WO2012162367A1 - Methods of treating systemic lupus erythematosus, scleroderma, and myositis with an antibody against interferon-alpha - Google Patents
Methods of treating systemic lupus erythematosus, scleroderma, and myositis with an antibody against interferon-alpha Download PDFInfo
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
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- C07—ORGANIC CHEMISTRY
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- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A61P19/00—Drugs for skeletal disorders
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
- C07K16/4208—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig
- C07K16/4241—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-human or anti-animal Ig
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
Definitions
- the present disclosure provides methods for treatment of autoimmune diseases such as systemic lupus erythematosus, scleroderma, and myositis with anti-IFN-alpha antibodies.
- Type I interferons (IFN-alpha, IFN-beta, IFN-omega, IFN-tau) are a family of structurally related cytokines having antiviral, antitumor and immunomodulatory effects (Hardy et al. (2001 ) Blood 97:473; Cutrone and Langer (2001 ) J. Biol. Chem. 276:17140).
- the human IFN-alpha locus includes two subfamilies. The first subfamily consists of at least 14 non allelic genes and 4 pseudogenes having at least 75% homology. The second subfamily, alpha-ll or omega, contains 5 pseudogenes and 1 functional gene which exhibits 70% homology with the IFN-alpha genes.
- IFN-alpha The subtypes of IFN-alpha have different specific activities but they possess the same biological spectrum (Streuli et al. (1981 ) Proc. Natl. Acad. Sci. USA 78:2848) and have the same cellular receptor (Agnet M. et al. (1983) in "Interferon 5" Ed. I. Gresser p. 1 -22, Academic Press, London).
- SLE Systemic Lupus Erythematosus
- lupus is a prototypic systemic autoimmune disease.
- the disease includes constitutional symptoms and signs, musculoskeletal, cutaneous, renal, gastrointestinal, pulmonary, cardiac, reticuloendothelial, hematological and neuropsychiatric manifestations.
- the cutaneous manifestations are among the most common in SLE.
- type I interferons IFNs
- IFNs systemic lupus erythematosus
- Scleroderma or systemic sclerosis (SSC) is a progressive, debilitating autoimmune disorder characterized by excess protein deposition into the extracellular matrix by dermal fibroblasts, also referred to as dermal fibrosis.
- dermal fibrosis Patients with diffuse cutaneous disease often present unique markers such as upregulation of type I interferon (IFN)-induced genes in skin. Supporting the idea that IFN plays a role in dermal fibrosis are recent reports of scleroderma arising in patients receiving IFN therapy for chronic viral infection.
- IFN type I interferon
- Myositis a general term for inflammation of the muscles, is a group of conditions that are frequently associated with autoimmune conditions.
- Types of myositis include, e.g., myositis ossificans, fibromyositis, (idiopathic) inflammatory myopathies, dermatomyositis, juvenile dermatomyositis, polymyositis, inclusion body myositis, and pyomyositis
- IFN-alpha has been reported to exacerbate underlying disease in patients with psoriasis, autoimmune thyroiditis and multiple sclerosis and to induce an SLE like syndrome in patients without a previous history of autoimmune disease. Interferon a has also been shown to induce glomerulonephritis in normal mice and to accelerate the onset of the spontaneous autoimmune disease of NZB/W mice. Further, IFN-alpha therapy has been shown in some cases to lead to undesired side effects, including fever and neurological disorders. Thus, there are pathological situations in which inhibition of IFN-alpha activity may be beneficial to the patient and a need exists for methods of treatment effective in inhibiting IFN-alpha activity.
- the disclosure provides methods of treating autoimmune diseases such as SLE, SSC, and myositis in a human subject comprising administration of an anti-interferon alpha antibody. These methods can be used for therapeutic, including prophylactic, purposes, for example in situations where the production or expression of interferon alpha is associated with pathological symptoms.
- sifalimumab (MEDI-545)
- an investigational fully human lgG1 monoclonal antibody against interferon-alpha is used.
- the disclosure provides a method of treating an autoimmune disorder in a human subject comprising administering to the subject an antibody, or antigen-binding fragment thereof, which specifically binds to human interferon alpha, wherein one or more pharmacokinetic characteristics chosen from a clearance rate (CL, CL SS , CL/F, or CL SS /F) of between about 99 and about 432 mL/day, an apparent volume of distribution (V ss or V z /F) of between about 3 and about 17 L, and a serum half-life of about 14 days to about 48 days is achieved following the administration; and wherein the autoimmune disorder is systemic lupus erythematosus, scleroderma, or myositis.
- a clearance rate CL, CL SS , CL/F, or CL SS /F
- V ss or V z /F apparent volume of distribution
- the antibody or antigen binding fragment thereof binds an epitope on human interferon alpha recognized by an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 19 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 22.
- the antibody or antigen binding fragment thereof comprises: (a) a heavy chain variable region CDR1 comprising SEQ ID NO: 1 ; (b) a heavy chain variable region CDR2 comprising SEQ ID NO: 4; (c) a heavy chain variable region CDR3 comprising SEQ ID NO: 7; (d) a light chain variable region CDR1 comprising SEQ ID NO: 10; (e) a light chain variable region CDR2 comprising SEQ ID NO: 13; and (f) a light chain variable region CDR3 comprising SEQ ID NO: 16.
- the antibody or antigen binding fragment thereof comprises: (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 19, SEQ ID NO:34, SEQ ID NO; 35, SEQ ID NO:36 or SEQ ID NO:37; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 22.
- the antibody or antigen binding fragment thereof can be a human antibody, a chimeric antibody, a humanized antibody, or an antigen binding fragment thereof.
- the antibody or antigen binding fragment thereof is an lgG1 or lgG4 antibody or antigen-binding fragment thereof.
- the antigen binding fragment is a Fab antibody fragment or a single chain antibody (scFv).
- the antibody or antigen-binding fragment thereof is administered in a dosage dependent on the subject's body weight.
- such weight-based dosage ranges from about 0.01 mg/kg to about 100 mg/kg of the subject's body weight.
- such weight- based dosage is chosen from about 0.3 mg/kg body weight, about 1 mg/kg body weight, about 3 mg/kg body weight, and about 10 mg/kg body weight.
- the antibody or antigen-binding fragment thereof is administered as a fixed dosage.
- such fixed dosage ranges from about 50 mg to about 2000 mg.
- the fixed dosage is chosen from about 100 mg, about 200 mg, about 600 mg, and about 1200 mg.
- the antibody or antigen-binding fragment thereof is administered as a single dose or is administered in two or more doses once per week, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3 months, once every six months, or at varying intervals.
- a loading dose is administered at Day 14.
- the administration is by a route chosen from intravenous, intramuscular, intraperitoneal, intracerobrospinal, subcutaneous, intra-articular, intrasynovial, intrathecal, oral, topical, inhalation, and a combination of two or more recited routes.
- the administration is intravenous (IV) administration.
- IV administration is by IV infusion over a period of time.
- T max or T max S s the time to reach maximum plasma concentration (T max or T max S s) following IV administration is about 0.13 days or less.
- a single IV administration of about 0.3 mg/kg achieves one or more pharmacokinetic characteristics chosen from: a T max of about 0.12 days or less, a maximum plasma concentration (C ma x) of about 7 to about 15 ⁇ g/mL, an area under the plasma concentration-time curve during a dosage interval ( ⁇ ) (AUC T ) of about 54 to about 104 ⁇ g day/mL, and a trough plasma concentration (C tr oug ) of about 2 to about 4 ⁇ g/mL.
- a single IV administration of about 0.3 mg/kg to a population of subjects achieves one or more pharmacokinetic characteristics chosen from: an average T max of about 0.07 days, an average C ma x of about 1 1 ⁇ g/mL, an average AUC T of about 79 ⁇ g day/mL, and an average Ctroug of about 3 ⁇ g/mL.
- a single IV administration of about 1 mg/kg achieves one or more pharmacokinetic characteristics chosen from: a T ma x of about 0.12 days or less, a C ma x of about 21 to about 43 ⁇ g/mL, an AUC T of about 153 to about 290 ⁇ g day/mL, and a Ctroug of about 4 to about 12 ⁇ g/mL.
- a single IV administration of about 1 mg/kg to a population of subjects achieves one or more pharmacokinetic characteristics chosen from: an average T max of about 0.08 days, an average C ma x of about 32 ⁇ g/mL, an average AUC T of about 221 ⁇ g day/mL, and an average Ctroug of about 8 ⁇ g/mL.
- a single IV administration of about 3 mg/kg achieves one or more pharmacokinetic characteristics chosen from: a T max of about 0.13 days or less, a C ma x of about 64 to about 143 ⁇ g/mL, an AUC T of about 469 to about 1010 ⁇ 9 day/mL, and a Ctroug of about 12 to about 35 ⁇ g/mL.
- a single IV administration of about 3 mg/kg to a population of subjects achieves one or more pharmacokinetic characteristics chosen from: an average T max of about 0.09 days, an average C ma x of about 103 g/mL, an average AUC T of about 739 ⁇ g day/mL, and an average Ctroug of about 23 ⁇ g/mL.
- a single IV administration of about 10 mg/kg achieves one or more pharmacokinetic characteristics chosen from: a T max of about 0.13 days or less, a C ma x of about 141 to about 318 g/mL, an AUC T of about 979 to about 2241 ⁇ g day/mL, and a Ctroug of about 27 to about 76 ⁇ g/mL.
- a single IV administration of about 10 mg/kg to a population of subjects achieves one or more pharmacokinetic characteristics chosen from: an average T ma x of about 0.09 days, an average C ma x of about 230 ⁇ g/mL, an average AUC T of about 1610 ⁇ g day/mL, and an average Ctroug of about 52 ⁇ g/mL.
- the administration of a sufficient number of IV doses of about 0.3 mg/kg at about 14-day intervals achieves a steady state, wherein one or more steady state pharmacokinetic characteristics chosen from: a max ss of about 0.60 days or less, a C ma x ss of about 1 1 to about 25 ⁇ g/mL, an AUC T SS of about 89 to about 197 ⁇ g day/mL, and a Ctrough ss of about 5 to about 1 1 ⁇ g/mL is achieved.
- a sufficient number of IV doses of about 0.3 mg/kg are administered to a population of subjects at about 14-day intervals to achieve a steady state, wherein one or more pharmacokinetic characteristics chosen from: an average T max ss of about 0.17 days, an average C ma x ss of about 18 ⁇ g/mL, an average AUC T ss of about 143 ⁇ g day/mL, and an average Ctrough ss of about 8 ⁇ g/mL is achieved.
- a sufficient number of IV doses of about 0.3 mg/kg are administered at about 14-day intervals to a achieve a steady state, wherein one or more pharmacokinetic characteristics chosen from a clearance rate (CL SS ) of between about 99 and about 271 mL/day, an apparent volume of distribution (V ss ) of between about 4 and about 9 L, and a serum half-life of about 15 days to about 43 days is achieved.
- CL SS clearance rate
- V ss apparent volume of distribution
- a sufficient number of IV doses of about 0.3 mg/kg are administered to a population of subjects at about 14-day intervals to achieve a steady state, wherein one or more pharmacokinetic characteristics chosen from an average clearance rate (CL SS ) of about 185 mL/day, an average apparent volume of distribution (V ss ) of about 6 L, and an average serum half-life of about 29 days is achieved.
- CL SS average clearance rate
- V ss average apparent volume of distribution
- a sufficient number of IV doses of about 1 mg/kg are administered at about 14-day intervals to achieve a steady state, wherein one or more steady state pharmacokinetic characteristics chosen from: a T max S s of about 0.1 1 days or less, a C ma x ss of about 29 to about 67 g/mL, an AUC T ss of about 213 to about 591 ⁇ g day/mL, and a Ct r0 ug ss of about 9 to about 30 ⁇ g/mL is achieved.
- a sufficient number of IV doses of about 1 mg/kg are administered to a population of subjects at about 14-day intervals to achieve a steady state, wherein one or more pharmacokinetic characteristics chosen from: an average T max ss of about 0.07 days, an average C ma x ss of about 48 ⁇ g/mL, an average AUC T S s of about 197 ⁇ g day/mL, and an average C tr oug ss of about 1 1 ⁇ g/mL is achieved.
- a sufficient number of IV doses of about 1 mg/kg are administered at about 14-day intervals to a achieve a steady state, wherein one or more pharmacokinetic characteristics chosen from a clearance rate (CL SS ) of between about 1 18 and about 348 mL/day, an apparent volume of distribution (Vss) of between about 4 and about 9 L, and a serum half-life of about 15 days to about 32 days is achieved.
- CL SS clearance rate
- Vss apparent volume of distribution
- a sufficient number of IV doses of about 1 mg/kg are administered to a population of subjects at about 14-day intervals to achieve a steady state, wherein one or more pharmacokinetic characteristics chosen from an average clearance rate (CL SS ) of about 233 mL/day, an average apparent volume of distribution (V ss ) of about 6 L, and an average serum half-life of about 23 days is achieved.
- CL SS average clearance rate
- V ss average apparent volume of distribution
- a sufficient number of IV doses of about 3 mg/kg are administered at about 14-day intervals to achieve a steady state, wherein one or more steady state pharmacokinetic characteristics chosen from: a T ma x ss of about 0.33 days or less, a C m ax ss of about 75 to about 232 g/mL, an AUC T S s of about 533 to about 1843 ⁇ g day/mL, and a Ct r0 ug ss of about 26 to about 74 ⁇ g/mL is achieved.
- a sufficient number of IV doses of about 3 mg/kg are administered to a population of subjects at about 14-day intervals to achieve a steady state, wherein one or more pharmacokinetic characteristics chosen from: an average T max ss of about 0.13 days, an average C ma x ss of about 153 ⁇ g/mL, an average AUC T ss of about 1 188 ⁇ g day/mL, and an average C tr oug ss of about 50 ⁇ g/mL is achieved.
- a sufficient number of IV doses of about 3 mg/kg are administered at about 14-day intervals to a achieve a steady state, wherein one or more pharmacokinetic characteristics chosen from a clearance rate (CL SS ) of between about 136 and about 304 mL/day, an apparent volume of distribution (V ss ) of between about 3 and about 7 L, and a serum half-life of about 14 days to about 26 days is achieved.
- CL SS clearance rate
- V ss apparent volume of distribution
- a sufficient number of IV doses of about 3 mg/kg are administered to a population of subjects at about 14-day intervals to achieve a steady state, wherein one or more pharmacokinetic characteristics chosen from an average clearance rate (CL SS ) of about 220 mL/day, an average apparent volume of distribution (V ss ) of about 5 L, and an average serum half-life of about 20 days is achieved.
- CL SS average clearance rate
- V ss average apparent volume of distribution
- a sufficient number of IV doses of about 10 mg/kg are administered at about 14-day intervals to achieve a steady state, wherein one or more steady state pharmacokinetic characteristics chosen from: a T max S s about 0.82 days or less, a Cmax ss of about 288 to about 595 ⁇ g/mL, an AUC T S s of about 2539 to about 4267 ⁇ g day/mL, and a C tr oug ss of about 93 to about 275 ⁇ g/mL is achieved.
- a sufficient number of IV doses of about 10 mg/kg are administered to a population of subjects at about 14-day intervals to achieve a steady state, wherein one or more pharmacokinetic characteristics chosen from: an average T max ss of about 0.23 days, an average C ma x ss of about 232 ⁇ g/mL, an average AUC T S s of about 3403 ⁇ g day/mL, and an average Ctroug ss of about 184 ⁇ g/mL is achieved.
- a sufficient number of IV doses of about 10 mg/kg are administered at about 14-day intervals to a achieve a steady state, wherein one or more pharmacokinetic characteristics chosen from a clearance rate (CL SS ) of between about 157 and about 319 mL/day, an apparent volume of distribution (V ss ) of between about 4 and about 7 L, and a serum half-life of about 15 days to about 29 days is achieved.
- CL SS clearance rate
- V ss apparent volume of distribution
- a sufficient number of IV doses of about 10 mg/kg are administered to a population of subjects at about 14-day intervals to achieve a steady state, and wherein one or more pharmacokinetic characteristics chosen from an average clearance rate (CL SS ) of about 238 mL/day, an average apparent volume of distribution (V ss ) of about 6 L, and an average serum half-life of about 22 days is achieved.
- CL SS average clearance rate
- V ss average apparent volume of distribution
- the number of IV doses at about 14-day intervals required to achieve steady state is about 5 to about 8 doses.
- the administration is subcutaneous (SC) administration.
- the dosage is 100 mg administered as a single SC dose, or is administered weekly, bi-weekly, or monthly.
- a T max or T max S s of between about 2 and about 10 days is achieved after SC administration.
- a single SC administration of about 100 mg achieves one or more pharmacokinetic characteristics chosen from: a T max of about 2 to about 10 days, a C ma x of about 4 to about 21 g/mL, an area under the plasma concentration-time curve from time zero to time of last measurable concentration (AUCi as t) of about 175 to about 666 ⁇ g day/mL, and an area under the plasma concentration-time curve from time zero to infinity (AUC ⁇ ) of about 204 to about 751 ⁇ g day/mL.
