, comprising:

[0125] Embodiment 18c is a method for treating IFN-α / ω antibodies, the entire contents of which are incorporated herein by reference. IFWM3405, IFWM ...505, IFWM605, IFWM705, IFWM805, IFWM905, IFWM1005, IFWM113, 3442, IFWM3525, IFWM3423, IFWM3444, or IFWM34 21. The method according to embodiment 18,

[0126] Embodiment 18d is a method for treating IFN-α / ω deficiency, wherein the anti-IFN-α / ω antibody is a fully human antibody. The method according to any one of claims 1 to 18c.

[0127] Embodiment 19 is a method for treating the IFN-I mediated disease, comprising administering to the patient a therapeutically effective amount of the IFN-I mediated disease, such as systemic lupus erythematosus (SLE), Type I diabetes, psoriasis, primary Sjogren's disease, systemic sclerosis, rheumatoid arthritis, transplant rejection, skin Dermatomyositis, polymyositis, Aicardi-Goutières syndrome, infantile-onset Sting-related Chronic Atypical Neutrophilic Skin with Vascular Injury (SAVI) or Lipodystrophy and Hyperthermia Syndrome The method according to any one of embodiments 18 to 18d, wherein the method is selected from the group consisting of: This is the method.

[0128] Embodiment 20 is a method for treating a subject having mild to moderate systemic lupus erythematosus (SLE). 20. The method of embodiment 19, wherein the patient is in need of treatment for

[0129] Embodiment 21 is a method for administering the pharmaceutical composition intravenously to a human subject over a period of 30 minutes or more. The method according to any one of embodiments 18 to 20,

[0130] In embodiment 21a, the total dose of the anti-IFN-α / ω antibody administered is 22. The method of embodiment 21, wherein the dose is 10 mg / kg of the subject's body weight.

[0131] Embodiment 21b is an embodiment in which the pharmaceutical composition is administered to the human subject once every two weeks. The method according to embodiment 21a.

[0132] Embodiment 22 is a method according to any one of embodiments 18 to 10, wherein the pharmaceutical composition is administered subcutaneously to the human subject. 20. The method according to claim 1 , wherein

[0133] In embodiment 22a, the total dose of the anti-IFN-α / ω antibody administered is and 1 mg / kg (body weight of the subject).

[0134] In embodiment 23, administration of the anti-IFN-α / ω antibody does not result in the anti-IFN-α / ω antibody being administered to the subject. In any one of embodiments 18 to 22a, antibodies against FN-α / ω antibodies are not produced. This is the method described.

[0135] Embodiment 24 relates to a method for producing, in the plasma of a subject, a pharmaceutical composition comprising administering the pharmaceutical composition to the subject, (i) about Area under the concentration-time curve (AUC) from 50 μg.day / mL to approximately 7000 μg.day / mL (0- t) and (ii) the maximum observed concentration (C max )from Any one of embodiments 18 to 23, in which at least one selected parameter is achieved The present invention relates to a method for

[0136] Embodiment 24a relates to a method for determining, in the plasma of a subject, the administration of the pharmaceutical composition: Area under the concentration-time curve (AUC) from about 800 μg.day / mL to about 3500 μg.day / mL ( 0-14d) and (ii) the maximum observed concentration (C max 25. The method according to claim 24, wherein at least one parameter selected from the following is achieved: This is the method.

[0137] In embodiment 24b, the pharmaceutical composition contains 10 mg / kg of the anti-IFN antibody per dose. - an α / ω antibody administered intravenously to the human subject once every two weeks, and after the first administration, The dose-interval concentration in the plasma of the subject was 1387 (354) μg.day / mL. Area under the degree time curve (AUC) (0-14d) The method according to embodiment 24a, in which It is.

[0138] In embodiment 24c, the pharmaceutical composition contains 10 mg / kg of the anti-IFN antibody per dose. - an α / ω antibody administered intravenously to the human subject once every 2 weeks, and after the sixth administration, The plasma concentration of 2340 (690) μg.day / mL was obtained during the dosing interval. Area under the degree time curve (AUC) (0-14d) In the embodiment 24a or 24b, This is the method described.

[0139] Embodiment 24d is a first intravenous administration of 10 mg / kg of the anti-IFN-α / ω antibody. The maximum observed concentration (C max )but The method according to any one of embodiments 24a to 24c is achieved.

[0140] Embodiment 24e describes a sixth intravenous administration of 10 mg / kg of the anti-IFN-α / ω antibody. The maximum observed concentration (C max )but and each administration of the pharmaceutical composition is administered to the human subject once every two weeks. The method according to any one of modes 24a to 24d.

[0141] Embodiment 25 is a method for treating a patient with a pulmonary edema by administering the pharmaceutical composition to a human subject, the method comprising administering the pharmaceutical composition to a patient with a pulmonary edema by administering the pharmaceutical composition to a human subject. A decrease in the Systemic Lupus Erythematosus Responder Index (SRI), preferably a decrease of 4 points, more preferably Preferably, a 5 point reduction, most preferably a 6 point reduction, any one of embodiments 18 to 24e. This is a method according to the present invention.

[0142] Embodiment 26 is a method for determining whether a new inflammatory bowel disease occurs in a human subject by 100 days after administration of the pharmaceutical composition. Not shifting to British Isles Lupus Assessment Group (BILAG) A or 2B, implementation form The method according to any one of modes 18 to 25.

