WO2018096467A1 - Méthodes de traitement de l'acné à l'aide d'antagonistes de l'interleukine-17 (il -17) - Google Patents

Méthodes de traitement de l'acné à l'aide d'antagonistes de l'interleukine-17 (il -17) Download PDF

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WO2018096467A1
WO2018096467A1 PCT/IB2017/057330 IB2017057330W WO2018096467A1 WO 2018096467 A1 WO2018096467 A1 WO 2018096467A1 IB 2017057330 W IB2017057330 W IB 2017057330W WO 2018096467 A1 WO2018096467 A1 WO 2018096467A1
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seq
antibody
antigen
binding fragment
immunoglobulin
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Pascal Espie
Christian Loesche
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Novartis AG
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Novartis AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present disclosure relates to methods for treating acne, e.g., moderate to severe inflammatory acne, using IL-17 antagonists, e.g., an IL-17 antibody or antigen-binding fragment thereof, such as secukinumab or CJM112.
  • IL-17 antagonists e.g., an IL-17 antibody or antigen-binding fragment thereof, such as secukinumab or CJM112.
  • the current treatment for moderate to severe inflammatory acne is often a combination or association of several topical treatments (such as topical retinoids and antibacterials such as benzoylperoxide and antibiotics) with oral antibiotics, and/or hormonal treatment or retinoids, such as isotretinoin.
  • topical treatments such as topical retinoids and antibacterials such as benzoylperoxide and antibiotics
  • hormonal treatment or retinoids such as isotretinoin.
  • Kistowska et al. show that the mRNA expression levels of Thl and Thl7 effector cytokines, transcription factors, IL-17A, and chemokine receptors is strongly upregulated in acne lesions, and that P. acnes can promote mixed Thl7/Thl responses in vitro by inducing concomitant secretion of IL-17 and IFN- ⁇ from CD4+ T cells.
  • P. acnes can promote mixed Thl7/Thl responses in vitro by inducing concomitant secretion of IL-17 and IFN- ⁇ from CD4+ T cells.
  • IL-17 antagonists e.g., IL-17 antibodies, e.g., secukinumab and CJM112
  • IL-17 antagonist e.g., an anti-JL-17 antibody or antigen-binding fragment thereof
  • the IL-17 antibody or antigen-binding fragment thereof is: a) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of IL-17: i) between residues Arg 55 and Trp 67; ii) comprising Arg 55, CHu 57, and Trp 67; iii) comprising: Arg 55, CHu 57, Trp 67, Tyr 62, and Arg 101; iv) comprising Arg 55, Glu 57, Trp 67, Tyr 62, Arg 101, Pro 59, Ser 64, and Val 65; or v) comprising Arg 55, Glu 57, Trp 67, Tyr 62, Arg 101, Pro 59, Ser 64, Val 65; or v) comprising Arg 55, Glu 57, Trp 67, Tyr 62, Arg 101, Pro 59, Ser 64, Val 65, Val 22*, Leu 26, Asp 58, Glu 60, Pro 63, Pro 107, Phe 110
  • the IL-17 antagonist is an IL-17 antibody or antigen-binding fragment thereof.
  • the IL-17 antibody or antigen-binding fragment thereof is selected from the group consisting of: a) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of IL-17 comprising Leu74, Tyr85, His86, Met87, Asn88, Vall24, Thrl25, Prol26, Ilel27, Vall28, Hisl29; b) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of IL-17 comprising Tyr43, Tyr44, Arg46, Ala79, Asp80; c) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of an IL-17 homodimer having two mature IL-17 protein chains, said epitope comprising Leu74, Tyr85, His86, Met87, Asn88,
  • the IL-17 antibody or antigen-binding fragment thereof is secukinumab (AIN457) or CJM112.
  • Secukinumab and CJM112 are high-affinity recombinant, fully human monoclonal anti-human interleukin-17A antibodies of the IgGl/ic-class. Secukinumab and CJM112 bind to human IL-17A and neutralize the bioactivity of this cytokine.