- pharmacokinetic characteristics chosen from: a T max of about 2 to about 10 days, a C ma x of about 4 to about 21 g/mL, an area under the plasma concentration-time curve from time zero to time of last measurable concentration (AUCi as t) of about 175 to about 666 ⁇ g day/mL, and an area under the plasma concentration-time curve from time zero to infinity (AUC ⁇ ) of about 204 to about 751 ⁇ g day/mL.
- a single SC administration of about 100 mg to a population of subjects achieves one or more pharmacokinetic characteristics chosen from: a T max of about 6 days, a C ma x of about 13 g/mL, an AUCiast of about 421 ⁇ g day/mL, and an AUC ⁇ of about 477 ⁇ g day/mL.
- a single SC administration of about 100 mg achieves one or more pharmacokinetic characteristics chosen from a clearance rate (CL/F) of between about 1 18 and about 432 mL/day, an apparent volume of distribution (V z /F) of between about 5 and about 12 L, and a serum half-life of about 15 days to about 34 days.
- CL/F clearance rate
- V z /F apparent volume of distribution
- a single SC administration of about 100 mg to a population of subjects achieves one or more pharmacokinetic characteristics chosen from an average clearance rate (CL/F) of about 275 mL/day, an apparent volume of distribution (V z /F) of about 8 L, and a serum half-life of about 25 days.
- CL/F average clearance rate
- V z /F apparent volume of distribution
- a sufficient number of SC doses of about 100 mg are administered at about 7-day (weekly) intervals to achieve a steady state, wherein one or more steady state pharmacokinetic characteristics chosen from: a Tmax ss of about 2 to about 7 days, a C ma x ss of about 37 to about 93 g/mL, an AUC T SS of about 248 to about 638 ⁇ g day/mL, and a Ct r0 ug ss of about 38 to about 80 ⁇ g/mL is achieved.
- a sufficient number of SC doses of about 100 mg are administered to a population of subjects at about 7-day (weekly) intervals to achieve a steady state, wherein one or more steady state pharmacokinetic characteristics chosen from: an average T max S s of about 4 days, an average C ma x ss of about 65 g/mL, an average AUC T S s of about 443 ⁇ g day/mL, and a C tr oug ss of about 59 ⁇ g/mL is achieved.
- a sufficient number of SC doses of about 100 mg are administered at about 7-day (weekly) intervals to achieve a steady state, wherein one or more steady state pharmacokinetic characteristics chosen from: a clearance rate (CL SS /F) of between about 168 and about 396 mL/day, an apparent volume of distribution (V z /F) of between about 7 and about 15 L, and a serum half-life of about 22 days to about 35 days is achieved.
- CL SS /F clearance rate
- V z /F apparent volume of distribution
- a sufficient number of SC doses of about 100 mg are administered to a population of subjects at about 7-day (weekly) intervals to achieve a steady state, wherein one or more steady state pharmacokinetic characteristics chosen from an average clearance rate (CL SS ) of about 282 mL/day, an average apparent volume of distribution (V z /F) of about 1 1 L, and an average serum half-life of about 28 days is achieved.
- CL SS average clearance rate
- V z /F average apparent volume of distribution
- a sufficient number of SC doses of about 100 mg are administered at about 14-day (bi-weekly) intervals to achieve a steady state, wherein one or more steady state pharmacokinetic characteristics chosen from: a Tmax ss of about 2 to about 7 days, a C ma x ss of about 30 to about 49 g/mL, an AUC T SS of about 424 to about 567 ⁇ g day/mL, and a Ctrough ss of about 21 to about 40 ⁇ g/mL is achieved.
- a sufficient number of SC doses of about 100 mg are administered to a population of subjects at about 14-day (bi-weekly) intervals to achieve a steady state, wherein one or more steady state pharmacokinetic characteristics chosen from: an average T max S s of about 4 days, an average C ma x ss of about 39 g/mL, an average AUC T S s of about 495 ⁇ g day/mL, and a C tr oug ss of about 30 ⁇ g/mL is achieved.
- a sufficient number of SC doses of about 100 mg are administered at about 14-day (bi-weekly) intervals to achieve a steady state, wherein one or more steady state pharmacokinetic characteristics chosen from: a clearance rate (CL SS /F) of between about 172 and about 240 mL/day, an apparent volume of distribution (V z /F) of between about 6 and about 10 L, and a serum half-life of about 19 days to about 37 days is achieved.
- CL SS /F clearance rate
- V z /F apparent volume of distribution
- a sufficient number of SC doses of about 100 mg are administered to a population of subjects at about 14-day (bi-weekly) intervals to achieve a steady state, wherein one or more steady state pharmacokinetic characteristics chosen from an average clearance rate (CL SS ) of about 406 mL/day, an average apparent volume of distribution (V z /F) of about 8 L, and an average serum half-life of about 28 days is achieved.
- CL SS average clearance rate
- V z /F average apparent volume of distribution
- a sufficient number of SC doses of about 100 mg are administered at about 30-day (monthly) intervals to achieve a steady state, wherein one or more steady state pharmacokinetic characteristics chosen from: a max ss of about 3 to about 8 days, a Cmax ss of about 14 to about 34 g/mL, an AUC T SS of about 326 to about 641 ⁇ g day/mL, and a Ctroug ss of about 6 to about 15 ⁇ g/mL is achieved.
- a sufficient number of SC doses of about 100 mg are administered to a population of subjects at about 30-day (monthly) intervals to achieve a steady state, wherein one or more steady state pharmacokinetic characteristics chosen from: an average T max S s of about 6 days, an average C ma x ss of about 49 g/mL, an average AUC T S s of about 483 ⁇ g day/mL, and a C tr oug ss of about 1 1 ⁇ g/mL is achieved.
- a sufficient number of SC doses of about 100 mg are administered at about 30-day (monthly) intervals to achieve a steady state, wherein one or more steady state pharmacokinetic characteristics chosen from: a clearance rate (CL SS /F) of between about 152 and about 302 mL/day, an apparent volume of distribution (V z /F) of between about 5 and about 17 L, and a serum half-life of about 19 days to about 47 days is achieved.
- CL SS /F clearance rate
- V z /F apparent volume of distribution
- a sufficient number of SC doses of about 100 mg are administered to a population of subjects at about 30-day (monthly) intervals to achieve a steady state, wherein one or more steady state pharmacokinetic characteristics chosen from an average clearance rate (CL SS ) of about 227 mL/day, an average apparent volume of distribution (V z /F) of about 1 1 L, and an average serum half-life of about 33 days is achieved.
- CL SS average clearance rate
- V z /F average apparent volume of distribution
- the administration of a sufficient number of doses of an anti-IFN-alpha antibody or antigen-binding fragment thereof suppresses an IFN pharmacodynamic signature.
- the IFN pharmacodynamic signature is a Type I IFN-alpha inducible expression profile.
- the Type I IFN-alpha inducible expression profile can comprises the up-regulated expression of a gene marker set comprising IFI44, IFI27, IFI44L, NAPTP, LAMP3, LY6E, RSAD2, HERC5, IFI6, ISG15, OAS3, RTP4, IFIT1 , MX1 , SIGLEC1 , OAS2, USP18, OAS1 , EPSTI1 , PLSCR1 and IFRG28.
- the anti-IFN antibody or antigen-binding fragment thereof neutralizes the pharmacodynamic expression profile of the patient by at least 10%, at least 20%, at least 30% or at least 40%.
- the method the reduces at least one disease symptom .
- the reduction in symptoms reduces the SLEDAI or BILAG score.
- the SLEDAI score is reduced by at least 1 , at least 2, at least 3, at least 4, or more points.
- FIG. 1 is a graph showing mean sifalimumab concentrations over 14 IV infusion doses. Sifalimumab was administered at 0.3 mg/kg ( ⁇ ), 1 .0 mg/kg ( ⁇ ), 3.0 mg/kg ( ⁇ ) and 10 mg/kg (A) doses. Error bars show the standard deviation.
- FIG. 2A is a graph showing frequency of anti-sifalimumab antibody titer in a group administered 0.3 mg/kg IV infusion doses.
- FIG. 2B is a graph showing frequency of anti-sifalimumab antibody titer in a group administered 1 .0 mg/kg IV infusion doses.
- FIG. 2C is a graph showing frequency of anti-sifalimumab antibody titer in a group administered 3.0 mg/kg IV infusion doses.
- FIG. 2D is a graph showing frequency of anti-sifalimumab antibody titer in a group administered 10 mg/kg IV infusion doses.
- FIG. 3 is a graph showing steady state clearance of sifalimumab by titer of anti-sifalimumab antibodies (IM titer).
- Sifalimumab was administered at 0.3 mg/kg ( ⁇ ), 1 .0 mg/kg ( ⁇ ), 3.0 mg/kg ( ⁇ ) and 10 mg/kg (A) IV infusion doses.
- FIG. 4 is a graph showing steady state clearance of sifalimumab by IM status of patients receiving 0.3, 1 .0, 3.0 and 10 mg/kg doses of sifalimumab.
- IM + and IM " patients are patients testing positive or negative for the presence of anti- sifalimumab antibodies, respectively.
- FIG. 5 summarizes the final model goodness-of-fit plots for sifalimumab serum concentrations.
- the thin solid line (diagonal and horizontal) and thick line represent line of unity and loess fit, respectively.
- Panel (a) shows population predictions versus observed serum concentrations
- panel (b) shows individual predictions versus observed serum concentrations
- panel (c) shows population predictions versus weighted residuals
- panel (d) shows time versus weighted residuals.
- FIG. 6 provides graphs depicting a visual predictive check for sifalimumab serum concentrations. Panels shows the time versus serum concentration graphs corresponding to 0.3, 1 .0, 3.0 and 10 mg/kg doses, respectively. Observed median (solid line) and corresponding simulation based 95% confidence interval
- FIG. 7 is a graph showing the similarity of predicted PK profiles (median,
- FIG. 8 is a graph showing predicted serum concentrations following 200
- FIG. 9 is a graph showing the mean concentration of sifalimumab over 168 days. Sifalimumab was administered in a single subcutaneous dose ( ⁇ ), weekly ( ⁇ ), bi-weekly (A) or monthly ( ⁇ ).
- FIG. 10 is a graph showing sifalimumab clearance by immunogenicity titer in IM + and IM " patients. Sifalimumab was administered in a single subcutaneous dose ( ⁇ ), weekly (A), bi-weekly ( ⁇ ) or monthly ( ⁇ ).
- FIG. 1 1 is a graph showing the inhibition of the type 1 IFN pharmacodynamic gene signature by sifalimumab. Sifalimumab was administered in a single 100 mg subcutaneous dose once, once a week, biweekly, or monthly.
- autoimmune disease refers to a disorder, disease state or condition associated with the formation of autoantibodies reactive with the patient's own cells to form antigen-antibody complexes.
- the term "autoimmune disease” includes conditions such as, e.g., systemic lupus erythematosus, as well as those disorders which are triggered by a specific external agent, e.g., acute rheumatic fever.
- autoimmune disorders include, but are not limited to, autoimmune hemolytic anemia, autoimmune hepatitis, Berger's disease, chronic fatigue syndrome, Crohn's disease, dermatomyositis, fibromyalgia, Graves' disease, Hashimoto's thyroiditis, idiopathic thrombocytopenia purpura, lichen planus, multiple sclerosis, myasthenia gravis, psoriasis, rheumatic fever, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, type 1 diabetes, ulcerative colitis, and vitiligo.
- the autoimmune disease is systemic lupus erythematosus, scleroderma, or myositis.
- the term “antibody” is used in its broadest sense and includes monoclonal antibodies, polyclonal antibodies, multivalent antibodies, multispecific antibodies, chimeric antibodies, and humanized antibodies.
- the term “antibody” as referred to herein includes whole antibodies.
- An “antibody” refers to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, or an antigen binding portion thereof.
- Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region.
- the heavy chain constant region is comprised of three domains, CH1 , CH2 and CH3.
- Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region.
- the light chain constant region is comprised of one domain, CL.
- the VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
- CDR complementarity determining regions
- FR framework regions
- Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1 , CDR1 , FR2, CDR2, FR3, CDR3, FR4.
- the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
- the constant regions of the antibodies can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C
- fragment thereof refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., IFN-alpha). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.
- binding fragments encompassed within the term "antigen-binding portion" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., (1989) Nature 341 :544-546), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR).
- a Fab fragment a monovalent fragment consisting of the VL, VH, CL and CH1 domains
- a F(ab')2 fragment a bivalent fragment comprising two Fab fragments linked by
- the two domains of the Fv fragment, VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883).
- single chain Fv single chain Fv
- Such single chain antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody.
- an "isolated antibody”, as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds IFN-alpha is substantially free of antibodies that specifically bind antigens other than IFN-alpha).
- An isolated antibody that specifically binds IFN-alpha can, however, have cross-reactivity to other antigens, such as IFN-alpha molecules from other species.
- an isolated antibody can be substantially free of other cellular material and/or chemicals.
- monoclonal antibody or “monoclonal antibody composition” as used herein refer to a preparation of antibody molecules of single molecular composition.
- a monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.
- human antibody is intended to include antibodies having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region also is derived from human germline immunoglobulin sequences.
- the human antibodies of the disclosure can include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo).
- the term "human antibody”, as used herein is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
- human monoclonal antibody refers to antibodies displaying a single binding specificity which have variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences.
- the human monoclonal antibodies are produced by a hybridoma which includes a B cell obtained from a transgenic nonhuman animal, e.g., a transgenic mouse, having a genome comprising a human heavy chain transgene and a light chain transgene fused to an immortalized cell.
- recombinant human antibody includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as (a) antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom (described further below), (b) antibodies isolated from a host cell transformed to express the human antibody, e.g., from a transfectoma, (c) antibodies isolated from a recombinant, combinatorial human antibody library, and (d) antibodies prepared, expressed, created or isolated by any other means that involve splicing of human immunoglobulin gene sequences to other DNA sequences.
- Such recombinant human antibodies have variable regions in which the framework and CDR regions are derived from human germline immunoglobulin sequences.
- such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.
- isotype refers to the antibody class (e.g., IgM or lgG1 ) that is encoded by the heavy chain constant region genes.
- the antibodies herein specifically include "chimeric" antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Patent No. 4,816,567; and Morrison et al, Proc. Natl. Acad. Sci. USA 87:6851 -6855 (1984)).
- CDR complementarity determining region
- Kabat et al. also defined a numbering system for variable domain sequences that is applicable to any antibody.
- Kabat numbering refers to the numbering system set forth by Kabat et al. (1983) U.S. Dept. of Health and Human Services, "Sequence of Proteins of Immunological Interest.” Unless otherwise specified, references to the numbering of specific amino acid residue positions in an anti-IL-33 antibody or antigen-binding fragment, variant, or derivative thereof of the present disclosure are according to the Kabat numbering system.
- Antibodies or antigen-binding fragments, variants, or derivatives thereof of the disclosure include, but are not limited to, polyclonal, monoclonal, multispecific, mouse, human, humanized, primatized, or chimeric antibodies, single-chain antibodies, epitope-binding fragments, e.g., Fab, Fab' and F(ab') 2 , Fd, Fvs, single-chain Fvs (scFv), disulfide-linked Fvs (sdFv), fragments comprising either a VL or VH domain, fragments produced by a Fab expression library, and anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Id antibodies to anti-IL-33 antibodies disclosed herein).
- ScFv molecules are known in the art and are described, e.g., in U.S. Pat. No. 5,892,019.
- affinity refers to a measure of the strength of the binding of an individual epitope with the CDR of an immunoglobulin molecule. See, e.g., Harlow et al. (1988) Antibodies: A Laboratory Manual (Cold Spring Harbor Laboratory Press, 2nd ed.) pages 27-28.
- telomere binding refers to antibody binding to a predetermined antigen.
- the antibody binds with a dissociation constant (K D ) of 10 "8 M or less, and binds to the predetermined antigen with a K D that is at least two-fold less than its K D for binding to a non-specific antigen (e.g., BSA, casein) other than the predetermined antigen or a closely-related antigen.
- K D dissociation constant
- K asS oc or "K a ", as used herein, is intended to refer to the association rate of a particular antibody-antigen interaction
- Kdis or “Kd,” as used herein, is intended to refer to the dissociation rate of a particular antibody-antigen interaction
- K D is intended to refer to the dissociation constant, which is obtained from the ratio of K d to K a and is expressed as a molar concentration (M).
- K D values for antibodies can be determined using methods well established in the art. One method for determining the K D of an antibody is by using surface plasmon resonance, e.g., by using a biosensor system such as a Biacore.RTM. system.
- high affinity for an IgG antibody refers to an antibody having a K D of 10 "8 M or less, 10 "9 M or less, or 10 "10 M or less.
- high affinity binding can vary for other antibody isotypes.
- “high affinity” binding for an IgM isotype refers to an antibody having a K D of 10 "7 M or less, or 10 "8 M or less.
- Anti-IFN-alpha binding molecules e.g., antibodies or antigen-binding fragments, variants or derivatives thereof of the disclosure can also be described or specified in terms of their binding affinity to a polypeptide of the disclosure, e.g., IFN- alpha, e.g., human, primate, murine, or any combination of human, primate and murine IFN-alpha.