[0143] Embodiment 27 is a method for treating a patient with rheumatoid arthritis by administering the pharmaceutical composition to a human subject, the method comprising administering to the human subject a total of 100 days after administration of the pharmaceutical composition. Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) was used as a baseline score. The method according to any one of embodiments 18 to 26, wherein the concentration of

[0144] Embodiment 28 is a method for treating a patient with a chronic rheumatoid arthritis (CR) syndrome by 100 days after administration of the pharmaceutical composition in a human subject. Systemic lupus erythematosus 2000 Responder Index 50 (S2K RI-50) was baseline 28. The method according to any one of embodiments 18 to 27, wherein the amount of the serotonin produced is reduced from the in-

[0145] Embodiment 29 is a method for treating a patient suffering from a pulmonary edema by administering the pharmaceutical composition to a human subject within 100 days after administration of the pharmaceutical composition. The nurse's global assessment of disease activity (PGA) is reduced from baseline, 28. The method according to any one of claims 1 to 28.

[0146] In embodiment 30, the human subject achieves a steady state of the antibody within 40 to 50 days after administration. The method according to any one of embodiments 18 to 29,

[0147] Embodiment 31 is a method for treating a malignant disease in a subject, comprising administering the anti-IFN-α / ω antibody to the subject. or treatment-emergent adverse events (TEAEs) related to anaphylaxis or serum sickness-type reactions. 31. The method according to any one of embodiments 18 to 30, wherein no

[0148] Embodiment 32 is a method according to any one of embodiments 1 to 31, comprising: a. providing a biological sample from the human subject; b. one or more of the genes DHX58, EIF2AK in a biological sample of the human subject 2, HERC5, IFI44, IFI44L, IFI6, IRF7, PARP9, PLS Assaying gene expression of CR1 and SAMD9L; c. administering to the subject a pharmaceutical composition comprising the antibody and the pharma- ceutical acceptable carrier. prior to identifying said human subject as responsive to treatment with said antibody; The method further comprises:

[0149] Embodiment 33 is the method of embodiment 32, comprising: a. providing a biological sample from the human subject; b. The genes DHX58, EIF2AK2, and HER in a biological sample of the human subject. C5, IFI44, IFI44L, IFI6, IRF7, PARP9, PLSCR1, and and assaying gene expression of SAMD9L. c. The genes DHX58, EIF2AK2, HERC5, and IF I44, IFI44L, IFI6, IRF7, PARP9, PLSCR1, and SAMD Obtaining a composite expression value of 9L; d. administering to the subject a pharmaceutical composition comprising the antibody and the pharma- ceutical acceptable carrier. prior to identifying said human subject as responsive to treatment with said antibody; The method includes:

[0150] Embodiment 34 is the method of embodiment 33, comprising: a. providing a biological sample from the human subject; b. The genes DHX58, EIF2AK2, and HER in a biological sample of the human subject. C5, IFI44, IFI44L, IFI6, IRF7, PARP9, PLSCR1, and and assaying gene expression of SAMD9L. c. The genes DHX58, EIF2AK2, HERC5, and IF I44, IFI44L, IFI6, IRF7, PARP9, PLSCR1, and SAMD Obtaining a composite expression value of 9L; d. If the composite expression value is equal to or greater than a threshold, the human subject has an elevated IFN-I signature. determining that the sample has char; b. administering to the subject a pharmaceutical composition comprising the antibody and the pharma- ceutical acceptable carrier. prior to identifying said human subject as responsive to treatment with said antibody; The method includes:

[0151] In embodiment 35, the pharmaceutical composition contains the antibody at a concentration of 1 mg / mL to 100 mg / mL. Any one of embodiments 1 to 34, comprising an IFN-α / ω antibody and a pharma- ceutical acceptable carrier. The present invention relates to a method for

[0152] Embodiment 35a is a method for treating a patient with an IFN-α / ω antibody comprising administering to said patient a therapeutically effective amount of at least one of the following: L, 20mg / mL, 30mg / mL, 40mg / mL, 50mg / mL, 60mg / m L, 70 mg / mL, 80 mg / mL, 90 mg / mL, or 100 mg / mL, or is any concentration therebetween.

[0153] Embodiment 35b is a method of administering a pharmaceutical composition comprising administering to a subject the pharmaceutical composition of the present invention, the pharmaceutical composition comprising: % (w / v), e.g., lactose, maltose, sucrose, etc., at concentrations of 5% to 10% (w / v). The method according to any one of embodiments 35 to 35a, further comprising one or more carbohydrates of the formula.

[0154] Embodiment 35c is a method for preparing a pharmacopoeitic agent comprising administering to a subject the pharmacopoeitic agent of the present invention at a concentration of 1% (w / v), 1.5% (w / v), v), 2%(w / v), 2.5%(w / v), 3%(w / v), 3.5%(w / v), 4 %(w / v), 4.5%(w / v), 5%(w / v), 5.5%(w / v), 6%(w / v), 6.5%(w / v), 7%(w / v), 7.5%(w / v), 8%(w / v), 8 0.5% (w / v), 9% (w / v), 9.5% (w / v), or 10% (w / v), or any concentration therebetween of at least one of lactose, maltose, and sucrose. The method according to embodiment 35b, including any one of the above.

[0155] Embodiment 35d is a method for treating a medicament comprising administering to a subject the medicament a medicament comprising administering to said subject a ... (w / v) or polysorbate 2 at a concentration of 0.02% (w / v) to 0.08% (w / v) Any of embodiments 35 to 35c, further comprising one or more surfactants such as polysorbate 80, polysorbate 80, etc. The method is any one of the above.