  • Figure 1 shows a comparison of skin and cell type derived IL17A signaling signatures with disease vs normal differentially expressed genes from a public Acne and Psoriasis study. P- values of a fisher exact T-test
  • Figure 2 shows the influence of all-trans retinoic acid (ATRA) on the priming of Thl7 T cells in Donor 1 (A) and Donor 2 (B).
  • ATRA all-trans retinoic acid
  • Figure 3 shows the study design for the clinical trial set forth in Example 3.
  • Figure 4 shows results from the clinical trial set forth in Example 3 on facial inflammatory lesion count.
  • the invention relates to an IL-17 antagonist, e.g. an IL-17 binding molecule, e.g. an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112, for use in treating or preventing acne, e.g. moderate to severe acne, e.g. moderate to severe inflammatory acne.
  • an IL-17 antagonist e.g. an IL-17 binding molecule, e.g. an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112
  • acne e.g. moderate to severe acne, e.g. moderate to severe inflammatory acne.
  • the invention in another embodiment, relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an IL-17 antagonist, e.g. an IL-17 binding molecule, e.g. an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM 112, and at least one pharmaceutically acceptable excipient, for use in treating or preventing acne, e.g. moderate to severe acne, e.g. moderate to severe inflammatory acne.
  • an IL-17 antagonist e.g. an IL-17 binding molecule, e.g. an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM 112
  • at least one pharmaceutically acceptable excipient for use in treating or preventing acne, e.g. moderate to severe acne, e.g. moderate to severe inflammatory acne.
  • the invention relates to a method of treating or preventing acne, e.g. moderate to severe acne, e.g. moderate to severe inflammatory acne, comprising administering a therapeutically effective amount of an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112, to a patient in need thereof.
  • a therapeutically effective amount of an IL-17 antibody or antigen-binding fragment thereof e.g., secukinumab or CJM112
  • An IL-17 antibody or antigen-binding fragment thereof for use in treating or preventing acne, e.g. moderate to severe acne, e.g. moderate to severe inflammatory acne.
  • IL-17 antibody or antigen-binding fragment thereof for use in treating or preventing acne according to embodiment 1, wherein the IL-17 antibody or antigen-binding fragment thereof binds to an epitope of mature human IL-17: a) between residues Arg 55 and Trp 67; b) comprising residues Arg 55, Glu 57, and Trp 67; c) comprising residues Arg 55, Glu 57, Trp 67, Tyr 62, and Arg 101; d) comprising residues Arg 55, Glu 57, Trp 67, Tyr 62, Arg 101, Pro 59, Ser 64, and Val 65; or e) comprising residues Arg 55, Glu 57, Trp 67, Tyr 62, Arg 101, Pro 59, Ser 64, Val 65; or e) comprising residues Arg 55, Glu 57, Trp 67, Tyr 62, Arg 101, Pro 59, Ser 64, Val 65, Val 22*, Leu 26, Asp 58,
  • amino acids marked with (*) designate a residue contributed by the second IL-17 subunit of the IL-17A homodimer, and further wherein the IL-17 antibody or antigen-binding fragment thereof has a KD for human IL-17 of about 1-10 pM and an in vivo half-life of about 2-4 weeks, e.g., about 3 weeks.
  • the IL-17 antibody or antigen-binding fragment thereof for use in treating or preventing acne according to embodiment 1, wherein the IL-17 antibody or antigen-binding fragment thereof binds to an epitope of a human IL-17 homodimer having two mature human IL-17 protein chains, said epitope comprising residues Leu74, Tyr85, His86, Met87, Asn88, Val 124, Thrl25, Prol26, Ilel27, Vail 28, Hisl29 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain, wherein the IL-17 antibody or antigen-binding fragment thereof has a K D for human IL-17 of about 100-200 pM, and wherein the IL-17 antibody or antigen-binding fragment thereof has an in vivo half-life of about 3-5 weeks, e.g., about 4 weeks.
