JP2014516970A - Methods of treating systemic lupus erythematosus, scleroderma, and myositis with antibodies to interferon-α - Google Patents

Abstract

  The present invention relates to a method of treating systemic lupus erythematosus, scleroderma, and myositis comprising administering an anti-interferon-α antibody. In particular, the present invention provides weight based dosage and fixed dose regimens based on pharmacokinetic properties. Further disclosed are the sequences of the complementarity determining regions (CDRs) of the heavy and light chain variable regions of an antibody. The present invention also provides a method of suppressing an interferon (IFN) pharmacodynamic signature.

Description

  The present invention provides methods of treating autoimmune diseases such as systemic lupus erythematosus, scleroderma, and myositis with anti-IFN-α antibodies.

  Type I interferons (IFN) (IFN-α, IFN-β, IFN-ω, IFN-τ) are a family of structurally related cytokines that have antiviral, antitumor, and immunomodulatory effects (Hardy et al. al. (2001) Blood 97: 473; Cutrone and Langer (2001) J. Biol. Chem. 276: 17140). The human IFN-α locus includes two subfamilies. The first subfamily consists of at least 14 non-allelic genes and 4 pseudogenes with at least 75% homology. The second subfamily, α-II or ω, contains 5 pseudogenes and one functional gene that shows 70% homology with the IFN-α gene. Although the subtypes of IFN-α have different specific activities, they have the same biological spectrum (Strulei et al. (1981) Proc. Natl. Acad. Sci. USA 78: 2848) and the same cell receptor (Agnet M. et al. (1983) in “Interferon 5” Ed. I. Gresser p. 1-22, Academic Press, London).

  In many autoimmune diseases, increased expression of type I interferon has been described (Foulis et al. (1987) Lancet 2: 1423; Hooks et al. (1982) Arthritis Rheum 25: 396; Hertzog et al. (1988). ) Clin. Immunol.Immunopathol.48: 192; Hopkins and Meager (1988) Clin.Exp.Immunol.73: 88; Arvin and Miller (1984) Arthritis Rheum.27: 582). This best studied example is insulin dependent diabetes mellitus (IDDM) (Foulis (1987) supra), systemic lupus erythematosus (SLE) (Hooks (1982) supra; all associated with elevated IFN-α levels; Blanco et al. (2001) Science 294: 1540; Ytterberg and Schnitzer (1982) Arthritis Rheum. 25: 401; Batteux et al. (1999) Eur. 2003) Thyroid 13: 547; Mazziotti et al. (2002) J. Endocrinol.Invest. 25: 624; al. (1999) Chin.Med.J. 112: 61; Koh et al. (1997) Thyroid 7: 891), all of which are associated with increased levels of IFNα, in which IFN-β is more important Rheumatoid arthritis (RA) (Hertzog (1988); Hopkins and Meager (1988); Arvin and Miller (1984), supra). For a review of the role of IFN-α in organ-targeted autoimmune and inflammatory diseases, see Crow (2010) Arthritis Res. Ther. 12: See S5.

  Systemic lupus erythematosus (SLE), often referred to as lupus, is a prototypic systemic autoimmune disease. Diseases include systemic symptoms and signs, musculoskeletal, skin, kidney, digestive, lung, heart, reticuloendothelial, hematological and neuropsychiatric manifestations. In SLE, skin manifestations are the most common. A series of evidence suggests that type I interferon (IFN), particularly IFN-α, plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). For a review of the use of anti-cytokine therapy in the treatment of SLE, see Yoo (2010) Lupus 19: 1460.

  Scleroderma or systemic sclerosis (SSC) is a progressive, debilitating autoimmune disorder characterized by excessive protein deposition on the extracellular matrix by dermal fibroblasts, also called dermal fibrosis. is there. Patients with diffuse skin disease often present unique markers in the skin, such as upregulation of type I interferon (IFN) -inducible genes. Supporting the view that IFNs play a role in dermal fibrosis, it has recently been reported that scleroderma has occurred in patients who have received IFN therapy for chronic viral infections. For a review of systemic sclerosis, see Varga & Abraham (2007) J. MoI. Clin. Invest. 117: 557-567. Coelho et al. (2008) Immunol. Lett. See also 118: 110-115.

  Myositis, a general term for muscle inflammation, is a group of conditions that often accompany autoimmune conditions. Types of myositis include, for example, osteomyositis, fibromyositis, (idiopathic) inflammatory myopathy, dermatomyositis, juvenile dermatomyositis, polymyositis, inclusion body myositis, and purulent myositis.

  Administration of IFN-α may exacerbate the underlying disease in patients with psoriasis, autoimmune thyroiditis, and multiple sclerosis and induce SLE-like syndrome in patients with no previous autoimmune disease history It has been reported. Interferon-α has been shown to induce glomerulonephritis in normal mice and accelerate the onset of idiopathic autoimmune disease in NZB / W mice. In addition, IFN-α therapy has been shown to cause undesirable side effects, including fever and neurological disorders in some cases. Thus, there are pathological situations where inhibition of IFN-α activity may be beneficial to the patient, and there is a need for an effective treatment for inhibiting IFN-α activity.

  The present invention provides a method of treating autoimmune diseases, such as SLE, SSC, and myositis, in a human subject comprising administering an anti-interferon alpha antibody. These methods can be used for therapeutic purposes including prophylaxis, for example, in situations where the production or expression of interferon alpha is associated with pathological symptoms. In some embodiments, cifarimumab (MEDI-545), a fully human IgG1 monoclonal antibody under investigation against interferon-α, is used.

In one embodiment, the present invention provides a method of treating an autoimmune disorder in a human subject comprising administering to the subject an antibody that specifically binds human interferon alpha, or an antigen-binding fragment thereof. Following administration, a clearance rate of about 99 to about 432 mL / day (CL, CL _ss , CL / F, or CL _ss / F), an apparent distribution volume of about 3 to about 17 L (V _ss or V _z / F) and one or more pharmacokinetic properties selected from a serum half-life of about 14 to about 48 days are achieved; the autoimmune disorder is systemic lupus erythematosus, scleroderma, or myositis .

  In some embodiments, the antibody or antigen-binding fragment thereof comprises 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. It binds to an epitope on human interferon alpha that is recognized by the antibody. In another embodiment, 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 sequence Heavy chain variable region CDR3 comprising number 7; (d) light chain variable region CDR1 comprising SEQ ID NO: 10; (e) light chain variable region CDR2 comprising SEQ ID NO: 13; and (f) SEQ ID NO: A light chain variable region CDR3 comprising 16; In another embodiment, the antibody or antigen-binding fragment thereof (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; b) comprising 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. In some embodiments, the antibody or antigen-binding fragment thereof is an IgG1 or IgG4 antibody or antigen-binding fragment thereof. In certain embodiments, the antigen binding fragment is a Fab antibody fragment or a single chain antibody (scFv).

  In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dosage that depends on the body weight of the subject. In certain embodiments, such body weight-based dosage ranges from about 0.01 mg / kg to about 100 mg / kg subject body weight. In some embodiments, such body weight based dosage is selected 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.

  In another embodiment, the antibody or antigen-binding fragment thereof is administered as a fixed dose. In certain embodiments, such fixed doses range from about 50 mg to about 2000 mg. In another embodiment, the fixed dose is selected from about 100 mg, about 200 mg, about 600 mg, and about 1200 mg.

  In some embodiments, the antibody or antigen-binding fragment thereof is administered as a single dose, or once a week, once every two weeks, once every three weeks, once every four weeks, once a month Administered in two or more doses once, once every three months, once every six months, or at varying intervals. In some embodiments, the loading dose is administered on day 14.

  In certain embodiments, administration is intravenous, intramuscular, intraperitoneal, intracerebral spinal, subcutaneous, intraarticular, intrasynovial, intrathecal, oral, topical, inhalation, and two or more listed Depending on the route selected from the combination of routes.

In some embodiments, the administration is intravenous (IV) administration. In some embodiments, IV administration is by IV infusion over a period of time. In some embodiments, the time to reach maximum plasma concentration (T _max or T _{max ss} ) following IV administration is about 0.13 days or less. In some embodiments, a single IV administration of about 0.3 mg / kg has a T _max of about 0.12 days or less, a maximum plasma concentration (C _max ) of about 7 to about 15 μg / mL, about 54 to about 104μg Date / mL plasma concentration in dosing interval (tau) of the - area under the curve (AUC _tau), and is selected from the trough plasma concentration of from about 2 to about _{4μg / mL (C trough),} 1 or more Achieve pharmacokinetic properties. In another embodiment, a single IV administration of about 0.3 mg / kg to the subject population. One or more pharmacokinetics selected from an average T _max of about 0.07 days, an average C _max of about 11 μg / mL, an average AUC _τ of about 79 μg day / mL, and an average C _trough of about 3 μg / mL Achieve properties.

In some embodiments, a single IV administration of about 1 mg / kg has a T _max of about 0.12 days or less, a C _{max of} about 21 to about 43 μg / mL, an AUC _{τ of} about 153 to about 290 μg day / mL. And achieving one or more pharmacokinetic properties selected from about 4 to about 12 μg / mL C _trough . In some embodiments, a single IV administration of about 1 mg / kg to a subject population has an average T _{max of} about 0.08 days, an average C _max of about 32 μg / mL, an average AUC _τ of about 221 μg day / mL. And achieving one or more pharmacokinetic properties selected from an average C _trough of about 8 μg / mL.

In some embodiments, a single IV administration of about 3 mg / kg has a T _max of about 0.13 days or less, a C _max of about 64 to about 143 μg / mL, an AUC _{τ of} about 469 to about 1010 μg day / mL. And achieving one or more pharmacokinetic properties selected from about 12 to about 35 μg / mL C _trough . In another embodiment, a single IV administration of about 3 mg / kg to a subject population has an average T _max of about 0.09 days, an average C _max of about 103 μg / mL, an average AUC _τ of about 739 μg day / mL, And achieving one or more pharmacokinetic properties selected from an average C _trough of about 23 μg / mL.

In some embodiments, a single IV administration of about 10 mg / kg has a T _max of about 0.13 days or less, a C _max of about 141 to about 318 μg / mL, an AUC _{τ of} about 979 to about 2241 μg day / mL. And achieving one or more pharmacokinetic properties selected from about 27 to about 76 μg / mL C _trough . In another embodiment, a single IV administration of about 10 mg / kg to a subject population has an average T _max of about 0.09 days, an average C _max of about 230 μg / mL, an average AUC _τ of about 1610 μg day / mL, And achieving one or more pharmacokinetic properties selected from an average C _trough of about 52 μg / mL.

In some embodiments, a sufficient number of IV doses of about 0.3 mg / kg are administered at about 14 day intervals to achieve steady state, T _{max ss} of about 0.60 days or less, about 11 to One or more steady state pharmacokinetic properties selected from about 25 μg / mL C _{max ss} , about 89 to about 197 μg day / mL AUC _{τ ss} , and about 5 to about 11 μg / mL C _{trough ss} Achieved.

In some embodiments, the subject population is administered a sufficient number of IV doses of about 0.3 mg / kg at about 14 day intervals to achieve steady state, with an average T _{max ss} of about 0.17 days, One or more pharmacokinetic properties selected from an average C _{max ss} of about 18 μg / mL, an average AUC _{τ ss} of about 143 μg day / mL, and an average C _{trough ss} of about 8 μg / mL are achieved.

In some embodiments, a sufficient number of IV doses of about 0.3 mg / kg are administered at about 14 day intervals to achieve steady state and a clearance rate (CL _ss ) of about 99 to about 271 mL / day, One or more pharmacokinetic properties selected from an apparent volume of distribution (V _ss ) of about 4 to about 9 L and a serum half-life of about 15 days to about 43 days are achieved.

In certain embodiments, the subject population is administered a sufficient number of IV doses of about 0.3 mg / kg at about 14 day intervals to achieve steady state and an average clearance rate (CL _ss ) of about 185 mL / day. One or more pharmacokinetic properties are achieved, selected from an average apparent volume of distribution (V _ss ) of about 6 L, and an average serum half-life of about 29 days.

In some embodiments, a sufficient number of about 1 mg / kg IV dose is administered at about 14 day intervals to achieve steady state, T _{max ss} of about 0.11 days or less, about 29 to about 67 μg / kg. One or more steady state pharmacokinetic properties selected from C _{max ss of} mL, AUC _{τ ss of} about 213 to about 591 μg day / mL, and C _{trough ss of} about 9 to about 30 μg / mL are achieved. .

In another embodiment, the subject population is administered a sufficient number of IV doses of about 1 mg / kg at about 14 day intervals to achieve steady state, with an average T _{max ss} of about 0.07 days, about 48 μg / kg. One or more pharmacokinetic properties selected from an average C _{max ss of} mL, an average AUC _{τ ss} of about 197 μg day / mL, and an average C _{trough ss} of about 11 μg / mL are achieved.

In some embodiments, at about 14 day intervals, a sufficient number of IV doses of about 1 mg / kg are administered to achieve steady state and a clearance rate (CL _ss ) of about 118 to about 348 mL / day, about One or more pharmacokinetic properties are achieved, selected from an apparent volume of distribution (V _ss ) of 4 to about 9 L, and a serum half-life of about 15 days to about 32 days.

In some embodiments, the subject population is administered a sufficient number of IV doses of about 1 mg / kg at about 14 day intervals to achieve steady state, with an average clearance rate (CL _ss ) of about 233 mL / day, One or more pharmacokinetic properties are achieved, selected from an average apparent volume of distribution (V _ss ) of about 6 L and an average serum half-life of about 23 days.

In some embodiments, at about 14 day intervals, a sufficient number of IV doses of about 3 mg / kg are administered to achieve steady state, with a T _{max ss} of about 0.33 days or less, about 75 to about 232 μg. One or more steady state pharmacokinetic properties selected from C _{max ss} of about 533 to about 1843 μg day / mL of AUC _{τ ss} and about 26 to about 74 μg / mL of C _{trough ss} are achieved. The

In some embodiments, the subject population is administered a sufficient number of IV doses of about 3 mg / kg at about 14 day intervals to achieve steady state, with an average T _{max ss} of about 0.13 days, about 153 μg. One or more pharmacokinetic properties are achieved that are selected from an average C _{max ss of} / mL, an average AUC _{τ ss} of about 1188 μg day / mL, and an average C _{trough ss} of about 50 μg / mL.

In some embodiments, at about 14 day intervals, a sufficient number of about 3 mg / kg IV dose is administered to achieve steady state and a clearance rate (CL _ss ) of about 136 to about 304 mL / day, about One or more pharmacokinetic properties selected from an apparent volume of distribution (V _ss ) of 3 to about 7 L and a serum half-life of about 14 to about 26 days are achieved.

In some embodiments, the subject population is administered a sufficient number of IV doses of about 3 mg / kg at about 14 day intervals to achieve steady state, with an average clearance rate (CL _ss ) of about 220 mL / day, One or more pharmacokinetic properties are achieved, selected from an average apparent volume of distribution (V _ss ) of about 5 L and an average serum half-life of about 20 days.

In some embodiments, at about 14 day intervals, a sufficient number of about 10 mg / kg IV dose is administered to achieve steady state, T _{max ss} of about 288 days to about 595 μg or less. One or more steady state pharmacokinetic properties selected from C _{max ss} of about 2539 to about 4267 μg day / mL of AUC _{τ ss} , and about 93 to about 275 μg / mL of C _{trough ss} are achieved. The

In some embodiments, the subject population is administered a sufficient number of IV doses of about 10 mg / kg at about 14 day intervals to achieve steady state, with an average T _{max ss} of about 232 μg for about 0.23 days. One or more pharmacokinetic properties are achieved that are selected from an average C _{max ss of} / mL, an average AUC _{τ ss} of about 3403 μg days / mL, and an average C _{trough ss} of about 184 μg / mL.

In some embodiments, at about 14 day intervals, a sufficient number of about 10 mg / kg IV dose is administered to achieve steady state and a clearance rate (CL _ss ) of about 157 to about 319 mL / day, about One or more pharmacokinetic properties are achieved, selected from an apparent volume of distribution (V _ss ) of 4 to about 7 L, and a serum half-life of about 15 days to about 29 days.

In some embodiments, the subject population is administered a sufficient number of IV doses of about 10 mg / kg at about 14 day intervals to achieve steady state, with an average clearance rate (CL _ss ) of about 238 mL / day, One or more pharmacokinetic properties are achieved, selected from an average apparent volume of distribution (V _ss ) of about 6 L and an average serum half-life of about 22 days.

  In some embodiments, the number of IV doses at about 14 day intervals required to achieve steady state is about 5 to about 8 doses.

In some embodiments, the administration is subcutaneous (SC) administration. In certain embodiments, a 100 mg dose is administered as a single SC dose, or weekly, biweekly, or monthly. In some embodiments, a T _max or T _{max ss of} about 2 to about 10 days is achieved after SC administration.

In some embodiments, a single SC dose of about 100 mg is about 2 to about 10 days T _max , about 4 to about 21 μg / mL C _max , about 175 to about 666 μg day / mL from 0 hour to final 1 selected from the area under the plasma concentration-time curve of measurable concentration time (AUC _last ), and the area under the plasma concentration-time curve from time 0 to infinity from about 204 to about 751 μg day / mL (AUC _∞ ) Achieve one or more pharmacokinetic properties.

In some embodiments, administration of about 100 mg of a single SC to a subject population has a T _{max of} about 6 days, a C _{max of} about 13 μg / mL, an AUC _last of about 421 μg day / mL, and about 477 μg day / mL. selected for AUC _∞ et al, to achieve one or more pharmacokinetic properties.

In some embodiments, a single SC dose of about 100 mg is about 118 to about 432 mL / day clearance rate (CL / F), about 5 to about 12 L apparent distribution volume (V _z / F), and One or more pharmacokinetic properties are achieved selected from a serum half-life of about 15 days to about 34 days.

In some embodiments, administration of about 100 mg of a single SC to a subject population has an average clearance rate (CL / F) of about 275 mL / day, an apparent volume of distribution (V _z / F) of about 8 L, and about To achieve one or more pharmacokinetic properties selected from a serum half-life of 25 days.

In some embodiments, at about 7 day intervals (weekly), a sufficient number of SC doses of about 100 mg are administered to achieve steady state, T _{max ss} for about 2 to about 7 days, about 37 to about Achieved one or more steady state pharmacokinetic properties selected from 93 μg / mL C _{max ss} , about 248 to about 638 μg day / mL AUC _{τ ss} , and about 38 to about 80 μg / mL C _{trough ss} Is done.

In some embodiments, the subject population is administered a sufficient number of about 100 mg of SC dose at about 7 day intervals (weekly) to achieve steady state, with an average T _{max ss} for about 4 days, about 65 μg / One or more steady state pharmacokinetic properties are achieved selected from an average C _{max ss of} mL, an average AUC _{τ ss} of about 443 μg day / mL, and a C _{trough ss} of about 59 μg / mL.

In some embodiments, at about 7 day intervals (weekly), a sufficient number of about 100 mg SC dose is administered to achieve steady state and a clearance rate of about 168 to about 396 mL / day (CL _ss / F ), An apparent volume of distribution (V _z / F) of about 7 to about 15 L, and a serum half-life of about 22 days to about 35 days is achieved. .

In some embodiments, the subject population is administered a sufficient number of SC doses of about 100 mg at about 7 day intervals (weekly) to achieve steady state and an average clearance rate (CL _ss ) of about 282 mL / day. One or more steady state pharmacokinetic properties are achieved, selected from: an average apparent volume of distribution (V _z / F) of about 11 L, and an average serum half-life of about 28 days.

In some embodiments, at about 14 day intervals (biweekly), a sufficient number of about 100 mg of SC dose is administered to achieve steady state, T _{max ss} for about 2 to about 7 days, about 30 to about One or more steady state pharmacokinetic properties selected from 49 μg / mL C _{max ss} , about 424 to about 567 μg day / mL AUC _{τ ss} , and about 21 to about 40 μg / mL C trough ss are achieved. The

In some embodiments, the subject population is administered a sufficient number of about 100 mg of SC dose at about 14 day intervals (weekly) to achieve steady state, with an average T _{max ss} of about 4 μg / One or more steady state pharmacokinetic properties are achieved, selected from an average C _{max ss of} mL, an average AUC _{τ ss} of about 495 μg day / mL, and an average C _{trough ss} of about 30 μg / mL.

In some embodiments, at about 14 day intervals (each week), a sufficient number of about 100 mg SC dose is administered to achieve steady state and a clearance rate of about 172 to about 240 mL / day (CL _ss / F ), An apparent volume of distribution (V _z / F) of about 6 to about 10 L, and a serum half-life of about 19 days to about 37 days is achieved. .

In some embodiments, the subject population is administered a sufficient number of about 100 mg of SC dose at about 14 day intervals (each week) to achieve steady state and an average clearance rate (CL _ss ) of about 406 mL / day. One or more steady state pharmacokinetic properties are achieved, selected from: an average apparent volume of distribution (V _z / F) of about 8 L, and an average serum half-life of about 28 days.

In some embodiments, at about 30 day intervals (monthly), a sufficient number of SC doses of about 100 mg are administered to achieve steady state, T _{max ss} for about 3 to about 8 days, about 14 to about One or more steady state pharmacokinetic properties selected from 34 μg / mL C _{max ss} , about 326 to about 641 μg day / mL AUC _{τ ss} , and about 6 to about 15 μg / mL C _{trough ss} are achieved Is done.