[0156] Embodiment 35e is an embodiment in which the pharma- ceutical acceptable carrier is 0.01%, 0.02%, 0.0 3%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, young or 0.1% (w / v), or any concentration therebetween of polysorbate 20 and polysorbate The method of embodiment 35d, comprising at least one of sorbate 80.

[0157] Embodiment 35f is an embodiment in which the pharma- ceutical acceptable carrier is in an amount of lactate or acetate, respectively. Based on the concentration of 10mM~20mM, lactic acid, sodium lactate, acetic acid, sodium acetate, etc. The method according to any one of embodiments 35 to 35e, comprising one or more acids and / or salts of It is.

[0158] Embodiment 35g is a further embodiment in which the pharma- ceutical acceptable carrier is at least 10 mM, 11 mM, 12 mM, 13mM, 14mM, 15mM, 16mM, 17mM, 18mM, 19mM, 20mM, or at least one of sodium lactate and sodium acetate in any concentration therebetween The method of embodiment 35f, comprising:

[0159] In embodiment 35h, the pharmaceutical composition has a pH of 5.0 to 6.0, for example, 5.0, 5. 1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, or The method according to any one of embodiments 35 to 35g, having a pH of any value therebetween. It is law.

[0160] In embodiment 36, the medicament contains 20 mg / mL to 80 mg / mL of the anti-IFN-α / The method of any one of embodiments 1 to 34, comprising an ω antibody and a pharma- ceutical acceptable carrier. It is law.

[0161] Embodiment 36a is a method in which the pharma- ceutically acceptable carrier comprises 1 mM to 20 mM acetate. 37. The method according to embodiment 36.

[0162] Embodiment 36b is a method in which the pharma- ceutically acceptable carrier comprises between 1 mM and 20 mM lactate. 37. The method according to embodiment 36.

[0163] In embodiment 36c, the pharma- ceutical acceptable carrier is 5% to 10% (w / v) lactose. The method according to any one of embodiments 36 to 36b, further comprising:

[0164] Embodiment 36d is a process in which the pharma- ceutical acceptable carrier is 5% to 10% (w / v) maltodextrin. The method according to any one of embodiments 36 to 36b, further comprising:

[0165] Embodiment 36e is a method for preparing a pharmaceutical composition comprising administering to a patient a pharmaceutical composition comprising 5% to 10% (w / v) of sucrose. The method according to any one of embodiments 36 to 36b, further comprising:

[0166] Embodiment 36f is a method for treating a medicament comprising administering to a subject the medicament a medicament comprising administering to said subject a ... ) polysorbate 20 (PS20) according to any one of embodiments 36 to 36e. This is the method described above.

[0167] In embodiment 36g, the pharma- ceutical acceptable carrier is 0.01% to 0.10% (w / v ) polysorbate 80 (PS80) according to any one of embodiments 36 to 36e. This is the method described above.

[0168] In embodiment 36h, the pharmaceutical composition has a pH of 5.0 to 6.0, for example, 5.0, 5. 1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, or The method according to any one of embodiments 36 to 36g, having a pH of any value therebetween. It is law.

[0169] Embodiment 37 is a method for treating a medicament comprising administering to a subject a therapeutically effective amount of an anti-IFN-α / ω antibody at 30 mg / mL, an anti-IFN-α / ω antibody at 5 mM, Lactate, 5% (w / v) lactose, and 0.02% (w / v) polysorbate 80 (PS80) (pH 5.5). do.

[0170] Embodiment 38 is a method for treating a medicament comprising administering to a subject a therapeutically effective amount of an anti-IFN-α / ω antibody at 40 mg / mL, an IFN-α / ω antibody at 8 mM, acetate, 8% (w / v) maltose, and 0.06% (w / v) polysorbate 20 (PS20) (pH 5.0). do.

[0171] Embodiment 39 is a method for preparing a pharmaceutical composition comprising administering to a patient a therapeutically effective amount of an anti-IFN-α / ω antibody at a concentration of 50 mg / mL, 3 mM acetate, 8.0% (w / v) sucrose, and 0.04% (w / v) polysorbate The composition according to any one of embodiments 1 to 34, comprising PS20 (pH 5.2). This is the method described above.

[0172] Embodiment 40 is a method for treating a medicament comprising administering to a subject a subject a subject an anti-IFN-α / ω antibody at 60 mg / mL, acetate, 8% (w / v) lactose, and 0.06% (w / v) polysorbate 2 0 (PS20) (pH 5.4), be.

[0173] Embodiment 41 is a method for treating a medicament comprising administering to a subject a subject a subject an anti-IFN-α / ω antibody at 70 mg / mL, lactate, 10% (w / v) maltose, and 0.06% (w / v) polysorbate 80 (PS80) (pH 5.0). It is.

[0174] Having generally described the present invention, the same is provided by way of illustration and not limitation. This will be more readily understood by reference to the following examples, which are not intended to be exhaustive. Further details of the present invention are illustrated by the following non-limiting examples. The disclosures of all citations are expressly incorporated herein by reference. EXAMPLES

[0175] Example 1: A Phase 1 Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study in Healthy Subjects Multiple-dose study of antibody A in subjects with mild to moderate systemic lupus erythematosus. This clinical trial is the first in humans to demonstrate a fully human anti-IFN-α / ω antibody ("Antibody A"). Antibody A has the heavy chain variable region (VH) amino acid sequence of SEQ ID NO: 28 and SEQ ID NO: The antibody has a light chain variable region (VL) amino acid sequence of No. 29 and is an IgG1κ antibody. Part A is a randomized, multicenter, randomized, double-blind ...group study of single-dose escalating intravenous (IV) and single-dose subcutaneous (SC) doses in healthy subjects. ), as well as multiple myeloma in subjects with mild to moderate systemic lupus erythematosus (SLE) The objective of this study was to evaluate the safety and tolerability of Antibody A via single IV administration (Part B).