  • V H immunoglobulin heavy chain variable domain
  • V L immunoglobulin light chain variable domain
  • an immunoglobulin V H domain comprising the amino acid sequence set forth as SEQ ID NO: 30 and an immunoglobulin V L domain comprising the amino acid sequence set forth as SEQ ID NO:22; or an amino acid sequence having at least about 95%, 98% or 99% overall sequence identity thereto;
  • an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO:24, SEQ ID NO:26, and SEQ ID NO:28; or an amino acid sequence having at least about 95%, 98% or 99% overall sequence identity thereto;
  • an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO: 16, SEQ ID NO: 18 and SEQ ID NO:20; or an amino acid sequence having at least about 95%, 98% or 99% overall sequence identity thereto;
  • an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO:25, SEQ ID NO:27 and SEQ ID NO:29; or an amino acid sequence having at least about 95%, 98% or 99% overall sequence identity thereto;
  • an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO: 17, SEQ ID NO: 19 and SEQ ID NO:21; or an amino acid sequence having at least about 95%, 98% or 99% overall sequence identity thereto; viii) an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO:24, SEQ ID NO:26, and SEQ ID NO:28 and an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO: 16, SEQ ID NO: 18 and SEQ ID NO:20; or an amino acid sequence having at least about 90%, 95%, 98% or 99% overall sequence identity thereto;
  • an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO:25, SEQ ID NO:27, and SEQ ID NO:29 and an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO: 17, SEQ ID NO: 19 and SEQ ID NO:21; or an amino acid sequence having at least about 90%, 95%, 98% or 99% overall sequence identity thereto;
  • x) a light chain comprising SEQ ID NO:23; or an amino acid sequence having at least about 90%, 95%, 98% or 99% overall sequence identity thereto;
  • xi a heavy chain comprising SEQ ID NO:31; or an amino acid sequence having at least about 90%, 95%, 98% or 99% overall sequence identity thereto;
  • xii a light chain comprising SEQ ID NO:23 and a heavy chain comprising SEQ ID NO:31; or an amino acid sequence having at least about 90%, 95%, 98% or 99% overall sequence identity thereto.
  • IL-17 antibody or antigen-binding fragment thereof for use in treating or preventing acne according to embodiment 1 or 3, wherein the IL-17 antibody or antigen-binding fragment thereof comprises:
  • V H immunoglobulin heavy chain variable domain
  • V L immunoglobulin light chain variable domain
  • an immunoglobulin V H domain comprising the amino acid sequence set forth as SEQ ID NO: 8 and an immunoglobulin V L domain comprising the amino acid sequence set forth as SEQ ID NO: 10; or an amino acid sequence having at least about 95%, 98% or 99% overall sequence identity thereto;
  • an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO:l, SEQ ID NO:2, and SEQ ID NO:3; or an amino acid sequence having at least about 90%, 95%, 98% or 99% overall sequence identity thereto;
  • an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6; or an amino acid sequence having at least about 90%, 95%, 98% or 99% overall sequence identity thereto;
  • an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO:l 1, SEQ ID NO: 12 and SEQ ID NO: 13; or an amino acid sequence having at least about 90%, 95%, 98% or 99% overall sequence identity thereto;
  • an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO: 1, SEQ ID NO:2, and SEQ ID NO:3 and an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6; or an amino acid sequence having at least about 90%, 95%, 98% or 99% overall sequence identity thereto;
  • an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 and an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 ; or an amino acid sequence having at least about 90%, 95%, 98% or 99% overall sequence identity thereto;
  • an immunoglobulin light chain comprising the amino acid sequence set forth as SEQ ID NO: 14; or an amino acid sequence having at least about 90%, 95%, 98% or 99% overall sequence identity thereto;
  • an immunoglobulin heavy chain comprising the amino acid sequence set forth as SEQ ID NO:15; or an amino acid sequence having at least about 90%, 95%, 98% or 99% overall sequence identity thereto; or
  • an immunoglobulin light chain comprising the amino acid sequence set forth as SEQ ID NO: 14 and an immunoglobulin heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 15; or an amino acid sequence having at least about 90%, 95%, 98% or 99% overall sequence identity thereto.
  • IL-17 antibody or antigen-binding fragment thereof for use in treating or preventing acne according to any of the above embodiments, wherein the IL-17 antibody or antigen-binding fragment thereof is administered for up to 24 weeks.
  • IL-17 antibody or antigen-binding fragment thereof for use in treating or preventing acne according to any the above embodiments, wherein the IL-17 antibody or antigen-binding fragment thereof is administered subcutaneously at an unit dose of about 75 mg to about 600 mg, about 75mg to about 450mg, or about 75 mg to about 300 mg, quarterly, monthly or weekly, e.g. monthly.