In some embodiments, the subject population is administered a sufficient number of about 100 mg of SC dose at about 30 day intervals (monthly) to achieve steady state, with an average T _{max ss} of about 49 μg / One or more steady state pharmacokinetic properties are achieved, selected from mL C _{max ss} , average AUC _{τ ss} of about 483 μg day / mL, and average C _{trough ss} of about 11 μg / mL.

In some embodiments, at about 30 day intervals (monthly), a sufficient number of about 100 mg SC dose is administered to achieve steady state and a clearance rate of about 152 to about 302 mL / day (CL _ss / F ), An apparent volume of distribution (V _z / F) of about 5 to about 17 L, and a serum half-life of about 19 to about 47 days is achieved. .

In some embodiments, the subject population is administered a sufficient number of SC doses of about 100 mg at intervals of about 30 days (monthly) to achieve steady state and an average clearance rate (CL _ss ) of about 227 mL / day. One or more steady state pharmacokinetic properties are achieved, selected from: an average apparent volume of distribution (V _z / F) of about 11 L, and an average serum half-life of about 33 days.

  In certain embodiments, administration of a sufficient dose number of an anti-IFN-α antibody or antigen-binding fragment thereof suppresses the IFN pharmacodynamic signature. In some embodiments, the IFN pharmacodynamic signature is a type I IFN-α-induced expression profile. The type I IFN-α inducible expression profiles are IFI44, IFI27, IFI44L, NAPTP, LAMP3, LY6E, RSAD2, HERC5, IFI6, ISG15, OAS3, RTP4, IFIT1, MX1, SIGLEC1, OAS2, USP18, OAS1, EPS1 And an up-regulated gene expression marker set comprising IFRG28. In some embodiments, the anti-IFN antibody or antigen-binding fragment thereof neutralizes the patient's pharmacodynamic expression profile by at least 10%, at least 20%, at least 30% or at least 40%.

  In certain embodiments, the method reduces at least one disease symptom. In certain embodiments, symptom relief reduces the SLEDAI or BILAG score. In certain embodiments, the SLEDAI score is reduced by at least 1, at least 2, at least 3, at least 4 points, or more.

FIG. 1 is a graph showing the average sifalimab concentration over 14 IV infusion doses. Cifarimumab was administered at doses of 0.3 mg / kg (●), 1.0 mg / kg (■), 3.0 mg / kg (▼), and 10 mg / kg (▲). Error bars indicate standard deviation. FIG. 2A is a graph showing the frequency of anti-cifarimumab antibody titers in the 0.3 mg / kg IV infusion dose administration group. FIG. 2B is a graph showing the frequency of anti-cifarimumab antibody titers in the 1.0 mg / kg IV infusion dose administration group. FIG. 2C is a graph showing the frequency of anti-cifarimumab antibody titers in the IV infusion dose group at 3.0 mg / kg. FIG. 2D is a graph showing the frequency of anti-cifarimumab antibody titers in the 10 mg / kg IV infusion dose group. FIG. 3 is a graph showing the steady state clearance of cifarimumab by anti-cifarimumab antibody titer (IM titer). Cifarimumab was administered at infusion doses of 0.3 mg / kg (●), 1.0 mg / kg (■), 3.0 mg / kg (▼), and 10 mg / kg (▲). FIG. 4 is a graph showing the steady state clearance of cifarimumab according to the IM status of patients receiving 0.3, 1.0, 3.0, and 10 mg / kg doses of cifarimumab. IM ⁺ and IM ⁻ patients are patients who test positive or negative for the presence of anti-cifarimumab antibody, respectively. FIG. 5 is a summary of the final model fit plot of cifarimumab serum concentration. Thin solid lines (diagonal and horizontal) and thick lines represent unity and loss fit lines, respectively. Panel (a) shows the population prediction for the observed serum concentration, panel (b) shows the individual prediction for the observed serum concentration, and panel (c) shows the population prediction for the weighted residual. Panel (d) shows the weighted residual over time. FIG. 6 provides a graph depicting a control standard that provides a visual test of cifarimumab serum concentration. The panel shows a serum concentration graph over time corresponding to doses of 0.3, 1.0, 3.0, and 10 mg / kg, respectively. Corresponding simulation based on observed median value (solid line), 95% confidence interval (light colored area between shaded areas), 5% -95% data percentile value (dashed line), 95% CI (shaded) Corresponding simulations based on (region). FIG. 7 shows the similarity of the predicted PK profiles (median, 5 and 95 percentile values) following fixation of cifarimumab (200 mg every 14 days) and body weight based (3 mg / kg every 14 days) IV dosing. It is a graph to show. FIG. 8 is a graph showing the predicted serum concentration following monthly IV dosing of 200, 600, and 1200 mg of cifarimumab (single loading dose on day 14). FIG. 9 is a graph showing the mean concentration of cifarimumab over 168 days. Cifalimumab was administered at a single (●), weekly (■), biweekly (▲) or monthly (▼) subcutaneous dose. FIG. 10 is a graph showing clearance of cifarimumab by immunogenic titer in IM ⁺ and IM ⁻ patients. Cifalimumab was administered at a single (■), weekly (▲), biweekly (▼) or monthly (♦) subcutaneous dose. FIG. 11 is a graph showing the inhibition of type 1 IFN pharmacodynamic gene signature by sifalimumab. Cifarimumab was administered as a single, weekly, biweekly, or monthly subcutaneous dose of 100 mg.

  It should be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly indicates otherwise. It is. The terms “a” (or “an”) and the terms “one or more” and “at least one” may be used interchangeably herein.

  Further, “and / or” as used herein should be considered a specific disclosure of each of the two specified features or components, with or without the other. Accordingly, as used herein, the term “and / or” as used in phrases such as “A and / or B” refers to “A and B”, “A or B”, “A” (alone), and “ B ”(single) is intended to be included. Similarly, the term “and / or” as used in phrases such as “A, B, and / or C” is intended to encompass each of the following embodiments: A, B, and C A or B; B or C; A and C; A and B; B and C; A (single); B (single); and C (single).

  Where embodiments are described herein in terms of “comprises”, they are otherwise described by “consisting of” and / or “consisting essentially of” It is understood that such embodiments are also provided.

  Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. For example, Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed. , 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed. , 1999, Academic Press; and Oxford Dictionary Of Biochemistry And Molecular Biology, Revised, 2000, Oxford University Press provides those skilled in the art with many general dictionaries of terms used in the present invention.

  Units, prefixes, and symbols are shown in the format accepted by their international unit system (SI). Numeric ranges are inclusive of the numbers defining the range. Unless otherwise noted, amino acid sequences are written from left to right in the amino to carboxy direction. The headings provided herein do not limit the various aspects or embodiments of the present invention that may be obtained with reference to the entire specification. Accordingly, the terms defined immediately below are more fully defined with reference to the entire contents of the specification. Amino acids are referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Committee. Similarly, nucleotides are referenced by their normally accepted single letter code.

  As used herein, the term “autoimmune disease” means a disorder, condition or condition associated with the formation of an autoantibody that reacts with the patient's own cells to form an antigen-antibody complex. The term “autoimmune disease” includes pathologies such as systemic lupus erythematosus, as well as disorders caused by certain external agents such as acute rheumatic fever. Examples of autoimmune disorders include 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 I diabetes, ulcerative colitis, and vitiligo However, the present invention is not limited to this. In certain embodiments, the autoimmune disease is systemic lupus erythematosus, scleroderma, or myositis.

  As used herein, 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. “Antibody” means a glycoprotein comprising at least two heavy chains (H) and two light chains (L), or antigen-binding portions thereof, interconnected by disulfide bonds. Each heavy chain comprises a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1, CH2 and CH3. Each light chain comprises a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region comprises one domain of CL. The VH and VL regions can be further subdivided into hypervariable regions termed complementarity determining regions (CDRs) interspersed with more conserved regions termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs arranged from the amino terminus to the carboxy terminus in the order FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable region of the heavy and light chains contains a binding region that interacts with an antigen. The constant region of an antibody can mediate immunoglobulin binding to host tissues or elements, including various cells of the immune system (eg, effector cells) and the first component of the classical complement system (C1q). .

The terms “fragment thereof,” “antigen-binding fragment,” and “antigen-binding portion” (or simply “antibody portion”) of an antibody are used interchangeably herein and are specific to an antigen (eg, IFN-α). Means one or more antibody fragments that retain the ability to bind selectively. It has been shown that the antigen-binding function of an antibody can be exerted by fragments of a full-length antibody. Examples of binding fragments encompassed by the term “antigen-binding portion” are: (i) a Fab fragment that is a monovalent fragment consisting of VL, VH, CL, and CH1 domains; (ii) a disulfide bridge at the hinge region F (ab ′) ₂ fragment, which is a bivalent fragment comprising two Fab fragments ligated by: (iii) an Fd fragment consisting of VH and CH1 domains; (iv) a single arm VL of an antibody An Fv fragment consisting of and VH domains; (v) a dAb fragment consisting of VH domains (Ward et al., (1989) Nature 341: 544-546); and (vi) an isolated complementarity determining region (CDR) And other antibodies. In addition, the two domains of the Fv fragment, VL and VH, are encoded by distinct genes, but they are single, in which the VL and VH regions pair to form a monovalent molecule. Protein chains (known as single chain Fv (scFv); see, for example, Bird et al. (1988) Science 242: 423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85: 5879. Can be linked using recombinant methods with synthetic linkers, such as to form -5883). Such single chain antibodies are also intended to be encompassed within the term “antigen-binding portion” of an antibody. These antibody fragments are obtained using conventional techniques known to those skilled in the art, and the fragments are screened for utility in the same manner as intact antibodies.

  An “isolated antibody” is intended to refer to an antibody that is substantially free of other antibodies with different antigen specificities as used herein (eg, an isolated antibody that specifically binds IFN-α is And substantially free of antibodies that specifically bind antigens other than IFN-α). However, an isolated antibody that specifically binds IFN-α may have cross-reactivity with other antigens, such as IFN-α molecules from other species. Furthermore, an isolated antibody can be substantially free of other cellular material and / or chemicals.

  The terms “monoclonal antibody” or “monoclonal antibody composition” refer to a preparation of antibody molecules of single molecular composition as used herein. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.

  The term “human antibody”, as used herein, is intended to include antibodies having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. In addition, if the antibody contains a constant region, the constant region is also derived from a human germline immunoglobulin sequence. Human antibodies of the invention may contain amino acid residues that are not encoded by human germline immunoglobulin sequences (eg, mutations introduced by in vitro random or site-directed mutagenesis, or by in vivo somatic mutation). However, the term “human antibody” as used herein includes an antibody in which a CDR sequence derived from the germline of another mammalian species, such as a mouse, is grafted onto a human framework sequence. Is not intended.

  The term “human monoclonal antibody” means an antibody exhibiting a single binding specificity, having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. In one embodiment, the human monoclonal antibody comprises a human heavy chain transgene and a light chain transgene fused to an immortalized cell, including B cells obtained from a transgenic non-human animal such as a transgenic mouse. Produced by a hybridoma having a genome comprising.

  The term “recombinant human antibody” refers to an animal (eg, a mouse) that is genetically modified or chromosomally transferred, as used herein for (a) a human immunoglobulin gene or a hybridoma prepared therefrom (described in further detail below). Isolated from a host cell transformed to express a human antibody, such as from a transfectoma, (c) from a recombinant combinatorial human antibody library Isolated antibodies, and (d) antibodies prepared, expressed, produced or isolated by any other means involving the step of splicing human immunoglobulin gene sequences into other DNA sequences All human antibodies prepared, expressed, produced or isolated by recombinant means Including the. Such recombinant human antibodies have variable regions in which the framework and CDR regions are derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies may be subject to in vitro mutagenesis (or in vivo somatic mutagenesis if animals that are genetically modified for human Ig sequences are used). Thus, the amino acid sequences of the VH and VL regions of the recombinant antibody are derived from and related to the human germline VH and VL sequences, but are not naturally present in the human antibody germline repertoire in vivo. Is a good arrangement.

  As used herein, “isotype” refers to the antibody class (eg, IgM or IgG1) that is encoded by heavy chain constant region genes.

  As used herein, an antibody is specifically in an antibody in which a portion of the heavy and / or light chain is derived from a particular species or belongs to a particular antibody class or subclass. The corresponding sequence in an antibody that is identical or homologous to the corresponding sequence while the rest of the chain is from another species or belonging to another antibody class or subclass, as well as the desired biological activity As well as “chimeric” antibodies that are identical or homologous to fragments of such antibodies (US Pat. No. 4,816,567; and Morrison et al, Proc. Natl. Acad. Sci. USA 81: 6851-6855 (1984)).

  The basic antibody structure in vertebrate systems is relatively well known. For example, Harlow et al. (1988) Antibodies: A Laboratory Manual (2nd ed .; Cold Spring Harbor Laboratory Press).

  Where a term has two or more definitions that are used and / or recognized within the art, all definitions of terms used herein are expressly defined unless explicitly stated otherwise. Is intended to include such a meaning. A specific example is the use of the term “complementarity determining region” (“CDR”) to describe non-adjacent antigen binding positions found within the variable regions of both heavy and light chain polypeptides. For this particular region, see Kabat et al., Which is incorporated herein by reference. (1983) U.S. Pat. S. Dept. of Health and Human Services, “Sequences of Proteins of Immunological Interest”; and Chothia and Lesk, J. et al. Mol. Biol. 196: 901-917 (1987), the definition includes overlapping or subset of amino acid residues when compared to each other. Nevertheless, the application of any definition that refers to the CDRs of an antibody or variant thereof is intended to be within the scope of the terms as defined and used herein. Appropriate amino acid residues, including CDRs, as defined by each of the above references are listed in Table 1 below for comparison. The exact number of residues encompassing a particular CDR will vary depending on the sequence and size of the CDR. One skilled in the art can routinely determine which residues comprise a particular CDR given the variable region amino acid sequence of the antibody.

  Kabat et al. Also defined a numbering system for variable region sequences that can be applied to any antibody. One of ordinary skill in the art can unambiguously assign this “Kabat numbering” scheme to any variable region sequence without depending on any experimental data other than the sequence itself. As used herein, “Kabat numbering” refers to Kabat et al. (1983) U.S. Pat. S. Dept. means the numbering system described by of Health and Human Services, “Sequence of Proteins of Immunological Interest”. Unless otherwise noted, references to numbering at specific amino acid residue positions in anti-IL-33 antibodies or antigen-binding fragments, variants, or derivatives thereof of the invention follow the Kabat numbering system.

Antibodies or antigen-binding fragments, variants or derivatives thereof of the invention include polyclonal, monoclonal, multispecific, mouse, human, humanized, primatized, or chimeric antibodies; single chain antibodies; eg, Fab, Fab ′ and Epitope binding fragments such as F (ab ′) ₂ , Fd, Fvs, single chain Fvs (scFv), disulfide bond Fvs (sdFv); fragments comprising either VL or VH domains; generated by Fab expression library And anti-idiotype (anti-Id) antibodies (including, but not limited to, anti-Id antibodies to anti-IL-33 antibodies disclosed herein). ScFv molecules are known in the art and are described, for example, in US Pat. No. 5,892,019.

  As used herein, the term “affinity” refers to a measure of the strength of binding of individual epitopes to the CDRs of immunoglobulin molecules. For example, Harlow et al. (1988) Antibodies: A Laboratory Manual (Cold Spring Harbor Laboratory Press, 2nd ed.) P. See 27-28.

As used herein, “specific binding” refers to antibody binding to a given antigen. Typically, the antibody 10-8 was coupled with ^M following dissociation constant (K _D), the binding to nonspecific antigens other than the predetermined antigen or a closely related antigen (e.g., BSA, casein) K _{D Binds} to a given antigen with a KD of at least one-half of The phrases “an antibody recognizing an antigen” and “an antibody specific for an antigen” are used interchangeably herein with the term “an antibody that binds specifically to an antigen”.

The term “K _assoc ” or “K _a ” is intended to refer to the binding rate of a particular antibody-antigen interaction as used herein, whereas the term “K _dis ” or “K _d ” , As used herein, is intended to refer to the dissociation rate of a particular antibody-antigen interaction. The term “K _D ” is intended to refer to the dissociation constant obtained from the ratio of K _d and K _{a as} used herein and is expressed as molar concentration (M). K _D values for antibodies can be determined using methods established in the art. One method for measuring the K _D of an antibody is for example Biacore using the biosensor device, such as (R) device, such as by use of surface plasmon resonance.

The term "high affinity" for an IgG antibody, as used herein, ^{10 -8} M or less, ^{10 -9} M or less, or refers to an antibody having a ^{10 -10} M or less for _{K D.} However, “high affinity” binding can vary with other antibody isotypes. For example, "high affinity" binding the IgM isotype refers to an antibody having a ^{10 -7} M or less, or ^{10 -8} M or less for _{K D.}

For example, an anti-IFN-α binding molecule such as an antibody or antigen-binding fragment of the invention, variant or derivative thereof is also a human, primate, mouse IFN-α, or any combination of human, primate and mouse IFN-α. Can be described or defined in terms of their binding affinity for the polypeptides of the present invention. Exemplary binding affinities include 5 × 10 ⁻² M, 10 ⁻² M, 5 × 10 ⁻³ M, 10 ⁻³ M, 5 × 10 ⁻⁴ M, 10 ⁻⁴ M, 5 × 10 ^−5. M, 10 ⁻⁵ M, 5 × 10 ⁻⁶ M, 10 ⁻⁶ M, 5 × 10 ⁻⁷ M, 10 ⁻⁷ M, 5 × 10 ⁻⁸ M, 10 ⁻⁸ M, 5 × 10 ⁻⁹ M, 10 ⁻⁹ M, 5 × 10 ⁻¹⁰ M, 10 ⁻¹⁰ M, 5 × 10 ⁻¹¹ M, 10 ⁻¹¹ M, 5 × 10 ⁻¹² M, 10 ⁻¹² M, 5 × 10 ⁻¹³ M, 10 ^{− 13 M, 5 × 10 -14 M} , 10 -14 M, 5 × 10 -15 M or that there is a ^{10 -15} M below a dissociation constant or _{K D,} and the like.

  As used herein, the term “treat” or “treatment” refers to therapeutic treatment and prevention or prevention whose purpose is to prevent or delay (reduce) undesirable physiological changes or disorders such as progression of inflammatory conditions. Means both means. Beneficial or desired clinical outcomes, whether detectable or undetectable, alleviate symptoms, reduce disease severity, stabilize disease state (ie non-aggravation), delay or slow disease progression, restore disease state Or includes, but is not limited to, temporary relief and remission (whether partial or complete). “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those who already have a medical condition or disorder, as well as those who are likely to have a medical condition or disorder, or those in whom the medical condition or disorder is prevented.

  The term “effective amount” or “effective amount to” or “therapeutically effective amount” includes reference to a dose of the therapeutic agent sufficient to produce the desired result.

  “Subject” or “individual” or “animal” or “patient” or “mammal” means any subject for which diagnosis, prognosis, or therapy is desired, in particular a mammalian subject. As used herein, the term “subject” includes any human or non-human animal. The term “non-human animals” includes all vertebrates such as non-human primates, sheep, dogs, cats, horses, cows, bears, chickens, amphibians, reptiles, and other mammals and non-mammals. As used herein, phrases such as “subjects who will benefit from administration of anti-IFN-α antibodies” are used, for example, for detection of anti-IFN-α polypeptides (eg, for diagnostic procedures). Includes subjects such as mammalian subjects that would benefit from administration of anti-IFN-α antibody and / or treatment with anti-IFN-α antibody, ie, temporary alleviation or prevention of disease.

Interferon alpha
The terms “interferon α” and “IFN-α” are used interchangeably and have 75% or more sequence identity with IFN-α1 (the protein encoded by Genbank number NP-076918; or Genbank number NM-024013). It is intended to refer to an IFN-α protein encoded by a functional gene at an interferon α locus. Examples of IFN-α subtypes include IFN-α1, α2a, α2b, α4, α5, α6, α7, α8, α10, α13, α14, α16, α17, and α21. The term “interferon α” is intended to encompass recombinant forms of the various IFN-α subtypes and natural preparations comprising IFN-α proteins such as leukocyte IFN and lymphoblastoma IFN. .

Interferon α antibodies The present invention is directed to a method of treating an autoimmune disorder in a subject in need of such treatment comprising the step of administering an anti-IFN-α antibody to the subject. Anti-IFN-α antibodies can be found in, for example, US Pat. No. 7,741,449, which further provides chimeric, humanized, or human versions of these antibodies (if not already chimeric, humanized, or human versions). And can further include fragments or derivatives thereof.

SLE
Patients suffering from SLE may exhibit any of several symptoms discussed in, for example, International Application No. PCT / US2007 / 024941, or have a clinical SLEDAI score or BILAG score discussed in that document Good. These symptoms include fatigue, organ damage, cheek rash, and alopecia. Patients may be scored using a known clinical scoring system, such as SLEDAI, which is an index of SLE disease activity, measured and evaluated within the last 10 days (Bombardier C, Gladman DD, Urowitz, for example). MB, Caron D, Chang CH and the Committee on Progressive Studies in SLE: Derivation of the SLEDAI for Lupus Patents. Arthritis Rheum 35: 630-640. Disease activity under the SLEDAI scoring system can range from 0-105. The following SLEDAI activity categories are defined: no activity (SLEDAI = 0); mild activity (SLEDAI = 1-5); moderate activity (SLEDAI = 6-10); high activity Sex (SLEDAI = 11-19); very high activity (SLEDAI = 20 or more). (Griffiths, et al., Assessment of Patties with System Lupus Erythematosus and the use of Lupus Disease Activity Indices).