[0176] the purpose Main purpose 1) Single ascending IV doses in healthy subjects and a single SC dose of 1 mg / kg in healthy subjects To evaluate the safety and tolerability of Antibody A following administration (Part A); 2) Safety and efficacy of Antibody A after multiple IV administration in subjects with mild to moderate SLE Evaluate efficacy and tolerability (Part B).

[0177] secondary purpose 1) Single ascending IV doses in healthy subjects and a single SC dose of 1 mg / kg in healthy subjects Post-dose (Part A) and multiple IV dosing in subjects with mild-to-moderate SLE and (Part B) to evaluate the PK and immunogenicity of Antibody A; 2) Pharmacodynamic (PD) and clinical outcomes following a single IV or SC administration of antibody A in healthy subjects To evaluate the bed response (Part A) and multiple antibody A responses in subjects with mild to moderate SLE Part B: Evaluate PD and clinical response after single IV administration of 100 mg / kg / day.

[0178] Experimental Purpose 1) After a single IV or SC administration of Antibody A in healthy subjects (Part A) and mild-to-moderate Biomarkers after multiple IV administration of Antibody A in subjects with SLE (Part B) Evaluate; 2) the level of dysregulation of IFN signaling and whether this dysregulation is responsive to administration of the test agent; assess how changes in other biomarkers and measures of clinical response correlate with those of other studies; 3) Variation in IFN signatures across different racial / ethnic groups and response to test agents Investigate its potential impact on exposure-related clinical responses; 4) PK / PD of Antibody A through analysis of biomarkers, PD markers, and clinical response Investigate relationships.

[0179] Methods and Subjects Study design overview Part A of the study included healthy subjects with no significant confounding medical problems or chronic medications. To evaluate the safety, tolerability, PK, and immunogenicity of a single dose of Antibody A or placebo in Here, PK sampling was performed at high frequency, and biomarkers and PD were also evaluated. 3mg / kg, 1.0mg / kg, 3.0mg / kg, 10.0mg / kg, or 15. Successive cohorts of healthy subjects received single ascending IV doses of 0 mg / kg antibody A or placebo. The antibody was administered as an IV infusion over at least 30 minutes. Additional cohorts received 1 mg / kg of the antibody. Body A was administered as a single SC dose.

[0180] Part B of the study evaluated clinical response, safety and efficacy in subjects with mild to moderate SLE. In addition, target engagement (total and free IFN), IFN-related RNA expression, and tolerability were investigated. Evaluate the impact on current signatures and associated proteins and other biomarkers over time The incremental effect on biomarker readouts was further investigated to assess the effect of different races / ethnic groups. We assessed variation in the ability to attenuate IFN-mediated signaling across tribe populations Subgroup analyses of clinical response and safety parameters will be performed to assess variability, where appropriate. In Part B, the effect of treatment across different subpopulations was investigated. or placebo was administered as an IV infusion over at least 30 minutes every 2 weeks for six doses. According to ethnic subgroup (Asian / non-Asian) and elevated levels of serologic disease activity (presence / absence), Randomization was stratified.

[0181] The duration of subject participation was approximately 13 weeks for healthy subjects and 22 weeks for SLE subjects. weeks, including the screening visit up to 28 days prior to study drug administration. The healthy subjects were hospitalized for 5 nights and 6 days. All subjects were administered the test Drugs were administered and SLE subjects received additional doses on days 15, 29, 43, 57, and 71. went.

[0182] A diagram of the study design is shown in Figure 1.

[0183] Test drug Antibody A is a frozen, preservative-free final antibody suitable for IV and SC administration. It is supplied in liquid-in-vial (LIV) form.

[0184] subject Part A: A total of 48 healthy adults with no confounding significant medical problems or chronic medications Subjects (40 men, 8 women) were enrolled. Thirty subjects received a single ascending IV dose (0. 3–15.0 mg / kg) of antibody A, and 6 subjects received a SC dose (1.0 mg / kg g) and 12 subjects received a placebo. Two subjects from antibody group A were Figure 2 depicts the disposition of subjects in Part A.

[0185] Part B: Subjects eligible for enrollment met the following key criteria: 3) Systemic lupus erythematosus disease activity index 20 within 3 months prior to the first administration of the study drug Non-serological clinical activity as defined by SLEDAI-2K (SLEDAI-2K) was at least 1. Meets Systemic Lupus International Collaborating Clinics (SLICC) criteria for diagnosing lupus It is necessary to be. 4) In addition to meeting the SLICC criteria, the patient has been diagnosed with pulmonary hypertension within 2 months prior to screening or at the time of screening. At the time of screening, serological positivity must be defined as: e) Positive antinuclear antibody (ANA) titer of ≥ 1:80; or f) Positive anti-double-stranded deoxyribonucleic acid test (Note: Anti-dsDNA is an enzyme-linked immunosorbent assay) When performed by adsorption assay, a serum concentration of 2% above the upper limit of normal is required to be considered clearly positive. (double the test value required) or g) Positive anti-Smith antibody and / or anti-ribonucleoprotein (RNP) antibody and / or anti-Ro antibody positive, and in addition to at least one of the above , h) A positive Lupus IFN Profile Score during screening (prior to randomization) be.