  • the IL-17 antibody or antigen-binding fragment thereof for use in treating or preventing acne according to embodiment 8, wherein the IL-17 antibody or antigen-binding fragment thereof is administered subcutaneously at an unit dose of about 75mg, about 150mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, or about 600mg.
  • the unit dose is administered quarterly, monthly or weekly, e.g. monthly or weekly, e.g. monthly.
  • the IL-17 antibody or antigen-binding fragment thereof for use in treating or preventing acne according to any of the above embodiments, wherein the IL-17 antibody or antigen-binding fragment thereof is administered by subcutaneous injection at an unit dose of about 75 mg to about 600 mg, preferably about 75 mg to about 300 mg, preferably about 300 mg to about 450 mg, wherein said administering is not preceded by administering said IL-17 antibody or antigen- binding fragment in a loading regimen.
  • the unit dose is administered quarterly, monthly or weekly, e.g. monthly or weekly, e.g. monthly. 11.
  • the IL-17 antibody or antigen-binding fragment thereof for use in treating or preventing acne according to any of the above embodiments, wherein the IL-17 antibody or antigen-binding fragment thereof is administered by subcutaneous injection, at a loading dose of about 75 mg to about 600 mg, preferably about 75 mg to about 300 mg, preferably about 300 mg to about 450 mg.
  • the loading dose is administered e.g. weekly.
  • IL-17 antibody or antigen-binding fragment thereof for use in treating or preventing acne according to embodiment 12, wherein the IL-17 antibody or antigen-binding fragment thereof is administered subcutaneously at a dosing of about 75 mg to about 600 mg, preferably about 75 mg to about 300 mg or about 300 mg to about 450 mg, weekly during week 0, 1, 2, 3, and 4, and then monthly thereafter.
  • IL-17 antibody or antigen-binding fragment thereof for use in treating or preventing acne according to any one of embodiments 1 to 6, wherein the IL-17 antibody or antigen-binding fragment thereof is administered as a single dose.
  • This single dose can be administered subcutaneously and be of about 150 mg to about 600 mg, e.g. of about 75 mg to about 300 mg or about 300 mg to about 450 mg.
  • IL-17 antibody or antigen-binding fragment thereof for use in treating or preventing acne according to embodiment 4 or any one of embodiments 6 to 14, wherein the IL-17 antibody or antigen-binding fragment thereof is CJM112, a functional derivative or biosimilar thereof, e.g. CJM112.
  • the IL- 17 antibody or antigen-binding fragment thereof for use in treating or preventing acne according to embodiment 15, wherein the IL-17 antibody or antigen-binding fragment thereof is CJM112, a functional derivative or biosimilar thereof, e.g. CJM112, and the IL-17 antibody or antigen-binding fragment thereof is administered subcutaneously at an unit dose of about 75mg to about 600mg, e.g. about 150 mg to about 600 mg, e.g. about 150 mg to about 450 mg, e.g. about 300 mg to about 450 mg.
  • Such administrations are for example weekly or monthly; they can be weekly for several weeks (e.g 1 to 8 weeks, e.g. 4 or 5 weeks) and then monthly.
  • IL-17 antibody or antigen-binding fragment thereof for use in treating or preventing acne according to any one of embodiments 5 to 14, wherein the IL-17 antibody or antigen- binding fragment thereof is secukinumab, a functional derivative or biosimilar thereof, e.g. secukinumab.
  • the IL-17 antibody or antigen-binding fragment thereof for use in treating or preventing moderate to severe acne comprising administering the patient a single dose of about 75mg to about 600mg, e.g. about 150 mg to about 600 mg, e.g. about 150 mg to about 450 mg, e.g. about 300 mg to about 450 mg, of secukinumab, a functional derivative or biosimilar thereof, e.g. Secukinumab, by subcutaneous injection.