- Exemplary binding affinities include those with a dissociation constant or K D less than 5 x 10 "2 M, 10 "2 M, 5 x 10 "3 M, 10 “3 M, 5 x 10 " 4 M, 10 “4 M, 5 x 10 "5 M, 10 “5 M, 5 x 10 "6 M, 10 “6 M, 5 x 10 "7 M, 10 “7 M, 5 x 10 “8 M, 10 “8 M, 5 x 10 "9 M, 10 “9 M, 5 x 10 "10 M, 10 “10 M, 5 x 10 "11 M, 10 "11 M, 5 x 10 "12 M, 10 “12 M, 5 x 10 "13 M, 10 “13 M, 5 x 10 "14 M, 10 “14 M, 5 x 10 "15 M, or 10 "15 M.
- the terms “treat” or “treatment” refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as the progression of an inflammatory condition.
- Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
- Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
- Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
- subject or “individual” or “animal” or “patient” or “mammal,” is meant any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired.
- subject includes any human or nonhuman animal.
- nonhuman animal includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows, bears, chickens, amphibians, reptiles, etc.
- phrases such as "a subject that would benefit from administration of an anti-IFN- alpha antibody” includes subjects, such as mammalian subjects, that would benefit from administration of an anti-IFN-alpha antibody used, e.g., for detection of an anti-IFN-alpha polypeptide (e.g., for a diagnostic procedure) and/or from treatment, i.e., palliation or prevention of a disease, with an anti-IFN-alpha antibody.
- interferon alpha and "IFN-alpha” are used interchangeably and intended to refer to IFN-alpha proteins encoded by a functional gene of the interferon alpha gene locus with 75% or greater sequence identity to IFN-alpha 1 (Genbank number NP— 076918 or protein encoded by Genbank number NM— 024013).
- IFN-alpha subtypes include IFN-alpha 1 , alpha 2a, alpha 2b, alpha 4, alpha 5, alpha 6, alpha 7, alpha 8, alpha 10, alpha 13, alpha 14, alpha 16, alpha 17 and alpha 21 .
- interferon alpha is intended to encompass recombinant forms of the various IFN-alpha subtypes, as well as naturally occurring preparations that comprise IFN-alpha proteins, such as leukocyte IFN and lymphoblastoid IFN.
- the present disclosure is directed to methods of treating an autoimmune disorder in a subject in need of such treatment comprising administering to the subject an anti-IFN-alpha antibody.
- Anti-IFN-alpha antibodies can be found in, for example, U.S. Pat. No. 7,741 ,449, and can further include chimeric, humanized, or human versions of these antibodies (if not already a chimeric, humanized, or human version), and can further include fragments or derivatives thereof.
- Patients suffering from SLE may exhibit any of a number of symptoms as discussed in, e.g., International Application No. PCT/US2007/024941 , or may have a clinical SLEDAI score or BILAG score as discussed in the same. These symptoms may include fatigue, organ damage, malar rash, and alopecia.
- the patient may be scored using a known clinical scoring system, e.g., SLEDAI which is an index of SLE disease activity as measured and evaluated within the last 10 days (Bombardier C, Gladman D D, Urowitz M B, Caron D, Chang C H and the Committee on Prognosis Studies in SLE: Derivation of the SLEDAI for Lupus Patients. Arthritis Rheum 35:630-640, 1992.).
- SLEDAI SLEDAI scoring system
- SLEDAI no activity
- SLEDAI 1
- SLEDAI mild activity
- SLEDAI 6-10
- BILAG index is an activity index of SLE that is based on specific clinical manifestations in eight organ systems: general, mucocutaneous, neurological, musculoskeletal, cardiovascular, respiratory, renal, and hematology results. Scoring is based on a letter system, but weighted numerical scores can also be assigned to each letter, making it possible to calculate a BILAG score in the range of 0-72. (Griffiths, et al., Assessment of Patients with Systemic Lupus Erythematosus and the use of Lupus Disease Activity Indices). Other scoring indices include the PGA score, the composite responder index (CRI), and the ANAM4TM test.
- the methods described herein, e.g., of treating an autoimmune disorder may be used for any subject identified as having any activity level of disease activity as measured by any classification methodology known in the art, e.g., mild, moderate, high, or very high.
- the methods described herein, e.g., of treating an autoimmune disorder may result in a decrease in a patient's symptoms or may result in an improvement in a score of disease for the patient's type I IFN or an IFN-alpha- inducible disease, disorder, or condition.
- antibodies for use in the treatment methods of the disclosure include the human monoclonal antibodies 13H5, 13H7, and 7H9, isolated and structurally characterized as described in the U.S. Patent No. 7,741 ,449.
- the VH amino acid sequences of 13H5, 13H7, and 7H9 are shown in SEQ ID NOs: 19, 20, and 21 , respectively.
- the VL amino acid sequences of 13H5, 13H7, and 7H9 are shown in SEQ ID NOs: 22, 23 and 24, respectively. Given that each of these antibodies can bind to IFN-alpha, the VH and VL sequences can be "mixed and matched" to create other anti-IFN-alpha binding molecules of the disclosure.
- VH sequences of 13H5 and 7H9 are mixed and matched, since these antibodies use VH sequences derived from the same germline sequence (VH 1 -18) and thus they exhibit structural similarity.
- VH 1 -18 the same germline sequence
- VL sequences of 13H5, 13H7 and 7H9 can be mixed and matched, since these antibodies use VL sequences derived from the same germline sequence (Vk A27) and thus they exhibit structural similarity.
- an antibody for use in the methods of the disclosure is an isolated monoclonal antibody, or antigen binding portion thereof, comprising:
- the antibody inhibits the biological activity of interferon alpha.
- heavy and light chain combinations include:
- the treatment methods of the present disclosure comprise the administration of antibodies that comprise the heavy chain and light chain CDR1 s, CDR2s, and CDR3s of 13H5, 13H7, and 7H9, or combinations thereof.
- the amino acid sequences of the VH CDR1 s of 13H5, 13H7, and 7H9 are shown in SEQ ID NOs: 1 , 2, and 3.
- the amino acid sequences of the VH CDR2s of 13H5, 13H7, and 7H9 are shown in SEQ IN NOs: 4, 5, and 6.
- the amino acid sequences of the VH CDR3s of 13H5, 13H7, and 7H9 are shown in SEQ IN NOs: 7, 8, and 9.
- the amino acid sequences of the VL CDR1 s of 13H5, 13H7, and 7H9 are shown in SEQ IN NOs: 10, 1 1 , and 12.
- the amino acid sequences of the VL CDR2s of 13H5, 13H7, and 7H9 are shown in SEQ IN NOs: 13, 14, and 15.
- the amino acid sequences of the VL CDR3s of 13H5, 13H7, and 7H9 are shown in SEQ IN NOs: 16, 17, and 18.
- the CDR regions are delineated using the Kabat system (Kabat. E. A., et al. (1991 ) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91 -3242).
- VH CDR1 , 2 and 3 sequences and VL CDR1 , 2 and 3 sequences can be "mixed and matched" (i.e., CDRs from different antibodies can be mixed and match, although each antibody must contain a VH CDR1 , 2 and 3 and a VL CDR1 , 2 and 3) to create other anti-IFN-alpha molecules of the disclosure.
- IFN-alpha binding of such "mixed and matched" antibodies can be tested using the binding assays described in the Examples (e.g., ELISA and/or Biacore).
- the CDR1 , CDR2 and/or CDR3 sequence from a particular VH sequence is replaced with a structurally similar CDR sequence(s).
- the CDR1 , CDR2 and/or CDR3 sequence from a particular VL sequence can be replaced with a structurally similar CDR sequence(s).
- the VH CDR1 s of 13H5 and 7H9 share some structural similarity and therefore are amenable to mixing and matching.
- VH and VL sequences can be created by substituting one or more VH and/or VL CDR region sequences with structurally similar sequences from the CDR sequences disclosed herein for monoclonal antibodies 13H5, 13H7 and 7H9.
- the methods of the present disclosure provide for administration of an isolated monoclonal antibody, or antigen binding portion thereof comprising:
- the antibody inhibits the biological activity of interferon alpha.
- the antibody comprises:
- the antibody comprises:
- the antibody comprises:
- an antibody to be administered according to the methods of the disclosure comprises a heavy chain variable region from a particular germline heavy chain immunoglobulin gene and/or a light chain variable region from a particular germline light chain immunoglobulin gene.
- the disclosure provides a method of treating an autoimmune disorder in a subject in need thereof, comprising administering to the subject an isolated monoclonal antibody, or an antigen- binding fragment thereof, where the antibody:
- (a) comprises a heavy chain variable region of a human VH 1 -18 or 4-61 gene
- (b) comprises a light chain variable region of a human VK A27 gene
- the antibody comprises a heavy chain variable region of a human VH 1 -18 gene.
- Examples of antibodies having a VH and VK gene sequence of VH 1 -18 and VK A27, respectively, include 13H5 and 7H9.
- the antibody comprises a heavy chain variable region of a human VH 4-61 gene.
- An example of an antibody having a VH and VK gene sequence of VH 4-61 and VK A27, respectively, is 13H7.
- a human antibody comprises heavy or light chain variable regions "of (i.e., the products of) or "derived from” a particular germline sequence if the variable regions of the antibody are obtained from a system that uses human germline immunoglobulin genes.
- Such systems include immunizing a transgenic mouse carrying human immunoglobulin genes with the antigen of interest or screening a human immunoglobulin gene library displayed on phage with the antigen of interest.
- a human antibody that is "of (i.e., the product of) or "derived from” a human germline immunoglobulin sequence can be identified as such by comparing the amino acid sequence of the human antibody to the amino acid sequences of human germline immunoglobulins and selecting the human germline immunoglobulin sequence that is closest in sequence (i.e. , greatest % identity) to the sequence of the human antibody.
- a human antibody that is "of (i. e. , the product of) or "derived from” a particular human germline immunoglobulin sequence can contain amino acid differences as compared to the germline sequence, due to, for example, naturally-occurring somatic mutations or intentional introduction of site-directed mutation.
- a selected human antibody typically is at least 90% identical in amino acids sequence to an amino acid sequence encoded by a human germline immunoglobulin gene and contains amino acid residues that identify the human antibody as being human when compared to the germline immunoglobulin amino acid sequences of other species (e.g. , murine germline sequences).
- a human antibody can be at least 95%, or even at least 96%, 97%, 98%, or 99% identical in amino acid sequence to the amino acid sequence encoded by the germline immunoglobulin gene.
- a human antibody derived from a particular human germline sequence will display no more than 10 amino acid differences from the amino acid sequence encoded by the human germline immunoglobulin gene.
- the human antibody can display no more than 5, or even no more than 4, 3, 2, or 1 amino acid difference from the amino acid sequence encoded by the germline immunoglobulin gene.
- an antibody for use in the treatment methods of the disclosure comprises heavy and light chain variable regions comprising amino acid sequences that share amino acid similarity with or are homologous to the amino acid sequences of the antibodies described herein, where the antibodies retain the desired functional properties of the anti-IFN-alpha antibodies of the disclosure.
- the disclosure provides a method of treating an autoimmune disorder in a subject in need thereof, comprising administering to the subject an isolated monoclonal antibody, or antigen binding fragment thereof, comprising a heavy chain variable region and a light chain variable region, wherein:
- the heavy chain variable region comprises an amino acid sequence that is at least 80% homologous to an amino acid sequence chosen from SEQ ID NOs: 19, 20, and 21 ;
- the light chain variable region comprises an amino acid sequence that is at least 80% homologous to an amino acid sequence chosen from SEQ ID NOs: 22, 23, and 24;
- the antibody inhibits the biological activity of multiple IFN-alpha subtypes but does not substantially inhibit the biological activity of IFN-alpha 21 ;
- the antibody exhibits at least one of the following properties: (i) the antibody does directly inhibit the biological activity of IFN-beta or IFN-omega, but may indirectly inhibit the biological activity of I FN-beta or IFN-omega by interfering with interferon receptor function; (ii) the antibody inhibits IFN-induced surface expression of CD38 or MHC Class I on peripheral blood mononuclear cells; (iii) the antibody inhibits IFN-induced expression of IP-10 by peripheral blood mononuclear cells; (iv) the antibody inhibits dendritic cell development mediated by systemic lupus erythematosus (SLE) plasma.
- SLE systemic lupus erythematosus
- the VH and/or VL amino acid sequences can be 85%, 90%, 95%, 96%, 97%, 98% or 99% homologous to the sequences set forth above.
- An antibody having VH and VL regions having high (i.e. , 80% or greater) homology to the VH and VL regions of SEQ ID NOs: 19, 20, and 21 and 22, 23, and 24, respectively, can be obtained by mutagenesis (e.g. , site-directed or PCR- mediated mutagenesis) of nucleic acid molecules encoding SEQ ID NOs: 1 9, 20, and 21 and/or 22, 23, and 24, followed by testing of the encoded altered antibody for retained function (i. e. , the functions set forth in (c) and (d) above) using the functional assays described herein.
- the percent homology or percent similarity between two amino acid sequences is equivalent to the percent identity between the two sequences.
- the comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm, as described in the non-limiting examples below.
- the percent identity between two amino acid sequences can be determined using the algorithm of E. Meyers and W. Miller (Comput. Appl. Biosci., 4: 1 1 -17 (1988)) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.
- the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch (J. Mol. Biol.
- the protein sequences of the present disclosure can further be used as a "query sequence" to perform a search against public databases to, for example, identify related sequences.
- Such searches can be performed using the XBLAST program (version 2.0) of Altschul, et at. (1990) J. Mol. Biol. 215:403-10.
- Gapped BLAST can be utilized as described in Altschul ei a/., (1997) Nucleic Acids Res. 25(17):3389-3402.
- the default parameters of the respective programs e.g., XBLAST and NBLAST
- the default parameters of the respective programs e.g., XBLAST and NBLAST
- an antibody for use in the methods of the present disclosure comprises a heavy chain variable region comprising CDR1 , CDR2 and CDR3 sequences and a light chain variable region comprising CDR1 , CDR2 and CDR3 sequences, wherein one or more of these CDR sequences comprise specified amino acid sequences based on antibodies described herein (e.g., 13H5, 13H7, or 7H9), or conservative modifications thereof, and wherein the antibodies retain the desired functional properties of the anti-IFN-alpha antibodies of the disclosure.
- certain antibodies of the disclosure include those in which the heavy chain variable region CDR3 sequence comprises the amino acid sequence of SEQ ID NO: 3, or conservative modifications thereof, and the light chain variable region CDR3 sequence comprises the amino acid sequence of SEQ ID NO: 6, or conservative modifications thereof.
- the disclosure provides a method for treating an autoimmune disorder in a subject, comprising administering to the subject an isolated monoclonal antibody, or antigen binding fragment thereof, comprising a heavy chain variable region comprising CDR1 , CDR2, and CDR3 sequences and a light chain variable region comprising CDR1 , CDR2, and CDR3 sequences, wherein:
- the heavy chain variable region CDR3 sequence comprises the amino acid sequence chosen from SEQ ID NO: 7, 8, and 9, and conservative
- the light chain variable region CDR3 sequence comprises the amino acid
- the antibody inhibits the biological activity of multiple IFN-alpha subtypes but does not substantially inhibit the biological activity of IFN-alpha 21 ;
- the antibody exhibits at least one of the following properties: (i) the antibody does not directly inhibit the biological activity of IFN-beta or IFN-omega, but may indirectly inhibit the biological activity of IFN-beta or IFN-omega by interfering with interferon receptor function; (ii) the antibody inhibits IFN- induced surface expression of CD38 or MHC Class I on peripheral blood mononuclear cells; (iii) the antibody inhibits IFN-induced expression of IP-10 by peripheral blood mononuclear cells; (iv) the antibody inhibits dendritic cell development mediated by systemic lupus erythematosus (SLE) plasma.
- SLE systemic lupus erythematosus
- the heavy chain variable region CDR2 sequence comprises the amino acid sequence chosen from amino acid sequences of SEQ ID NO: 4, 5, and 6, and conservative modifications thereof; and the light chain variable region CDR2 sequence comprises the amino acid sequence chosen from amino acid sequences SEQ ID NO: 13, 14, and 15, and conservative modifications thereof.
- the heavy chain variable region CDR1 sequence comprises the amino acid sequence chosen from amino acid sequences of SEQ ID NO: 1 , 2, and 3, and conservative modifications thereof; and the light chain variable region CDR1 sequence comprises the amino acid sequence chosen from amino acid sequences of SEQ ID NO: 10, 1 1 , and 12, and conservative modifications thereof.
- conservative sequence modifications is intended to refer to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions and deletions. Modifications can be introduced into an antibody of the disclosure by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are ones in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art.
- amino acids with basic side chains e.g., lysine, arginine, histidine
- acidic side chains e.g., aspartic acid, glutamic acid
- uncharged polar side chains e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan
- nonpolar side chains e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine
- beta-branched side chains e.g., threonine, valine, isoleucine
- aromatic side chains e.g., tyrosine, phenylalanine, tryptophan, histidine
- one or more amino acid residues within the CDR regions of an antibody of the disclosure can be replaced with other amino acid residues from the same side chain family and the altered antibody can be tested for retained function (i.e., the functions set forth in (c) and (d) above) using the functional assays described herein.
- the disclosure provides a method of treating an autoimmune disorder in a subject, comprising administering to the subject an antibody that binds to the same epitope as do the various human IFN-alpha antibodies as described herein, such as other human antibodies that bind to the same epitope as the 13H5, 13H7, and 7H9 antibodies.