[0186] A total of 28 subjects (27 women: 1 man) with mild to moderate SLE were enrolled in the part B (20 subjects: 10 mg / kg IV dose; 8 subjects: Plasma Three subjects from antibody A group did not complete the study. Figure 3 shows the results in Part B. Represents the placement of the object.

[0187] evaluation Safety assessment Physical examination, infusion reactions, injection site reactions, laboratory tests, vital signs, concomitant medications, and treatments. Safety and tolerability of Antibody A, including time-emergent adverse events (TEAEs), were summarized by treatment group. Safety and tolerability of Antibody A, including physical examination, infusion reactions, and injection site.

[0188] Pharmacokinetics and immunogenicity Serum samples were used to assess PK and immunological outcomes of Antibody A in all study subjects. Epidemiogenicity was assessed. Serum samples were collected at the indicated times relative to the start of infusion / injection as listed in Figure 1. The samples were collected.

[0189] Serum samples were analyzed and validated with a lower limit of quantification (LLOQ) of 0.06 μg / mL. Antibody A concentrations were determined using a validated immunoassay method. Detection and characterization of antibodies against Antibody A was performed.

[0190] Pharmacodynamic evaluation (Optional) Biopsy of skin lesions and biopsies of lesioned skin before and after treatment were taken from subjects who gave consent for biopsy. Biopsies (two pre-treatment and two post-treatment; 4 mm punch) were taken. was assessed by targeted mRNA expression and specific immunohistochemical staining.

[0191] Clinical Response Assessment Response assessment and patient-reported quality of life measures included the SLEDAI-2K / SLEDAI -2K Responder Index (S2K RI-50), British Isles Lupus Evaluation Group (BI LAG), Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), Physician-Assessed Disease Patient Activity Global Assessment (PGA), Short 36 Questionnaire, EuroQol-5 Dimension-5 Level ( A questionnaire was provided to participants with SLE who provided consent for EQ-5D-5L patient diaries, joint assessments, and photographs. Photographs of elephant skin lesions were included.

[0192] Glycoform analysis In Part A, serum samples were collected and stored in subjects receiving the 15 mg / kg dose. The samples were then analyzed to determine potential changes in glycoform levels of Antibody A. I was able to do it.

[0193] Biomarkers Biomarkers will be analyzed as part of the exploratory analysis for Part A and Part B subjects. This included serum levels of IFN as well as molecular pathway profiling. Biomarkers include inflammatory markers, RNA, cell surface markers, autoantibodies, T cells and Involved in B cell repertoire, target specific markers, and the development and progression of SLE Other categories of potential biomarkers included, but were not limited to:

[0194] Pharmacological evaluation Variability in RNA, DNA, protein expression, and IFN signature changes , samples were analyzed, with the hypothesis that this could help resolve the clinical data issue. If so, further analysis was performed.

[0195] statistical methods Clinical response analysis in Part B will include a summary of SLE assessments, including organ domain-specific changes It included:

[0196] Pharmacokinetics: Individual subject serum concentration-time data for Antibody A were analyzed by non-compartmental analysis (NCA). PK parameters were summarized by treatment group and planned sampling time points. , and graphically displayed the PK data. A plot of the mean serum concentration of Antibody A over time was provided. Descriptive statistics were calculated for all individual derived PK parameters including exposure information for Antibody A. I calculated it.

[0197] Immunogenicity: After administration of antibody A, a sample suitable for detecting antibodies against antibody A is prepared. Antibody A antibody status was summarized for all subjects who had baseline positive Subjects with a positive sample who did not have an increased titer after treatment were anti-drug antibody (ADA) positive. I didn't consider it to be there.

[0198] All TEAEs were analyzed by treatment group and by MedDRA version 18.1 (Part A) and In Part B of 1.0, the groups of healthy subjects and SLE subjects were summarized by SOC and PT. Ta.

[0199] Safety Results The safety analysis set included 48 subjects in Part A and 26 subjects in Part B. Overall, 39 (81.3%) subjects in Part A and 2 (1.0%) in Part B were included. 0 (76.9%) subjects reported one or more TEAEs during the course of the study. Evidence-based TEAEs were reported in the infection and invasion system organ classes for both parts of the study.

[0200] In Part A, one subject treated with Antibody A 0.3 mg / kg IV developed non-severe T The patient developed bullous myringitis in the right ear due to EAE. The event was reported as resolved. No infusion reactions were reported. No serious adverse events were reported in Part A, and no local injection site reactivity was attributed to study drug. E was not reported.

[0201] In Part B, serious TEAEs were reported in 2 (7.7%) subjects from the Antibody A cohort. Herpes zoster (HZ) in 2 (7.7%) subjects and pulmonary embolism in 1 (3.8%) subject No serious TEAEs were reported in the placebo cohort. Antibody A 10. One subject treated with 0 mg / kg IV was considered possibly related to antibody A. The study was discontinued due to a non-serious TEAE of groin pain (lymphadenopathy). No reports of adverse events were reported and no local injection site reactivity was attributed to the study drug. No reported TEAEs or anaphylactic or serum sickness-type reactions.

[0202] Overall, Antibody A was well tolerated in normal healthy volunteers and SLE subjects. No deaths were reported in the study.