  • An IL-17 antibody or antigen-binding fragment thereof for use in treating or preventing moderate to severe acne that is secukinumab, a functional derivative or biosimilar thereof, e.g., secukinumab, wherein the IL-17 antibody or antigen-binding fragment thereof is administered subcutaneously at a dosing of about 75 mg to about 600 mg, preferably about 75 mg to about 300 mg or about 300 mg to about 450 mg, weekly, during 1 to 8 weeks and then monthly thereafter.
  • IL-17 antibody or antigen-binding fragment thereof for use in treating or preventing moderate to severe acne according to embodiment 19, wherein secukinumab, a functional derivative or biosimilar thereof, e.g. secukinumab, is administered during week 0, 1, 2, 3 and 4, and then monthly thereafter.
  • IL-17 antibody or antigen-binding fragment thereof for use in treating or preventing acne according to embodiment 15 or 17, wherein the IL-17 antibody or antigen-binding fragment thereof is administered intravenously at a dose of about 10mg/kg, e.g. monthly or weekly.
  • IL-17 antibody or antigen-binding fragment thereof for use in treating or preventing acne according to any one of the embodiments above, wherein the patient was previously treated for acne with a topical anti-acne treatment, an oral/systemic anti-acne treatment, a systemic or lesional injected anti-acne treatment, or surgical, physical, light or laser therapy.
  • a method of treating acne comprising administering a therapeutically effective amount of an IL-17 antibody or antigen-binding fragment thereof to a patient in need thereof, wherein the IL-17 antibody or antigen-binding fragment thereof binds to an epitope of mature human IL- 17: a) between residues Arg 55 and Trp 67; b) comprising residues Arg 55, Glu 57, and Trp 67; c) comprising residues Arg 55, Glu 57, Trp 67, Tyr 62, and Arg 101; d) comprising residues Arg 55, Glu 57, Trp 67, Tyr 62, Arg 101, Pro 59, Ser 64, and Val 65; or e) comprising residues Arg 55, Glu 57, Trp 67, Tyr 62, Arg 101, Pro 59, Ser 64, Val 65; or e) comprising residues Arg 55, Glu 57, Trp 67, Tyr 62, Arg 101, Pro 59, Ser 64, Val 65
  • a method of treating acne comprising administering a therapeutically effective amount of an IL-17 antibody or antigen-binding fragment thereof to a patient in need thereof, wherein the IL-17 antibody or antigen-binding fragment thereof binds to an epitope of a human IL-17 homodimer having two mature human IL-17 protein chains, said epitope comprising residues Leu74, Tyr85, His86, Met87, Asn88, Vall24, Thrl25, Prol26, Ilel27, Vall28, Hisl29 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain, wherein the IL-17 antibody or antigen-binding fragment thereof has a KD for human IL-17 of about 100-200 pM, and wherein the IL-17 antibody or antigen-binding fragment thereof has an in vivo half-life of about 3-5 weeks, e.g., about 4 weeks. 24.
  • IL-17 antibody or antigen-binding fragment thereof comprises:
  • V H immunoglobulin heavy chain variable domain
  • V L immunoglobulin light chain variable domain
  • an immunoglobulin V H domain comprising the amino acid sequence set forth as SEQ ID NO: 30 and an immunoglobulin V L domain comprising the amino acid sequence set forth as SEQ K> NO:22;
  • an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO:24, SEQ ID NO:26, and SEQ ID NO:28;
  • an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO: 16, SEQ ID NO: 18 and SEQ ID NO:20;
  • an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO:25, SEQ ID NO:27 and SEQ ID NO:29;
  • an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO: 17, SEQ ID NO: 19 and SEQ ID NO:21;
  • an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO:24, SEQ ID NO:26, and SEQ ID NO:28 and an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO: 16, SEQ ID NO: 18 and SEQ ID NO:20;
  • an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO:25, SEQ ID NO:27, and SEQ ID NO:29 and an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO: 17, SEQ ID NO: 19 and SEQ ID NO: 21 ;
  • a method of treating a patient having acne, e.g. moderate to severe inflammatory acne comprising monthly administering the patient about 75 mg to about 600 mg, about 75mg to about 600mg, e.g. about 150 mg to about 600 mg, e.g. about 150 mg to about 4S0 mg, e.g. about 300 mg to about 450 mg, of CJM112 (or a functional derivative or biosimilar thereof, preferably CJM112) by subcutaneous injection, wherein said monthly administering is optionally not preceded by administering the patient CJM112 in a loading regimen.