- epitope refers to a protein determinant capable of binding to an antibody of the disclosure. Epitopes usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually have specific three dimensional structural characteristics, as well as specific charge characteristics.
- Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents.
- Such antibodies can be identified based on their ability to cross-compete (e.g., to competitively inhibit the binding of, in a statistically significant manner) with antibodies such as 13H5, 13H7 or 7H9, in standard IFN-alpha binding assays.
- 13H5 binds with high affinity to IFN-alpha 2a and IFN-alpha 2b.
- the disclosure provides antibodies, such as human antibodies, that compete for binding to IFN-alpha 2a or IFN-alpha 2b with another antibody, such as13H5, 13H7 or 7H9.
- Another antibody such as13H5, 13H7 or 7H9.
- 13H5, 13H7 or 7H9 to IFN-alpha 2a or IFN-alpha 2b demonstrates that the test antibody can compete with that antibody for binding to IFN-alpha 2a or IFN-alpha 2b; such an antibody can, according to non-limiting theory, bind to the same or a related (e.g., a structurally similar or spatially proximal) epitope on IFN-alpha 2a or IFN- alpha 2b as the antibody with which it competes.
- the antibody that binds to the same epitope on IFN-alpha 2a or IFN-alpha 2b as, e.g., 13H5, 13H7, or 7H9 is a human monoclonal antibody. Such human monoclonal antibodies can be used in the methods disclosed herein.
- the IFN-alpha antibody antagonist is sifalimumab.
- Sifalimumab is a fully human, 147,000 Dalton IgGlk monoclonal antibody (Mab) that selectively binds to multiple interferon-alpha subtypes.
- Sifalimumab is made from 100% human protein sequences, thereby making it a fully human monoclonal antibody.
- Fully human monoclonal antibodies have advantages over other forms of monoclonal antibodies, such as chimeric and humanized antibodies, as they have a more favorable safety profile and can be eliminated less rapidly from the human body, thereby reducing the frequency of dosing.
- Sifalimumab was derived from the lgG4k antibody, 13H5 described above and in U.S. Patent No. 7,741 ,449, which was selected based on functional assays as having the most desirable properties for a potential therapeutic agent. 13H5 was subsequently converted to an IgGI antibody isotype, produced in CHO cells. See U.S. Patent No. 7,741 ,449, U.S. Patent Pub. Nos. 2010-0143372 and 2010- 0266610, and PCT Pub. Nos.
- VH CDR1 , CDR2, and CDR3 amino acid sequences of 13H5 are shown in SEQ ID NOs: 1 , 4, and 7, respectively.
- nucleotide and amino acid sequences of the light chain variable region of 13H5 are shown in SEQ ID NOs: 28 and 22, respectively.
- VL CDR1 , CDR2, and CDR3 amino acid sequences of 13H5 are shown SEQ ID NOs: 10, 13, and 16, respectively.
- the disclosure includes methods of dosing to achieve a desired PK characteristic.
- the dose is chosen to achieve a desired characteristic chosen from Tmax (time of maximum observed concentration), Tmax ss (time of maximum observed concentration at steady state), Cmax (maximum observed concentration), Cmax ss (maximum observed concentration at steady state), AUCT, (area under the curve over the dosing interval), AUCT SS (area under the curve over the dosing interval at steady state), Ctrough (trough observed concentration), Ctrough ss (trough observed concentration at steady state), half-life (terminal elimination half-life, defined as ln(2)/lambda z), CLss (serum steady state clearance, defined as Dose/Alld ss), Vss (steady state volume of distribution), AUCIast (area under the curve from time 0 to last observed concentration, i.e., Clast), AUCinf (area under the curve from 0 to infinity, defined as (
- the methods of dosing produce a PK parameter of at least one of the values for the PK characteristics shown in Tables 2, 3, 6, 7, and 8-1 1 .
- the values of such desired PK characteristics are understood to encompass the CV% as shown in the tables.
- the methods of the disclosure produce a value chosen from the PK characteristics shown in Tables 2, 3, 6, 7, and 8-1 1 and neutralization of a the 21 -gene or 4- gene PD marker discussed herein.
- the methods of the disclosure produce a value chosen from the PK characteristics shown in Tables 2, 3, 6, 7, and 8-1 1 , a neutralization of a the 21 -gene or 4-gene PD marker discussed herein, and a reduction in symptoms of SLE, such as a reduction in SLEDAI score.
- the term "dosage form” refers to a pharmaceutical composition comprising one or more active pharmaceutical ingredients (API), e.g., an anti-IFN-alpha antibody or antigen-binding fragment thereof, such as sifalimumab, the composition optionally containing pharmacologically inactive ingredients, i.e., pharmaceutically acceptable carriers, fillers, excipients or combinations thereof such as polymers, suspending agents, surfactants, disintegrants, dissolution modulating components, binders, fillers, lubricants, glidants, stabilizers, antioxidants, osmotic agents, colorants, plasticizers, coatings and the like, that are used to manufacture and deliver active pharmaceutical agents.
- active pharmaceutical ingredients e.g., an anti-IFN-alpha antibody or antigen-binding fragment thereof, such as sifalimumab
- the composition optionally containing pharmacologically inactive ingredients, i.e., pharmaceutically acceptable carriers, fillers, excipients or combinations thereof
- An anti-IFN-alpha antibody or antigen-binding fragment thereof e.g., sifalimumab
- a formulation comprising an anti-IFN-alpha antibody or antigen-binding fragment thereof, such as sifalimumab for use in the methods of the disclosure is for parenteral administration.
- a formulation of the disclosure comprising an anti-IFN-alpha antibody or antigen- binding fragment thereof, such as sifalimumab is an injectable formulation.
- a formulation of the disclosure comprising an anti-IFN-alpha antibody or antigen-binding fragment thereof, such as sifalimumab is for intravenous, subcutaneous, or intramuscular administration.
- a formulation of the disclosure comprises an anti-IFN-alpha antibody or antigen-binding fragment thereof, such as sifalimumab wherein said formulation is for subcutaneous injection.
- intravenous administration refers to the introduction of a composition to a patient into a vein.
- An anti-IFN-alpha antibody or antigen-binding fragment thereof can be administered intravenously (IV), e.g., as an intravenous infusion or as an intravenous bolus.
- IV intravenously
- intravenous infusion refers to introduction of a drug, e.g., an anti-IFN-alpha antibody or antigen-binding fragment thereof, such as sifalimumab, into the vein of an animal or human patient over a period of time greater than approximately 5 minutes, for example, between approximately 30 to 90 minutes, although, according to the disclosure, intravenous infusion is alternatively administered for 10 hours or less.
- the duration of the infusion is at least 60 minutes.
- intravenous bolus or “intravenous push” refers to drug administration, e.g., of an anti-IFN-alpha antibody or antigen-binding fragment thereof, such as sifalimumab, into a vein of an animal or human such that the body receives the drug in approximately 15 minutes or less, for example, 5 minutes or less.
- an anti-IFN-alpha antibody or antigen-binding fragment thereof such as sifalimumab
- subcutaneous administration refers to introduction of a drug, e.g., an anti-IFN-alpha antibody or antigen-binding fragment thereof, such as sifalimumab, under the skin of an animal or human patient, for example, within a pocket between the skin and underlying tissue, by relatively slow, sustained delivery from a drug receptacle.
- the pocket can be created by pinching or drawing the skin up and away from underlying tissue.
- a composition comprising an anti-IFN-alpha antibody or antigen-binding fragment thereof, such as sifalimumab is introduced under the surface of the skin of the patient with a hypodermic needle.
- subcutaneous infusion refers to introduction of a drug, e.g., an anti-IFN-alpha antibody or antigen-binding fragment thereof, such as sifalimumab, under the skin of an animal or human patient, for example, within a pocket between the skin and underlying tissue, by relatively slow, sustained delivery from a drug receptacle for a period of time including, but not limited to, 30 minutes or less, or 90 minutes or less.
- a drug e.g., an anti-IFN-alpha antibody or antigen-binding fragment thereof, such as sifalimumab
- the infusion can be made by subcutaneous implantation of a drug delivery pump implanted under the skin of the animal or human patient, wherein the pump delivers a predetermined amount of drug for a predetermined period of time, such as 30 minutes, 90 minutes, or a time period spanning the length of the treatment regimen.
- a drug delivery pump implanted under the skin of the animal or human patient, wherein the pump delivers a predetermined amount of drug for a predetermined period of time, such as 30 minutes, 90 minutes, or a time period spanning the length of the treatment regimen.
- subcutaneous bolus refers to drug administration beneath the skin of an animal or human patient of an anti-IFN-alpha antibody or antigen- binding fragment thereof, such as sifalimumab, where bolus drug delivery is less than about 15 minutes, less than about 5 minutes, or less than about 60 seconds. Administration can be within a pocket between the skin and underlying tissue, where the pocket is created, for example, by pinching or drawing the skin up and away from underlying tissue.
- a formulation for use in the methods of the disclosure is for aerosol administration.
- the dosage of anti-IFN-alpha antibody or antigen- binding fragment thereof administered to a patient is calculated, e.g., as a function of the patient body mass (weight), height, or body surface.
- the dosage of anti-IFN-alpha antibody or antigen-binding fragment thereof administered to a patient depends on the patient's body weight.
- the weight-based dose is generally provided in mg/kg.
- an anti-IFN-alpha antibody or antigen-binding fragment thereof is administered at a weight-based dosage of about 0.1 mg/kg, or about 0.2 mg/kg, or about 0.3 mg/kg, or about 0.4 mg/kg, or about 0.5 mg/kg, or about 0.6 mg/kg, or about 0.7 mg/kg, or about 0.8 mg/kg, or about 0.9 mg/kg.
- an anti-IFN-alpha antibody or antigen-binding fragment hereof is administered at a weight-based dosage of about 1 mg/kg, or about 2 mg/kg, or about 3 mg/kg, or about 4 mg/kg, or about 5 mg/kg, or about 6 mg/kg, or about 7 mg/kg, or about 8 mg/kg, or about 9 mg/kg.
- an anti-IFN-alpha antibody or antigen-binding fragment thereof is administered at a weight-based dosage of about 10 mg/kg, or 15 mg/kg, or 20 mg/kg, or about 25 mg/kg, or about 30 mg/kg, or about 35 mg/kg, or about 40 mg/kg, or about 45 mg/kg, or about 50 mg/kg, or about 55 mg/kg, or about 60 mg/kg, or about 65 mg/kg, or about 70 mg/kg, or about 75 mg/kg, or about 80 mg/kg, or about 85 mg/kg, or about 90 mg/kg, or about 95 mg/kg, or about 100 mg/kg.
- the anti-IFN-alpha antibody or antigen-binding fragment thereof is administered at a weight-base dosage about 0.3 mg/kg, or about 1 .0 mg/kg, or about 3.0 mg/kg, or about 10 mg/kg.
- the weight-based dosage is administered intravenously.
- the weight-based dosage is administered subcutaneously.
- the an anti-IFN-alpha antibody is sifalimumab.
- weight-based doses of an anti-IFN-alpha antibody or antigen-binding fragment thereof such as sifalimumab
- these doses can, for example, be administered approximately every week, approximately every 2 weeks, approximately every 3, or about every 4 weeks.
- weight-based doses of an anti-IFN-alpha antibody or antigen-binding fragment thereof are administered approximately every day, approximately every two days, approximately every three days, approximately every 4 days, approximately every 5 days, approximately every 6 days, or approximately every seven days.
- weight-based doses of an anti-IFN-alpha antibody or antigen-binding fragment are administered every 2 weeks.
- the weight-based doses of anti-IFN-alpha antibody or an antigen-binding fragment thereof can be administered, for example, for about 1 month, or about 2 months, or about 3 months, or about 4 months, or about 5 months, or about 6 months.
- the weight-based doses of anti-IFN-alpha antibody or an antigen-binding fragment thereof can, for example, continue to be administered until disease progression, adverse event, or other parameter occurs as determined by the physician.
- weight-based doses of anti-IFN-alpha antibody or an antigen-binding fragment thereof are administered for about 6 months.
- weight-based doses anti-IFN-alpha antibody or an antigen-binding fragment thereof are administered for about 26 weeks.
- patients can be administered at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 1 1 , at least 12, at least 13, at least 14 or at least 15 weight- based doses of an anti-IFN-alpha antibody or antigen-binding fragment thereof, such as sifalimumab.
- patients are administered at least 14 doses of an anti-IFN-alpha antibody or antigen-binding fragment thereof, such as sifalimumab.
- patients can be administered at least 14 IV weight-based doses of an anti-IFN-alpha antibody or antigen-binding fragment thereof, such as sifalimumab.
- weight-based doses of anti-IFN-alpha antibody or an antigen-binding fragment thereof are administered at equal time intervals. In other embodiment, such weight-based doses are administered at varying intervals. In some embodiments, all administered weight-based doses as essentially identical. In other embodiments, at least one weight-based dose is different with respect to the other doses, e.g., in volume, concentration, route of administration, formulation, etc.
- a "fixed dose” or “fixed dosage” of a therapeutic agent herein refers to a dose that is administered to a human patient without regard for the weight (WT) or body surface area (BSA) of the patient.
- the fixed dose of anti-IFN-alpha antibody or an antigen-binding fragment thereof, e.g., sifalimumab, is therefore not provided as a mg/kg dose or mg/m 2 dose, but rather as an absolute amount of the therapeutic agent.
- an anti-IFN-alpha antibody or antigen-binding fragment thereof is administered at a fixed dosage of about 10 mg, or about 20 mg, or about 30 mg, or about 40 mg, or about 50 mg, or about 60 mg, or about 70 mg, or about 80 mg, or about 90 mg, or about 100 mg.
- an anti-IFN-alpha antibody or antigen-binding fragment thereof is administered at a fixed dosage of about 100 mg, or about 150 mg, about 200 mg, or about 300 mg, or about 400 mg, or about 500 mg, or about 600 mg, or about 700 mg, or about 800 mg, or about 900 mg, or about 100 mg, or about 1 100 mg, or about 1200 mg, or about 1300 mg, or about 1400 mg, or about 1500 mg, or about 1600 mg, or about 1700 mg, or about 1800 mg, or about 1900 mg, or about 2000 mg.
- the anti-IFN-alpha antibody or antigen-binding fragment thereof is administered intravenously at a fixed dosage about 100 mg, or about 150 mg, or about 200 mg, or about 600 mg, or about 1200 mg. In a specific embodiment, the anti-IFN antibody or antigen-binding fragment thereof is administered subcutaneously at a fixed dosage of about 100 mg, or about 200 mg, or about 600 mg, or about 1200 mg. In some embodiments, a loading dose is administered. In some specific embodiments, the anti-IFN-alpha antibody is sifalimumab, or an antigen-binding fragment thereof.
- the anti-IFN-alpha antibody or antigen-binding fragment thereof is administered intravenously at a fixed dosage about 100 mg, or about 150 mg, or about 200 mg, or about 600 mg, or about 1200 mg once per month, with loading dose at Day 14.
- a series of fixed doses of an anti-IFN-alpha antibody or antigen- binding fragment thereof are administered, for example, be administered approximately every week, approximately every 2 weeks, approximately every 3, or about every 4 weeks.
- fixed doses of an anti-IFN-alpha antibody or antigen-binding fragment thereof are administered approximately every day, approximately every two days, approximately every three days, approximately every 4 days, approximately every 5 days, approximately every 6 days, or approximately every seven days.
- the fixed dose of anti-IFN-alpha antibody or antigen- binding fragment thereof is a 100 mg dose administered daily.
- the fixed dose of anti-IFN-alpha antibody or antigen-binding fragment thereof is a 150 mg dose administered daily.
- the fixed dose of anti-IFN-alpha antibody is a 100 mg daily dose or a 150 mg daily dose of sifalimumab.
- fixed doses of anti-IFN-alpha antibody or antigen-binding fragment thereof are administered every 2 weeks. These fixed doses can be administered, for example, for about 1 month, or about 2 months, or about 3 months, or about 4 months, or about 5 months, or about 6 months. Such fixed doses can, for example, continue to be administered until disease progression, adverse event, or other parameter occurs as determined by the physician..
- patients can be administered at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 1 1 , at least 12, at least 13, at least 14 or at least 15 fixed doses of anti-IFN-alpha antibody or antigen-binding fragment thereof.
- patients are administered at least 13 doses of anti-IFN- alpha antibody or antigen-binding fragment thereof.
- patients can be administered at least 13 subcutaneous fixed doses of sifalimumab.
- fixed doses of anti-IFN-alpha antibody or antigen- binding fragment thereof are administered at equal time intervals. In other embodiment, fixed doses of anti-IFN-alpha antibody or antigen-binding fragment thereof are administered at varying intervals. In some embodiments, all administered fixed doses are essentially identical. In other embodiments, at least one fixed dose is different with respect to the other doses, e.g., in volume, concentration, route of administration, formulation, etc.
- the fixed dose or weight-based of anti-IFN-alpha antibody e.g., sifalimumab, or antigen-binding fragment thereof will depend on the type of disease to be treated, as defined above, the severity and course of the disease, whether the antibody is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the antibody, and the discretion of the attending physician.
- one or more loading dose(s) of the anti-IFN-alpha antibody or antigen-binding fragment thereof can be administered, followed by one or more maintenance dose(s), either weigh-based or fixed doses, of the antibody.