[0203] In addition, laboratory parameters, vital signs, physical examination, or ECG findings may be reviewed. No clinically significant changes from Sline were observed.

[0204] Pharmacokinetic results Part A Separate cohorts of healthy subjects received a single ascending dose of I over the dose range of 0.3 to 15 mg / kg. V dose of Antibody A or placebo. In addition, one cohort of healthy subjects received 1 mg 100 / kg of Antibody A or placebo was administered as a single SC dose.

[0205] The linear mean serum concentration-time profiles of antibody A for cohorts 1–5 (IV infusion) are shown in Figure 4. Cohort 2 (1.0 mg / kg, IV infusion) and Cohort 6 (1.0 mg / kg, The linear mean serum concentration-time profiles of 100 mg / mL SC injection are shown in Figure 5.

[0206] A summary list of key PK parameters for Antibody A in Cohorts 1-5 is shown below in Table 11. Overall, Part A will assess the maximum observed serum concentration (Cmax) and area under the curve (AUC) of antibody A. AUC) was measured at doses of 0.3 mg / kg to 15 mg / kg after a single IV injection in healthy subjects. The mean total IV doses increased approximately in a dose-dependent and dose-proportional manner over the entire dose range. The total body clearance (CL) and the terminal volume of distribution (Vz) after a single IV injection were The ranges were 2.28 to 3.09 mL / day / kg and 67.2 to 102 mL / kg, respectively. I did.

[0207] [Table 2] a AUC 0-t , AUC 0-inf , C.L., V. z , AUC 0-t、正規化された用量 , and AUC 0-inf、正規化された用量 For n=5 b AUC 0-inf , C.L., V. z , and AUC 0-inf、正規化された用量 About n=5 c AUC 0-inf , T 1 / 2 , C.L., V. z , and AUC 0-inf、正規化された用 量 For n=5

[0208] A summary list of the key PK parameters of Antibody A in Cohorts 2 and 6 is shown below in Table 2. After a single SC injection, the mean Cmax (7.96 μg / mL) was reached 7 days later (T max After IV administration, the mean total systemic clearance / (CL / F) and Vz / F were 3. The terminal half-life (T1 / 2) was 96 mL / day / kg and 119 mL / kg, respectively, for IV injection. The mean T1 / 2 after a single IV injection was 20.7–24. The mean T ranged from 0.01 to 0.6 days after SC injection, whereas the ... and Based on a comparison with SC injection, the bioavailability of antibody A administered as a SC injection was The average rates for FAUC0-t and FAUC0-inf were 78.7% and 81.9%, respectively. I did.

[0209] [Table 3]

[0210] Part B Part B of this study randomized 28 subjects with mild to moderate SLE. 10 mg / kg of antibody A or placebo as an IV infusion over at least 30 minutes every 2 weeks The linear mean serum concentration-time profiles of antibody A at doses 1 and 6 are shown in Fig. Shown in 6.

[0211] Antibody A was administered IV for six doses at 10 mg / kg every two weeks, followed by administration of doses 1 and 6. The shapes of the PK profiles were generally similar up to 14 days post-dose, i.e., one dosing interval. The PK profiles after doses 1 and 6 were similar to those observed in healthy volunteers. The peak serum concentrations were similar and biphasic in nature after dose 6 compared with dose 1. The exposure of antibody A during the dosing interval (area under the curve from days 0 to 14 [AUC0- 14d]) was higher after dose 6 compared with dose 1.

[0212] A summary list of the main PK parameters of Antibody A is shown in Table 3 below. Pre-dose plasma concentrations of and 6 (C predose ) concentration, treatment with Antibody A (administration 4 Steady state of antibody A was considered to be achieved within 43 days of administration. Mean accumulation based on AUC The mean accumulation based on Cmax was 1.86-fold higher after dose 6 compared with dose 1. The CL and distribution volume (V ss ) are the average values ​​of The mean T1 / after the sixth dose was 4.73 mL / day / kg and 92.6 mL / kg. 2 was 14.8 days.

[0213] Although no formal comparisons were performed, exposure in subjects with mild to moderate SLE was 1 This appears to be slightly lower compared to healthy subjects at an IV dose of 0 mg / kg.

[0214] [Table 4]

[0215] Immunogenicity Results (Part A and Part B) 0.3 mg / kg to 15 mg / kg IV or 1 mg / kg IV of antibody A in healthy subjects A single dose of 10 mg / kg of antibody A SC or 10 mg / kg / day in subjects with mild to moderate SLE After multiple doses of IV antibody A at 100 mg / kg, no subjects developed antibodies to antibody A. Therefore, the incidence of ADA was not calculated or reported.

[0216] Clinical response results from Part B SLE Responder Index (SRI)-4, 5, and 6 The number of subjects with an SRI-4, SRI-5, or SRI-6 response at day 100 is shown in Table 4. Data from overall SRI response at day 100 shows that subjects from the Antibody A treatment group achieved showed a numerically greater response rate than the placebo cohort (31.3% vs 0% respectively) as shown.

[0217]

Table 5

[0218] BILAG As shown in Table 5 below, no new shift to BILAG A or 2B was observed .

[0219]

Table 6

[0220] SLEDAI-2K The changes from baseline and percent changes over time in SLEDAI-2K are shown in Table 6. Overall, the data from the antibody A cohort showed a numerically greater decrease than from the placebo cohort: mean (SD) percent change from baseline at day 100 for SLEDAI-2K: -23.74 (27.061) vs - 8.93 (13.139) respectively. 8.93 (13.139). - 8.93 (13.139).