  Another disease scoring index is the activity index of SLE based on specific clinical signs in eight organ systems: whole body, mucocutaneous, neurological, musculoskeletal, cardiovascular, respiratory, renal, and hematological outcomes. It is a certain BILAG index. Although scoring is based on the script system, each character can also be assigned a weighted numerical score, allowing a BILAG score to be calculated in the range of 0-72. (Griffiths, et al., Assessment of Patties with System Lupus Erythematosus and the use of Lupus Disease Activities Indices). Other scoring indicators include PGA score, composite response index (CRI), and ANAM4 ™ test. For example, the methods described herein, such as the treatment of autoimmune disorders, can be measured at any activity level, such as mild, moderate, advanced, or very high, as measured by any classification procedure known in the art. May be used against any subject identified as having any disease activity. For example, the methods described herein, such as the treatment of autoimmune disorders, may result in patient symptom relief, or a disease of the patient's type I IFN or IFN-α-induced disease, disorder, or condition May result in improved scores.

Monoclonal antibodies 13H5, 13H7, and 7H9
In certain embodiments, the antibodies used for the therapeutic methods of the invention include humans isolated and structurally characterized as described in US Pat. No. 7,741,449. And monoclonal antibodies 13H5, 13H7, and 7H9. 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-α, the VH and VL sequences can be “combined” to create other anti-IFN-α binding molecules of the invention. Such “combined” antibody IFN-α binding or neutralizing activity can be tested using the binding assays described above and in the examples (eg, ELISA, Biacore analysis, Daudi cell proliferation assay). In certain embodiments, 13H5 and 7H9 use VH sequences derived from the same germline sequence (VH 1-18) and thus show structural similarity, thus combining the VH sequences of these antibodies. In addition or as an alternative, 13H5, 13H7, and 7H9 use VL sequences derived from the same germline sequence (Vk A27) and thus show structural similarity, so the VL sequences of these antibodies are Can be combined.

Thus, in one aspect, the antibodies used in the methods of the invention are
(A) a heavy chain variable region comprising an amino acid sequence selected from SEQ ID NOs: 19, 20, and 21; and (b) comprising an amino acid sequence selected from SEQ ID NOs: 22, 23, and 24. An isolated monoclonal antibody comprising a light chain variable region, or an antigen-binding portion thereof, in which the antibody inhibits the biological activity of interferon alpha.

In certain embodiments, the combination of heavy and light chains is
(A) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 19;
(B) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 22; or (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 20;
(B) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 23; or (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 21;
(B) comprising a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24.

  In another aspect, the therapeutic methods of the invention comprise administering an antibody comprising 13H5, 13H7, and 7H9 heavy and light chain CDR1, CDR2, and CDR3, or combinations thereof. The amino acid sequences of VH CDR1 of 13H5, 13H7, and 7H9 are shown in SEQ ID NOs: 1, 2, and 3. The amino acid sequence of VH CDR2 of 13H5, 13H7, and 7H9 is shown in SEQ ID NOs: 4, 5, and 6. The amino acid sequences of VH CDR3 of 13H5, 13H7, and 7H9 are shown in SEQ ID NOs: 7, 8, and 9. The amino acid sequences of VL CDR1 of 13H5, 13H7, and 7H9 are shown in SEQ ID NOs: 10, 11, and 12. The amino acid sequences of VL CDR2 of 13H5, 13H7, and 7H9 are shown in SEQ ID NOs: 13, 14, and 15. The amino acid sequences of VL CDR3 of 13H5, 13H7, and 7H9 are shown in SEQ ID NOs: 16, 17, and 18. CDR regions are described using the Kabat system (Kabat. EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U. S. Department of Health and Health Health. No. 91-3242).

  Each of these antibodies is selected based on IFN binding activity, and given that antigen binding specificity is provided primarily by the CDR1, 2, and 3 regions, the VH CDR1, 2, and 3 sequences; VL CDR1, 2, and 3 sequences can be “combined” (ie, each antibody must contain VH CDR1, 2, and 3 and VL CDR1, 2, and 3, but CDRs from different antibodies). Other anti-IFN-α molecules of the invention can be made. Such “combination” antibodies can be tested for IFN-α binding using the binding assays described in the Examples (eg, ELISA and / or Biacore). In certain embodiments, when VH CDR sequences are combined, CDR1, CDR2 and / or CDR3 sequences from a particular VH sequence are replaced with structurally similar CDR sequences. Similarly, when VL CDR sequences are combined, CDR1, CDR2 and / or CDR3 sequences from a particular VL sequence can be replaced with structurally similar CDR sequences. For example, 13H5 and 7H9 VH CDR1s share some structural similarity and are therefore suitable for combination. Replacing one or more VH and / or VL CDR range sequences with structurally similar sequences from the CDR sequences of the monoclonal antibodies 13H5, 13H7, and 7H9 disclosed herein to generate the new VH and One skilled in the art will readily appreciate that VL sequences can be generated.

Thus, in another aspect, the method of the invention comprises:
(A) a heavy chain variable region CDR1 comprising an amino acid sequence selected from SEQ ID NOs: 1, 2, and 3;
(B) a heavy chain variable region CDR2 comprising an amino acid sequence selected from SEQ ID NOs: 4, 5, and 6;
(C) a heavy chain variable region CDR3 comprising an amino acid sequence selected from SEQ ID NOs: 7, 8, and 9;
(D) a light chain variable region CDR1 comprising an amino acid sequence selected from SEQ ID NOs: 10, 11, and 12;
(E) a light chain variable region CDR2 comprising an amino acid sequence selected from SEQ ID NOs: 13, 14, and 15; and (f) an amino acid sequence selected from SEQ ID NOs: 16, 17, and 18. , Light chain variable region CDR3
Providing an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising
Among them, the antibody inhibits the biological activity of interferon α.

In one embodiment, the antibody is
(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) 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
Comprising.

In another embodiment, the antibody is
(A) a heavy chain variable region CDR1 comprising SEQ ID NO: 2;
(B) a heavy chain variable region CDR2 comprising SEQ ID NO: 5;
(C) the heavy chain variable region CDR3 comprising SEQ ID NO: 8;
(D) a light chain variable region CDR1 comprising SEQ ID NO: 11;
(E) a light chain variable region CDR2 comprising SEQ ID NO: 14; and (f) a light chain variable region CDR3 comprising SEQ ID NO: 17
Comprising.

In another embodiment, the antibody is
(A) a heavy chain variable region CDR1 comprising SEQ ID NO: 3;
(B) a heavy chain variable region CDR2 comprising SEQ ID NO: 6;
(C) heavy chain variable region CDR3 comprising SEQ ID NO: 9;
(D) a light chain variable region CDR1 comprising SEQ ID NO: 12;
(E) a light chain variable region CDR2 comprising SEQ ID NO: 15; and (f) a light chain variable region CDR3 comprising SEQ ID NO: 18
Comprising.

Antibodies with specific germline sequences In certain embodiments, antibodies administered in accordance with the methods of the present invention may comprise heavy chain variable regions from specific germline heavy chain immunoglobulin genes and / or specific germline It comprises a light chain variable region from a light chain immunoglobulin gene.

For example, in one embodiment, the invention provides a method of treating an autoimmune disorder in a subject in need comprising administering to the subject an isolated monoclonal antibody, or antigen-binding fragment thereof, The antibody
(A) comprising the heavy chain variable region of the human VH 1-18 or 4-61 gene;
(B) comprising the light chain variable region of the human Vκ A27 gene;
(C) The antibody inhibits the biological activity of interferon α.

  In one embodiment, the antibody comprises the heavy chain variable region of the human VH 1-18 gene. Examples of antibodies having VH 1-18 and Vκ A27 VH and Vκ gene sequences, respectively, include 13H5 and 7H9. In another embodiment, the antibody comprises the heavy chain variable region of the human VH 4-61 gene. An example of an antibody having the VH and Vκ gene sequences of VH 4-61 and Vκ A27, respectively, is 13H7.

  Where the variable region of an antibody used herein is obtained from a system that uses a human germline immunoglobulin gene, the human antibody comprises a heavy or light chain variable region of a particular germline sequence. Is (ie is its product) or “derived from”. Such systems include immunizing transgenic mice carrying human immunoglobulin genes with the antigen of interest, or screening a human immunoglobulin gene library displayed on the phage with the antigen of interest. A human germline immunoglobulin sequence “of” a human antibody (ie, a product thereof), or a “human antibody” human antibody, compares the amino acid sequence of a human antibody with the amino acid sequence of a human germline immunoglobulin, One can identify by selecting the human germline immunoglobulin sequence whose sequence is closest to the human antibody sequence (ie, maximal% identity). A human antibody (ie, its product) or “derived from” a human antibody of a particular human germline immunoglobulin sequence may be produced by, for example, natural somatic mutation, or deliberate introduction of site-specific mutations. It may contain amino acid differences in light of the cell line sequence. However, selected human antibodies typically have an amino acid sequence that is at least 90% identical to the amino acid sequence encoded by the human germline immunoglobulin gene, and other species of germline immunoglobulin amino acid sequences (eg, mouse) Compared to germline sequences), it contains amino acid residues that identify human antibodies as human. In particular examples, the human antibody is identical in amino acid sequence to at least 95%, or at least 96%, 97%, 98%, or even 99%, with the amino acid sequence encoded by the germline immunoglobulin gene. obtain. Typically, human antibodies derived from a particular human germline sequence exhibit no more than 10 amino acid differences from the amino acid sequence encoded by the human germline immunoglobulin gene. In particular examples, human antibodies may exhibit amino acid differences that range from no more than 5, or no more than 4, 3, 2, or even 1 amino acid sequence from the germline immunoglobulin gene.

  In yet another embodiment, the antibody used in the therapeutic methods of the invention exhibits amino acid similarity to the amino acid sequences of the antibodies described herein that retain the desired functional properties of the anti-IFN-α antibodies of the invention. It comprises heavy and light chain variable regions comprising amino acid sequences that are shared or homologous.

For example, the present invention relates to an autoimmune disorder in a subject in need 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. Provide a way to treat
(A) the heavy chain variable region comprises an amino acid sequence at least 80% homologous to an amino acid sequence selected from SEQ ID NOs: 19, 20, and 21;
(B) the light chain variable region comprises an amino acid sequence at least 80% homologous to an amino acid sequence selected from SEQ ID NOs: 22, 23, and 24;
(C) the antibody inhibits the biological activity of multiple IFN-α subtypes but does not substantially inhibit the biological activity of IFN-α21;
(D) The antibody exhibits at least one of the following properties: (i) The antibody directly inhibits the biological activity of IFN-β or IFN-ω, but interferes with interferon receptor function, It may indirectly inhibit the biological activity of IFN-β or IFN-ω; (ii) the antibody inhibits IFN-induced surface expression of CD38 or MHC class I on peripheral blood mononuclear cells (Iii) antibodies inhibit IFN-induced expression of IP-10 by peripheral blood mononuclear cells; (iv) antibodies inhibit dendritic cell development mediated by systemic lupus erythematosus (SLE) plasma;

  In another embodiment, the VH and / or VL amino acid sequence may be 85%, 90%, 95%, 96%, 97%, 98% or 99% homologous to the sequence described above. Antibodies having VH and VL regions with high (ie, 80% or greater) homology with the VH and VL regions of SEQ ID NOs: 19, 20, and 21 and 22, 23, and 24, respectively, are SEQ ID NOs: 19, 20, And nucleic acids encoding 21 and / or 22, 23, and 24 are mutagenized (eg, site-specific or PCR-mediated mutagenesis) followed by retention using the functional assays described herein Can be obtained by testing the encoded modified antibody for the function to be performed (ie the functions described in (c) and (d) above).

  As used herein,% homology or% similarity between two amino acid sequences corresponds to% identity between the two sequences. The percent identity between two sequences is a function of the number of identical positions shared by the sequences (ie,% homology = number of identical positions / total number of positions × 100), not introduced for optimal alignment of the two sequences The number of gaps and the length of each gap should be considered. Sequence comparison between two sequences and determination of percent identity can be accomplished using a mathematical algorithm, as described in the non-limiting examples below.

  The% identity between two amino acid sequences is incorporated into the ALIGN program (version 2.0) using the PAM120 weight residue table, gap length penalty = 12 and gap penalty = 4, E.I. Meyers and W.M. It can be determined using the algorithm of Miller (Comput. Appl. Biosci., 4: 11-17 (1988)). In addition, the percent identity between the two amino acid sequences is: BLOSUM62 matrix or PAM250 matrix, and gap weight = 16, 14, 12, 10, 8, 6, or 4 and length weight = 1, 2, 3, Needleman and Wunsch (J. Mol. Biol., Incorporated in the GAP program of GCG software package (available at http://www.gcg.com) using either 4, 5, or 6. 48: 444-453 (1970)) algorithm.

  In addition, or alternatively, the protein sequences of the present invention can be further used as “query sequences” to perform searches against public databases to identify, for example, related sequences. Such a search is described in Altschul, et al. (1990) J. MoI. Mol. Biol. 215: 403-10 XBLAST program (version 2.0). BLAST protein searches can be performed using the XBLAST program, score = 50, wordlength = 3 to obtain amino acid sequences that are homologous to the antibody molecules of the present invention. To obtain a gapped alignment for comparison purposes, see Altschul et al. (1997) Nucleic Acids Res. 25 (17): 3389-3402. Gapped BLAST can be used. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (eg, XBLAST and NBLAST) can be used. http: // www. ncbi. nlm. nih. See gov.

Antibodies with Conservative Modifications In certain embodiments, an antibody used in the methods of the invention comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences and a CDR1, CDR2, and CDR3 sequence. Wherein one or more of these CDR sequences retains the desired functional properties of an anti-IFN-α antibody of the invention (ie, 13H5, It comprises an amino acid sequence defined on the basis of 13H7, or 7H9), or conservative modifications thereof. For example, in the specific antibody of the present invention, the heavy chain variable region CDR3 sequence comprises the amino acid sequence of SEQ ID NO: 3 or a conservative modification thereof, and the light chain variable region CDR3 sequence of SEQ ID NO: 6 Those comprising amino acid sequences or conservative modifications thereof. Accordingly, the present invention provides an isolated monoclonal antibody or antigen binding 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. Providing a method of treating an autoimmune disorder in a subject comprising administering a fragment to the subject;
(A) the heavy chain variable region CDR3 sequence comprises an amino acid sequence selected from SEQ ID NOs: 7, 8, and 9, and conservative modifications thereof;
(B) the light chain variable region CDR3 sequence comprises an amino acid sequence selected from SEQ ID NOs: 16, 17, and 18, and conservative modifications thereof;
(C) the antibody inhibits the biological activity of multiple IFN-α subtypes but does not substantially inhibit the biological activity of IFN-α21;
(D) The antibody exhibits at least one of the following properties: (i) The antibody does not directly inhibit the biological activity of IFN-β or IFN-ω, but interferes with interferon receptor function. May indirectly inhibit the biological activity of IFN-β or IFN-ω; (ii) antibodies inhibit IFN-induced surface expression of CD38 or MHC class I on peripheral blood mononuclear cells (Iii) antibodies inhibit IFN-induced expression of IP-10 by peripheral blood mononuclear cells; (iv) antibodies inhibit dendritic cell development mediated by systemic lupus erythematosus (SLE) plasma .

  In a further embodiment, the heavy chain variable region CDR2 sequence comprises an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 4, 5, and 6, and conservative modifications thereof; the light chain variable region CDR2 sequence is Amino acid sequences selected from the amino acid sequences of SEQ ID NOs: 13, 14, and 15 and conservative modifications thereof. In still further embodiments, the heavy chain variable region CDR1 sequence comprises an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 1, 2, and 3, and conservative modifications thereof; the light chain variable region CDR1 sequence Comprises an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 10, 11, and 12, and conservative modifications thereof.

  The term “conservative sequence modifications” as used herein is intended to refer to amino acid modifications that do not significantly affect or alter the binding properties of an antibody containing amino acid sequence. Such conservative modifications include amino acid substitutions, additions and deletions. Modifications can be introduced into the antibodies of the present invention by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. A conservative amino acid substitution is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. A family of amino acid residues having similar side chains has been defined in the art. These families include basic side chains (eg lysine, arginine, histidine), acidic side chains (eg aspartic acid, glutamic acid), uncharged polar side chains (eg glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine). , Tryptophan), nonpolar side chains (eg alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), β-branched side chains (eg threonine, valine, isoleucine), and aromatic side chains (eg tyrosine, phenylalanine) , Tryptophan, histidine). Thus, one or more amino acid residues within the CDR regions of the antibodies of the invention can be substituted with other amino acid residues from the same side chain family, and the modified antibodies can be functional assays as described herein. Can be used to test for retained functions (ie functions described in (c) and (d) above).

Antibodies that bind to the same epitope as an anti-IFN-α antibody of the invention In another embodiment, the invention provides herein, for example, other human antibodies that bind to the same epitope as the 13H5, 13H7, and 7H9 antibodies. There is provided a method of treating an autoimmune disorder in a subject comprising administering to the subject an antibody that binds to the same epitope as the various human IFN-α antibodies described. The term “epitope” means a protein determinant capable of binding to an antibody of the invention as used herein. Epitopes usually consist of chemically active surface populations 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 by the absence of binding to the former but not the latter in the presence of denaturing solvents. Such antibodies cross-compete with antibodies such as 13H5, 13H7 or 7H9 (eg, competitively inhibit their binding in a statistically significant manner) in standard IFN-α binding assays. Identification based on For example, in the example of US Pat. No. 7,741,449, 13H5 binds with high affinity to IFN-α 2a and IFN-α 2b, as demonstrated by Biacore analysis. Accordingly, in one embodiment, the invention provides an antibody, such as a human antibody, that competes with another antibody, such as 13H5, 13H7, or 7H9, for binding to IFN-α 2a or IFN-α 2b. The ability of a test antibody to inhibit the binding of 13H5, 13H7 or 7H9 to, for example, IFN-α 2a or IFN-α 2b is competitive with that antibody for binding to IFN-α 2a or IFN-α 2b. According to non-limiting theory, such an antibody is the same or related (eg structurally similar) on IFN-α 2a or IFN-α 2b as the antibody it competes with. Alternatively, it can bind to epitopes that are spatially adjacent). In one embodiment, the antibody that binds to the same epitope on IFN-α 2a or IFN-α 2b, such as 13H5, 13H7, or 7H9, is a human monoclonal antibody. Such human monoclonal antibodies can be used in the methods disclosed herein.

  In one embodiment, the IFN-α antibody antagonist is cifarimumab. Cifarimumab is a fully human, 147,000 dalton IgGIk monoclonal antibody (Mab) that selectively binds to multiple interferon-α subtypes. Cifarimumab is made up of 100% human protein sequence, thus it becomes a fully human monoclonal antibody. Fully human monoclonal antibodies have advantages over other monoclonal antibody forms such as chimeric and humanized antibodies because they have a more favorable safety profile and can be eliminated more slowly from the human body, thereby reducing the frequency of dosing Have Cifarimumab was derived from the IgG4k antibody, 13H5, described above and in US Pat. No. 7,741,449, selected as having the most desirable properties as a possible therapeutic based on functional assays . 13H5 was subsequently converted to the IgGl antibody isotype and produced in CHO cells. U.S. Patent No. 7,741,449, U.S. Patent Publication No. 2010-0143372, and U.S. Patent Publication No. 2010-0266610, each of which is hereby incorporated by reference. No. 2008/070135, International Publication No. 2009/061818, International Publication No. 2008/137838, International Publication No. 2008/070137, International Publication No. 2008/137835, International Publication No. 2009/155559 See the pamphlet, WO 2008/121616 pamphlet, and WO 2008/121615 pamphlet.

  The nucleotide and amino acid sequences of the heavy chain variable region of 13H5 are shown in SEQ ID NOs: 25 and 19, respectively.

  The VH CDR1, CDR2, and CDR3 amino acid sequences of 13H5 are shown in SEQ ID NOs: 1, 4, and 7, respectively.

  The nucleotide and amino acid sequences of the light chain variable region of 13H5 are shown in SEQ ID NOs: 28 and 22, respectively.

  The VL CDR1, CDR2, and CDR3 amino acid sequences of 13H5 are shown in SEQ ID NOs: 10, 13, and 16, respectively.

Treatment and Dosing with Anti-IFN-α Antibodies The present invention includes methods of dosing to achieve the desired PK properties. In certain embodiments, the dose is Tmax (maximum observation concentration time), Tmax ss (maximum observation concentration time in steady state), Cmax (maximum observation concentration), Cmax ss (maximum observation concentration in steady state), AUCτ, (Area under the curve over the dosing interval), AUCτ ss (area under the curve over the dosing interval at steady state), C trough (observed trough concentration), C trough ss (observed trough concentration at steady state), half-life (ln (2) / λz Final elimination half-life defined as), CLss (dose / AUC _{τ ss} , defined as serum steady-state clearance), Vss (steady-state distribution volume), AUClast (curve from 0 hour to final observed concentration, ie Clast) Lower area), AUCinf ((AUClast + Clast) / λz Defined as 0, infinity under the curve), AUCinf extrapolation (percentage of extrapolation AUCinf curve defined as ((Clast / λz) / AUCinf) * 100), CL (apparent from drug plasma) Complete body clearance), CL / F (apparent serum clearance), Vz / F (apparent final distribution volume), CLss / F (apparent serum steady state clearance), Vc (central volume), Vp (peripheral volume) Or selected to achieve the desired properties, selected from λ z (gradient of the final drain phase).