- a plurality of the same fixed doses of anti-IFN-alpha antibody or antigen-binding fragment thereof are administered to the patient.
- one or more weigh-based or fixed loading doses of anti-IFN-alpha antibody (e.g. sifalimumab) or an antigen-binding fragment can be administered, followed by one or more weigh-based or fixed maintenance doses of the antibody.
- one or more weigh- based or fixed dose(s) of anti-IFN-alpha antibody e.g. sifalimumab
- an antigen-binding fragment can be administered for up a number of cycles.
- a weigh-based or fixed dose of anti-IFN-alpha antibody (e.g., sifalimumab) or an antigen-binding fragment can be administered as a loading dose, followed by one or more maintenance dose(s). About one, two or more maintenance doses of anti-IFN-alpha antibody or antigen-binding fragment thereof can be administered to the patient according to this embodiment.
- the disclosure provides a method of treating an autoimmune disorder, e.g., SLE, scleroderma, or myositis in a human patient comprising administering at least one fixed dose of sifalimumab to the patient, wherein the fixed dose is about 100 mg, about 200 mg, about 600 mg, or about 1200 mg of sifalimumab.
- an autoimmune disorder e.g., SLE, scleroderma, or myositis
- PK characteristics refers to parameters describing the mechanisms of absorption and distribution of an administered drug, e.g., an anti-IFN-alpha antibody such as sifalimumab or an antigen-binding fragment thereof, the rate at which a drug action begins and the duration of the effect, the physicochemical chemical changes of the substance in the body and the effects and routes of excretion of the metabolites of the drug.
- an administered drug e.g., an anti-IFN-alpha antibody such as sifalimumab or an antigen-binding fragment thereof
- the methods disclosed herein permit dose selection to achieve desired PK characteristics, whether the dosing be based on weight, fixed dosing, and whether the route of administration is, for example, intravenous or subcutaneous.
- Such pharmacokinetic characteristics comprise, e.g., T max (time of maximum observed concentration), T max S s (time of maximum observed concentration at steady state), C ma x (maximum observed concentration), C ma x ss (maximum observed concentration at steady state), AUC T , (area under the curve over the dosing interval), AUC T S s (area under the curve over the dosing interval at steady state), Ct r0 ug (trough observed concentration), C tr oug ss (trough observed concentration at steady state), half-life (terminal elimination half-life, defined as ⁇ (2)/ ⁇ ⁇ ), CLss (serum steady state clearance, defined as Dose/AUC T ss), V ss (steady state volume of distribution), AUCiast (area under the curve from time 0 to last observed concentration, i.e., Ci as t) > AUC inf (area under the curve from 0 to infinity, defined as (AUCi as t
- Pharmacokinetic characteristics can be used to determine the appropriate dosage of a drug of interest, e.g. , an anti-IFN-alpha antibody or antigen-binding fragment thereof. Characteristics describing the blood plasma curve can be obtained in clinical trials by administration of the active agent to a number of test subjects. The blood plasma values of the individual test persons are then averaged.
- a drug of interest e.g. , an anti-IFN-alpha antibody or antigen-binding fragment thereof.
- Characteristics describing the blood plasma curve can be obtained in clinical trials by administration of the active agent to a number of test subjects. The blood plasma values of the individual test persons are then averaged.
- pharmacokinetic characteristics e.g., AUC, C ma x and T ma x refer to mean values corresponding to a population of subjects.
- in vivo parameters such as values for AUC, C ma x, T max refer to parameters or values obtained after administration at steady state to human patients.
- the patient group comprises between 10 to 200 patients.
- a reasonable number of patients is, e.g., 10, 20, 30, 40, 50, 75, 100, 125, 150, 175 or 200 patients.
- Patients are be selected according to inclusion and exclusion criteria related to the ability of a physician to adequately discern the symptoms of the condition to be treated and the effect of the tested drug over those symptoms.
- bioavailability is defined for purposes of the present disclosure as the extent to which an active agent such as an anti-IFN-alpha antibody, e.g., sifalimumab, or an antigen-binding fragment thereof is absorbed from the unit dosage forms.
- AUC provides a measure of bioavailability.
- steady state means that a plasma level for a given drug, e.g., an anti-INF-alpha antibody, e.g., sifalimumab, or an antigen binding fragment thereof, has been achieved and which is maintained with subsequent doses of the drug at a level which is at or above the minimum effective therapeutic level and is below the minimum toxic plasma level.
- a plasma level for a given drug e.g., an anti-INF-alpha antibody, e.g., sifalimumab, or an antigen binding fragment thereof.
- the curve passes through a second maximum after the second dose has been administered, which is above the first maximum, and drops to a second minimum, which is above the first minimum.
- the blood plasma curve escalates due to the repeated doses and the associated step-by- step accumulation of active agent, until it levels off to a point where dose administered and elimination are in balance. This state, at which dose administered and elimination are in equilibrium and the concentration oscillates constantly between a defined minimum and a defined maximum, is called steady state.
- the term "clearance rate” refers to CL (apparent total body clearance of the drug from plasma),CL ss ( serum steady state clearance), CL/F (apparent serum clearance) and CL SS /F (apparent serum steady state clearance).
- apparent volume of distribution refers to V ss (steady state volume of distribution) and Vz/F (apparent terminal volume of distribution).
- half-life refers to a biological half-life of a particular binding agent (e.g., an anti-INF-alpha antibody, such as sifalimumab, or an antigen binding fragment thereof) in vivo. Half-life can be represented by the time required for half the quantity administered to a subject to be cleared from the circulation and/or other tissues in the subject.
- an anti-IFN-alpha or antigen-binding fragment thereof is administered in a dosage, such that an effective exposure is provided in a patient, for example as measured by, e.g., clearance rate, apparent volume of distribution, or half-life.
- the disclosure also includes methods which combine achieving two or more favorable pharmacokinetic characteristics or combinations thereof. Examples of those pharmacokinetic parameters include clearance rate clearance rate (CL, CL SS , CL/F, or CL SS /F), an apparent volume of distribution (V ss or V z /F), and a serum half-life.
- the formulation administered through the methods of the disclosure can be selected such that when administered to a patient in need thereof, the selected formulation provides the patient with one or more of the desired pharmacokinetic characteristics.
- one or more desired pharmacokinetic characteristics is achieved after the administration of one or more doses of an anti-INF antibody or an antigen binding fragment thereof to a subject suffering from an autoimmune disorder.
- such interferon alpha is human interferon alpha.
- the one or more desired pharmacokinetic characteristics are selected, e.g., from the group consisting of from the group consisting of a clearance rate (CL, CL SS , CL/F, or CL SS /F), apparent volume of distribution (V ss or V z /F), and a serum half-life.
- the immune disorder is systemic lupus erythematosus, scleroderma, or myositis.
- the desired pharmacokinetic characteristics are selected from the group consisting for a clearance rate (CL, CL SS , CL/F, or CLss/F) of between about 99 and about 432 mL/day, an apparent volume of distribution (V ss or V z /F) of between about 3 and about 17 L, and a serum half-life of about 14 days to about 47 days is achieved following the administration of the anti-IFN antibody or antigen-binding fragment thereof.
- the desired clearance rate (CL, CL SS , CL/F, or CL SS /F) is about 90, about 100, about 1 10, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290, about 300, about 310, about 320, about 330, about 340, about 350, about 360, about 370, about 380, about 390, about 400, about 410, about 420, about 430, or about 440 mL/day .
- the desired apparent volume of distribution (V ss or V z /F) of about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 1 1 , about 12, about 13, about 14, about 15, about 16, or about 17 L.
- the desired serum half-life is about 10, about 1 1 , about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21 , about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31 , about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41 , about 42, about 43, about 44, about 45, about 46, or about 47 days.
- such desired pharmacokinetic characteristics are achieved after the administration of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, or 15 doses. In some embodiments, such desired pharmacokinetic characteristics are achieved after the administration of at least 15 doses of an anti-IFN-alpha antibody, e.g., sifalimumab, or an antigen-binding fragment thereof. In some embodiments, such doses are intravenous. In other embodiments, such doses are subcutaneous. In other embodiments, such doses are weight-based, whereas in other cases such doses are fixed doses.
- an anti-IFN-alpha antibody or antigen-binding fragment thereof can be of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg.
- an anti-IFN-alpha antibody or antigen-binding fragment thereof is administered at a fixed dosage of about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 100 mg, about 1 100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg.
- a loading dose is administered.
- the anti-IFN-alpha antibody or antigen-binding fragment thereof is administered intravenously at a fixed dosage about 100 mg, or about 150 mg, or about 200 mg, or about 250 mg, or about 300 mg, or about 400 mg, or about 500 mg, or about 600 mg, or about 700 mg, or about 800 mg, or about 900 mg, or about 1000 mg, or about 1 100 mg, or about 1200 mg, or about 1300 mg, or about 1400 mg, or about 1500 mg, or about 1600 mg, or about 1700 mg, or about 1800 mg, or about 1900 mg, or about 2000 mg once per month, with a loading dose at Day 14.
- the desired pharmacokinetic characteristics can be achieved by administering doses of an anti-IFN-alpha antibody or antigen-binding fragment thereof approximately every day, approximately every two days, approximately every three days, approximately every 4 days, approximately every 5 days or approximately every 6 days.
- the desired pharmacokinetic characteristics can be achieved by administering doses of an anti-IFN-alpha antibody or antigen-binding fragment thereof approximately every week, approximately every 2 weeks, approximately every 3 weeks, or about every 4 weeks.
- weight-based doses of anti-IFN-alpha antibody or antigen-binding fragment thereof are administered every 2 weeks.
- the desired pharmacokinetic characteristics can be achieved by administering doses of an anti-IFN-alpha antibody or antigen binding fragment thereof, for example, for about 1 month, or about 2 months, or about 3 months, or about 4 months, or about 5 months, or about 6 months.
- the time to reach maximum plasma concentration ( max or Tmax ss) following IV administration of an anti-IFN-alpha, such as sifalimumab, or an antigen-binding fragment thereof is about 0.13 days or less.
- an anti-IFN-alpha such as sifalimumab, or an antigen-binding fragment thereof achieves a desired pharmacokinetic characteristics chosen from clearance rate (CL, CL SS , CL/F, or CL SS /F), apparent volume of distribution (V ss or V z /F), a serum half-life, T max (time of maximum observed concentration), T max S s (time of maximum observed concentration at steady state), C ma x (maximum observed concentration), C ma x ss (maximum observed concentration at steady state), AUC T , (area under the curve over the dosing interval), AUC T S s (area under the curve over the dosing interval at steady state), Ct r0 ug (trough observed concentration), C tr oug ss (trough observed concentration at steady state), half-life (terminal elimination half-life, defined as ⁇ (2)/ ⁇ ⁇ ), CLss (serum steady state clearance, defined
- a single IV administration of about 0.3 mg/kg achieves one or more pharmacokinetic characteristics chosen from: a T max of about 0.12 days or less, a maximum plasma concentration (C ma x) of about 7, about 8, about 9, about 10, about 1 1 , about 12, about 13, about 14 or about 15 ⁇ g/mL, an area under the plasma concentration-time curve during a dosage interval ( ⁇ ) (AUC T ) of about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, or about 1 10 ⁇ 9 day/mL, and a trough plasma concentration (Ctroug ) of about 2.0, about 2.2, about 2.4, about 2.6, about 2.8, about 3.0, about 3.2, about 3.4, about 3.6, about 3.8, or about 4.0 ⁇ g/mL .
- a single IV administration of about 0.3 mg/kg to a population of subjects achieves one or more pharmacokinetic characteristics chosen from: an average T max of about 0.07 days, an average C ma x of about 1 1 ⁇ g/mL, an average AUC T of about 79 ⁇ g day/mL, and an average Ctroug of about 3 ⁇ g/mL.
- a single IV administration of about 1 mg/kg achieves one or more pharmacokinetic characteristics chosen from: a T max of about 0.12 days or less, a C ma x of about 20, about 25, about 30, about 35, about 40, or about 45 g/mL, an AUC T of about 150, about 175, about 200, about 225, about 250, about 275, or about 300 ⁇ g day/mL, and a C tr oug of about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 1 1 , about 12, about 13, about, or about 15 ⁇ g/mL .
- a single IV administration of about 1 mg/kg to a population of subjects achieves one or more pharmacokinetic characteristics chosen from: an average T max of about 0.08 days, an average C ma x of about 32 ⁇ g/mL, an average AUC T of about 221 ⁇ g day/mL, and an average Ctroug of about 8 ⁇ g/mL.
- a single IV administration of about 3 mg/kg achieves one or more pharmacokinetic characteristics chosen from: a T max of about 0.13 days or less, a C ma x of about 60, about 70, about 80, about 90, about 100, about 1 10, about 120, about 130, about 140, or about 150 ⁇ g/mL, an AUC T of about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950, about 1000, or about 1050 ⁇ g day/mL, and a Ctroug of about 12, about 14, about 16, about 18, about 20, about 22, about 24, about 26, about 28, about 30, about 32, about 34, or about 36 ⁇ g/mL .
- a single IV administration of about 3 mg/kg to a population of subjects achieves one or more pharmacokinetic characteristics chosen from: an average T max of about 0.09 days, an average C ma x of about 103 ⁇ g/mL, an average AUC T of about 739 ⁇ g day/mL, and an average Ctroug of about 23 ⁇ g/mL.
- a single IV administration of about 10 mg/kg achieves one or more pharmacokinetic characteristics chosen from: a T max of about 0.13 days or less, a C ma x of about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290, about 300, about 310, or about 320 ⁇ g/mL, an AUC T of about 900, about 1000, about 1 100, about 1200, about 1300, about 1400, about 1500, about 1600, about 1700, about 1800, about 1900, about 2000, about 2100, about 2200, or about 2300 ⁇ g day/mL, and a Ctroug of about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, or about 80 ⁇ 9/ ⁇ _ .
- a single IV administration of about 10 mg/kg to a population of subjects achieves one or more pharmacokinetic characteristics chosen from: an average T max of about 0.09 days, an average C ma x of about 230 ⁇ g/mL, an average AUC T of about 1610 ⁇ g day/mL, and an average Ctroug of about 52 ⁇ g/mL.
- a sufficient number of IV doses of about 0.3 mg/kg are administered at about 14-day intervals to achieve a steady state, and wherein one or more steady state pharmacokinetic characteristics are chosen from: a T m a X ss of about 0.60 days or less, a C ma x ss of about 1 1 , about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21 , about 22, about 23, about 24, or about 25 ⁇ g/mL, an AUC T S s of about 80, about 90 , about 100, about 1 10, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, or about 200 ⁇ g day/mL, and a Ctroug ss of about 5 of less, about 6, about 7, about 8, about 9, about 10, or about 1 1 ⁇ g/mL is achieved.
- a sufficient number of IV doses of about 0.3 mg/kg are administered to a population of subjects at about 14-day intervals to achieve a steady state, and wherein one or more pharmacokinetic characteristics chosen from: an average T m a X of about 0.17 days, an average C ma x of about 18 ⁇ g/mL, an average AUC T of about 143 ⁇ g day/mL, and an average Ctrough of about 8 ⁇ g/mL is achieved.
- a sufficient number of IV doses of about 0.3 mg/kg are administered at about 14-day intervals to a achieve a steady state, and wherein one or more pharmacokinetic characteristics selected from the group consisting of a clearance rate (CL SS ) of about 90, about 100, about 1 10, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 240, about 250, about 260, or about 270 mL/day, an apparent volume of distribution (V ss ) of about 4, about 5, about 6, about 7, about 8, or about 9 L, and a serum half-life of about 15 days, about 20 days, about 25 days, about 30 days, about 35 days, about 40 days, or about to about 45 days is achieved.
- CL SS clearance rate
- V ss apparent volume of distribution
- a sufficient number of IV doses of about 0.3 mg/kg are administered to a population of subjects at about 14-day intervals to achieve a steady state, and wherein one or more pharmacokinetic characteristics selected from the group consisting of an average clearance rate (CL SS ) of about 185 mL/day, an average apparent volume of distribution (V ss ) of about 6 L, and an average serum half-life of about 29 days is achieved.
- CL SS average clearance rate
- V ss average apparent volume of distribution
- a sufficient number of IV doses of about 1 mg/kg are administered at about 14-day intervals to achieve a steady state, and wherein one or more steady state pharmacokinetic characteristics chosen from: a T max S s of about 0.1 1 days or less, a Cmax ss of about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, or about 70 g/mL, an AUC T S s of about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 550, or about 600 ⁇ g day/mL, and a C tr oug ss of about 9, about 1 1 , about 13, about 15, about 17, about 19, about 21 , about 23, about 25, about 27, about 29, or about 31 ⁇ g/mL is achieved.
- a sufficient number of IV doses of about 1 mg/kg are administered to a population of subjects at about 14-day intervals to achieve a steady state, and wherein one or more pharmacokinetic characteristics chosen from: an average T max ss of about 0.07 days, an average C ma x ss of about 48 ⁇ g/mL, an average AUC T S s of about 197 ⁇ g day/mL, and an average C tr oug ss of about 1 1 ⁇ g/mL is achieved.