[0221]

Table 7-1

[0222] [Table 7-2]

[0223] S2K RI-50 Change and percent change from baseline in S2K RI-50 over time The results are shown in Table 7. Overall, the data from the Antibody A cohort were significantly stronger than those from the placebo cohort. The decrease in the baseline at 100 days for S2K ​​RI-50 was numerically greater than that for S2K ​​RI-50. Mean (SD) percentage change from baseline: -51.77 (24.760) vs. - 25.84(22.163).

[0224] [Table 8-1]

[0225] [Table 8-2]

[0226] PGA A summary of the changes and percent changes from baseline in PGA are shown in Table 8. Specifically, data from the Antibody A cohort were numerically more consistent with PGA than data from the placebo cohort. A large reduction in mean (SD) percent change from baseline at day 100 was observed :-19.60(36.250) vs. -6.09(29.154) respectively).

[0227] [Table 9-1]

[0228] [Table 9-2]

[0229] Joint Evaluation: Pain over time for subjects with at least two affected joints at baseline A summary of the change from baseline in the number of joints with signs of inflammation is shown in Table 9.

[0230] [Table 10-1]

[0231] [Table 10-2]

[0232] Table 1. Summary of changes from baseline in number of joints with signs of pain and inflammation over time. Shown in Figure 10.

[0233] [Table 11-1]

[0234] [Table 11-2]

[0235] [Table 11-3]

[0236] Overall, data from the Antibody A cohort showed a greater number of swollen joints than the placebo cohort. showed a greater decrease in

[0237] Sudden First SLEDAI, Severe SLEDAI, or BILAG Outbreak on Days 1-100 Summary of time to disease onset is shown above in Table 6. Due to the small number of total outbreaks, comparisons between cohorts are limited. Comparisons were difficult; however, there were no notable differences between the treatment groups.

[0238] CLASI The low baseline activity scores made interpretation difficult. (defined as a change in CLASI score of 3 points from baseline at day 100) As judged by the percentage of subjects who declined by 18% or more, the Antibody A cohort was showed a higher response rate than Hort (44.4% vs. 25.0%, respectively).

[0239] EQ-5D-5L and SF-36 No changes in overall scores or individual domains across cohorts were evident.

[0240] Those skilled in the art may make changes to the above-described embodiments without departing from the broad inventive concept. It will be understood that the invention is therefore not limited to the particular embodiments disclosed. However, the present invention is not limited to the above, and covers modifications within the spirit and scope of the present invention as defined by the specific description. It is understood that the present invention is intended to

Claims

1. Administration of a clinically proven and safe amount of anti-IFN-α / ω antibody to a human subject in need thereof The method includes administering to the subject a pharmaceutical composition comprising the antibody and a pharma- ceutical acceptable carrier. subcutaneously or intravenously, wherein the antibody comprises a heavy chain variable region and a light chain variable region. and the heavy chain variable region is selected from the heavy chain complementarity determining regions of SEQ ID NOs: 33, 34, and 35, respectively. (HCDR) The light chain may include HCDR1, HCDR2, and HCDR3 amino acid sequences. The variable regions are the light chain complementarity determining regions (LCDRs) L of SEQ ID NOs: 30, 31, and 32, respectively. The total amount of the antibody administered comprises the CDR1, LCDR2, and LCDR3 amino acid sequences. The dosage is 0.1 mg / kg to 20 mg / kg (body weight of the subject) per administration; method.

2. The antibody comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 28 and a heavy chain variable region (VL) having the amino acid sequence of SEQ ID NO: The method of claim 1, comprising a light chain variable region (VL) having a sequence of 29 amino acids.

3. The pharmaceutical composition is administered intravenously, and the anti-IFN-α / The total dose of ω antibody was 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg g, 10 mg / kg, 15 mg / kg, or 20 mg / kg of the subject's body weight, or and any dosage therebetween.

4. The pharmaceutical composition is administered subcutaneously, and the anti-IFN-α / ω is administered per administration. The total antibody dose was 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, g / kg, 1mg / kg, 1.2mg / kg, 1.5mg / kg, 1.7mg / kg, 2 mg / kg, 2.3 mg / kg, or 2.5 mg / kg (body weight of the subject), or The method of claim 1 or 2, wherein the dosage is any amount therebetween.

5. in the subject's plasma, (i) from about 50 μg.day / mL to about 7000 μg.day / mL Area under the concentration time curve (AUC) （０－ｔ） and (ii) from about 5 μg / mL to about 500 μg / mL The highest observed concentration in mL (C ｍａｘ At least one parameter selected from the following is achieved: The method according to any one of claims 1 to 4,

6. The administration of the anti-IFN-α / ω antibody does not result in the anti-IFN-α / ω antibody being detected in the subject. The method according to any one of claims 1 to 5, wherein no antibodies against the

7. The human subject is a patient suffering from an IFN-I mediated disease, e.g., systemic lupus erythematosus (SLE). , type I diabetes, psoriasis, primary Sjogren's disease, systemic sclerosis, rheumatoid arthritis, transplant rejection, Dermatomyositis, polymyositis, Aicardi-Goutieres syndrome, infantile onset Sting-related hematoma Chronic atypical neutrophilic dermatosis syndrome with lipodystrophy and fever (SAVI) The method according to any one of claims 1 to 6, wherein the patient is in need of treatment for a group (CANDLE). 。

8. The human subject is in need of treatment for mild to moderate systemic lupus erythematosus (SLE). The method according to any one of claims 1 to 7,

9. The pharmaceutical composition is administered at 10 mg / kg (body weight of the subject) per dose. The total dose of the anti-IFN-α / ω antibody is administered intravenously to the human subject over a period of 30 minutes or more. Preferably, the pharmaceutical composition is administered to the patient repeatedly, more preferably once every two weeks.