  In certain embodiments, the dosing regimen results in at least one PK parameter of the PK characteristic values shown in Tables 2, 3, 6, 7, and 8-11. It is understood that such desired PK characteristic values include the CV% shown in the table. In certain embodiments, the methods of the invention comprise a value selected from the PK characteristics shown in Tables 2, 3, 6, 7, and 8-11 and the 21 genes or 4 genes discussed herein. Resulting in neutralization of PD markers. In certain embodiments, the methods of the invention comprise a value selected from the PK characteristics shown in Tables 2, 3, 6, 7, and 8-11 and the 21 genes or 4 genes discussed herein. It causes neutralization of PD markers and reduction of SLE symptoms such as SLEDAI score reduction.

  The term “dosage form” refers to a pharmaceutical composition comprising one or more active pharmaceutical ingredients (APIs), such as an anti-IFN-α antibody or antigen-binding fragment thereof, such as, for example, cifarimumab, Physically inactive ingredients, ie polymers used to produce and deliver active pharmaceuticals, suspensions, surfactants, disintegrants, dissolution modifiers, binders, extenders, lubricants, glidants, stable Optionally containing pharmaceutically acceptable carriers, fillers, excipients or combinations thereof, such as agents, antioxidants, osmotic agents, colorants, plasticizers, coatings and the like. Examples of pharmaceutical compositions comprising anti-interferon α antibodies are found in US Patent Application Publication No. 2010-0209434 A1, entitled “Antibody Formulation,” which is incorporated herein by reference in its entirety. It is done.

  For example, an anti-IFN-α antibody or antigen-binding fragment thereof, such as cyfarimumab, is intramuscular, intraperitoneal, intracerebral spinal, subcutaneous, joint, according to known methods such as intravenous administration as a bolus, or by continuous infusion over a period of time. Administration to human patients may be by the internal, intrasynovial, intrathecal, oral, topical, or inhalation route, or a combination of two or more listed routes.

  In one embodiment, the formulation comprising an anti-IFN-α antibody or antigen-binding fragment thereof, such as cifarimumab, used in the methods of the invention is for parenteral administration. In one embodiment, a formulation of the invention comprising an anti-IFN-α antibody or antigen-binding fragment thereof, such as cifarimumab, is an injectable formulation. In one embodiment, a formulation of the invention comprising an anti-IFN-α antibody or antigen-binding fragment thereof, such as cifarimumab, is for intravenous, subcutaneous, or intramuscular administration. In certain embodiments, the formulations of the invention comprise an anti-IFN-α antibody, such as cyfarimumab, or an antigen-binding fragment thereof, wherein the formulation is for subcutaneous injection.

  As used herein, the term “intravenous administration” refers to the introduction of a composition into a patient's vein. The anti-IFN-α antibody or antigen-binding fragment thereof can be administered intravenously (IV), for example, as an intravenous infusion or as an intravenous bolus. The term “intravenous infusion” refers to the infusion of an agent, such as an anti-IFN-α antibody or antigen-binding fragment thereof, such as cifarimumab, into the vein of an animal or human patient, for example, over about 5 minutes, such as about 30-90 minutes. Refers to introduction over a period of time, but as an alternative, intravenous fluids are administered for 10 hours or less in accordance with the present disclosure. In one particular embodiment, the duration of the infusion is at least 60 minutes.

  The term “intravenous bolus” or “intravenous” refers to an anti-IFN-α antibody or antigen-binding fragment thereof, such as, for example, cyfarimumab, such that the body is administered the drug in approximately 15 minutes or less, such as 5 minutes or less. Or the like is administered to an animal or human intravenously.

  The term `` subcutaneous administration '' refers to drugs such as anti-IFN-α antibodies or antigen-binding fragments thereof, such as, for example, cifarimumab, by relatively slow sustained delivery from a drug receptacle, for example, in a pocket between the skin and underlying tissue. It is meant to be introduced subcutaneously in an animal or human patient. A pocket may be created by picking up or pulling the skin from the underlying tissue. In some embodiments, a composition comprising an anti-IFN-α antibody, such as cifarimumab, or an antigen-binding fragment thereof is introduced under the skin surface of a patient using a hypodermic needle.

  The term “subcutaneous infusion” is a comparison from a drug receptacle in a pocket between skin and underlying tissue over a period of time, including, but not limited to, 30 minutes or less, or 90 minutes or less. By slow and sustained delivery is meant the introduction of an agent, such as an anti-IFN-α antibody or antigen binding fragment thereof, such as cifarimumab, under the skin of an animal or human patient. Optionally, the infusion can be performed by subcutaneous implantation of a drug delivery pump implanted subcutaneously in an animal or human patient, the pump being at a predetermined time, such as 30 minutes, 90 minutes, or a time spanning a treatment planning period. Over a given amount of drug.

  The term “subcutaneous bolus” refers to drug administration of an anti-IFN-α antibody or antigen-binding fragment thereof, such as cifarimumab, directly under the skin of an animal or human patient, and bolus drug delivery is less than about 15 minutes, about 5 Less than a minute, or less than about 60 seconds. Administration can be in a pocket between the skin and the underlying tissue, which can be created, for example, by picking up or lifting the skin from the underlying tissue.

  In one embodiment, the formulation used in the method of the invention is for spray administration.

Administration of body weight-based dosage In some embodiments, the dose of anti-IFN-α antibody or antigen-binding fragment thereof administered to a patient is calculated as a function of, for example, patient body weight (weight), height, or body surface area. . In certain embodiments, the dose of anti-IFN-α antibody or antigen-binding fragment thereof administered to a patient depends on the weight of the patient. Body weight based doses are generally provided in mg / kg.

  In some embodiments, the anti-IFN-α antibody or antigen-binding fragment thereof is about 0.1 mg / kg, or about 0.2 mg / kg, or about 0.3 mg / kg, or about 0.4 mg / kg, Or administered at a body weight based dose of 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. In another embodiment, the anti-IFN-α antibody or hereof antigen-binding fragment is 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 administered at a body weight based dose of about 6 mg / kg, or about 7 mg / kg, or about 8 mg / kg, or about 9 mg / kg. In certain embodiments, the anti-IFN-α antibody or antigen-binding fragment thereof is 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 It is administered at a body weight based dose of 80 mg / kg, or about 85 mg / kg, or about 90 mg / kg, or about 95 mg / kg, or about 100 mg / kg. In certain embodiments, the anti-IFN-α antibody or antigen-binding fragment thereof is administered at a body weight base of about 0.3 mg / kg, or about 1.0 mg / kg, or about 3.0 mg / kg, or about 10 mg / kg. Administered in an amount. In certain embodiments, the body weight based dose is administered intravenously. In another embodiment, the body weight based dose is administered subcutaneously. In some specific embodiments, the anti-IFN-α antibody is cifarimumab.

  When a series of body weight-based doses of an anti-IFN-α antibody or antigen-binding fragment thereof such as sifalimab is administered, these doses may be administered, for example, approximately weekly, approximately every 2 weeks, approximately every 3 weeks, or approximately every 4 weeks. Can be administered. In some embodiments, the body weight-based dose of the anti-IFN-α antibody or antigen-binding fragment thereof is about daily, about every 2 days, about every 3 days, about every 4 days, about every 5 days, about every 6 days, or about 7 Dosed daily.

  In certain embodiments, a weight-based dose of anti-IFN-α antibody or antigen-binding fragment is administered every two weeks. The body weight-based dose of the anti-IFN-α antibody or antigen-binding fragment thereof is, for example, about 1 month, or about 2 months, or about 3 months, or about 4 months, or about 5 months, or about 6 Can be administered for months. The body weight-based dose of the anti-IFN-α antibody or antigen-binding fragment thereof can be continued until disease progression, adverse events, or other parameters occur, as determined by, for example, a physician. In certain embodiments, the weight-based dose of anti-IFN-α antibody or antigen-binding fragment thereof is administered for about 6 months. In a more particular embodiment, the weight-based dose of anti-IFN-α antibody or antigen-binding fragment thereof is administered for about 26 weeks.

  In some embodiments, the patient has at least 1, 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 11, at least 12, at least 13, at least An anti-IFN-α antibody or antigen-binding fragment thereof, such as 14 or at least 15 body weight based doses of cifarimumab may be administered. In certain embodiments, the patient is administered at least 14 doses of an anti-IFN-α antibody, such as cifarimumab, or an antigen-binding fragment thereof. In some specific embodiments, the patient may be administered an anti-IFN-α antibody or antigen-binding fragment thereof, such as at least a 14 IV body weight-based dose of cifarimumab.

  In some embodiments, the body weight-based dose of anti-IFN-α antibody or antigen-binding fragment thereof is administered at equal time intervals. In other embodiments, such weight-based dosages are administered at variable intervals. In some embodiments, all administered body weight based doses are essentially the same. In another embodiment, the at least one body weight based dose differs from other doses, for example in volume, concentration, route of administration, formulation and the like.

Administration of Fixed Dosage A “fixed dose” or “fixed dose” of a therapeutic agent is used herein to refer to the dose administered to a human patient, regardless of the patient's body weight (WT) or body surface area (BSA). means. Thus, a fixed dose of an anti-IFN-α antibody or antigen-binding fragment thereof, such as, for example, cyfarimumab, is provided as an absolute amount of therapeutic agent, rather than as a mg / kg dose or mg / m ² dose.

  In some embodiments, the anti-IFN-α antibody or antigen-binding fragment thereof is 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 at a fixed dose of about 90 mg, or about 100 mg. In another embodiment, the anti-IFN-α antibody or antigen-binding fragment thereof is 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 1100 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 It is administered at a fixed dose.

  In certain embodiments, the anti-IFN-α antibody or antigen-binding fragment thereof is administered intravenously at a fixed dose of about 100 mg, or about 150 mg, or about 200 mg, or about 600 mg, or about 1200 mg. In certain embodiments, the anti-IFN antibody or antigen-binding fragment thereof is administered subcutaneously at a fixed dose 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-α antibody is cifarimumab, or an antigen-binding fragment thereof. In certain embodiments, the anti-IFN-α antibody or antigen-binding fragment thereof is administered in a loading dose on day 14 and at a fixed dose of about 100 mg, or about 150 mg, or about 200 mg, or about 600 mg, or about 1200 mg. Administered intravenously once a month.

  Where a series of fixed doses of anti-IFN-α antibody or antigen-binding fragment thereof are administered, these doses may be administered, for example, approximately every week, approximately every 2 weeks, approximately every 3 weeks, or approximately every 4 weeks. In some embodiments, the fixed dose of anti-IFN-α antibody or antigen-binding fragment thereof is about every day, about every 2 days, about every 3 days, about every 4 days, about every 5 days, about every 6 days, or about every 7 days. Be administered. In certain embodiments, the fixed administration of the anti-IFN-α antibody or antigen-binding fragment thereof is a 100 mg dose administered daily. In certain embodiments, the fixed administration of the anti-IFN-α antibody or antigen-binding fragment thereof is a 150 mg dose administered daily. In certain embodiments, the fixed dose of the anti-IFN-α antibody is 100 mg daily dose or 150 mg daily dose of cyfarimumab.

  In certain embodiments, a fixed dose of anti-IFN-α antibody or antigen-binding fragment is administered every two weeks. These fixed doses may 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 may continue to be administered until disease progression, adverse events, or other parameters occur, as determined by a physician, for example. In some embodiments, the patient has 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 11, at least 12, at least 13, At least 14 or at least 15 fixed doses of anti-IFN-α antibody or antigen-binding fragment thereof may be administered. In certain embodiments, the patient is administered at least 13 doses of an anti-IFN-α antibody or antigen-binding fragment thereof. In some specific embodiments, the patient may be administered at least 13 subcutaneous fixed doses of cyfarimumab.

  In some embodiments, fixed doses of anti-IFN-α antibody or antigen-binding fragment thereof are administered at equal time intervals. In other embodiments, the fixed dose of anti-IFN-α antibody or antigen-binding fragment thereof is administered at varying time intervals. In some embodiments, all administered fixed doses are essentially the same. In another embodiment, the at least one fixed dose differs from the other doses, for example in volume, concentration, route of administration, formulation and the like.

  For the prevention or treatment of autoimmune diseases such as SLE, scleroderma, or myositis, for example, a fixed dose or body weight base of an anti-IFN-α antibody or antigen-binding fragment thereof such as cifarimumab is intended for the prevention or treatment of the antibody. Depending on the type of disease being treated, disease severity and course, as defined above, regardless of whether it is administered at any time, previous therapy, patient history, and response to antibodies, and the physician's discretion The

  In some embodiments, one or more loading doses of an anti-IFN-α antibody or antigen-binding fragment thereof, either body weight based or fixed dose, can be administered, either weight based or fixed dose Followed by one or more maintenance doses of antibody. In another embodiment, multiple identical fixed doses of an anti-IFN-α antibody or antigen-binding fragment thereof are administered to a patient. In accordance with one embodiment of the present invention, one or more body weight based or fixed loading doses of an anti-IFN-α antibody (eg, cifarimumab) or antigen binding fragment may be administered to produce one or more body weight based or fixed maintenance doses. Followed by antibodies. In accordance with another embodiment of the present invention, one or more body weight-based or fixed doses of anti-IFN-α antibody (eg, cifarimumab) or antigen-binding fragment may be administered up to several cycles. In another embodiment, a body weight based or fixed dose of an anti-IFN-α antibody (eg, cifarimumab) or antigen-binding fragment can be administered as a loading dose followed by one or more maintenance doses. According to this embodiment, about one, two, or more maintenance doses of anti-IFN-α antibody or antigen-binding fragment thereof may be administered to the patient.

  Accordingly, the present invention provides a method of treating an autoimmune disorder, such as SLE, scleroderma, or myositis in a human patient, for example, comprising administering to the patient at least one fixed dose of cyfarimumab; The fixed dose is about 100 mg, about 200 mg, about 600 mg, or about 1200 mg of cifarimumab.

Dosing to achieve the desired pharmacokinetic properties The term “pharmacokinetic properties” or “PK properties” refers to the absorption and distribution mechanism of an administered drug, such as an anti-IFN-α antibody or antigen-binding fragment thereof, such as cyfarimumab, drug It refers to the rate at which the action begins and the duration of the effect, the physicochemical changes of the substance in the body, and the parameters that describe the effect and excretion pathway of the drug metabolite. The methods disclosed herein allow for dose selection that achieves the desired PK characteristics, regardless of whether the medication is based on weight, a fixed dose, and whether the route of administration is, for example, intravenous or subcutaneous.

Such pharmacokinetic properties include, for example, T _max (maximum observation concentration time), T _{max ss} (maximum observation concentration time in steady state), C _max (maximum observation concentration time), C _{max ss} (maximum observation concentration in steady state). Time), AUC _τ , (area under the curve over the dosing interval), AUC _{τ ss} (area under the curve over the dosing interval at steady state), C _trough ) (observed trough concentration), C _{trough ss} (observed trough concentration at steady state) half-life (ln (2) / λ final elimination half-life, defined as _{z), CL ss,} (defined as the dose / AUC _{tau ss,} serum steady state _{clearance), V ss} (steady state volume of distribution), AUC _last (area under the curve from time zero the last observation concentration, i.e. up to _{C last), AUC inf ((} AUC _ast + _{C last)} / _{λ z} is defined as the area under the curve of infinity from _0), the extrapolated _{AUC inf} curve defined as _{AUC inf} extrapolation _{(((C last / λ z} ) / AUC inf) * 100 %), CL (apparent total body clearance of drug from plasma), CL / F (apparent serum clearance), V _z / F (apparent final distribution volume), CL _ss / F (apparent serum steady state) Clearance), V _c (central volume), V _p (peripheral volume) or λ _z (final drain phase gradient).

  The pharmacokinetic properties can be used to determine the appropriate dose of the subject agent, eg, an anti-IFN-α antibody or antigen-binding fragment thereof. Properties that describe plasma curves can be obtained in clinical trials by administering an active agent to several subjects. The individual subject's plasma values are then averaged.

In the context of the present invention, pharmacokinetic properties such as, for example, AUC, C _max and T _max mean the mean value corresponding to the subject population. Further, in the context of the present invention, in vivo parameters such as AUC, C _max , T _max values mean parameters or values obtained after administration in steady state to human patients.

  In order to quantify pharmacokinetic properties in patients, the patient group comprises 10-200 patients. A reasonable number of patients is 10, 20, 30, 40, 50, 75, 100, 125, 150, 175 or 200 patients and the like. Patients are selected according to inclusion and exclusion criteria related to the physician's ability to properly identify the symptoms of the condition being treated and the effect of the test agent on these symptoms.

  The calculation of pharmacokinetic properties may be performed using the WinNonlin program of any version and / or platform implementation. Those skilled in the art will appreciate that such calculations can also be performed using other available software packages or by manual calculations according to equations and methods known in the art. .

  For clarity and convenience herein, the drug administration time or study start is 0 hours (t = 0 hours) or 0 days (0 days) and the time following administration is, for example, t = 30 minutes or 68 days. The convention of specifying the appropriate time unit is used.

  The term “bioavailability” is defined for the purposes of the present invention as the extent to which an active agent, such as an anti-IFN-α antibody or antigen-binding fragment thereof, such as cifarimumab, is absorbed from a unit dosage form. AUC provides a measure of bioavailability.

  The term “steady state” means that a plasma level of a given agent, such as an anti-INF-α antibody or antigen-binding fragment thereof, such as cyfarimumab, has been achieved and is above the minimum therapeutic effect level and below the minimum toxic plasma level. Means that it is maintained by a level of drug administration. It is well known by those skilled in the medical art that the concentration passes the maximum value after each dose and drops back to the minimum value. Thus, the steady state can be described as follows: At time t = 0, which is the time when the first dose is administered, the concentration C is also zero. The concentration then passes through a first maximum value and then drops to a first minimum value. Another dose is administered so that the second increase in concentration does not begin at zero before the concentration drops to zero. Stacked on top of this first minimum concentration, the curve passes a second maximum above the first maximum and is above the first minimum after the second dose is administered. Decrease to a minimum value of 2. The plasma curve therefore increases in steps due to repeated administration and the gradual accumulation of the active agent, to the point where dose and elimination are balanced. This state in which dose and elimination are balanced and the concentration constantly fluctuates between a defined minimum value and a defined maximum value is referred to as a steady state.

As used herein, the term “clearance rate” refers to CL (apparent full body clearance of drug from plasma), CL _ss (serum steady state clearance), CL / F (apparent serum clearance), and CL _ss / F (apparent serum steady state clearance). As used herein, the term “apparent distributed capacity” means V _ss (steady state distributed capacity) and Vz / F (apparent final distributed capacity). As used herein, the term “half-life” refers to the biological half-life of a specific binding agent (eg, an anti-INF-α antibody such as cifarimumab, or an antigen-binding fragment thereof) in vivo. Half-life may be expressed as the time it takes for half of the amount administered to a subject to be removed from the subject's circulation and / or other tissues.

In some embodiments of the invention, the anti-IFN-α or antigen-binding fragment thereof is dosed such that effective exposure is provided to the patient, for example as measured by clearance rate, apparent volume of distribution, or half-life. Is administered. The invention also includes methods that combine the achievement of two or more preferred pharmacokinetic properties or combinations thereof. Examples of these pharmacokinetic parameters include clearance rate (CL, CL _ss , CL / F, or CL _ss / F), apparent volume of distribution (V _ss or V _z / F), and serum half-life. Can be mentioned. For example, a formulation administered through the methods of the invention may be selected such that the selected formulation provides the patient with one or more desired pharmacokinetic properties upon administration to a patient in need thereof.

In some embodiments, one or more desired pharmacokinetic properties are achieved after administering one or more doses of an anti-INF antibody or antigen-binding fragment thereof to a subject suffering from an autoimmune disorder. Is done. In some embodiments, such interferon alpha is human interferon alpha. In another embodiment, the one or more desired pharmacokinetic properties include, for example, clearance rate (CL, CL _ss , CL / F, or CL _ss / F), apparent distribution volume (V _ss or V _z / F ), And serum half-life. In some embodiments, the immune disorder is systemic lupus erythematosus, scleroderma, or myositis.

In some embodiments, a clearance rate of about 99 to about 432 mL / day (CL, CL _ss , CL / F, or CL _ss / F), an apparent distribution volume (V _ss or V _z ) of about 3 to about 17 L. / F), and the desired pharmacokinetic properties selected from the group consisting of about 14 days to about 47 days of serum half-life are achieved following administration of the anti-IFN antibody or antigen-binding fragment thereof.

In some embodiments, the desired clearance rate (CL, CL _ss , CL / F, or CL _ss / F) is about 90, about 100, about 110, 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.

In some embodiments, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, or Desired apparent distributed volume (V _ss or V _z / F) of about 17 L. In some embodiments, the desired serum half-life is about 10, about 11, 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.

  In some embodiments, such desired pharmacokinetic properties are obtained after administration of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 doses. Achieved. In some embodiments, such desired pharmacokinetic properties are achieved after administration of an anti-IFN-α antibody, such as cifarimumab, or an antigen-binding fragment thereof, eg, at least 15 doses. In some embodiments, such a dose is an intravenous dose. In another embodiment, such a dose is a subcutaneous dose. In another embodiment, such doses are weight based, while in other cases such doses are fixed doses.

  When a fixed dose is administered to achieve the desired pharmacokinetic properties, such doses of anti-IFN-α antibody or antigen binding fragment thereof are 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. In another embodiment, the anti-IFN-α antibody or antigen-binding fragment thereof is 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 1100 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. In some embodiments, a loading dose is administered.