  • CJM112 or a functional derivative or biosimilar thereof, preferably CJM112
  • a method of treating a patient having acne, e.g. moderate to severe inflammatory acne comprising monthly administering the patient about about 75 mg to about 300 mg or about 300 mg to about 450 mg, of CJM112 (or a functional derivative or biosimilar thereof, preferably CJM112) by subcutaneous injection, wherein said monthly administering is not preceded by administering the patient CJM112 in a loading regimen.
  • CJM112 or a functional derivative or biosimilar thereof, preferably CJM112
  • a method of treating a patient having acne comprising administering the patient a single dose of about 75 mg to about 600 mg, e.g about 75 mg to about 300 mg, e.g. about 150 mg to about 600 mg, e.g. about 150 mg to about 450 mg, e.g. about 300 mg to about 450 mg, of CJM112 (or a functional derivative or biosimilar thereof, preferably CJM112) by subcutaneous injection.
  • IL-17 antibody or antigen-binding fragment thereof comprises: i) an immunoglobulin heavy chain variable domain (V H ) comprising the amino acid sequence set forth as SEQ ID NO: 8;
  • V L immunoglobulin light chain variable domain
  • an immunoglobulin V H domain comprising the amino acid sequence set forth as SEQ ID NO: 8 and an immunoglobulin V L domain comprising the amino acid sequence set forth as SEQ ID NO: 10;
  • an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO: 1, SEQ ID NO:2, and SEQ ID NO:3;
  • an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13;
  • an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO: 1, SEQ ID NO:2, and SEQ ID NO:3 and an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO:4, SEQ ID NO: 5 and SEQ ID NO: 6;
  • an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO:ll, SEQ ID NO:12 and SEQ ID NO:13 and an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6;
  • an immunoglobulin heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 15;
  • an immunoglobulin light chain comprising the amino acid sequence set forth as SEQ ID NO: 14 and an immunoglobulin heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 15.
  • IL-17 antibody or antigen-binding fragment thereof is a human antibody. 38. The method according to embodiment 37, wherein the IL-17 antibody or antigen-binding fragment thereof is secukinumab, a functional derivative or biosimilar thereof, e.g. secukinumab.
  • a method of treating a patient having acne comprising administering the patient a single dose of about 75 mg to about 600 mg, e.g. about 150 mg to about 600 mg, e.g. about 150 mg to about 4S0 mg, e.g. about 300 mg to about 4S0 mg, e.g. about 75 mg to about 300 mg of secukinumab (or a functional derivative or biosimilar thereof, e.g. Secukinumab) by subcutaneous injection.
  • a method of treating a patient having acne comprising subcutaneously administering to the patient about 75 mg to about 600 mg, e.g. about 150 mg to about 600 mg, e.g. about 150 mg to about 450 mg, e.g. about 300 mg to about 450 mg, e.g. about 75 mg to about 300 mg, of Secukinumab (or a functional derivative or biosimilar thereof, e.g. Secukinumab), weekly during week 0, 1, 2, 3, and 4, and then monthly thereafter.
  • Secukinumab or a functional derivative or biosimilar thereof, e.g. Secukinumab
  • a method of treating a patient having acne comprising intraveneously administering to the patient about 10mg/kg.
  • an IL-17 antibody or antigen-binding fragment thereof in the preparation of a medicament for treating or preventing acne, e.g. moderate to severe acne, e.g. moderate to severe inflammatory acne.