9. The method of claim 8, wherein the therapeutic agent is administered intravenously to a subject.

10. The pharmaceutical composition is administered at 1 mg / kg (body weight of the subject) per dose. The method of claim 8, wherein the total dose of anti-IFN-α / ω antibody is administered subcutaneously to the human subject. Law.

11. The administration of the pharmaceutical composition results in: (i) about 1000 μg of Area under the concentration-time curve (AUC) from about 3500 μg.days / mL to about 3500 μg.days / mL （０－１４ｄ） and (ii) a maximum observed concentration (C ｍａｘ )from 10. The method according to claim 8 or 9, wherein at least one selected parameter is achieved.

12. In said human subject, systemic lupus erythema is reduced by 100 days after said administration of said pharmaceutical composition. Systemic Lupus Erythematosus Responder Index (SRI) is decreased, preferably by 4 points, more preferably by 5 points, and most preferably by 6 points; The method according to any one of claims 8 to 11.

13. The human subject has a new British Isles disease by 100 days after administration of the pharmaceutical composition. British Isles Lupus Assessment Group (BILAG) score of A or The method according to any one of claims 8 to 12, wherein there is no shift to 2B.

14. In said human subject, systemic lupus erythematosus (SLE) is improved by 100 days after said administration of said pharmaceutical composition. Systemic Lupus Erythematosus Disease Activity Index 2000 dex, SLEDAI-2K) from baseline. The method according to claim 5.

15. In said human subject, systemic lupus erythematosus (SLE) is improved by 100 days after said administration of said pharmaceutical composition. Systemic Lupus Erythematosus 2000 Responder Index 50 The method according to any one of claims 8 to 14, wherein the S2K RI Index-50, S2K RI-50) are reduced from baseline. The method according to any one of claims 1 to 5.

16. A physician-determined disease in the human subject within 100 days after administration of the pharmaceutical composition. Physician's Global Assessment of Disease Activity (PGA) The method of any one of claims 8 to 15, wherein the decrease is from baseline.

17. 9. The method of claim 8, wherein the human subject achieves a steady state of the antibody within 40 to 50 days after administration.

17. The method according to any one of claims 1 to 16.

18. The administration of the anti-IFN-α / ω antibody does not result in malignant or anaphylactic shock in the subject. Treatment emergent adverse events related to laxity or serum sickness-type reactions The method according to any one of claims 8 to 17, wherein no adverse event (TEAE) occurs.

19. The method according to any one of claims 1 to 18, a. one or more genes DHX58, EIF2AK in a biological sample of the human subject 2, HERC5, IFI44, IFI44L, IFI6, IRF7, PARP9, PLS Assaying gene expression of CR1, and SAMD9L; b. administering to the subject the pharmaceutical composition comprising the antibody and the pharma- ceutical acceptable carrier. identifying said human subject as responding to said antibody treatment prior to said administration of said antibody; The method further comprises:

20. 20. The method of claim 19, a. The genes DHX58, EIF2AK2, HER2 and DHX58 in a biological sample of the human subject C5, IFI44, IFI44L, IFI6, IRF7, PARP9, PLSCR1, and and assaying gene expression of SAMD9L. b. The genes DHX58, EIF2AK2, HERC5, IF I44, IFI44L, IFI6, IRF7, PARP9, PLSCR1, and SAMD determining a composite expression value of 9L; c. if the composite expression value is equal to or greater than a threshold, the human subject will respond to treatment with the antibody; Answer: Identify A method comprising:

21. The human subject is administered chloroquine, hydroxychloroquine, methotrexate, or have been treated with topical corticosteroids, or any combination thereof, 21. The method according to any one of items 1 to 20.

22. Chloroquine, hydroxychloroquine, methotrexate, or systemic corticosteroids 4. The method of claim 3, further comprising administering to the human subject a 22. The method according to any one of items 1 to 21.

23. The method according to any one of claims 1 to 22, wherein the anti-IFN-α / ω antibody is 30 g / mL of the anti-IFN-α / ω antibody, 5 mM lactate, 5% (w / v) lactate and 0.02% (w / v) polysorbate 80 (PS80) (pH 5.5), 40 mg / mL of the anti-IFN-α / ω antibody, 8 mM acetate, 8% (w / v) malt tosine, and 0.06% (w / v) polysorbate 20 (PS20) (pH 5.0); 50 mg / mL of the anti-IFN-α / ω antibody, 13 mM acetate, 8.0% (w / v) of sucrose, and 0.04% (w / v) polysorbate 20 (PS20) (pH 5. 2) 60 mg / mL of the anti-IFN-α / ω antibody, 10 mM acetate, 8% (w / v) of lactose, and 0.06% (w / v) polysorbate 20 (PS20) (pH 5. 4); and 70 mg / mL of the anti-IFN-α / ω antibody, 15 mM lactate, 10% (w / v) Maltose, and 0.06% (w / v) polysorbate 80 (PS80) (pH 5.0 ） The method of claim 1, wherein the compound is administered in a formulation selected from the group consisting of:

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