  In certain embodiments, the anti-IFN-α antibody or antigen-binding fragment thereof is administered at a loading dose on day 14 and is 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 1100 mg, or about 1200 mg, or about 1300 mg, or about 1400 mg, or about 1500 mg, or about 1600 mg, or It is administered intravenously once a month at a fixed dose of about 1700 mg, or about 1800 mg, or about 1900 mg, or about 2000 mg.

  In some embodiments, the desired pharmacokinetic properties include administering a dose of an anti-IFN-α antibody or antigen-binding fragment thereof almost daily, about every other day, about every 3 days, about every 4 days, about every 5 days, or about every 6 days. Can be achieved. In some embodiments, the desired pharmacokinetic properties are such that a dose of anti-IFN-α antibody or antigen-binding fragment thereof is administered approximately weekly, approximately every 2 weeks, approximately every 3 weeks, or approximately every 4 weeks. Can be achieved. In certain embodiments, a weight-based dose of anti-IFN-α antibody or antigen-binding fragment thereof is administered every 2 weeks. In another embodiment, the desired pharmacokinetic profile is that the dose of the anti-IFN-α antibody or antigen-binding fragment thereof is, for example, about 1 month, or about 2 months, or about 3 months, or about 4 months, Alternatively, it can be achieved by administering for about 5 months or about 6 months.

In some embodiments, the time to reach maximum plasma concentration (T _max or T _{max ss} ) following IV administration of an anti-IFN-α, such as cifarimumab, or an antigen-binding fragment thereof is about 0.13 days or less.

In some embodiments, administration of an anti-IFN-α, such as cifarimumab, or an antigen-binding fragment thereof, results in clearance rate (CL, CL _ss , CL / F, or CL _ss / F), apparent volume of distribution (V _ss Or V _z / F), serum half-life, T _max (maximum observed concentration time), T _{max ss} (maximum observed concentration time in steady state), C _max (maximum observed concentration time), C _{max ss} (maximum in steady state) Observation concentration time), AUC _τ , (area under the curve over the dosing interval), AUC _{τ ss} (area under the curve over the dosing interval at steady state), C _trough ), C _{trough ss} (observed trough concentration at steady state), half-life (ln (2) / lambda final elimination half-life, defined as _{z), CL ss,} defined as (dose / AUC _{tau ss} Serum steady state _{clearance), V ss} (steady state volume of _{distribution), AUC last} (last observation concentration from 0 hours, i.e. the area under the curve up to _{C last), AUC inf ((} AUC last + C last) is defined as a / lambda _z Area under the curve from 0 to infinity), AUC _inf extrapolation (percentage of extrapolated AUC _inf curve defined as ((C _last / λ _z ) / AUC _inf ) * 100), CL / F (apparent Serum clearance), V _z / F (apparent final distribution volume), CL _ss / F (apparent serum steady state clearance), V _c (central volume), V _p (peripheral volume), λ _z (final elimination phase) A desired pharmacokinetic property selected from a gradient), or a combination thereof.

In some embodiments, a single IV dose of about 0.3 mg / kg provides a T _max of about _0.12 days or less, about 7, about 8, about 9, about 10, about 11, about 12, about 13. , About 14 or about 15 μg / mL maximum plasma concentration (C _max ), 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 110μg day / plasma concentration in a dose interval (tau) of mL, - area under the curve (AUC _tau), and about 2.0, about 2.2, about 2.4, about 2.6, Selected from _trough plasma concentration (C _trough ) of about 2.8, about 3.0, about 3.2, about 3.4, about 3.6, about 3.8, or about 4.0 μg / mL; Achieving one or more pharmacokinetic properties.

In some embodiments, a single IV administration of about 0.3 mg / kg to a subject population has an average T _max of about 0.07 days, an average C _max of about 11 μg / mL, an average of about 79 μg day / mL. AUC _tau, and is selected from the mean _{C trough} of about 3 [mu] g / mL, to achieve one or more pharmacokinetic properties.

In some embodiments, a single IV administration of about 1 mg / kg provides a T _max of about _0.12 days or less, about 20, about 25, about 30, about 35, about 40, or about 45 μg / mL C. _max, about 150, about 175, about 200, about 225, about 250, about 275 or about 300μg day / mL of AUC _tau, and about 4, about 5, about 6, about 7, about 8, about 9, about Achieve one or more pharmacokinetic properties selected from 10, about 11, about 12, about 13, or about 15 μg / mL of C _trough .

In some embodiments, a single IV administration of about 1 mg / kg to a subject population has an average T _{max of} about 0.08 days, an average C _max of about 32 μg / mL, an average AUC _τ of about 221 μg day / mL. And achieving one or more pharmacokinetic properties selected from an average C _trough of about 8 μg / mL.

In some embodiments, a single IV administration of about 3 mg / kg has a T _max of about _0.13 days or less, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, or about 150 μg / mL C _max , 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 1050μg date / mL of AUC _tau, and 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 .mu.g, Achieves one or more pharmacokinetic properties selected from C _trough / mL.

In some embodiments, a single IV administration of about 3 mg / kg to a subject population has an average T _max of about 0.09 days, an average C _max of about 103 μg / mL, an average AUC _τ of about 739 μg day / mL. And achieving one or more pharmacokinetic properties selected from an average C _trough of about 23 μg / mL.

In some embodiments, a single IV administration of about 10 mg / kg has a T _max of about _0.13 days or less, 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 μg / mL C _max , about 900, about 1000, about 1100, about 1200, about 1300, about 1400, about 1500, about 1600, about 1700, about 1800, about 1900, about 2000, about 2100, about 2200L or about 2300μg Date / mL of AUC _τ, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, are selected from _{C trough} of about 75 or about 80 [mu] g / m,, 1 or double To achieve the pharmacokinetic properties.

In some embodiments, a single IV administration of about 10 mg / kg to a subject population has an average T _max of about 0.09 days, an average C _max of about 230 μg / mL, an average AUC _τ of about 1610 μg day / mL. And achieving one or more pharmacokinetic properties selected from an average C _trough of about 52 μg / mL.

In some embodiments, at about 14 day intervals, a sufficient number of IV doses of about 0.3 mg / kg are administered to achieve steady state and a T _{max ss} of about _0.60 days or less, about 11, 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 μg / mL C _{max ss} , about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, or about 200 μg day / mL AUC _{τ ss} , and about 5 or less (Of less), one or more steady state pharmacokinetic properties selected from about 6, about 7, about 8, about 9, about 10, or about 11 μg / mL C _{trough ss} are achieved.

In some embodiments, the subject population is administered a sufficient number of IV doses of about 0.3 mg / kg at about 14 day intervals to achieve steady state, with an average T _max of about _0.17 days, about One or more pharmacokinetic properties selected from an average C _max of 18 μg / mL, an average AUC _τ of about 143 μg day / mL, and an average C _trough of about 8 μg / mL are achieved.

In some embodiments, at about 14 day intervals, a sufficient number of about 0.3 mg / kg IV dose is administered to achieve steady state and about 90, about 100, about 110, 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 of clearance Rate (CL _ss ), apparent distribution volume (V _ss ) of about 4, about 5, about 6, about 7, about 8, or about 9 L, and about 15 days, about 20 days, about 25 days, about 30 days One or more pharmacokinetic properties selected from the group consisting of a serum half-life of about 35 days, about 40 days, or about 45 days.

In some embodiments, the subject population is administered a sufficient number of IV doses of about 0.3 mg / kg at about 14 day intervals to achieve steady state and 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, one or more pharmacokinetic properties are achieved.

In some embodiments, at about 14 day intervals, a sufficient number of about 1 mg / kg IV dose is administered to achieve steady state, with a T _{max ss} of about _0.11 or less, about 25, about 30. , About 35, about 40, about 45, about 50, about 55, about 60, about 65, or about 70 μg / mL C _{max ss} , about 200, about 250, about 300, about 350, about 400, about 450, AUC _{τ ss of} about 500, about 550, or about 600 μg day / mL, and about 9, about 11, about 13, about 15, about 17, about 19, about 21, about 23, about 25, about 27, about 29 Or one or more steady state pharmacokinetic properties selected from about 31 μg / mL C _{trough ss} .

In some embodiments, the subject population is administered a sufficient number of IV doses of about 1 mg / kg at about 14 day intervals to achieve steady state, an average T _{max ss} of about 0.07 days, about 48 μg. One or more pharmacokinetic properties are achieved selected from an average C _{max ss of} / mL, an average AUC _{τ ss} of about 197 μg day / mL, and an average C _{trough ss} of about 11 μg / mL.

In some embodiments, at about 14 day intervals, a sufficient number of about 1 mg / kg IV dose is administered to achieve steady state and 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 clearance rate (CL _ss ), about 4, about 5, about 6, about 7, about 8, or about 9L apparent distribution volume (V _ss ), and 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 One or more pharmacokinetic properties selected from the group consisting of a serum half-life of about 28, about 29, about 30, about 31, or about 32 days.

In some embodiments, the subject population is administered a sufficient number of IV doses of about 1 mg / kg at about 14 day intervals to achieve steady state and an average clearance rate (CL _ss ) of about 223 mL / day, One or more pharmacokinetic properties selected from the group consisting of an average apparent volume of distribution (V _ss ) of about 6 L and an average serum half-life of about 23 days are achieved.

In some embodiments, at about 14 day intervals, a sufficient number of IV doses of about 3 mg / kg are administered to achieve steady state, with a T _{max ss} of about _0.35 days or less, about 75, about 100. , About 125, about 150, about 175, about 200, about 225, or about 250 μg / mL C _{max ss} , about 500, about 600, about 700, about 800, about 900, about 1000, about 1100, about 1200, AUC _{τ ss of} about 1300, about 1400, about 1500, about 1600, about 1700, about 1800, or about 1900 μg day / mL, and about 25, about 30, about 35, about 40, about 45, about 50, about 55 One or more steady state pharmacokinetic properties selected from about 60, about 65, about 70, or about 75 μg / mL C _{trough ss} are achieved.

In some embodiments, the subject population is administered a sufficient number of IV doses of about 3 mg / kg at about 14 day intervals to achieve steady state, with an average T _{max ss} of about 0.13 days, about 153 μg. One or more pharmacokinetic properties are achieved that are selected from an average C _{max ss of} / mL, an average AUC _{τ ss} of about 1188 μg day / mL, and an average C _{trough ss} of about 50 μg / mL.

In some embodiments, at about 14 day intervals, a sufficient number of about 3 mg / kg IV dose is administered to achieve steady state, 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 clearance rate (CL _ss ) , 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 of apparent distribution volume (V _ss ) , And about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, or Achieve one or more pharmacokinetic properties selected from the group consisting of a serum half-life of about 26 days Made.

In some embodiments, the subject population is administered a sufficient number of IV doses of about 3 mg / kg at about 14 day intervals to achieve steady state, with an average clearance rate (CL _ss ) of about 220 mL / day, One or more pharmacokinetic properties selected from the group consisting of an average apparent volume of distribution (V _ss ) of about 5 L and an average serum half-life of about 20 days are achieved.

In some embodiments, at about 14-day intervals, a sufficient number of about 10 mg / kg IV dose is administered to achieve steady state, with a T _{max ss} of about 0.85 days or less, 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 μg / mL C _{max ss} , 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 4300μg date / mL of AUC _{tau ss,} and about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 1 0, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 260, about 270, are selected from _{C trough ss} of about 280 or about 290 micrograms / mL,, 1 One or more of the steady state pharmacokinetic properties are achieved.

In some embodiments, the subject population is administered a sufficient number of IV doses of about 10 mg / kg at about 14 day intervals to achieve steady state, with an average T _{max ss} of about 232 μg for about 0.23 days. One or more pharmacokinetic properties are achieved that are selected from an average C _{max ss of} / mL, an average AUC _{τ ss} of about 3403 μg days / mL, and an average C _{trough ss} of about 184 μg / mL.

In some embodiments, at about 14 day intervals, a sufficient number of about 10 mg / kg IV dose is administered to achieve steady state, about 150, about 160, about 170, about 180, about 190, about Clearance rate (CL _ss ) of 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, about 4 0.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, or about 7 L of apparent volume of distribution (V _ss ), and 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 Achieve one or more pharmacokinetic properties selected from the group consisting of 29 days serum half-life Made.

In some embodiments, the subject population is administered a sufficient number of IV doses of about 10 mg / kg at about 14 day intervals to achieve steady state, with an average clearance rate (CL _ss ) of about 238 mL / day, One or more pharmacokinetic properties are achieved, selected from an average apparent volume of distribution (V _ss ) of about 6 L and an average serum half-life of about 22 days.

  In some embodiments, the number of IV doses at about 14 day intervals required to achieve steady state is about 5 to about 8 doses. In some embodiments, the antibody or antigen-binding fragment thereof is administered as a single dose or once a week, once every two weeks, once every three weeks, once every four weeks, once a month Desired pharmacokinetic properties are achieved after administration of more than one dose once, once every three months, once every six months, or at varying intervals. In some embodiments, the desired pharmacokinetic parameter is achieved after subcutaneous (SC) administration.

  In some embodiments, the desired pharmacokinetic properties are achieved after administration of 100 mg of anti-IFN-α administered as a single dose or administered weekly, biweekly, or monthly. In some embodiments, the desired pharmacokinetic properties are achieved after administration of 150 mg of anti-IFN-α administered as a single dose or administered weekly, biweekly, or monthly. In some embodiments, the dose is administered intravenously. In another embodiment, the dose is administered subcutaneously.

In some embodiments, a T _max or T _{max ss of} about 1.8 to about 9.4 days is achieved. In some embodiments, T _max or T _{max ss} is about 2 days or less, about 3 days or less, about 4 days or less, about 5 days or less, about 6 days or less, about 7 days or less, about 8 days or less, about 9 days or less, or about 10 days or less.

In some embodiments, a single SC dose of about 100 mg / kg is about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 days T _max , About 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20 Or about 21 μg / mL C _max , 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 The area under the plasma concentration-time curve (AUC _last ) from 0 to the last measurable concentration time of 500, about 525, about 550, about 575, about 600, about 625, about 650, or about 675 μg day / mL, and 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, about 675, about 700, about 725, about 750, or about 775μg day / infinity plasma concentration from 0 hours mL - it is selected from the area under the curve (AUC _∞), to achieve one or more pharmacokinetic properties.

In some embodiments, administration of about 100 mg of a single SC to a subject population has an average T _max of about 6 days, an average C _max of about 13 μg / mL, a final measurable concentration from about 0 hours of about 421 μg day / mL. One or more selected from the mean plasma concentration-time area under the curve (AUC _last ) and the mean plasma concentration-time area under the curve (AUC _∞ ) from 0 to infinity of about 477 μg day / mL Achieve pharmacokinetic properties.

In some embodiments, a single SC dose of about 100 mg is 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 clearance rate (CL / F), 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 11, about 11.5 or about 12 L of apparent distributed volume (V _z / F ), And about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, Selected from a serum half-life of about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, or about 34 days To achieve one or more pharmacokinetic properties.

In some embodiments, administration of about 100 mg of a single SC to a subject population has an average clearance rate (CL / F) of about 275 mL / day, an apparent volume of distribution (V _z / F) of about 8 L, and about To achieve one or more pharmacokinetic properties selected from a serum half-life of 25 days.

In some embodiments, at about 7 days (weekly) intervals, a sufficient number of SC doses of about 100 mg are administered to achieve steady state, 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 T _{max ss} , 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 μg / mL C _{max ss} , 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 μg day / mL AUC _{τ ss} , and about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, C of about 75 or about 80 [mu] g / mL, It is selected from the _{rough ss,} 1 or more steady state pharmacokinetic properties are achieved.

In some embodiments, the subject population is administered a sufficient number of about 100 mg of SC dose at about 7 day intervals (weekly) to achieve steady state, with an average T _{max ss} for about 4 days, about 65 μg / One or more steady state pharmacokinetic properties are achieved selected from an average C _{max ss of} mL, an average AUC _{τ ss} of about 443 μg day / mL, and an average C _{trough ss} of about 59 μg / mL.

In some embodiments, at about 7-day intervals (weekly), a sufficient number of SC doses of about 100 mg are administered to achieve steady state and 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 clearance rate (CL _ss / F), about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, about An apparent distributed volume (V _{z) of} 10, about 10.5, about 11, about 11.5, about 12, about 12.5, about 13, about 13.5, about 14, about 14.5, or about 15 L / F), and about 22, about 23, about 24 or less (of less) One or more steady-states selected from a serum half-life of about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, or about 35 days Pharmacokinetic properties are achieved.

In some embodiments, the subject population is administered a sufficient number of SC doses of about 100 mg at about 7 day intervals (weekly) to achieve steady state and an average clearance rate (CL _ss ) of about 282 mL / day. One or more steady state pharmacokinetic properties are achieved, selected from: an average apparent volume of distribution (V _z / F) of about 11 L, and an average serum half-life of about 28 days.

In some embodiments, at 14-day intervals (biweekly), a sufficient number of SC doses of about 100 mg are administered to achieve steady state, 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 T _{max ss} , about 30, about 32, about 34, about 36, about 38, about 40, about 42, about 44, about 46, about 48, or about 50 μg / mL C _{max ss} , 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 μg day / mL AUC _{τ ss} , 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 3 , About 37, about 38, are selected from _{C trough ss} of about 39, or about 40 [mu] g / mL,, 1 or more steady state pharmacokinetic properties are achieved.

In some embodiments, the subject population is administered a sufficient number of about 100 mg SC dose at about 14-day intervals (biweekly) to achieve steady state, with an average T _{max ss} of about 4 μg / One or more steady state pharmacokinetic properties are achieved, selected from an average C _{max ss of} mL, an average AUC _{τ ss} of about 495 μg day / mL, and an average C _{trough ss} of about 30 μg / mL.

In some embodiments, at about 14 day intervals (biweekly), a sufficient number of about 100 mg of SC dose is administered to achieve steady state, about 170, about 175, about 180, about 185, about 190, A clearance rate (CL _ss / F) of about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 235, or about 240 mL / day, about 6 or less (of less), An apparent distribution volume (V _z / F) of about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10 L, and about 18, about 20 Achieve one or more steady-state pharmacokinetic properties selected from serum half-life of about 22, about 24, about 26, about 28, about 30, about 32, about 34, about 36, or about 38 days Is done.

In some embodiments, the subject population is administered a sufficient number of about 100 mg of SC dose at about 14-day intervals (biweekly) to achieve steady state and an average clearance rate (CL _ss ) of about 406 mL / day. One or more steady state pharmacokinetic properties are achieved, selected from: an average apparent volume of distribution (V _z / F) of about 8 L, and an average serum half-life of about 28 days.

In some embodiments, at about 30 day intervals (monthly), a sufficient number of about 100 mg of SC dose is administered to achieve steady state, 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 T _{max ss} , 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 μg / mL C _{max ss} 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 μg day / mL AUC _{tau ss,} and about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, about 0, about 10.5, about 11, about 11.5, about 12, about 12.5, about 13, selected from about 13.5, about 14, _{C trough ss} of about 14.5, or about 15 [mu] g / mL, One or more steady state pharmacokinetic properties are achieved.

In some embodiments, the subject population is administered a sufficient number of about 100 mg of SC dose at about 30 day intervals (monthly) to achieve steady state, with an average T _{max ss} of about 49 μg / One or more steady state pharmacokinetic properties are achieved, selected from an average C _{max ss of} mL, an average AUC _{τ ss} of about 483 μg day / mL, and an average C _{trough ss} of about 11 μg / mL.

In some embodiments, a sufficient number of SC doses of about 100 mg are administered at about 30 day intervals (monthly) to achieve steady state, 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 clearance rate (CL _ss / F), about 5, An apparent distributed volume (V _z / F) of about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, or about 17 L, and 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 of serum One or more steady state pharmacokinetic properties selected from half-life Is achieved.

In some embodiments, the subject population is administered a sufficient number of SC doses of about 100 mg at intervals of about 30 days (monthly) to achieve steady state and an average clearance rate (CL _ss ) of about 227 mL / day. One or more steady state pharmacokinetic properties are achieved, selected from: an average apparent volume of distribution (V _z / F) of about 11 L, and an average serum half-life of about 33 days.

Dosing that achieves the desired pharmacodynamic properties The term “pharmacodynamic properties” includes parameters that describe the biological effects of an administered drug, such as, for example, an anti-IFN-α antibody or antigen-binding fragment thereof, such as cyfarimumab. One such characteristic is the expression of specific genes that can serve as PD markers. In particular, certain genes, when overexpressed in patients suffering from autoimmune diseases, are compared to gene expression in healthy patients or compared to a number of housekeeping genes, type I IFN or IFN- It may serve as an α-inducible PD marker expression profile.

  The group of genes included in a patient's type I IFN or IFN-α-inducible PD marker expression profile is (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.

  In certain embodiments, the group of genes included in the patient's type I IFN or IFN-α-inducible PD marker expression profile comprises IFI27, IFI44, IFI44L, IFI6, and RSAD2. In another specific embodiment, the group of genes included in the patient's type I IFN or IFN-α-inducible PD marker expression profile consists of IFI27, IFI44, IFI44L, IFI6, and RSAD2. In a further specific embodiment, the group of genes included in the patient's type I IFN or IFN-α-inducible PD marker expression profile comprises IFI27, IFI44, IFI44L, and RSAD2. In another specific embodiment, the group of genes included in the patient's type I IFN or IFN-α-inducible PD marker expression profile consists of IFI27, IFI44, IFI44L, and RSAD2.