  • IL-17 antibody or antigen-binding fragment thereof binds to an epitope of mature human IL-17: a) between residues Arg 55 and Trp 67; b) comprising residues Arg 55, Glu 57, and Trp 67; c) comprising residues Arg 55, Glu 57, Trp 67, Tyr 62, and Arg 101; d) comprising residues Arg 55, Glu 57, Trp 67, Tyr 62, Arg 101, Pro 59, Ser 64, and Val 65; or e) comprising residues Arg 55, Glu 57, Trp 67, Tyr 62, Arg 101, Pro 59, Ser 64, Val 65, Val 22*, Leu 26, Asp 58, Glu 60, Pro 63, Pro 107, Phe 110, and Lys 114*, where amino acids marked with (*) designate a residue contributed by the second IL-17 subunit of the IL-17A homodimer, and further
  • the IL-17 antibody or antigen-binding fragment thereof binds to an epitope of a human IL-17 homodimer having two mature human IL- 17 protein chains, said epitope comprising residues Leu74, Tyr85, His86, Met87, Asn88, Vall24, Thrl25, Prol26, Ilel27, Vall28, Hisl29 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain, wherein the IL-17 antibody or antigen-binding fragment thereof has a K D for human IL-17 of about 100-200 pM, and wherein the IL-17 antibody or antigen-binding fragment thereof has an in vivo half-life of about 3-5 weeks, e.g., about 4 weeks.
  • IL-17 antibody or antigen-binding fragment thereof comprises:
  • V H immunoglobulin heavy chain variable domain
  • V L immunoglobulin light chain variable domain
  • an immunoglobulin V H domain comprising the amino acid sequence set forth as SEQ ID NO: 30 and an immunoglobulin V L domain comprising the amino acid sequence set forth as SEQ ID NO:22; or an amino acid sequence having at least about 95%, 98% or 99% overall sequence identity thereto;
  • an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO:24, SEQ ID NO:26, and SEQ ID NO:28; or an amino acid sequence having at least about 95%, 98% or 99% overall sequence identity thereto;
  • an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO: 16, SEQ ID NO: 18 and SEQ ID NO:20; or an amino acid sequence having at least about 95%, 98% or 99% overall sequence identity thereto;
  • an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO:25, SEQ ID NO:27 and SEQ ID NO:29; or an amino acid sequence having at least about 95%, 98% or 99% overall sequence identity thereto;
  • an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO: 17, SEQ ID NO: 19 and SEQ ID NO:21; or an amino acid sequence having at least about 95%, 98% or 99% overall sequence identity thereto;
  • an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO:24, SEQ ID NO:26, and SEQ ID NO:28 and an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO: 16, SEQ ID NO: 18 and SEQ ID NO:20; or an amino acid sequence having at least about 90%, 95%, 98% or 99% overall sequence identity thereto;
  • an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO:25, SEQ ID NO:27, and SEQ ID NO:29 and an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO: 17, SEQ ID NO: 19 and SEQ ID NO:21; or an amino acid sequence having at least about 90%, 95%, 98% or 99% overall sequence identity thereto;
  • x) a light chain comprising SEQ ID NO:23; or an amino acid sequence having at least about 90%, 95%, 98% or 99% overall sequence identity thereto;
  • xi a heavy chain comprising SEQ ID NO:31; or an amino acid sequence having at least about 90%, 95%, 98% or 99% overall sequence identity thereto;
  • IL-17 antibody or antigen-binding fragment thereof comprises:
  • V H immunoglobulin heavy chain variable domain
  • V L immunoglobulin light chain variable domain
  • an immunoglobulin V H domain comprising the amino acid sequence set forth as SEQ ID NO: 8 and an immunoglobulin V L domain comprising the amino acid sequence set forth as SEQ ID NO: 10; or an amino acid sequence having at least about 95%, 98% or 99% overall sequence identity thereto;
  • an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO:l, SEQ ID NO:2, and SEQ ID NO:3; or an amino acid sequence having at least about 90%, 95%, 98% or 99% overall sequence identity thereto;
  • an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6; or an amino acid sequence having at least about 90%, 95%, 98% or 99% overall sequence identity thereto;
  • an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO:l 1, SEQ ID NO: 12 and SEQ ID NO: 13; or an amino acid sequence having at least about 90%, 95%, 98% or 99% overall sequence identity thereto;
  • an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO: 1, SEQ ID NO:2, and SEQ ID NO:3 and an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6; or an amino acid sequence having at least about 90%, 95%, 98% or 99% overall sequence identity thereto;
  • an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO:ll, SEQ ID NO:12 and SEQ ID NO:13 and an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO:4, SEQ ID NO: 5 and SEQ ID NO:6 ; or an amino acid sequence having at least about 90%, 95%, 98% or 99% overall sequence identity thereto;
  • an immunoglobulin light chain comprising the amino acid sequence set forth as SEQ ID NO: 14; or an amino acid sequence having at least about 90%, 95%, 98% or 99% overall sequence identity thereto;
  • an immunoglobulin heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 15; or an amino acid sequence having at least about 90%, 95%, 98% or 99% overall sequence identity thereto; or
  • an immunoglobulin light chain comprising the amino acid sequence set forth as SEQ ID NO: 14 and an immunoglobulin heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 15; or an amino acid sequence having at least about 90%, 95%, 98% or 99% overall sequence identity thereto.