- a sufficient number of IV doses of about 1 mg/kg are administered at about 14-day intervals to a achieve a steady state, and wherein one or more pharmacokinetic characteristics selected from the group consisting of a clearance rate (CL SS ) of about 120, about 140, about 160, about 180, about 200, about 220, about 240, about 260, about 280, about 300, about 320, about 340, or about 360 mL/day, an apparent volume of distribution (V ss ) of about 4, about 5, about 6, about 7, about 8, or about 9 L, and a serum half-life of about 15, about 16, about 17, about 18, about 19, about 20, about 21 , about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31 , or about 32 days is achieved.
- CL SS clearance rate
- V ss apparent volume of distribution
- a sufficient number of IV doses of about 1 mg/kg are administered to a population of subjects at about 14-day intervals to achieve a steady state, and wherein one or more pharmacokinetic characteristics selected from the group consisting of an average clearance rate (CL SS ) of about 223 mL/day, an average apparent volume of distribution (V ss ) of about 6 L, and an average serum half-life of about 23 days is achieved.
- CL SS average clearance rate
- V ss average apparent volume of distribution
- a sufficient number of IV doses of about 3 mg/kg are administered at about 14-day intervals to achieve a steady state, and wherein one or more steady state pharmacokinetic characteristics chosen from: a T max S s of about 0.35 days or less, a C ma x ss of about 75, about 100, about 125, about 150, about 175, about 200, about 225, or about 250 g/mL, an AUC T SS of about 500, about 600, about 700, about 800, about 900, about 1000, about 1 100 , about 1200, about 1300, about 1400, about 1500, about 1600, about 1700, about 1800, or about 1900 ⁇ g day/mL, and a C tr oug ss of about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, or about 75 ⁇ g/mL is achieved.
- a sufficient number of IV doses of about 3 mg/kg are administered to a population of subjects at about 14-day intervals to achieve a steady state, and wherein one or more pharmacokinetic characteristics chosen from: an average T max ss of about 0.13 days, an average C ma x ss of about 153 ⁇ g/mL, an average AUC T S s of about 1 188 ⁇ g day/mL, and an average Ctroug ss of about 50 ⁇ g/mL is achieved.
- a sufficient number of IV doses of about 3 mg/kg are administered at about 14-day intervals to a achieve a steady state, and wherein one or more pharmacokinetic characteristics selected from the group consisting of a clearance rate (CL SS ) of about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290, about 300, or about 310 mL/day, an apparent volume of distribution (V ss ) of about 3.0, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, or about 7.0 L, and a serum half-life of about 14 days, about 15, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, or about 26 days is achieved.
- CL SS clearance rate
- a sufficient number of IV doses of about 3 mg/kg are administered to a population of subjects at about 14-day intervals to achieve a steady state, and wherein one or more pharmacokinetic characteristics selected from the group consisting of an average clearance rate (CL SS ) of about 220 mL/day, an average apparent volume of distribution (V ss ) of about 5 L, and an average serum half-life of about 20 days is achieved.
- CL SS average clearance rate
- V ss average apparent volume of distribution
- a sufficient number of IV doses of about 10 mg/kg are administered at about 14-day intervals to achieve a steady state, and wherein one or more steady state pharmacokinetic characteristics chosen from: a T max S s of about 0.85 days or less, a C ma x ss of about 275, about 300, about 325, about 350, about 375, about 400, about 425, about 450, about 475, about 500, about 525, about 550, about 575, or about 600 g/mL, an AUC T SS of about 2500, about 2600, about 2700, about 2800, about 2900, about 3000, about 3100, about 3200, about 3300, about 3400, about 3500, about 3600, about 3700, about 3800, about 3900, about 4000, about 4100, about 4200, or about 4300 ⁇ g day/mL, and a Ctroug ss of about 90, about 100, about 1 10, about 120, about 130, about
- a sufficient number of IV doses of about 10 mg/kg are administered to a population of subjects at about 14-day intervals to achieve a steady state, and wherein one or more pharmacokinetic characteristics chosen from: an average T max ss of about 0.23 days, an average C ma x ss of about 232 ⁇ g/mL, an average AUC T S s of about 3403 ⁇ g day/mL, and an average Ctroug ss of about 184 ⁇ g/mL is achieved.
- a sufficient number of IV doses of about 10 mg/kg are administered at about 14-day intervals to a achieve a steady state, and wherein one or more pharmacokinetic characteristics selected from the group consisting of a clearance rate (CL SS ) of about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290, about 300, about 310, or about 320 mL/day, an apparent volume of distribution (V ss ) of about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, or about 7 L, and a serum half-life of about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, or about 29 days is achieved.
- CL SS clearance rate
- a sufficient number of IV doses of about 10 mg/kg are administered to a population of subjects at about 14-day intervals to achieve a steady state, and wherein one or more pharmacokinetic characteristics chosen from an average clearance rate (CL SS ) of about 238 mL/day, an average apparent volume of distribution (V ss ) of about 6 L, and an average serum half-life of about 22 days is achieved.
- CL SS average clearance rate
- V ss average apparent volume of distribution
- the number of IV doses at about 14-day intervals required to achieve steady state is about 5 to about 8 doses.
- the desired pharmacokinetic characteristics are achieved after the antibody or antigen-binding fragment thereof is administered as a single dose or is administered in two or more doses once per week, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3 months, once every six months, or at varying intervals.
- the desired pharmacokinetic parameters are achieved after subcutaneous (SC) administration.
- the desired pharmacokinetic characteristics are achieved after the administration of 100 mg of anti-IFN-alpha administered as a single dose, or administered weekly, bi-weekly, or monthly. In some embodiments, the desired pharmacokinetic characteristics are achieved after the administration of 150 mg of anti-IFN-alpha administered as a single dose, or administered weekly, bi-weekly, or monthly. In some embodiments, the dose is administered intravenously. In other embodiments the dose is administered subcutaneously. [0201] In some embodiments, at T ma x or T ma x ss of between about 1 .8 and about 9.4 days is achieved.
- the T max or T max S s is about 2 days or lower, about 3 days or lower, about 4 days or lower, about 5 days or lower, about 6 days or lower, about 7 days or lower, about 8 days or lower, about 9 days or lower, or about 10 days or lower.
- a single SC administration of about 100 mg achieves one or more pharmacokinetic characteristics chosen from: a T max of about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 days, a C ma x of about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 1 1 , about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, or about 21 ⁇ g/mL, an area under the plasma concentration- time curve from time zero to time of last measurable concentration (AUCi as t) of about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 425, about 450, about 475, about 500, about 525, about 550, about 575, about 600, about 625, about 650, or about 675 ⁇ g day/mL, and an area under the plasma concentration-time curve from time zero to infinity (AUC ⁇ ) of about 200, about 225, about
- a single SC administration of about 100 mg to a population of subjects achieves one or more pharmacokinetic characteristics chosen from: an average T max of about 6 days, an average Cmax of about 13 ⁇ g/mL, an average area under the plasma concentration-time curve from time zero to time of last measurable concentration (AUCi as t) of about 421 ⁇ g day/mL, and an average area under the plasma concentration-time curve from time zero to infinity (AUC ⁇ ) of about 477 ⁇ g day/mL.
- pharmacokinetic characteristics chosen from: an average T max of about 6 days, an average Cmax of about 13 ⁇ g/mL, an average area under the plasma concentration-time curve from time zero to time of last measurable concentration (AUCi as t) of about 421 ⁇ g day/mL, and an average area under the plasma concentration-time curve from time zero to infinity (AUC ⁇ ) of about 477 ⁇ g day/mL.
- a single SC administration of about 100 mg achieves one or more pharmacokinetic characteristics chosen from a clearance rate (CL/F) of about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 425, or about 450 mL/day, an apparent volume of distribution (V z /F) of about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, about 8.0, about 8.5, about 9.0, about 9.5, about 10, about 10.5, about 1 1 , about 1 1 .5 or about 12 L, and a serum half-life of about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days,
- a single SC administration of about 100 mg to a population of subjects achieves one or more pharmacokinetic characteristics chosen from an average clearance rate (CL/F) of about 275 mL/day, an apparent volume of distribution (V z /F) of about 8 L, and a serum half-life of about 25 days.
- CL/F average clearance rate
- V z /F apparent volume of distribution
- a sufficient number of SC doses of about 100 mg are administered at about 7-day (weekly) intervals to achieve a steady state, and wherein one or more steady state pharmacokinetic characteristics chosen from: a max ss of about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, or about 6.5 days, a C m ax ss of about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, or about 95 g/mL, an AUC T ss of about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 425, about 450, about 475, about 500, about 525, about 550, about 575, about 600, about 625, or about 650 ⁇ g day/mL, and a Ct r0 ug ss of about 35, about 40,
- a sufficient number of SC doses of about 100 mg are administered at about 7-day (weekly) intervals to a population of subjects to achieve a steady state, and wherein one or more steady state pharmacokinetic characteristics chosen from: an average T max S s of about 4 days, an average C ma x ss of about 65 g/mL, an average AUC T S s of about 443 ⁇ g day/mL, and a C tr oug ss of about 59 ⁇ g/mL is achieved.
- a sufficient number of SC doses of about 100 mg are administered at about 7-day (weekly) intervals to achieve a steady state, and wherein one or more steady state pharmacokinetic characteristics chosen from: a clearance rate (CL SS /F) of about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290, about 300, about 310, about 320, about 330, about 340, about 350, about 360, about 370, about 380, about 390, or about 400 mL/day, an apparent volume of distribution (V z /F) of about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, about 10, about 10.5, about 1 1 , about 1 1 .5, about 12, about 12.5, about 13, about 13.5, about 14, about 14.5, or about 15 L, and a serum half-life of about 22 , about 23, about
- a sufficient number of SC doses of about 100 mg are administered at about 7-day (weekly) intervals to a population of subjects to achieve a steady state, and wherein one or more steady state pharmacokinetic characteristics chosen from an average clearance rate (CL SS ) of about 282 mL/day, an average apparent volume of distribution (V z /F) of about 1 1 L, and an average serum half-life of about 28 days is achieved.
- CL SS average clearance rate
- V z /F average apparent volume of distribution
- a sufficient number of SC doses of about 100 mg are administered at about 14-day (bi-weekly) intervals to achieve a steady state, and wherein one or more steady state pharmacokinetic characteristics chosen from: a T max ss of about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, or about 7 days, a C m ax ss of about 30, about 32, about 34, about 36, about 38, about 40, about 42, about 44, about 46, about 48, or about 50 g/mL, an AUC T ss of about 420 , about 430, about 440, about 450, about 460, about 470, about 480, about 490, about 500, about 510, about 520, about 530, about 540, about 550, about 560, or about 570 ⁇ g day/mL, and a Ctroug ss of about 20, about 21 , about 22, about 23,
- a sufficient number of SC doses of about 100 mg are administered at about 14-day (bi-weekly) intervals to a population of subjects to achieve a steady state, and wherein one or more steady state pharmacokinetic characteristics chosen from: an average T max S s of about 4 days, an average C ma x ss of about 39 g/mL, an average AUC T S s of about 495 ⁇ g day/mL, and a Ctroug ss of about 30 ⁇ g/mL is achieved.
- a sufficient number of SC doses of about 100 mg are administered at about 14-day (bi-weekly) intervals to achieve a steady state, and wherein one or more steady state pharmacokinetic characteristics chosen from: a clearance rate (CL SS /F) of about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 235, or about 240 mL/day, an apparent volume of distribution (V z /F) of about 6 of less, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10 L, and a serum half-life of about 18, about 20, about 22, about 24, about 26, about 28, about 30, about 32, about 34, about 36, or about 38 days is achieved.
- CL SS /F clearance rate
- V z /F apparent volume of distribution
- a sufficient number of SC doses of about 100 mg are administered at about 14-day (bi-weekly) intervals to a population of subjects to achieve a steady state, and wherein one or more steady state pharmacokinetic characteristics chosen from an average clearance rate (CL SS ) of about 406 mL/day, an average apparent volume of distribution (V z /F) of about 8 L, and an average serum half-life of about 28 days is achieved.
- CL SS average clearance rate
- V z /F average apparent volume of distribution
- a sufficient number of SC doses of about 100 mg are administered at about 30-day (monthly) intervals to achieve a steady state, and wherein one or more steady state pharmacokinetic characteristics chosen from: a T max ss of about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, or about 8 days, a Cmax ss of about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21 , about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31 , about 32, about 33, or about 34 g/mL, an AUC T S s of about 325, about 350, about 375, about 400, about 425, about 450, about 475, about 500, about 525, about 550, about 575, about 600, about 625, or about 650 ⁇ g day/mL, and a C tr oug ss of about 6, about 6.5, about 7, about 7.5,
- a sufficient number of SC doses of about 100 mg are administered at about 30-day (monthly) intervals to a population of subjects to achieve a steady state, and wherein one or more steady state pharmacokinetic characteristics chosen from: an average T max S s of about 6 days, an average C ma x ss of about 49 g/mL, an average AUC T S s of about 483 ⁇ g day/mL, and a C tr oug ss of about 1 1 ⁇ g/mL is achieved.
- a sufficient number of SC doses of about 100 mg are administered at about 30-day (monthly) intervals to achieve a steady state, and wherein one or more steady state pharmacokinetic characteristics chosen from: a clearance rate (CL SS /F) of about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290, about 300, or about 310 mL/day, an apparent volume of distribution (V z /F) of about 5, about 6, about 7, about 8, about 9, about 10, about 1 1 , about 12, about 13, about 14, about 15, about 16, or about 17 L, and a serum half-life of about 18 , about 20, about 22, about 24, about 26, about 28, about 30, about 32, about 34, about 36, about 38, about 40, about 42, about 44, about 46, or about 48 days is achieved.
- CL SS /F clearance rate
- V z /F apparent volume of distribution
- a sufficient number of SC doses of about 100 mg are administered at about 30-day (monthly) intervals to a population of subjects to achieve a steady state, and wherein one or more steady state pharmacokinetic characteristics chosen from an average clearance rate (CL SS ) of about 227 mL/day, an average apparent volume of distribution (V z /F) of about 1 1 L, and an average serum half-life of about 33 days is achieved.
- CL SS average clearance rate
- V z /F average apparent volume of distribution
- the term "pharmacodynamic characteristics" includes parameters describing the biological effects of an administered drug, e.g., an anti-IFN-alpha antibody such as sifalimumab or an antigen-binding fragment thereof.
- an anti-IFN-alpha antibody such as sifalimumab or an antigen-binding fragment thereof.
- One such characteristic is the expression of specific genes, which can serve as PD markers.
- certain genes when overexpressed in a patient suffering from an autoimmune disease relative to the genes' expression in a healthy patient, or relative to the abundance of housekeeping genes, can serve as a type I IFN or IFN-alpha-inducible PD marker expression profile.
- the group of genes included in the type I IFN or IFN-alpha-inducible PD marker expression profile of the patient are (a) IFI27, IFI44, IFI44L, IFI6 and RSAD2; or (b) IFI44, IFI44L, IFI6 and RSAD2; or (c) IFI27, IFI44L, IFI6 and RSAD2; or (d) IFI27, IFI44, IFI6 and RSAD2; or (e) IFI27, IFI44, IFI44L, and RSAD2; or (f) IFI27, IFI44, IFI44L, and IFI6.
- the group of genes included in the type I IFN or IFN-alpha-inducible PD marker expression profile of the patient comprises IFI27, IFI44, IFI44L, IFI6 and RSAD2.
- the group of genes included in the type I IFN or IFN-alpha-inducible PD marker expression profile of the patient consists of IFI27, IFI44, IFI44L, IFI6 and RSAD2.
- the group of genes included in the type I IFN or IFN-alpha- inducible PD marker expression profile of the patient comprises IFI27, IFI44, IFI44L, and RSAD2.
- the group of genes included in the type I IFN or IFN-alpha-inducible PD marker expression profile of the patient consists of IFI27, IFI44, IFI44L, and RSAD2.
- the IFN-alpha-inducible PD markers in an expression profile may include (a) IFI27, IFI44, IFI44L, IFI6 and RSAD2; or (b) IFI44, IFI44L, IFI6 and RSAD2; or (c) IFI27, IFI44L, IFI6 and RSAD2; or (d) IFI27, IFI44, IFI6 and RSAD2; or (e) IFI27, IFI44, IFI44L, and RSAD2; or (f) IFI27, IFI44, IFI44L, and IFI6.
- the IFN-alpha-inducible PD markers in an expression profile may consist of (a) IFI27, IFI44, IFI44L, IFI6 and RSAD2; or (b) IFI44, IFI44L, IFI6 and RSAD2; or (c) IFI27, IFI44L, IFI6 and RSAD2; or (d) IFI27, IFI44, IFI6 and RSAD2; or (e) IFI27, IFI44, IFI44L, and RSAD2; or (f) IFI27, IFI44, IFI44L, and IFI6.
- An alternative set of genes that may serve as PD markers includes the 21 genes IFI44, IFI27, IFI44L, DNAPTP6, LAMP3, LY6E, RSAD2, HERC5, IFI6, ISG15, OAS3, SIGLEC1 , OAS2, USP18, RPT4, IFIT1 , MX1 , OAS1 , EPST1 , PLSCR1 , and IFRG28, as described in U.S. Patent Application 12/598, 526, file May 5, 2008. See Table 24 following paragraph [0500].