  IFN-α-inducible PD markers in the expression profile are (a) IFI27, IFI44, IFI44L, IFI6, and RSAD2; or (b) IFI44, IFI44L, IFI6, and RSAD2; or (c) IFI27, IFI44L, IFI6 And (d) IFI27, IFI44, IFI6, and RSAD2; or (e) IFI27, IFI44, IFI44L, and RSAD2; or (f) IFI27, IFI44, IFI44L, and IFI6.

  IFN-α-inducible PD markers in the expression profile are (a) IFI27, IFI44, IFI44L, IFI6, and RSAD2; or (b) IFI44, IFI44L, IFI6, and RSAD2; or (c) IFI27, IFI44L, IFI6 And (d) IFI27, IFI44, IFI6, and RSAD2; or (e) IFI27, IFI44, IFI44L, and RSAD2; or (f) IFI27, IFI44, IFI44L, and IFI6.

  Alternative gene sets that may serve as PD markers include IFI44, IFI27, IFI44L, DNAPTP6, described in US patent application Ser. No. 12 / 598,526 filed May 5, 2008, Examples include 21 genes of LAMP3, LY6E, RSAD2, HERC5, IFI6, ISG15, OAS3, SIGLEC1, OAS2, USP18, RPT4, IFIT1, MX1, OAS1, EPST1, PLSCR1, and IFRG28. See Table 24 in paragraph [0500] below.

  Up-regulation or down-regulation of type I IFN or IFN-α-inducible PD markers in a patient's expression profile is either from a sample that is not the patient's disease tissue (eg, non-lesional skin of a psoriatic patient), or a disease or disorder Compared to a sample from a control (which may be from an unaffected healthy person) or to a gene from a patient whose expression has not been altered by the disease (a so-called “housekeeping” gene) Any degree is acceptable.

  The degree of upregulation or downregulation is 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% of the control or control sample, 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 than that.

The type I IFN or IFN-α-inducible PD marker expression profile may be calculated as the mean fold increase in expression or activity of the gene set comprising the PD marker. Type I IFN or IFN-alpha-inducible PD marker expression profile also includes a mean _{C t} of the four target genes (cycle threshold) may be calculated as the difference between the average _{C t} of the three control genes.

  The average fold increase in expression or activity of the gene set may be at least about 2 to at least about 15, at least about 2 to at least about 10, or at least about 2 to at least about 5. The average fold increase in expression or activity of the gene set is 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 allows the identification of fold change cutoffs to identify signature positive and signature negative patients suffering from autoimmune disease. In one embodiment, 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 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 from about 2 to about 8. In one embodiment, the cutoff is the average of at least four increased expression levels of IFI27, IFI44, IFI44L, IFI6, and RSAD2. In another embodiment, the cutoff is the median level of increased expression of at least four of IFI27, IFI44, IFI44L, IFI6, and RSAD2.

The degree of increased expression also allows the identification of a ΔC _t cut-off to identify signature positive and signature negative patients suffering from autoimmune diseases. In one embodiment, the cutoff is at least about 7.6. In another embodiment, the cutoff is 7.56. A fold change cut-off may be used to determine an appropriate ΔC _t cut-off (eg, log 2 for fold change greater than 1 and less than 3 corresponds to a ΔC _t range of 8.65 to 6.56). ). Thus, in another embodiment, the ΔCt cutoff is from about 6.56 to about 8.56.

  Further, the patient has 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 of the type I IFN subtype. %, 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% May have a tissue that overexpresses. The type I IFN subtype may be any one of IFNα1, IFNα2, IFNα4, IFNα5, IFNα6, IFNα7, IFNα8, IFNα10, IFNα14, IFNα17, IFNα21, IFNβ, or IFNω. Type I IFN subtypes include all of IFNα1, IFNα2, IFNα8, and IFNα14.

  In an IFN-α-inducible PD marker expression profile, the up-regulated expression or activity of any gene detected in the sample by the probe or by the probe in the kit is, for example, that of healthy volunteer cells or control animals. At least 1.2 times, at least 1.25 times, at least 1.3 times, at least 1.4 times, at least compared to the baseline level of control cells, such as cells or cells not exposed to IFN in culture 1.5 times, at least 2.0 times, at least 2.25 times, at least 2.5 times, at least 2.75 times, at least 3.0 times, at least 3.5 times, at least 4.0 times, at least 4. 5 times, at least 5.0 times, at least 6.0 times, at least 7.0 times, at least 8.0 times, less 9.0-fold, at least 10.0-fold, at least 15.0-fold, at least 20.0-fold, it may be at least 25.0-fold, or at least 50.0-fold. All of the genes in the IFN-α-inducible PD marker expression profile may have up-regulated expression or activity with the same fold increase. Alternatively, genes in the PD marker expression profile may have varying levels of upregulated expression or activity.

Measurement of up-regulation Up- or down-regulation of gene expression or activity of an IFN-α-inducible PD marker may be measured by any means known in the art. For example, up or down regulation of gene expression may be detected by measuring mRNA levels. mRNA expression may be determined by Northern blotting, slot blotting, quantitative reverse transcriptase polymerase chain reaction, or gene chip hybridization techniques. See US Pat. No. 5,744,305 and US Pat. No. 5,143,854 for examples of creating nucleic acid arrays for gene chip hybridization techniques. For examples of the use of the TAQMAN® method to measure gene expression, see Establishing and functional charactarization of an HEK-293 cell line expressing autofluorescently-β-actin-pC R) Hrobat, A; Zavec, AB; Pogacnik, A; Frangez, R; Vrecl, M 2010 Cellular & Molecular Biology Letters 1, 55-69, Expression profiles of proliferators. gennes in sporadic and colitis-related mouse colon cancer models svec, J; Ergang, P; Mandys, V; Kment, M; Pacha, J 2010 International Journal. ribofuranosylbenzimidazole module the cellular accumulation and cytotoxity of cisplatin in a dependent-man Kuroka, T; HeGA; iddik, see ZH 2010 Cancer Chemotherapy and Pharmacology 3,427-436.

  A primer that selectively binds to a target during the polymerase chain reaction (PCR) empirically determines a primer that hybridizes during the PCR reaction and produces a signal sufficient to detect the target in the background. Can be selected on the basis of Maniatis et al. The primer: target duplex melting temperature as described in Molecular Cloning, Second Edition, Section 11.46.1989 can be used to predict. Similarly, probes or related methods for detecting PCR products in TAQMAN® can be empirically selected or predicted. Such primers and probes (collectively “oligonucleotides”) may be 10-30 nucleotides or more in length.

  Upregulation or downregulation of IFN-α-inducible PD marker gene expression or activity may be determined by detecting protein levels. Methods for detecting protein expression levels include immune-based assays such as enzyme-linked immunosorbent assays, Western blotting, protein arrays, and silver staining.

  The IFN-α-inducible PD marker expression profile may comprise a profile of protein activity. Up- or down-regulation of IFN-α-inducible PD marker gene expression or activity includes, but is not limited to, detectable phosphorylation activity, dephosphorylation activity, or cleavage activity You may determine by detecting activity. Furthermore, up- or down-regulation of gene expression or activity of IFN-α-inducible PD markers may be determined by detecting any combination of expression levels or activities of these genes.

Neutralization of Type I IFN or IFN-α-Inducible Profiles in Patients Treatment with an anti-IFN-α antibody or antigen-binding fragment thereof neutralizes the type I IFN or IFN-α-inducible profile. Treatment with an anti-IFN-α antibody or antigen-binding fragment thereof results in the alleviation of one or more symptoms of a type I IFN or IFN-α-mediated disease or disorder. Treatment with an anti-IFN-α antibody or antigen-binding fragment thereof reduces the rapid exacerbations associated with type I IFN or IFN-α mediated diseases or disorders. Treatment with an anti-IFN-α antibody or antigen-binding fragment thereof provides an improved prognosis for patients with type I IFN or IFN-α-mediated diseases or disorders. Treatment with an anti-IFN-α antibody or antigen-binding fragment thereof results in a higher quality of life for the patient. Treatment with an anti-IFN-α antibody or antigen-binding fragment thereof alleviates the need to co-administer a second agent (eg, a steroid) or reduces the dose of the second agent to the patient. good. Treatment with an anti-IFN-α antibody or antigen-binding fragment thereof reduces the number of patient hospitalizations associated with a type I IFN or IFN-α-mediated disease or disorder.

  The anti-IFN-α antibody or antigen-binding fragment thereof neutralizes the type I IFN or IFN-α-inducible profile. The neutralization of the type I IFN or IFN-α-inducible profile may be a reduction of at least 1, at least 2, at least 3, at least 4 genes. Neutralization of type I IFN or IFN-α-inducible profile is at least 1, at least 2, at least 3, at least 4 genes up-regulated in type I IFN or IFN-α-inducible profile 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%.

  Alternatively, neutralization of the type I IFN or IFN-α-inducible profile refers to an upregulated decrease in type I IFN or IFN-α-inducible gene expression, which is the control of these I Up to 50%, up to 45%, up to 40%, up to 35%, up to 30%, up to 25%, up to 20%, maximum of expression levels of type IFN or IFN-α-inducible genes 15% at maximum, 10% at maximum, 5% at maximum, 4% at maximum, 3% at maximum, 2% at maximum, or 1% at maximum. Anti-IFN-α antibodies or fragments thereof are 0.3-30 mg / kg, 0.3-10 mg / kg, 0.3-3 mg / kg, 0.3-1 mg / kg, 1-30 mg / kg, 3- Neutralizes type I IFN or IFN-α profiles at doses of 30 mg / kg, 5-30 mg / kg, 10-30 mg / kg, 1-10 mg / kg, 3-10 mg / kg, or 1-5 mg / kg May be. In certain embodiments, type I IFN or IFN-α profiles are neutralized by about 40% when cifarimumab is administered weekly at 100 mg subcutaneous dose.

  All of the references cited above, as well as all references cited herein, are hereby incorporated by reference in their entirety.

  The following examples are provided by way of illustration and are not intended to be limiting.

Example 1
Intravenous pharmacokinetics and immunogenicity of cifalimumab body weight-based regimen administered intravenously to SLE patients Cifalimumab intravenously administered every 14 days in a phase Ib study in adult patients with moderate to severe SLE Internal (IV) weight-based doses of PK and immunogenicity (IM) were studied to evaluate the safety profile of cyfarimumab.

1. Method 1.1. Study Design This was a 14-arm, multi-center, randomized, double-blind, placebo-controlled dose escalation study in 161 patients with moderate to severe SLE. 161 patients were randomized in a 3: 1 ratio to receive sifarimumab or placebo. Cifalimumab was administered every 14 days as a 60 minute IV infusion. Four IV cifarimumab doses of 0.3, 1.0, 3.0, and 10 mg / kg were used.

  Inclusion criteria for subjects who received an antibody or antigen-binding fragment thereof intravenously are US National Institutes of Health clinicaltrials. Summarized in the clinical trial identifier NCT00482989, accessible through the gov database. Accordingly, inclusion criteria comprise: adult males or females are about 18 to about 95 years old at the first dose of study drug; subjects are subject to the revised American College of Rheumatology classification criteria for 11 SLEs (Appendix A) , ACR, 1999); subjects had previously tested positive for antinuclear antibodies (ANA) at serum dilutions of ≧ 1: 80 at or prior to screening; At screening, the BILAG index had at least one system with a score A, or two systems with a score B, or had a SELENA-SLEDAI score of ≧ 6.

Exclusion criteria included: MEDI-545 was administered within 120 days prior to screening, or at the time of screening, detectable levels of MEDI-545 or anti-medi-545 antibody (> A history of allergy or reaction to any component of the study drug; within 14 days prior to randomization / participation,> 20 mg / day prednisone (or equivalent) Dose of another oral corticosteroid); within 28 days prior to randomization / participation,> 600 mg / day hydroxychloroquine,> 3 g / day mycophenolate mofetil,> 25 mg / week methotrexate, > 3 mg / kg / day azathioprine, or any dose of cyclophosphamide, cyclosporine, or Administered doses of Lidomide; received> 20 mg / day of leflunomide within 6 months prior to study day 0; variable doses of antimalarials within 28 days prior to randomization / participation; Received mycophenolate mofetil, methotrexate, leflunomide, or azathioprine, or received variable doses of NSAIDs or oral corticosteroids within 14 days prior to randomization / participation; 28 days prior to randomization / study participation Treatment with any investigational drug therapy within, randomization / B cell depletion therapy within 12 months prior to participation, or within 30 days prior to randomization / study participation or within 5 half-life of biological agent, whichever is longer Clinical treatment; evidence of clinically significant active infections, including ongoing chronic infections within 28 days prior to randomization / participation; cytomega History of severe viral infections at the discretion of the investigator, including a viral or disseminated herpes, herpes encephalitis, ophthalmic herpes, or any other herpes, such as ophthalmic herpes; randomized / pre-participation 3 Herpes zoster infection within months; evidence of infection with hepatitis B or C virus, or HIV-1 or HIV-2, or active infection with hepatitis A, as determined by screening test results; 28 prior to randomization / participation Vaccination with live attenuated virus within days; pregnancy (female, surgically sterile or at least 2 years after menopause, negative serum pregnancy test within 28 days before study drug administration, and negative before dosing on study day 0 Breastfeeding or lactating women; history of primary immunodeficiency; alcohol for less than 1 year prior to randomization / participation Or a history of drug abuse; a history of cancer (excluding basal cell tumors or cervical intraepithelial neoplasia that was clearly and successfully treated with curative therapy prior to one year prior to randomization / participation ); History of active TB infection; history of latent TB infection or a new positive TB skin test (response is systemic) where appropriate treatment has not been completed or preventive treatment is ongoing ≥10 mm diameter if not taking immunosuppressive drugs, ≥5 mm if taking systemic immunosuppressive drugs); premature surgery planned from screening to clinical trial 196; Any of the following in a screening blood test (within 28 days prior to randomization / participation): (i) AST at> 2 × upper limit of normal range (ULN), as determined by investigator, unless caused by SLE, (I )> 2 × ULN ALT, (iii)> 4.0 mg / dL creatinine, (iv) neutrophil “1,500 / μL (<1), as determined by investigators, except when caused by SLE .5 × 10 ⁹ / L) ”, (v) Platelet count“ platelet count <50,000 / μL (<50 × 10 ⁹ / L) ”; in the view of the researcher or medical monitor, History of any disease, evidence of any current disease (other than SLE), any findings during a physical examination, or any abnormal laboratory findings that could compromise safety or confound the analysis of the study.

  The inclusion and exclusion criteria listed above are not intended to limit the scope of the invention. One skilled in the art may use other inclusion and / or exclusion parameters to create a subject population so that subject selection does not compromise subject safety or confound study analysis. You will understand that.

  At multiple time points, trough serum samples were taken for PK concentration and IM titer. Samples were analyzed for PK using a validated enzyme-linked immunosorbent assay (ELISA) and analyzed for IM using a validated bridging electrochemiluminescence assay (ECL).

1.2. Measurement of anti-cifarimumab antibodies in human serum samples using a validated colorimetric bridging ELISA method (preliminary research screening sample)
As part of the subject's preliminary study evaluation for inclusion in the study, sera were evaluated for anti-cifarimumab antibody responses. Serum samples were measured for the presence of anti-cifarimumab antibodies using a colorimetric bridging ELISA. Serum samples were diluted 1:10 and placed in microtiter plates coated with cyfarimumab. Following the wash step, biotinylated cyfarimumab was added and allowed to bind to the captured anti-cifarimumab antibody. Plates were washed and horseradish peroxidase conjugated streptavidin was added followed by tetramethylbenzidine substrate for detection of cross-linked complexes. Plates were measured using a Molecular Devices SpectraMax microplate reader at a wavelength of 450 nm and the results were analyzed using SOFTmax® PRO software. The intensity of the reaction color was proportional to the amount of anti-cifarimumab antibody present in the sample.

  In the assay, three positive controls ranging from 15 to 1500 ng / mL and one negative spike control (0.75 ng / mL) prepared by adding goat anti-cifarimumab anti-idiotype antibody to pooled normal human serum. And were used. For each assay plate, the negative / positive cut-off value of the sample was determined and calculated by multiplying the average of 6 unique human serum samples measured on the plate by 1.5. Samples with responses below the plate cut-off value were classified as negative and assigned a titer of <10 (less than the reciprocal of the minimum required sample dilution). Samples with responses above the plate cutoff value were classified as positive and subsequently tested for titer. Titers were run with serial dilutions of samples in a pooled normal human serum matrix and the highest 1: 2 (minimum required sample dilution) that was determined to be positive in the assay before a negative response was returned. Reported as the reciprocal of the dilution (greater than 1:10).

  Validation methods include accuracy and accuracy of classification and titer, intermediate accuracy, reproducibility, robustness, linearity of dilution, specificity of detection, analyte stability in human serum, and in normal human and SLE patient serum samples Acceptability criteria were met for selectivity. The estimated concentration of assay cut-off was determined to be 4.5 ng / mL using a polyclonal goat anti-cifarimumab antibody surrogate control. In serum samples containing 100 ng / mL of cyfarimumab drug, an anti-cifarimumab antibody concentration of 500 ng / mL was detectable (but not 100 ng / mL).

1.3. Measurement of cifarimumab in human serum using a validated colorimetric ELISA method Cifarimumab was measured in human serum samples using a colorimetric ELISA method validated for human serum. In the assay, microtiter plates were coated with 0.5 μg / mL goat anti-sifalimumabu idiotype antibody, blocked with casein buffer and washed. Sifalimumab standards are diluted in human serum standards to prepare calibration standards (0.3-160 μg / mL) and control samples in assay buffer containing 0.5% casein and 5% goat serum. Controls and unknown samples were diluted 1: 1000 and placed in plates at 50 μL / well.

  Following the incubation, the plates were washed to remove unbound material and horseradish peroxidase conjugated goat anti-human IgG was added for binding of captured cyfarimumab. Plates were washed and pre-warmed 2,2'-azino-bis- (3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) peroxidase substrate was added. 1% sodium dodecyl sulfate (SDS) stop solution was added to stop the reaction.

  Plates were measured using a Molecular Devices SpectraMax microplate reader at a wavelength of 405 nm and the results analyzed using SOFTmax® PRO software. The intensity of the reaction color was proportional to the amount of anti-cifarimumab antibody present in the sample. The quality control and cyfarimumab concentration in the unknown samples were interpolated from the standard curve using a 4-parameter logistic fit. The lower limit of assay quantification (LLOQ) was determined to be 1.25 μg / mL and the upper limit of quantification (ULOQ) was determined to be 40 μg / mL.

  Method validation includes acceptable accuracy, reproducibility, intermediate accuracy, selectivity (evaluated in serum samples from humans with normal humans and SLE), specificity, linearity of dilution, robustness, and in human serum Demonstrated the stability of cifarimumab. Quantification of cifarimumab at the 3.0 and 36.0 μg / mL levels was not affected in the presence of 2 ng / mL interferon alpha target.

1.4. Measurement of anti-cifarimumab antibodies in human serum samples using a validated sensitive ECL method ECL, a solution-phase bridging immunoassay using mesoscale discovery (MSD) technology, was developed for anti-cifarimumab antibodies in human serum. Developed and validated for detection, confirmation, and dose setting. In this method, biotinylated cifarimumab and rutenylated cifarimumab were cultured overnight with human serum samples. Because of the bivalent nature of the antibody, some of the anti-cifarimumab antibody (ADA) present in the sample binds simultaneously to both conjugated forms of cifarimumab. Samples were then streptavidin-coated and cultured on MSD plates in order to capture ADA cross-linked complexes.

  The plate was then washed to remove unbound material, reading buffer was added, and the plate was placed on the MSDSector ™ Imager for generation and measurement of the ECL response. Application of current to the electrode-containing plate conjugated the ruthenium chelate to cifarimumab and allowed to emit light in the presence of a reading buffer containing tripropylamine. The sample containing ADA bound to both the biotin and ruthenium conjugated forms of cifarimumab and produced an ECL signal. The signal intensity as measured by MSD Sector Imager was proportional to the amount of anti-cifarimumab antibody present in the sample.

  The method uses pooled normal human sera as a negative control, with two levels (3.0 and 1000 ng / mL) of goat anti-sifalimumabu idiotype antibody (surrogate control) above the detection level as positive controls. Spiked, pooled standard human serum was used. The presence of anti-cifarimumab antibody was determined for each plate compared to the cut-off ECL value calculated by multiplying the average response of negative control 6-8 wells by a cut point factor of 1.18. A cut point factor of 1.18 was established during validation from 200 measurements of serum samples obtained from 50 normal individuals and was determined statistically to provide a false positive rate of 5%. Samples measured above the cut point ECL value are considered positive for anti-cifarimumab antibodies and are confirmed (specificity) assays in both the absence and presence of excess (300 μg / mL) cifarimumab. Retested.

  A confirmatory cut point was established during method validation using the percent inhibition measurements of the samples described above, tested both in the absence and presence of excess (300 μg / mL) cifarimumab. The confirmatory cut point was determined statistically to provide a false positive rate of 0.1% and was determined to be 27.0%. The screening cut-point factor and confirmatory cut-point for SLE serum samples were assessed using measurements of serum samples from 50 SLE patients and were calculated as 1.23% and 37.1%, respectively. A test sample was considered positive for anti-cifarimumab antibody if the percentage inhibition of response in the presence of excess cifarimumab was greater than 27%, a more conservative confirmatory cut point. The confirmed positive samples were then measured in a titer assay.

  The titer is determined by running serial dilutions of the sample with a negative control serum and the highest 1: 2 (minimum sample dilution of 1:10 required) measured positive in the assay before a negative response is returned. Reported as the reciprocal of dilution. The titer of the negative sample was reported as <10. Method validation met acceptance criteria for accuracy and accuracy of classification and titer, intermediate accuracy, reproducibility, robustness, linearity of dilution, specificity of detection, and analyte stability in human serum. Assay sensitivity was estimated using a polyclonal goat anti-cifarimumab antibody surrogate control, as well as a monoclonal anti-cifarimumab antibody of known affinity (Kd = 1.30 nM). The approximate concentration of the anti-cifarimumab 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-cifarimumab antibody levels of 250-500 ng / mL and polyclonal anti-cifarimumab antibody levels of 500 ng / mL were detectable in sera containing 100 μg / mL cyfarimumab.

1.5. Data Analysis Pharmacokinetic concentrations were analyzed using the non-compartment method of WinNonlin (version 5.2.1 Pharsight, Cary, NC).

2. Result 2.1. Pharmacokinetics Serum cifarimumab PK results are summarized in Table 2 and Table 3, respectively, following the first dose and after the final dose on day 182. After the first dose, cifarimumab peak plasma concentration (C _max ), the area under the plasma concentration-time curve from time 0 to the end of the dosing interval (AUC _τ ), and trough concentration (C _trough ) increase in proportion to the dose (Table 2). C _max values ranged from 10.90 μg / mL at a 0.3 mg / kg dose to 229.74 g / mL at a 10 mg / kg dose. AUC _τ values were 79.39 μg. At a dose of 0.3 mg / kg. From day / mL to 1,610 μg. At a dose of 10 mg / kg. The range was days / mL. C _trough values ranged from 2.75 μg / mL at a 0.3 mg / kg dose to 51.52 μg / mL at a 10 mg / kg dose.

  Steady-state trough concentrations at each test dose were achieved within 3 months (Figure 1, Table 3). Shown in the graph of FIG. 1 are the mean and standard deviation values of nominal time points (scheduled blood collection) of available patients. If the value was below the quantification limit, the value was treated as missing. The plotted values are shown in Table 9.

Steady-state peak plasma concentration (Cmax ss) values ranged from 17.74 μg / mL at a 0.3 mg / kg dose to 441.79 μg / mL at a 10 mg / kg dose. Plasma concentration within the dosing interval - time steady state area under the curve (AUC _{tau ss)} value, 143.2Myug in 0.3 mg / kg dose. From day / mL to 3,403 μg. At a dose of 10 mg / kg. The range was days / mL. Steady-state trough concentration (C _{trough ss} ) values ranged from 7.89 μg / mL at a 0.3 mg / kg dose to 183.97 μg / mL at a 10 mg / kg dose.

After the final dose on day 182, the mean steady state clearance (CL _ss ) ranges from 185 to 238 mL / day, the mean final half-life ranges from 20 to 29 days between dose groups, and the steady state distribution volume ( V _ss ) ranged from 5 to 6 L between dosing groups (Table 3).

2.2. Immunogenicity Of the 121 patients, 27 (22.3%) received the study drug, and one of 40 patients who received placebo (2.5%) received anti-cifalimumab antibody. Positive for presence. 3 of 26 patients (11% incidence) who received 0.3 mg / kg dose of cifalimumab (FIG. 2A), 7 of 25 patients who received 1 mg / kg dose (28%) (Incidence) (FIG. 2B) 7 out of 27 patients who received the 3 mg / kg dose (25.9% incidence) (FIG. 2C) and of 43 patients who received the 10 mg / kg dose Ten (23.3% incidence) (FIG. 2D) were judged positive for the presence of anti-cifarimumab antibody. Positive titers ranged from 10 to 1280 and 17 subjects were 80 or less, indicating low titers of anti-cifarimumab antibodies (FIG. 3).

  The presence of anti-cifarimumab antibody did not affect the clearance of cifarimumab (FIG. 4). Therefore, cyfarimumab had an acceptable safety and tolerability profile at the test dose.

3. Conclusion Cifarimumab PK was linear and dose proportional following intravenous administration over a dose range of 0.3 mg / kg to 10 mg / kg. The serum clearance, volume of distribution, and terminal half-life of cifarimumab are typical for monoclonal antibodies without a significant antigen sink. The overall incidence of anti-cifarimumab antibodies is 22%, with positive titers ranging from 10-1280. The presence of anti-cifarimumab antibody did not affect the pharmacokinetics of cifarimumab.

Example 2
Cifarimumab Population Pharmacokinetics in SLE Patients The primary objective of this analysis is to (a) model cifarimumab population pharmacokinetics (PK); (b) identify the impact of patient / disease characteristics on PK variability And (c) to evaluate a fixed dosing schedule versus weight-based dosing.

  Since most biologics are administered based on body weight, dosing based on a fixed body weight is unusual. However, for anti-Her2 antibodies, PK data suggested that fixed dosing may be possible. See for example US Pat. No. 7,449,184. Because the body weight of clinical trial subjects ranged from 43 kg to 120 kg, it was uncertain whether the PK data would support a fixed dose of cyfarimumab. Further, unlike the Her2 antibody discussed in US Pat. No. 7,449,184, cifarimumab binds to multiple targets whose expression may vary between patients, and thus potentially more complex PK profiles Have

1. Population Pharmacokinetic Analysis Procedure From the study described in Example 1, cifarimumab serum concentration-time data was collected. Cifarimumab serum concentration was determined by a validated colorimetric ELISA as described in Example 1. Cifarimumab pharmacokinetic data was analyzed using a non-linear mixed effects modeling approach. 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/). Data management and graphical analysis were performed using S-plus 8.1 (TIBCO Spotfire, Somerville, MA, USA), Xpose 4.0 (University of Uppsala, Uppsala, Sweden), and R2.7.1 (http: // cnt. -Implemented using project.org/) software. The various steps involved in the modeling process are described below.

  A series of structural models were evaluated for cifarimumab based on Akaike's Information Criterion (AIC) values, objective function values, accuracy, validity of parameter estimates, and goodness-of-fit plots. Inter-subject variability in pharmacokinetic parameters was assumed to follow a lognormal distribution and was modeled using an exponential function. Residual variability was assessed using isodisperse (additive), heterodisperse (proportional), or a combination of proportional and additive models. The accuracy of the population estimate was evaluated based on the relative standard deviation (RSE) percentage.

  After identifying the structural model, covariate model construction was performed to assess the effect of patient / disease characteristics on pharmacokinetic parameters. Age, gender, ethnicity, range, weight (WT), baseline steroid use (BSTEROID), baseline systemic lupus erythematosus disease activity index (BSLEDAI) score, baseline gene signature from 21 genes (BGENE21), and 4 Various patient / disease characteristics were assessed, including a baseline gene signature from the gene (BGENE4).

  A pre-assessment of the covariate effect was performed using a generalized additive modeling (GAM) approach implemented in Xpose (Jonsson et al, 1999). Based on GAM results and mechanistic understanding of the nature of cifarimumab, NONEMEM was used to further test the reasonable covariates of each parameter for significance. Model building is performed using a stepwise forward addition (p <0.05) (ΔOFV> 3.84) approach followed by a backward deletion (p <0.01) (ΔOFV> 6.63) process. It was. A covariate was included in the final model if the p value <0.01 (ΔOFV> 6.63), provided that the covariate was valid based on the pharmacology of cifarimumab.

  The following criteria were used to evaluate the improvement of the model at each step: (a) reduction in objective function values; (b) improved agreement between observed concentrations and population / individual predicted serum concentrations; (c) Reduced variability within subject and between subjects; (d) reduced range of weighted residuals; (e) uniformity of weighted residual distribution for predicted concentrations around a one-to-one corresponding line; and (f ) Improved parameter accuracy. All models were run using conditional first-order approximation (FOCE) by the interaction method.

式中、θは推定されるパラメータであり、θ１は共変量の中央値がある個人における薬物動態学的パラメータ（Ｐ）の典型的な値を表す。θ２は、特定の共変量効果の係数を表す。 Using the covariates normalized to the median population of the data set, the correlation between continuous covariates and pharmacokinetic parameters was modeled using a nonlinear power function [Equation (1)]. Category covariates were modeled using the fractional change rate function [Equation (2)].

Where θ is an estimated parameter and θ1 represents a typical value of the pharmacokinetic parameter (P) in an individual with a median covariate. θ2 represents a specific covariate effect coefficient.

  The performance of the final population pharmacokinetic model is the visual predictive test, a technique that uses the final model to test the validity of the model by means of comparing the prediction interval (PI) between observed and simulated data. VPC).

A population model was used to assess the effects of body weight-based and fixed doses of cyfarimumab by comparing predicted steady state serum concentrations (C _ss ) and variability. A covariate (demographic, BGENE21, BSTEROID) distribution morphology study MI-CP152 was used to simulate a population of 1000 SLE subjects. The population model was also utilized to support phase II dosing, predicting pharmacokinetic exposure, following various fixed intravenous doses of cifarimumab.

2. Result 2.1. Data A total of 120 patients provided evaluable PK data for a total of 2,370 serum concentrations (average 20 samples per person). One subject from the 10 mg / kg cohort was excluded from the analysis because the observed serum concentration was very low compared to the mean concentration of the 10 mg / kg cohort. Table 4 lists a 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; thus, in these subjects, the median population was diverted.

2.2. A population pharmacokinetic modeling two-compartment model was used to fit the cifarimumab concentration-time data. The model was parameterized using clearance (CL), central distribution volume (V _c ), peripheral distribution volume (V _p ), and inter-compartment clearance (Q). A multiplicative covariate modeling approach was used to investigate the effects of various covariates, including age, gender, ethnicity, range, WT, BSTEROID, BSLEDAI, BGENE21, and BGENE4.

式中、θ１は、ＷＴ＝７５ｋｇ、ＢＧＥＮＥ２１＝３２、用量＝１ｍｇ／ｋｇ、およびＢＳＴＥＲＯＩＤ＝０の標準被験者の典型的なＣＬである。θ_２およびθ_３は、それぞれＷＴ＝７５ｋｇの標準被験者のＶ_ｃおよびＶ_ｐを表す。θ_５〜θ_１０は、それぞれの薬物動態学的パラメータに対する、共変量効果の指数である。 The final model functions for typical values of CL, Vc, Vp, and Q are shown as follows (Equations 3-6):

Where θ1 is the typical CL of a standard subject with WT = 75 kg, BGENE21 = 32, dose = 1 mg / kg, and BSTEROID = 0. θ ₂ and θ ₃ represent V _c and V _p of a standard subject with WT = 75 kg, respectively. [theta] _5- [theta] ₁₀ is a covariate effect index for each pharmacokinetic parameter.

Final population pharmacokinetic parameters are presented in Table 5. Estimates of CL, V _c , V _p , and Q for standard subjects were approximately 176 mL / day, 2.9 L, 2.12 L, and 171 mL / day, respectively. Estimates of inter-subject variability (CV _s ) associated with CL, V _c , V _p , and Q were 28%, 31%, 58%, and 71%, respectively. All pharmacokinetic parameters were estimated with excellent accuracy as reflected in the RSE. The performance of the final model fit is represented by a goodness fit plot, as shown in FIG. Figure 5 Panels (a) and (b) show that all points are close to a one-to-one correspondence line, and the fitted spline curve almost overlaps the one-to-one correspondence line. Shows excellent agreement of sifalimumab serum concentration (individually predicted). The weighted residual plots against the population predicted concentration (FIG. 5 panel (c)) or against time (FIG. 5 panel (d)) do not show any obvious pattern. VPC results demonstrated the excellent predictability of the final population PK model, as shown in FIG.

Based on covariate relationships, subjects with higher baseline type I IFN gene signature (21 genes), body weight, cifarimumab dose, and steroid use were estimated to have higher cifarimumab CL. With increasing baseline body weight, both V _c and V _p also increased. Although the aforementioned covariates were identified as statistically significant covariates, they did not substantially explain the inter-individual variability (<7%) of CL, V _c and V _p . This means that the decrease or increase in concentration in individual patients in a dose group is not dominated by body weight, since the minimum magnitude of the overall concentration variability is explained by body weight. Therefore, no dose modification is required to administer cyfarimumab.

2.2.1. Comparison of fixed dose (mg) versus weight-based dose (mg / kg) In a simulated SLE population of 1000 subjects, comparison of 200 mg (fixed) and 3 mg / kg (weight-based) cyfarimumab dose every 14 days This evaluated the effect of fixed dosing versus weight based dosing. For the simulation, the weight distribution (43 kg-120 kg) from MI-CP152 was used. The final population PK model was used to predict the 5th, median, and 95th percentile values of the concentration-time profile. The simulation results demonstrate that both fixed and weight based dosing regimens produce similar median steady state concentrations (C _ss ) and variability, as shown in FIG.

2.2.2. Predicted serum concentrations Using the final population PK model, PK following a dose of 200, 600, and 1200 mg of cifarimumab (with additional dose on day 14) in a simulated SLE population of 1000 subjects monthly Predicted profile. The predicted PK profiles (median, 5th and 95th percentile values) are shown in FIG. Expected steady state PK parameters following monthly doses of 200, 600, and 1200 mg of cifarimumab (with additional dose on day 14) are provided in Table 6. The predicted PK exposure for 40 kg and 120 kg patients at the 5th and 95th percentile values is in Table 11.

3. Conclusion Cifarimumab PK was best described using a two-compartment linear model with primary removal. Following IV dosing, typical clearance (CL) and central distribution volume (V _c ) were estimated to be 176 mL / day and 2.9 L, respectively. Estimate of inter-subject variability of CL and _{V c} was 28% and 31%. Patient baseline body weight, IFN gene signature (21 genes), steroid use, and cifarimumab dose are identified as significant covariates of CL, whereas baseline body weight alone is a significant co-variance of V _c and V _p . It was a variable. Surprisingly, although the aforementioned covariates were statistically significant, they did not account for the variability of cifarimumab PK parameters to any reasonable degree. Therefore, the conclusion is reached that no adjustment of body weight-based medication is necessary to administer cyfarimumab. VPC results demonstrated the excellent predictability of the last population PK model.

Simulation results demonstrated that both fixed and weight-based dosing regimens produced similar median steady state concentrations (C _ss ) and variability. Therefore, monthly 200, 600, and 1200 mg fixed cifarimumab doses (loading dose on day 14) were selected for the Phase II clinical trial.

  A population PK model of cifarimumab was developed and validated. Population PK analysis also demonstrated the feasibility of assessing fixed doses of cyfarimumab in phase II clinical trials.

Example 3
Pharmacokinetics and immunogenicity of single and multiple fixed dosage regimens of cifarimumab administered subcutaneously to SLE patients Single and multiple subcutaneous (SC) fixed doses administered to adult patients with moderate to severe SLE The pharmacokinetics (PK) and immunogenicity (IM) of cifarimumab were investigated in a phase II clinical trial.

1. Method 1.1. Study Design This was a multicenter randomized, double-blind, placebo-controlled phase IIa parallel study with 5 evaluable arms (ratio 1: 1: 2: 2: 2).

  Inclusion criteria for subjects who have received antibodies or antigen-binding fragments thereof subcutaneously are US National Institutes of Health clinicaltrials. Summarized in the clinical trial identifier NCT00657189, accessible through the gov database. Accordingly, inclusion criteria comprise: male or female subjects who are 18 years or older and younger than 95 years upon first administration of study drug; subjects must have at least 4 out of 11 revised ACR classification criteria for SLE The subject has been demonstrated to be positive for antinuclear antibody testing (ANA) at ≧ 1: 80 serum dilution in the past or at screening; the subject has a BILAG index of score A at screening Had at least one system, or two systems with a score B, or had a SELENA-SLEDAI score of ≧ 6; an antimalarial, oral prednisone or another systemic corticosteroid, mycophenolate mofetil, methotrexate SLE treatment with leflunomide, azathioprine, or dapsone.

The exclusion criteria comprised: MEDI-545 was administered within 120 days prior to screening; history of allergy or response to any component of study drug; within 28 days prior to randomization, The following drugs were administered: systemic cyclophosphamide at any dose, cyclosporine at any dose, thalidomide at any dose,> 600 mg / day hydroxychloroquine,> 3 g / day mycophenolate mofetil, > 25 mg / week methotrexate,> 3 mg / kg / day azathioprine; within 28 days prior to randomization, the following drugs were administered at varying doses: antimalarial, mycophenolate mofetil, methotrexate, leflunomide , Azathioprine, dapsone; within 6 months prior to test day 0 > 20 mg / day of leflunomide; within 14 days prior to randomization,> 20 mg / day or variable dose of prednisone; within 14 days prior to randomization, variable dose Non-steroidal anti-inflammatory drugs; treatment with any investigational drug therapy within 28 days prior to randomization in the study, B cell depletion therapy within 12 months prior to randomization, or randomization in the study Biological therapy within 30 days before conversion or within 5 half-life of biological agent, whichever is longer; ongoing within 28 days prior to randomization, clinical trial in the opinion of researchers, including chronic infections Of active infections with specific significance; severe as determined by investigators, including cytomegalovirus, or severe infections of any herpes such as disseminated herpes, herpes encephalitis, ocular herpes No History of lupus infection; herpes zoster infection within 3 months prior to randomization; infection by hepatitis B or C virus, or human immunodeficiency virus (HIV-1) or HIV-2, as determined by screening test results, Or evidence of active infection due to hepatitis A; vaccination with live attenuated virus within 28 days prior to randomization; pregnancy (female, surgically sterile or at least 2 years after menopause, within 28 days prior to study drug administration Negative serum pregnancy tests and negative urine pregnancy tests before study drug administration on the day of study drug administration); breastfeeding or lactating women; history of primary immunodeficiency disease; prior to randomization1 History of alcohol or drug abuse for less than a year; History of cancer (basal cell tumors clearly treated successfully with curative therapy prior to one year prior to randomization / participation Or cervical intraepithelial neoplasia); history of active tuberculosis (TB) infection or a new positive TB skin test (diameter ≧ 10 mm in the absence of systemic immunosuppressant), without adequate treatment (Or defined as a ≥5 mm response if there is a systemic immunosuppressant), history of latent TB infection; premature surgery planned from screening to study day 168; (28 days prior to randomization) Any of the following in a screening blood test: (i) Except when caused by SLE,> 2.5 × AST of upper normal range (ULN), except when caused by SLE ,> 2.5 × ULN of ALT, (iii)> 4.0mg / dL of creatinine, (iv) <1,500 / mm 3 of neutrophils, (v) <blood 50,000 / mm ³ Number of plates; any disease history (other than SLE), which, in the opinion of the researcher or medical monitor, may compromise the safety of the subject under study or confound the analysis of the study, Any findings at the time of physical examination, or any abnormal findings.

  The inclusion and exclusion criteria listed above are not intended to limit the scope of the invention. One skilled in the art may use other inclusion and / or exclusion parameters to create a subject population so that subject selection does not compromise subject safety or confound study analysis. You will understand that.

  Patients received either up to 13 doses of cyfarimumab or placebo. Placebo was administered to 22 patients. Eleven patients received a single SC 100 mg fixed dose of cifarimumab. Twenty-one patients received a SC 100 mg fixed dose of cyfalimumab monthly, with a final dose on day 84. Twenty-three patients received an SC 100 mg fixed dose of cyfalimumab every other week, with a final dose on day 84. Ten patients received SC 100 mg fixed dose of cyfalimumab weekly and the final dose on day 84. Serum samples were taken at multiple time points for PK concentration and IM titer.

  Samples were analyzed for PK and IM using the validated ELISA and ECL assays described in Example 1, respectively.

1.2. Data Analysis Pharmacokinetic parameters were obtained using a non-compartmental method using WinNonlin (version 5.2.1 Pharsight, Cary, NC).

2. Result 2.1. Single Dose Administration The results corresponding to a single 100 mg fixed dose administration of cyfarimumab are summarized in Table 7 and FIG. 9 (●). The peak concentration of cyfarimumab appeared approximately 1 week after SC administration. The average apparent extravascular clearance (CL / F) was approximately 275 mL / day. The elimination half-life was approximately 25 days. The plotted values are shown in Table 10.

2.2. Multiple Dose Administration The results corresponding to multiple 100 mg fixed dose sifarimumab administration are summarized in Table 8 and FIG. 9 (weekly ■, biweekly ▲, or monthly ▼). C _{max ss} and _{C trough ss} increased with the number of administrations. AUC accumulation and trough concentrations were 11 and 6 times each weekly dose. The steady state AUC of the multiple dose group was similar to the AUC after a single dose. Average apparent extravascular steady state clearance (CL _ss / F) ranged from 206 to 282 mL / day between dose groups. The average half-life ranged from 28 to 33 days. The final phase of the apparent volume of distribution after non intravenous administration _(V z / F) ranged from 8L～11L.

2.3. Immunogenicity Eight of the 65 patients who received the study drug (12.3%) were judged positive for the presence of anti-cifalimumab antibody (FIG. 10). There was no increase in the incidence of immunogenicity throughout the dosing regimen. Of the 22 patients who received placebo, 2 (9.1%) were M ⁺ , ie positive for the presence of anti-cifarimumab antibody (titer range of 10-40). In 11 patients who received a single dose of cyfarimumab, there was no M ⁺ . In contrast, following the monthly dosing regimen, 3 out of 10 patients (30%) are M ⁺ (20-160 potency range), followed by the biweekly dosing regimen, 23 3 of 13 patients (13%) are M ⁺ (20-160 titer range), and 2 of 21 patients (9.5%) are M ⁺ following a weekly dosing regimen. (A titer range of 20 to 320).