- the upregulation or downregulation of the type I IFN or IFN-alpha- inducible PD markers in the patient's expression profile may be by any degree relative to that of a sample from a control (which may be from a sample that is not disease tissue of the patient (e.g., non-lesional skin of a psoriasis patient) or from a healthy person not afflicted with the disease or disorder) or may be relative to that of genes from the patient whose expression is not changed by the disease (so called "house keeping" genes.)
- the degree upregulation or downregulation may be at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85, at least 90%, at least 95%, at least 100%, at least 125%, at least 150%, or at least 200%, or at least 300%, or at least 400%, or at least 500% or more that of the control or control sample.
- Type I IFN or IFN-alpha-inducible PD marker expression profile may be calculated as the average fold increase in the expression or activity of the set of genes comprised by the PD marker.
- the Type I IFN or IFN-alpha-inducible PD marker expression profile may also be calculated as the difference between the mean Ct (cycle threshold) for the four target genes and the mean Ct of three control genes.
- the average fold increase in the expression or activity of the set of genes may be between at least about 2 and at least about 15, between at least about 2 and at least about 10, or between at least about 2 and at least about 5.
- the average fold increase in the expression or activity of the set of genes may be at least about 2, at least about 2.5, at least about 3, at least about 3.5, at least about 4, at least about 4.5, at least about 5, at least about 5.5, at least about 6, at least about 6.5, at least about 7, at least about 8, at least about 9 or at least about 10.
- the degree of increased expression permits the identification of a fold change cutoff for identifying signature positive and signature negative patients suffering from autoimmune diseases.
- the cutoff is at least about 2. In another embodiment, the cutoff is at least about 2.5. In another embodiment, the cutoff is at least about 3. In another embodiment, the cutoff is at least about 3.5. In another embodiment, the cutoff is at least about 4. In another embodiment, the cutoff is at least about 4.5. In another embodiment, the cutoff is chosen from at least 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1 , 4.2, 4.3, 4.4, and 4.5. In another embodiment the cutoff is between about 2 and about 8.
- the cutoff is the mean of the increased expression levels of at least four of IFI27, IFI44, IFI44L, IFI6 and RSAD2. In another embodiment, the cutoff is the median of the increased expression levels of at least four of IFI27, IFI44, IFI44L, IFI6 and RSAD2.
- the degree of increased expression also permits the identification of a delta Ct cutoff for identifying signature positive and signature negative patients suffering from autoimmune diseases.
- the cutoff is at least about 7.6.
- the cutoff is 7.56.
- the fold change cutoff may be used to determine an appropriate delta C t cutoff (e.g., 1 ⁇ log2 of the fold change ⁇ 3 corresponds to delta Ct range of 8.65 to 6.56.).
- the delta Ct cutoff is between about 6.56 to about 8.56.
- the patient may overexpress or have a tissue that overexpresses a type I IFN subtype at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 90%, at least 100%, at least 125%, at least 150%, or at least 200%, or at least 300%, or at least 400%, or at least 500% that of the control.
- the type I IFN subtype may be any one of IFNalphal, IFNalpha2, IFNalpha4, IFNalpha5, IFNalpha6, IFNalpha7, IFNalpha8, IFNalphalO, IFNalphaH, IFNalphaH, IFNalpha21, IFNbeta, or IFNomega.
- the type I IFN subtypes may include all of IFNalphal, IFNalpha2, IFNalpha8, and IFNalphaH.
- the up-regulated expression or activity of any gene detected in a sample, by probes, or by probes in kits in an IFN-alpha-inducible PD marker expression profile may be at least 1 .2-fold, at least 1 .25-fold, at least 1 .3-fold, at least 1 .4- fold, at least 1 .5-fold, at least 2.0-fold, at least 2.25-fold, at least 2.5-fold, at least 2.75-fold, at least 3.0-fold, at least 3.5-fold, at least 4.0-fold, at least 4.5-fold, at least 5.0-fold, at least 6.0-fold, at least 7.0-fold, at least 8.0-fold, at least 9.0-fold, at least 10.0-fold, at least 15.0-fold, at least 20.0-fold, at least 25.0-fold, or at least 50.0-fold relative to baseline levels of control cells, e.g., cells of healthy volunteers or cells of control animals or cells not exposed to IFN in culture. All of the genes in the IFN-alpha-in
- Up- or down-regulation of gene expression or activity of IFN-alpha- inducible PD markers may be determined by any means known in the art. For example, up- or down-regulation of gene expression may be detected by determining mRNA levels. mRNA expression may be determined by northern blotting, slot blotting, quantitative reverse transcriptase polymerase chain reaction, or gene chip hybridization techniques. See U.S. Pat. Nos. 5,744,305 and 5,143,854 for examples of making nucleic acid arrays for gene chip hybridization techniques.
- Primers that selectively bind to targets in polymerase chain reactions can be chosen based on empirically determining primers that hybridize in a PCR reaction and produce sufficient signal to detect the target over background, or can be predicted using the melting temperature of the primentarget duplex as described in Maniatis et al. Molecular Cloning, Second Edition, Section 1 1 .46. 1989. Similarly, probes for detecting PCR products in a TAQMAN® or related method can be empirically chosen or predicted. Such primers and probes (collectively “oligonucleotides”) may be between 10 and 30 nucleotides or greater in length.
- Up- or down-regulation of gene expression or activity of IFN-alpha- inducible PD markers may be determined by detecting protein levels.
- Methods for detecting protein expression levels include immuno-based assays such as enzyme-linked immunosorbant assays, western blotting, protein arrays, and silver staining.
- An IFN-alpha-inducible PD marker expression profile may comprise a profile of protein activity. Up- or down-regulation of gene expression or activity of IFN-alpha-inducible PD markers may be determined by detecting activity of proteins including, but not limited to, detectable phosphorylation activity, de- phosphorylation activity, or cleavage activity. Furthermore, up- or down- regulation of gene expression or activity of IFN-alpha-inducible PD markers may be determined by detecting any combination of these gene expression levels or activities.
- Treatment with the anti-IFN-alpha antibody or antigen-binding fragment thereof neutralizes the type I IFN or IFN-alpha-inducible profile. Treatment with the anti-IFN-alpha antibody or antigen-binding fragment thereof results in a decrease in one or more symptoms of the type I IFN or an IFN-alpha-mediated disease or disorder. Treatment with the anti-IFN-alpha antibody or antigen- binding fragment thereof results in fewer flare-ups related to the type I IFN or an IFN-alpha-mediated disease or disorder. Treatment with the anti-IFN-alpha antibody or antigen-binding fragment thereof results in improved prognosis for the patient having the type I IFN or an IFN-alpha-mediated disease or disorder.
- Treatment with the anti-IFN-alpha antibody or antigen-binding fragment thereof results in a higher quality of life for the patient.
- Treatment with the anti-IFN-alpha antibody or antigen-binding fragment thereof alleviates the need to co-administer second agents (e.g., steroids) or may lessen the dosage of administration of the second agent to the patient.
- Treatment with the anti-IFN-alpha antibody or antigen-binding fragment thereof reduces the number of hospitalizations of the patient that are related to the type I IFN or an IFN-alpha-mediated disease or disorder.
- the anti-IFN-alpha antibody or antigen-binding fragment thereof neutralizes a type I IFN or IFN-alpha-inducible profile.
- Neutralization of the type I IFN or IFN-alpha-inducible profile may be a reduction in at least one, at least two, at least three, at least four genes.
- Neutralization of the type I IFN or IFN-alpha- inducible profile is a reduction of at least 2%, at least 3%, at least 4%, at least 5%, at least 7%, at least 8%, at least 10%, at least 15%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, or at least 90% of any of the at least one, at least two, at least three, at least four genes up-regulated in the type I IFN or IFN- alpha-inducible profile.
- neutralization of the type I IFN or IFN-alpha-inducible profile refers to a reduction of expression of up-regulated type I IFN or IFN-alpha- inducible genes that is within at most 50%, at most 45%, at most 40%, at most 35%, at most 30%, at most 25%, at most 20%, at most 15%, at most 10%, at most 5%, at most 4%, at most 3%, at most 2%, or at most 1 % of expression levels of those type I IFN or IFN-alpha-inducible genes in a control sample.
- the anti-IFN-alpha antibody or fragment thereof may neutralize the type I IFN or IFN- alpha profile at doses of 0.3 to 30 mg/kg, 0.3 to 10 mg/kg, 0.3 to 3 mg/kg, 0.3 to 1 mg/kg, 1 to 30 mg/kg, 3 to 30 mg/kg, 5 to 30 mg/kg, 10 to 30 mg/kg, 1 to 10 mg/kg, 3 to 10 mg/kg, or 1 to 5 mg/kg.
- the type I IFN or IFN-alpha profile is neutralized by about 40% when sifalimumab is administered with weekly, subcutaneous dosing of 100 mg.
- inclusion criteria comprise: Male or female adults were between about 18 and about 95 years of age at the time of the first dose of study drug; subjects met at least 4 of the 1 1 revised American College of Rheumatology classification criteria for SLE (Appendix A, ACR,1999); subjects had positive anti-nuclear antibody (ANA) test at ⁇ 1 :80 serum dilution in the past or at screening; and subjects had at least one system with a score of A or two systems with a score of B on the BILAG index at screening, or had a SELENA- SLEDAI score ⁇ 6.
- Exclusion criteria comprised having received MEDI-545 within 120 days prior to screening or have either detectable levels of MEDI-545 or anti-MEDI-545 antibodies (positive at > 1 :10 serum dilution) in serum at screening; history of allergy or reaction to any component of the study drug formulation; have received prednisone > 20 mg/day (or an equivalent dose of another oral corticosteroid)within 14 days before randomization/entry; having received the following dosages of medications within 28 days before randomization/entry: hydroxychloroquine > 600 mg/day, mycophenolate mofetil > 3 g/day, methotrexate > 25 mg/week, azathioprine > 3 mg/kg/day, or any dose of cyclophosphamide, cyclosporine, or thalidomide; having received leflunomide >20 mg/day in the 6 months prior to Study Day 0; having received fluctuating doses of antimalarials, mycophenolate mofetil, methotrex
- inclusion and exclusion criteria listed above are not intended to limit the scope of the present disclosure. A person skilled in the art would understand that other inclusion and/or exclusion parameters may be used to generate a subject population such that the choice of subject does not compromise the safety of the subject or confounds the analysis of the study.
- Trough serum samples were collected for PK concentrations and IM titers at multiple time points. Samples were analyzed for PK using a validated enzyme linked immunosorbent assays (ELISA) and for IM using a validated bridging electrochemiluminescent assay (ECL).
- ELISA enzyme linked immunosorbent assays
- ECL bridging electrochemiluminescent assay
- Serum samples were measured for the presence of anti-sifalimumab antibodies using a colorimetric bridging ELISA. Serum samples were diluted 1 : 10 and were added to a microtiter plate coated with sifalimumab. Following a wash step, biotinylated- sifalimumab was added to bind the captured anti-sifalimumab antibodies. Plates were washed and streptavidin conjugated with horseradish peroxidase was added, followed by tetramethylbenzidine substrate for detection of bridged complexes.
- the assay employed three positive controls ranging from 15 to 1500 ng/mL and one negative spiked control (0.75 ng/mL) that were prepared by adding goat anti-sifalimumab anti-idiotypic antibody into pooled normal human serum.
- the negative/positive cutoff value for samples was determined for each assay plate and was calculated by multiplying the mean value of six unique human serum samples measured on the plate by 1 .5. Samples with responses below the plate cutoff value were classified as negative and were assigned a titer value of ⁇ 10, (less than the reciprocal of the minimum required sample dilution). Samples with responses greater than or equal to the plate cutoff value were classified as positive and were subsequently tested for titer.
- Titers were performed by serially diluting samples with pooled normal human serum matrix and were reported as the reciprocal of the highest 1 :2 dilution (over the 1 :10 minimum required sample dilution) that measured positive in the assay, before returning a negative response.
- Method validation met the acceptance criteria for accuracy and precision of classification and titer, intermediate precision, repeatability, robustness, linearity of dilution, specificity of detection, analyte stability in human serum and selectivity in normal human and SLE patient serum samples.
- the estimated concentration of the cutoff of the assay was determined to be 4.5 ng/mL using the polyclonal goat anti-sifalimumab antibody surrogate control. Concentrations of 500 ng/mL anti-sifalimumab antibody (but not 100 ng/mL) were detectable in serum samples containing 100 ng/mL sifalimumab drug.
- Sifalimumab was measured in human serum samples using a colorimetric ELISA method that was validated for human serum.
- assay microtiter plates were coated with 0 ⁇ g/mL goat anti-sifalimumab idiotype antibody, blocked with casein buffer and washed.
- Calibration standards 0.3 to 160 g/mL
- control samples were prepared by diluting sifalimumab reference standard into human serum Standards, controls and unknown samples were diluted 1 : 1000 in assay buffer that contained 0.5% casein and 5% goat serum and were added to the plate at 50 ⁇ - ⁇ /vell.
- Method validation demonstrated acceptable accuracy, repeatability, intermediate precision, selectivity (evaluated in serum samples from normal humans and humans with SLE), specificity, dilutional linearity, robustness, and stability of sifalimumab in human serum. Quantitation of sifalimumab at levels of 3.0 and 36.0 ⁇ g/mL was not affected in the presence of 2 ng/mL interferon alpha target.
- the plate was then washed to remove unbound materials, read buffer was added and the plate was placed on the MSD SectorTM Imager for generation and measurement of ECL response.
- Application of an electrical current to the electrode-containing plate caused the ruthenium chelate conjugated to sifalimumab to emit light in the presence of the tripropylamine-containing read buffer.
- Samples that contained ADA bound to both biotin and ruthenium conjugated forms of sifalimumab generated ECL signals.
- the signal intensity, measured by the MSD Sector Imager was proportional to the amount of anti- sifalimumab antibodies present in the sample.
- the method employed pooled normal human serum as the negative control and pooled normal human serum spiked with a goat anti-sifalimumab idiotype antibody (surrogate control) at two levels above detection (3.0 and 1000 ng/mL) as positive controls.
- the presence of anti- sifalimumab antibodies was determined relative to a cutoff ECL value that was calculated for each plate as the mean response of 6-8 wells of the negative control multiplied by a 1 .18 cut point factor.
- the 1 .18 cut point factor was established during validation from 200 measurements of serum samples obtained from 50 normal individuals and was statistically determined to provide a 5% false positive rate.
- the confirmatory cut point was established during method validation using the percent inhibition measurements of the above-mentioned samples tested both in the absence and presence of excess (300 ⁇ g/mL) sifalimumab.
- the confirmatory cut point was statistically determined to provide a 0.1 % false positive rate and was determined to be 27.0%.
- the screening cut point factor and confirmatory cut point for SLE serum samples were evaluated using the measured values of serum samples from fifty individual SLE patients and were calculated to be 1 .23% and 37.1 %, respectively.
- Study samples were considered positive for anti-sifalimumab antibodies if the percent inhibition of response in the presence of excess sifalimumab was greater than or equal to 27%, the more conservative confirmatory cut point. Confirmed positive samples were then measured in a titer assay.
- the approximate concentration of anti- sifalimumab antibody at the cut point was 0.2 ng/mL for the polyclonal antibody and 4.7 ng/mL for the monoclonal antibody.
- Monoclonal anti-sifalimumab antibody levels of 250-500 ng/mL and polyclonal anti-sifalimumab antibody levels of 500 ng/mL were detectable in serum containing 100 ⁇ g/mL of sifalimumab. (provide temperature at which experiments were conducted).
- Serum sifalimumab PK results following the first dose and after the last dose on Day 182 are summarized in TABLE 2 and TABLE 3, respectively.
- sifalimumab peak plasma concentration (C ma x) area under the plasma concentration-time curve from time zero to end of dosing interval (AUC T ) and trough concentration (Ct r0 ugh) increased dose-proportionally (TABLE 2).
- C ma x values ranged from 1 0.90 ⁇ g/mL for the 0.3 mg/kg dosage to 229.74 ⁇ g/mL for the 1 0 mg/kg dosage.
- AUC T values ranged from 79.39 ⁇ g.day/mL for the 0.3 mg/kg dosage to 1 ,61 0 ⁇ g.day/mL for the 1 0 mg/kg dosage.
- C tr oug values ranged from 2.75 ⁇ g/mL for the 0.3 mg/kg dosage to 51 .52 ⁇ g/mL for the 1 0 mg/kg dosage.
- Steady state peak plasma concentration (Cmax ss) values ranged from 1 7.74 ⁇ g/mL for the 0.3 mg/kg dosage to 441 .79 ⁇ g/mL for the 1 0 mg/kg dosage.
- Steady state area under the plasma concentration-time curve within a dosing interval (AUC T S s) values ranged from 1 43.2 ⁇ g.day/mL for the 0.3 mg/kg dosage to 3,403 ⁇ g.day/mL for the 1 0 mg/kg dosage.
- Steady state trough concentration (Ctrough ss) values ranged from 7.89 ⁇ g/mL for the 0.3 mg/kg dosage to 1 83.97 ⁇ g/mL for the 1 0 mg/kg dosage.
- Sifalimumab PK was linear and dose-proportional following intravenous administration over the dose range of 0.3 mg/kg to 10 mg/kg. Serum clearance, volume of distribution and terminal half-life of sifalimumab were representative of a monoclonal antibody without a significant antigen sink. The overall incidence of anti-sifalimumab antibodies was 22% with positive titers ranging from 10 to 1280. The presence of anti-sifalimumab antibody did not have an impact on the pharmacokinetics of sifalimumab.