  The presence of anti-cifarimumab antibody did not affect the serum concentration-time profile of cifarimumab. Cifarimumab had a safety / tolerability profile similar to placebo at the SC doses tested.

2.4. Effects on IFN gene signatures Pharmacokinetic (PD) markers may be used in methods of treating patients with therapeutic agents that bind to and modulate IFN-α activity, such as cifarimumab. See, for example, US Patent Application No. 2010-0143372, the entire contents of which are incorporated herein by reference. Specifically, Example 7 of US Patent Application 2010-0143372 describes 21 genes that may 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. In addition, US Patent Application No. 2010-0143372 provides methods for measuring levels of these 21 gene markers, such as Affymetrix arrays and Fluidigm dynamic arrays.

  Only once weekly administration of sifalimab resulted in sufficient PK exposure to induce a sustained decline in IFN gene signature over time (FIG. 11). In particular, weekly dosing resulted in up to 40% suppression of gene signature.

3. CONCLUSIONS: The pharmacokinetic exposure of cifarimumab and comparison with previous intravenous studies suggested an SC bioavailability of nearly 75%. Cifarimumab PK following SC administration was linear and proportional to dose. The pharmacokinetic parameters of cifarimumab following SC dosing well showed the characteristics of a monoclonal antibody without a significant target sink. Although the overall incidence of anti-cifarimumab antibodies was 12%, the presence of anti-cifarimumab antibodies did not affect the pharmacokinetics of cifarimumab.

Claims (75)

A method of treating an autoimmune disorder in a human subject comprising the step of administering to the subject an antibody that specifically binds human interferon alpha, or an antigen-binding fragment thereof, wherein said administration is followed by about 99 ~ About 432 mL / day clearance rate (CL, CL _ss , CL / F, or CL _ss / F), about 3 to about 17 L apparent distribution volume (V _ss or V _z / F), and about 14 days ~ A method wherein one or more pharmacokinetic properties selected from a serum half-life of about 48 days are achieved; wherein the autoimmune disorder is systemic lupus erythematosus, scleroderma, or myositis.   The antibody or antigen-binding fragment thereof is 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. 2. The method of claim 1, wherein the method binds to an epitope on human interferon alpha.   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) comprising SEQ ID NO: 7. A heavy chain variable region CDR3 comprising: (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) comprising SEQ ID NO: 16. The method according to claim 1 or 2, comprising the light chain variable region CDR3.   A heavy chain variable region wherein the antibody or antigen-binding fragment thereof comprises (a) 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) sequence 4. The method according to any one of claims 1 to 3, comprising a light chain variable region comprising the amino acid sequence of number 22.   The method according to any one of claims 1 to 4, wherein the antibody or antigen-binding fragment thereof is a human antibody or antigen-binding fragment thereof.   The method according to any one of claims 1 to 4, wherein the antibody or antigen-binding fragment thereof is a chimeric antibody or antigen-binding fragment thereof.   The method according to any one of claims 1 to 4, wherein the antibody or antigen-binding fragment thereof is a humanized antibody or antigen-binding fragment thereof.   The method according to any one of claims 1 to 7, wherein the antibody or antigen-binding fragment thereof is an IgG1 or IgG4 antibody or antigen-binding fragment thereof.   The method according to any one of claims 1 to 8, wherein the antigen-binding fragment is a Fab antibody fragment or a single chain antibody (scFv).   10. The method according to any one of claims 1 to 9, wherein the antibody or antigen-binding fragment thereof is administered at a dosage that depends on the body weight of the subject.   12. The method of claim 10, wherein the dosage ranges from about 0.01 mg / kg to about 100 mg / kg of subject body weight.   12. The method of claim 11, wherein the dosage is selected 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.   10. The method according to any one of claims 1 to 9, wherein the antibody or antigen-binding fragment thereof is administered at a fixed dose.   14. The method of claim 13, wherein the fixed dose ranges from about 50 mg to about 2000 mg.   15. The method of claim 14, wherein the fixed dose is selected from about 100 mg, about 200 mg, about 600 mg, and about 1200 mg.   Said antibody or antigen-binding fragment thereof is administered as a single dose or once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once a month 16. The method according to any one of claims 1 to 15, wherein the method is administered in two or more doses once, once every six months, or at variable intervals.   17. A method according to any one of claims 1 to 16, wherein the loading dose is administered on day 14.   The administration may be intravenous, intramuscular, intraperitoneal, intracerebral spinal, subcutaneous, intraarticular, intrasynovial, intrathecal, oral, topical, inhalation, and combinations of two or more listed routes. 17. A method according to any one of the preceding claims, depending on the route chosen.   The method of claim 18, wherein the administration is intravenous (IV) administration.   20. The method of claim 19, wherein IV administration is by IV infusion over a period of time. _21. The method of claim 19 or 20, wherein a time to reach a maximum plasma concentration (T _max or T _{max ss} ) following IV administration is achieved of about 0.13 days or less. A single IV dose of about 0.3 mg / kg has a T _{max of} about 0.12 days or less, a maximum plasma concentration (C _max ) of about 7 to about 15 μg / mL, a dose interval of about 54 to about 104 μg day / mL Achieving one or more pharmacokinetic properties selected from the area under the plasma concentration-time curve in ( _τ ) (AUC _τ ), and the trough plasma concentration (C _trough ) of about 2 to about 4 μg / mL, The method according to any one of claims 19 to 21. A single IV dose of about 0.3 mg / kg to the subject population resulted in an average T _max of about 0.07 days, an average C _max of about 11 μg / mL, an average AUC _τ of about 79 μg day / mL, and about 3 μg / mL. _22. A method according to any one of claims 19-21, wherein the method achieves one or more pharmacokinetic properties selected from an average C _{trough of} mL. A single IV dose of about 1 mg / kg results in a T _max of about 0.12 days or less, a C _{max of} about 21 to about 43 μg / mL, an AUC _{τ of} about 153 to about 290 μg day / mL, and about 4 to about 12 μg. _23. The method of any one of claims 19-21, wherein the method achieves one or more pharmacokinetic properties selected from C _trough / mL. A single IV dose of about 1 mg / kg to the subject population has an average T _{max of} about 0.08 days, an average C _max of about 32 μg / mL, an average AUC _τ of about 221 μg day / mL, and about 8 μg / mL. _22. A method according to any one of claims 19-21, wherein the method achieves one or more pharmacokinetic properties selected from the mean C _trough . A single IV dose of about 3 mg / kg provides a T _max of about 0.13 days or less, a C _max of about 64 to about 143 μg / mL, an AUC _{τ of} about 469 to about 1010 μg day / mL, and about 12 to about 35 μg. _23. The method of any one of claims 19-21, wherein the method achieves one or more pharmacokinetic properties selected from C _trough / mL. A single IV administration of about 3 mg / kg to the subject population resulted in an average T _max of about 0.09 days, an average C _max of about 103 μg / mL, an average AUC _τ of about 739 μg day / mL, and about 23 μg / mL. _22. A method according to any one of claims 19-21, wherein the method achieves one or more pharmacokinetic properties selected from the mean C _trough . A single IV dose of about 10 mg / kg results in a T _max of about 0.13 days or less, a C _max of about 141 to about 318 μg / mL, an AUC _{τ of} about 979 to about 2241 μg day / mL, and about 27 to about 76 μg. _23. The method of any one of claims 19-21, wherein the method achieves one or more pharmacokinetic properties selected from C _trough / mL. A single IV dose of about 10 mg / kg to the subject population has an average T _max of about 0.09 days, an average C _max of about 230 μg / mL, an average AUC _τ of about 1610 μg day / mL, and about 52 μg / mL. _22. A method according to any one of claims 19-21, wherein the method achieves one or more pharmacokinetic properties selected from the mean C _trough . At about 14 day intervals, a sufficient number of IV doses of about 0.3 mg / kg are administered to achieve steady state, T _{max ss} of about 0.60 days or less, C _{max of} about 11 to about 25 μg / mL. _ss, about 89 to about 197μg day / mL of AUC _{tau ss,} and are selected from _{C trough ss} of about 5 to about 11μg / mL, 1 or more steady state pharmacokinetic properties are achieved, according to claim 19 The method of any one of -21. The subject population is administered a sufficient number of about 0.3 mg / kg IV doses at about 14 day intervals to achieve steady state, an average T _{max ss} of about 0.17 days, an average C of about 18 μg / mL. 23. Any one or more pharmacokinetic properties selected from _{max ss} , an average AUC _{τ ss} of about 143 μg day / mL, and an average C _{trough ss} of about 8 μg / mL. The method according to one item. At about 14 day intervals, a sufficient number of IV doses of about 0.3 mg / kg are administered to achieve steady state, a clearance rate (CL _ss ) of about 99 to about 271 mL / day, about 4 to about 9 L. 22. One or more pharmacokinetic properties selected from an apparent volume of distribution (V _ss ) and a serum half-life of about 15 days to about 43 days, according to any one of claims 19 to 21. The method described. The subject population was administered a sufficient number of about 0.3 mg / kg IV doses at about 14 day intervals to achieve steady state, an average clearance rate (CL _ss ) of about 185 mL / day, an average appearance of about 6 L One or more pharmacokinetic properties selected from the volume of distribution (V _ss ) and the mean serum half-life of about 29 days are achieved. The method according to any one of claims 19 to 21. At about 14 day intervals, a sufficient number of IV doses of about 1 mg / kg are administered to achieve steady state, T _{max ss} of about 0.11 days or less, C _{max ss of} about 29 to about 67 μg / mL, 21. One or more steady state pharmacokinetic properties selected from about 213 to about 591 [mu] g day / mL AUC [ _{tau] ss} and about 9 to about 30 [mu] g / mL C _{trough ss} are achieved. The method as described in any one of. The subject population is administered a sufficient number of IV doses of about 1 mg / kg at about 14 day intervals to achieve steady state, an average T _{max ss} of about 0.07 days, an average C _{max ss} of about 48 μg / mL. One or more pharmacokinetic properties selected from: an average AUC _{τ ss} of about 197 μg day / mL, and an average C _{trough ss} of about 11 μg / mL. The method described in 1. At about 14 day intervals, a sufficient number of IV doses of about 1 mg / kg are administered to achieve steady state, a clearance rate (CL _ss ) of about 118 to about 348 mL / day, an apparent of about 4 to about 9 L 22. One or more pharmacokinetic properties selected from distribution volume (V _ss ) and serum half-life of about 15 days to about 32 days are achieved. Method. A sufficient population of about 1 mg / kg IV dose is administered to the subject population at about 14 day intervals to achieve steady state, an average clearance rate (CL _ss ) of about 233 mL / day, an average apparent distribution of about 6 L 22. The method according to any one of claims 19-21, wherein one or more pharmacokinetic properties selected from volume (V _ss ) and an average serum half-life of about 23 days are achieved. At about 14 day intervals, a sufficient number of IV doses of about 3 mg / kg are administered to achieve steady state, T _{max ss} of about 0.33 days or less, C _{max ss of} about 75 to about 232 μg / mL, 21. One or more steady state pharmacokinetic properties selected from about 533 to about 1843 μg day / mL AUC _{τ ss} and about 26 to about 74 μg / mL C _{trough ss} are achieved. The method as described in any one of. The subject population is administered a sufficient number of IV doses of about 3 mg / kg at about 14 day intervals to achieve steady state, an average T _{max ss} of about 0.13 days, an average C _{max ss} of about 153 μg / mL. One or more pharmacokinetic properties selected from: an average AUC _{τ ss} of about 1188 μg day / mL, and an average C _{trough ss} of about 50 μg / mL. The method described in 1. A sufficient number of IV doses of about 3 mg / kg are administered at about 14 day intervals to achieve steady state, a clearance rate (CL _ss ) of about 136 to about 304 mL / day, an apparent of about 3 to about 7 L 22. One or more pharmacokinetic properties selected from distribution volume (V _ss ) and serum half-life of about 14 to about 26 days are achieved. Method. A sufficient number of IV doses of about 3 mg / kg are administered to the subject population at about 14-day intervals to achieve steady state, an average clearance rate (CL _ss ) of about 220 mL / day, an average apparent distribution of about 5 L 22. The method according to any one of claims 19-21, wherein one or more pharmacokinetic properties selected from volume (V _ss ) and an average serum half-life of about 20 days are achieved. At about 14 day intervals, a sufficient number of IV doses of about 10 mg / kg are administered to achieve steady state, T _{max ss} of about 0.82 days or less, C _{max ss of} about 288 to about 595 μg / mL, One or more steady-state pharmacokinetic properties selected from about 2539 to about 4267 μg day / mL AUC _{τ ss} and about 93 to about 275 μg / mL C _{trough ss} are achieved. The method as described in any one of. The subject population is administered a sufficient number of IV doses of about 10 mg / kg at about 14 day intervals to achieve steady state, an average T _{max ss} of about 0.23 days, an average C _{max ss} of about 232 μg / mL. One or more pharmacokinetic properties selected from: an average AUC _{τ ss} of about 3403 μg day / mL, and an average C _{trough ss} of about 184 μg / mL. The method described in 1. At about 14 day intervals, a sufficient number of IV doses of about 10 mg / kg are administered to achieve steady state, a clearance rate (CL _ss ) of about 157 to about 319 mL / day, an apparent of about 4 to about 7 L 22. One or more pharmacokinetic properties selected from distribution volume (V _ss ) and serum half-life of about 15 days to about 29 days are achieved. Method. A sufficient number of IV doses of about 10 mg / kg are administered to the subject population at about 14 day intervals to achieve steady state, an average clearance rate (CL _ss ) of about 238 mL / day, an average apparent distribution of about 6 L 22. The method according to any one of claims 19-21, wherein one or more pharmacokinetic properties selected from volume (V _ss ) and an average serum half-life of about 22 days are achieved.   22. The method of any one of claims 19-21, wherein the number of IV doses at about 14 day intervals required to achieve steady state is from about 5 to about 8 doses.   19. The method of claim 18, wherein the administration is by subcutaneous (SC) administration.   48. The method of claim 47, wherein the dosage is 100 mg administered as a single dose or administered weekly, biweekly, or monthly. 49. The method of claim 47 or claim 48, wherein a _Tmax or _{Tmax ss} of about 2 to about 10 days is achieved. A single SC dose of about 100 mg is about 2 to about 10 days of T _max , about 4 to about 21 μg / mL C _max , about 175 to about 666 μg day / mL of 0 to the last measurable concentration time plasma concentration One or more pharmacokinetic properties selected from the area under the time curve (AUC _last ), and from about 204 to about 751 μg day / mL from 0 hour to infinite plasma concentration area under the time curve (AUC _∞ ) 50. A method according to any one of claims 47 to 49, wherein: A single SC dose of about 100 mg to the subject population is selected from about 6 days T _max , about 13 μg / mL C _max , about 421 μg day / mL AUC _last , and about 477 μg day / mL AUC _∞ 50. A method according to any one of claims 47 to 49, wherein the method achieves one or more pharmacokinetic properties. A single SC dose of about 100 mg is about 118 to about 432 mL / day clearance rate (CL / F), about 5 to about 12 L apparent distribution volume (V _z / F), and about 15 to about 34 days 50. The method of any one of claims 47 to 49, wherein the method achieves one or more pharmacokinetic properties selected from the serum half-life of A single SC dose of about 100 mg to the subject population is estimated from a mean 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. 50. The method of any one of claims 47-49, wherein the method achieves one or more selected pharmacokinetic properties. At about 7 day intervals (weekly), a sufficient number of SC doses of about 100 mg are administered to achieve steady state, T _{max ss from} about 2 days to about 7 days, C _{max from} about 37 to about 93 μg / mL. 48. One or more steady state pharmacokinetic properties selected from _ss , about 248 to about 638 μg day / mL AUC _{τ ss} , and about 38 to about 80 μg / mL C _{trough ss} are achieved. 50. A method according to any one of -49. The subject population is administered a sufficient number of about 100 mg IV doses at about 7 day intervals (weekly) to achieve steady state, an average T _{max ss} of about 4 days, an average C _{max ss} of about 65 μg / mL, 50. One or more steady-state pharmacokinetic properties selected from an average AUC _{τ ss} of about 443 μg day / mL and an average C _{trough ss} of about 59 μg / mL are achieved. The method according to item. At about 7 day intervals (weekly) a sufficient number of SC doses of about 100 mg are administered to achieve steady state, about 168 to about 396 mL / day clearance rate (CL _ss / F), about 7 to about 15 L 50. The one or more steady-state pharmacokinetic properties selected from an apparent volume of distribution (V _z / F) and a serum half-life of about 22 days to about 35 days are achieved. The method according to any one of the above. The subject population is administered a sufficient number of about 100 mg of SC dose at about 7 day intervals (weekly) to achieve steady state, an average clearance rate (CL _ss ) of about 282 mL / day, an average apparent appearance of about 11 L 50. One or more steady-state pharmacokinetic properties selected from distribution volume ( _Vz / F) and an average serum half-life of about 28 days are achieved. the method of. At about 14-day intervals (biweekly), a sufficient number of about 100 mg SC dose is administered to achieve steady state, T _{max ss from} about 2 to about 7 days, C _{max from} about 30 to about 49 μg / mL. 48. One or more steady-state pharmacokinetic properties selected from _ss , about 424 to about 567 μg day / mL AUC _{τ ss} , and about 21 to about 40 μg / mL C _{trough ss} are achieved. 50. A method according to any one of -49. The subject population is administered a sufficient number of about 100 mg of SC dose at about 14 day intervals (biweekly) to achieve steady state, an average T _{max ss} of about 4 days, an average C _{max ss} of about 39 μg / mL, 50. Any one or more steady state pharmacokinetic properties selected from an average AUC _{τ ss} of about 495 μg day / mL and an average C _{trough ss} of about 30 μg / mL are achieved. The method according to item. At about 14 day intervals (biweekly), a sufficient number of SC doses of about 100 mg are administered to achieve steady state, about 172 to about 240 mL / day clearance rate (CL _ss / F), about 6 to about 10 L 50. The one or more steady-state pharmacokinetic properties selected from an apparent volume of distribution (V _z / F) and a serum half-life of about 19 days to about 37 days are achieved. The method according to any one of the above. The subject population is administered a sufficient number of about 100 mg of SC dose at about 14 day intervals (biweekly) to achieve steady state, an average clearance rate (CL _ss ) of about 406 mL / day, an average apparent appearance of about 8 L 50. One or more steady-state pharmacokinetic properties selected from distribution volume ( _Vz / F) and an average serum half-life of about 28 days are achieved. the method of. At about 30 day intervals (monthly), a sufficient number of SC doses of about 100 mg are administered to achieve steady state, T _{max ss from} about 3 days to about 8 days, C _{max from} about 14 to about 34 μg / mL. 48. One or more steady state pharmacokinetic properties selected from _ss , about 326 to about 641 μg day / mL AUC _{τ ss} , and about 6 to about 15 μg / mL C _{trough ss} are achieved. 50. A method according to any one of -49. The subject population is administered a sufficient number of about 100 mg of SC dose at about 30 day intervals (monthly) to achieve steady state, with an average T _{max ss} of about 6 days, an average C _{max ss} of about 49 μg / mL, 50. One or more steady state pharmacokinetic properties selected from an average AUC _{τ ss} of about 483 μg day / mL and an average C _{trough ss} of about 11 μg / mL are achieved. The method according to item. At about 30 day intervals (monthly), a sufficient number of SC doses of about 100 mg are administered to achieve steady state, about 152 to about 302 mL / day clearance rate (CL _ss / F), about 5 to about 17 L 50. The one or more steady-state pharmacokinetic properties selected from an apparent volume of distribution (V _z / F) and a serum half-life of about 19 days to about 47 days are achieved. The method according to any one of the above. The subject population is administered a sufficient number of about 100 mg of SC dose at about 30 day intervals (monthly) to achieve steady state, an average clearance rate (CL _ss ) of about 227 mL / day, an average apparent appearance of about 11 L 50. One or more steady-state pharmacokinetic properties selected from distribution volume ( _Vz / F) and an average serum half-life of about 33 days are achieved. the method of.   66. The method of any one of claims 1 to 65, wherein administration of a sufficient dose number of an anti-IFN-α antibody or antigen-binding fragment thereof suppresses an IFN pharmacodynamic signature.   68. The method of claim 66, wherein the IFN pharmacodynamic signature is a type I IFN-α inducible expression profile.   The type I IFN-α inducible expression profile is IFI44, IFI27, IFI44L, NAPTP, LAMP3, LY6E, RSAD2, HERC5, IFI6, ISG15, OAS3, RTP4, IFIT1, MX1, SIGLEC1, OAS2, USP18, OAS1, EPS1, 68. The method of claim 67, comprising upregulated expression of a genetic marker set comprising PLSCR1 and IFRG28.   69. The method of claim 68, wherein the anti-IFN antibody or antigen-binding fragment thereof neutralizes a patient's pharmacodynamic expression profile by at least 10%, at least 20%, at least 30% or at least 40%.   70. The method of any one of claims 1 to 69, wherein at least one disease symptom is reduced.   71. The method of claim 70, wherein the reduction of the at least one disease symptom results in a decrease in SLEDAI score or BILAG score.   72. The method of claim 71, wherein the SLEDAI score is reduced by at least 1 point.   75. The method of claim 72, wherein the SLEDAI score is reduced by at least 2 points.   74. The method of claim 73, wherein the SLEDAI score is reduced by at least 3 points.   75. The method of claim 74, wherein the SLEDAI score is reduced by at least 4 points.

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