- the primary objectives of this analysis were to (a) model the population pharmacokinetics (PK) of sifalimumab; (b) to identify and quantitate the impact of patient/disease characteristics on PK variability; and (c) to evaluate fixed versus body weight based dosing regimens.
- PK pharmacokinetics
- Sifalimumab serum concentration-time data were collected from the study described in Example 1 .
- Sifalimumab serum concentrations were determined with the validated colorimetric ELISA described in Example 1 .
- a nonlinear mixed-effect modeling approach was used to analyze sifalimumab pharmacokinetic data.
- the population pharmacokinetic modeling was performed using NONMEM Version VII software (Globomax LLC, Ellicott City, MD, USA), G- Fortran (http://gcc.gnu.org/fortran/) and Perl-speaks-NONMEM (PSN) (http://psn.sourceforge.net/).
- a series of structural models were evaluated for sifalimumab based on Akaike information criteria (AIC) value, objective function values, precision, plausibility of parameter estimates, and goodness-of-fit plots.
- AIC Akaike information criteria
- the between- subject variability in pharmacokinetic parameters was assumed to follow a log- normal distribution and was modeled using exponential functions.
- the residual variability was evaluated using homoscedastic (additive), heteroscedastic (proportional), or combined proportional and additive models.
- the precision of the population estimates was evaluated based on percent relative standard errors (RSEs).
- a preliminary assessment of covariate influence was conducted using generalized additive modeling (GAM) approach as implemented in Xpose (Jonsson et al, 1999). Based on GAM results and mechanistic understanding of sifalimumab disposition, the relevant covariates for each parameter were further tested using NONMEM for their significance.
- the model building was carried out using step-wise forward addition (p ⁇ 0.05) (AOFV > 3.84), approach followed by backward elimination (p ⁇ 0.01 ) (AOFV > 6.63) process.
- the covariates were included in the final model if p-value ⁇ 0.01 (AOFV > 6.63), provided the covariates were reasonable based on the pharmacology of sifalimumab.
- Improvement in the model at each step was assessed using following criteria: (a) reduction in objective function value; (b) improvement in agreement between the observed and population/individual predicted serum concentrations; (c) reduction in between and within-subject variability; (d) reduction in the range of weighted residuals; (e) uniformity of the distribution of weighted residuals versus the predicted concentrations around the line of identity; and (f) improvement in parameter precision. All models were run using the first order conditional estimation (FOCE) with interaction method.
- FOCE first order conditional estimation
- ⁇ 1 represents the typical value of pharmacokinetic parameter (P) in an individual with the median value for the covariate.
- ⁇ 2 represents the coefficient for particular covariate effect.
- VPC visual predictive check
- a total of 120 patients provided evaluable PK data with a total of 2,370 serum concentrations (average of 20 samples per patient).
- One subject from the 10 mg/kg cohort was excluded from the analysis due to very low observed serum concentrations compared to the average concentrations in the 10 mg/kg cohort.
- TABLE 4 lists the summary of patient characteristics included in the pharmacokinetic database.
- a total of 8 subjects (6.67%) did not have baseline gene signature (4 genes) information available; hence a population median value was imputed for these subjects.
- a 2-compartment model was used to fit sifalimumab concentration-time data.
- the model was parameterized using clearance (CL), central volume of distribution (V c ), peripheral volume of distribution (V p ) and the inter- compartmental clearance (Q).
- CL clearance
- V c central volume of distribution
- V p peripheral volume of distribution
- Q inter- compartmental clearance
- the multiplicative covariate modeling approach was used to study the influence of various covariates including age, gender, ethnicity, region, WT, BSTEROID, BSLEDAI, BGENE21 and BGENE4.
- BGENE21 32
- Dose 1 mg/kg
- BSTEROID 0
- ⁇ 5 to ⁇ 10 are the exponents of covariate effect on respective pharmacokinetic parameters.
- the final population pharmacokinetic parameters are presented in TABLE 5.
- the estimated values of CL, V c , V p and Q for a standard subject were about 176 mL/day, 2.9 L, 2.12 L and 171 mL/day, respectively.
- the estimates of between-subject variability (CV S ) associated with CL, V c , V p and Q were 28%, 31 %, 58% and 71 %, respectively. All of the pharmacokinetic parameters were estimated with good precision, as reflected by RSEs.
- the performance of the final model fit is represented by goodness of fit plots as shown in FIG. 5.
- FIG.5 panels (a) and (b) show good agreement between observed and model predicted (population/individual predicted) sifalimumab serum concentrations, as all the points are close to the line of identity and the fitted spline curve almost overlap the line of identity.
- the plots of weighted residual versus the population predicted concentrations, FIG. 5 panel (c), or time, FIG. 5 panel (d), do not show any obvious pattern.
- VPC results demonstrated good predictability of the final population PK model as shown in FIG. 6.
- the final population PK model was used to predict PK profiles following 200, 600, and 1200 mg monthly (with an additional dose at Day 14) dose of sifalimumab in a simulated SLE population of 1000 subjects.
- the predicted PK profiles (median, 5th and 95th percentiles) are shown in FIG 8.
- the expected steady state PK parameters following 200, 600, and 1200 mg monthly (with an additional dose at Day 14) dose of sifalimumab are presented in TABLE 6.
- CL Linear clearance
- V c Central volume of distribution
- V p Peripheral volume of distribution
- Q Inter-compartmental clearance
- BGENE21 Baseline gene signature for 21 genes
- WT Baseline body weight
- CV Coefficient of variance.
- LD Loading dose
- QM Every 28 days.
- Sifalimumab PK was best described using a 2-compartment linear model with first order elimination. Following IV dosing, the typical clearance (CL) and central volume of distribution (V c ) were estimated to be 176 mL/day and 2.9 L, respectively. The estimates of between-subject variability for CL and V c were 28% and 31 %, respectively. Patient baseline body weight, IFN gene signature (21 genes), steroid use and sifalimumab dose were identified as significant covariates for CL, whereas only baseline body weight was significant covariate for V c and V p .
- a population PK model of sifalimumab was developed and validated. The population PK analysis also demonstrated the feasibility of evaluating fixed doses of sifalimumab in phase I I clinical trials.
- PK pharmacokinetics
- IM immunogenicity
- inclusion criteria comprise: Male or female subjects were over 18 years and below 95 years of age at the time of the first dose of study drug; subjects met at least 4 of the 1 1 revised ACR classification criteria for SLE; subjects had positive antinuclear antibody test (ANA) at ⁇ 1 :80 serum dilution documented in the past or at screening; subjects had at least 1 system with a score of A or 2 systems with a score of B on the BILAG index at screening, or have a SELENA-SLEDAI score ⁇ 6; and treatment for SLE with antimalarials, oral prednisone or another systemic corticosteroid, mycophenolate mofetil, methotrexate, leflunomide, azathioprine, or dapsone.
- Exclusion Criteria comprised: having received MEDI-545 within 120 days prior to screening; history of allergy or reaction to any component of the study drug formulation; having received the following medications within 28 days before randomization: systemic cyclophosphamide at any dose, cyclosporine at any dose, thalidomide at any dose, hydroxychloroquine > 600 mg/day, mycophenolate mofetil > 3 g/day, methotrexate > 25 mg/week, azathioprine > 3 mg/kg/day; having received fluctuating doses of the following within 28 days before randomization: antimalarials, mycophenolate mofetil, methotrexate, leflunomide, azathioprine, dapsone; having received leflunomide > 20mg/day in the 6 months prior to Study Day 0; having received prednisone > 20 mg/day or in fluctuating doses within 14 days before randomization; having received fluctuating doses of non-steroidal anti-inflammatory drugs within 14 days before
- inclusion and exclusion criteria listed above are not intended to limit the scope of the present disclosure. A person skilled in the art would understand that other inclusion and/or exclusion parameters may be used to generate a subject population such that the choice of subject does not compromise the safety of the subject or confounds the analysis of the study.
- Patients were administered up to 13 doses of either sifalimumab or placebo. Placebo was administered to 22 patients. Eleven patients received a single SC 100 mg fixed dose of sifalimumab. Twenty-one patients received a monthly SC 100 mg fixed dose of sifalimumab, with the last dose being administered on Day 84. Twenty-three patients received biweekly SC 100 mg fixed doses of sifalimumab, with the last dose being administered on Day 84. Ten patients received weekly SC 100 mg fixed doses of sifalimumab, with the last dose being administered on Day 84. Serum samples were collected for PK concentrations and IM titers at multiple time points.
- results corresponding to the administration of multiple 100 mg fixed doses of sifalimumab are summarized in TABLE 8, and FIG. 9 (weekly ⁇ , bi-weekly ⁇ , or monthly T ).
- C ma x ss and Ctroug ss increased with dosing frequency.
- Accumulation of AUC and trough concentrations was 1 1 -and 6-fold, respectively, for weekly administration.
- Steady state AUC for multiple dose groups was similar to AUC after a single dose.
- Mean apparent extravascular steady state clearance (CL SS /F) ranged from 206 to 282 mL/day across the dosing groups.
- Mean half-life ranged from 28 to 33 days.
- Apparent volume of distribution during terminal phase after non-intravenous administration (V z /F) ranged from 8 L to 1 1 L.
- Pharmacodynamics (PD) markers can be used in methods of treating patients with a therapeutic agent that binds to and modulates IFN-alpha activity such as sifalimumab. See, e.g., U.S. Patent Appl. No. 2010-0143372, which is hereby incorporated herein by reference in its entirety.
- Example 7 in the 2010-0143372 publication describes 21 genes that can be used as PD markers: IFI44, IFI27, IFI44L, NAPTP, LAMP3, LY6E, RSAD2, HERC5, IFI6, ISG15, OAS3, RTP4, IFIT1 , MX1 , SIGLEC1 , OAS2, USP18, OAS1 , EPSTI1 , PLSCR1 and IFRG28. Additionally, the 2010-0143372 publication provides methods for how to measure the levels of these 21 gene markers, e.g., Affymetrix arrays and Fluidigm dynamic arrays.
- Missing Missing Missing Missing 58.5 Missing 50.5 40.3 39.5 56.2 59.6 Missing
- Missing Missing Missing Missing 85.858 Missing 87.376 123.078 160.702 113.038 105.993 Missing
- Missing Missing Missing 96.182 Missing 95.198 358.791 381.682 181.495 155.792 Missing
- Missing Missing 1 20
- Missing Missing 20 Missing 19 7.353 Missing Missing 3.830
- 5.156 2.173 Missing Missing 1.283 Missing 0.208 3.293 Missing Missing Missing 2.264 1.822 Missing Missing 1.411 Missing 0.665 0.00 Missing Missing 3.83 2.09 0.00 Missing Missing 0.00 Missing 0.00 7.160 Missing Missing 3.830 4.960 1.980 Missing Missing 0.695 Missing 0.000 15.64 Missing Missing 3.83 11.40 5.73 Missing Missing 3.61 Missing 2.67 44.8 Missing Missing Missing 43.9 83.8 Missing Missing 110.0 Missing 319.2
- Missing Missing Missing 22 23 Missing Missing 22 1 21 17.751 Missing Missing Missing 9.783 4.345 Missing Missing 1.725 0.000 1.021 10.906 Missing Missing Missing 5.617 3.610 Missing Missing 1.998 Missing 1.253 0.00 Missing Missing Missing 0.00 0.00 Missing Missing 0.00 0.00 17.665 Missing Missing Missing 10.470 3.520 Missing Missing 1.635 0.000 0.000 46.89 Missing Missing Missing 21.93 14.35 Missing Missing 7.48 0.00 3.83 61.4 Missing Missing Missing 57.4 83.1 Missing Missing 115.8 Missing 122.7
Abstract
Description
Claims
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JP2014512069A JP2014516970A (en) | 2011-05-25 | 2012-05-23 | Methods of treating systemic lupus erythematosus, scleroderma, and myositis with antibodies to interferon-α |
MX2013013785A MX2013013785A (en) | 2011-05-25 | 2012-05-23 | Methods of treating systemic lupus erythematosus, scleroderma, and myositis with an antibody against interferon-alpha. |
BR112013030242A BR112013030242A2 (en) | 2011-05-25 | 2012-05-23 | Method of treating an autoimmune disorder in a human subject |
EP12789521.7A EP2714080A4 (en) | 2011-05-25 | 2012-05-23 | Methods of treating systemic lupus erythematosus, scleroderma, and myositis with an antibody against interferon-alpha |
CA2836926A CA2836926A1 (en) | 2011-05-25 | 2012-05-23 | Methods of treating systemic lupus erythematosus, scleroderma, and myositis with an antibody against interferon-alpha |
KR1020137033960A KR20140043402A (en) | 2011-05-25 | 2012-05-23 | Methods of treating systemic lupus erythematosus, scleroderma, and myositis with an antibody against interferon-alpha |
RU2013157177/15A RU2013157177A (en) | 2011-05-25 | 2012-05-23 | METHODS FOR TREATING SYSTEM RED LUPUS, SCLERODERMA AND MYOSITIS |
CN201280024982.7A CN103732251A (en) | 2011-05-25 | 2012-05-23 | Methods of treating systemic lupus erythematosus, scleroderma, and myositis with an antibody against interferon-alpha |
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BR (1) | BR112013030242A2 (en) |
CA (1) | CA2836926A1 (en) |
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Cited By (7)
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WO2013087911A1 (en) | 2011-12-16 | 2013-06-20 | Synthon Biopharmaceuticals B.V. | Compounds and methods for treating inflammatory diseases |
WO2013101771A3 (en) * | 2011-12-30 | 2013-10-10 | Genentech, Inc. | Compositions and method for treating autoimmune diseases |
CN103740755A (en) * | 2013-12-23 | 2014-04-23 | 中国农业大学 | Application of IFIT1 gene of pig in resisting PRRS (porcine reproductive and respiratory syndrome) virus |
EP3008175A4 (en) * | 2013-06-15 | 2016-11-30 | Tocagen Inc | Immunosuppressive components associated with retroviral replicating vectors |
WO2020074723A1 (en) * | 2018-10-11 | 2020-04-16 | Vivia Biotech Sl | A method for determining the efficacy of treatment with a combination of drugs in a subject diagnosed with a disease and a method for classifying the utility of drug combinations in treatment of said subject |
US20200317771A1 (en) * | 2019-04-04 | 2020-10-08 | Janssen Biotech, Inc. | Method of Administration of an Anti-IFN-alpha/-omega Antibody |
EP3873523A4 (en) * | 2018-10-26 | 2022-08-10 | Janssen Biotech, Inc. | Type i interferon signatures and methods of use |
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RU2580301C1 (en) * | 2015-04-21 | 2016-04-10 | Людмила Николаевна Хон | Method for treatment of human systemic lupus erythematosus |
CN107058521B (en) * | 2017-03-17 | 2019-12-27 | 中国科学院北京基因组研究所 | Detection system for detecting human body immunity state |
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Cited By (10)
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WO2013087911A1 (en) | 2011-12-16 | 2013-06-20 | Synthon Biopharmaceuticals B.V. | Compounds and methods for treating inflammatory diseases |
US9573996B2 (en) | 2011-12-16 | 2017-02-21 | Synthon Biopharmaceuticals B.V. | Monoclonal antibodies to human proinflammatory cytokines and methods for treating inflammatory diseases |
US9580501B2 (en) | 2011-12-16 | 2017-02-28 | Synthon Biopharmaceuticals B.V. | Anti-TNF alpha monoclonal secretory IgA antibodies and methods for treating inflammatory diseases |
WO2013101771A3 (en) * | 2011-12-30 | 2013-10-10 | Genentech, Inc. | Compositions and method for treating autoimmune diseases |
EP3008175A4 (en) * | 2013-06-15 | 2016-11-30 | Tocagen Inc | Immunosuppressive components associated with retroviral replicating vectors |
CN103740755A (en) * | 2013-12-23 | 2014-04-23 | 中国农业大学 | Application of IFIT1 gene of pig in resisting PRRS (porcine reproductive and respiratory syndrome) virus |
WO2020074723A1 (en) * | 2018-10-11 | 2020-04-16 | Vivia Biotech Sl | A method for determining the efficacy of treatment with a combination of drugs in a subject diagnosed with a disease and a method for classifying the utility of drug combinations in treatment of said subject |
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EP3873523A4 (en) * | 2018-10-26 | 2022-08-10 | Janssen Biotech, Inc. | Type i interferon signatures and methods of use |
US20200317771A1 (en) * | 2019-04-04 | 2020-10-08 | Janssen Biotech, Inc. | Method of Administration of an Anti-IFN-alpha/-omega Antibody |
Also Published As
Publication number | Publication date |
---|---|
CA2836926A1 (en) | 2012-11-29 |
MX2013013785A (en) | 2014-07-28 |
EP2714080A1 (en) | 2014-04-09 |
EP2714080A4 (en) | 2014-11-19 |
JP2014516970A (en) | 2014-07-17 |
BR112013030242A2 (en) | 2016-12-06 |
CN103732251A (en) | 2014-04-16 |
RU2013157177A (en) | 2015-06-27 |
KR20140043402A (en) | 2014-04-09 |
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