  • A8 Use according to any the above embodiments Al to A7, wherein the IL-17 antibody or antigen-binding fragment thereof is administered quarterly or monthly, e.g. subcutaneously at a dosing of about 75 mg to about 600 mg, about 75mg to about 450mg, or about 75 mg to about 300 mg.
  • IL-17 antibody or antigen-binding fragment thereof is administered monthly, by subcutaneous injection, at a dosing of about 75 mg, about 150mg, about 300mg, about 450mg or about 600mg.
  • IL-17 antibody or antigen-binding fragment thereof is administered by subcutaneous injection at a dosing of about 75 mg to about 600 mg, preferably about 75 mg to about 300 mg, wherein said administering is not preceded by administering said IL-17 antibody or antigen-binding fragment in a loading regimen.
  • Al 1 Use according to any of the above embodiments Al to A10, wherein the IL-17 antibody or antigen-binding fragment thereof is administered by subcutaneous injection, weekly, at a loading dose of about 75 mg to about 600 mg, preferably about 75 mg to about 300 mg.
  • IL- 17 antibody or antigen-binding fragment thereof is CJM112, a functional derivative or biosimilar thereof, e.g. CJM112, and the IL-17 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 75mg to about 600mg, e.g. about 150 mg to about 600 mg, e.g. about 150 mg to about 450 mg, e.g. about 300 mg to about 450 mg.
  • Such administrations are for example weekly or monthly; they can be weekly for several weeks (e.g 1 to 8 weeks, e.g. 4 or 5 weeks) and then monthly.
  • A17 Use according to any one of embodiments A5 to A14, wherein the IL-17 antibody or antigen-binding fragment thereof is secukinumab, a functional derivative or biosimilar thereof, e.g. secukinumab.
  • A18 Use according to embodiment A17, comprising administering the patient a single dose of about 75mg to about 600mg, e.g. about 150 mg to about 600 mg, e.g. about 150 mg to about 450 mg, e.g. about 300 mg to about 450 mg, of secukinumab, a functional derivative or biosimilar thereof, e.g. Secukinumab, by subcutaneous injection.
  • an IL-17 antibody or antigen-binding fragment thereof in the preparation of a medicament for treating or preventing moderate to severe acne, that is secukinumab, a functional derivative or biosimilar thereof, e.g., secukinumab, wherein the IL-17 antibody or antigen- binding fragment thereof is administered subcutaneously at a dosing of about 75 mg to about 600 mg, preferably about 75 mg to about 300 mg, weekly, during 1 to 8 weeks and then monthly thereafter.
  • A21 Use according to any one of the embodiments Al to A20, wherein the patient was previously treated for acne with a topical anti-acne treatment, an oral/systemic anti-acne treatment, a systemic or lesional injected anti-acne treatment, or surgical, physical, light or laser therapy.
  • Bl Use of a pharmaceutical composition comprising of an IL- 17 antibody or antigen-binding fragment thereof, and one or more pharmaceutically acceptable carriers, in the manufacture medicament for treating or preventing acne, according to any of the above embodiments (e.g. Al to A21).
  • IL-17 refers to interleukin-17A (IL-17A).
  • composition “comprising” encompasses “including” as well as “consisting,” e.g., a composition “comprising” X may consist exclusively of X or may include something additional, e.g., X + Y.
  • TNF-alpha antagonist refers to small molecules and biological molecules capable of inhibiting, reducing and/or blocking TNF-alpha signal, transduction, and/or activity.
  • TNF-alpha antagonists include Enbrel® (etanercept), Humira® (adalimumab), Remicade® (infliximab) and Simponi® (golimumab).
  • antibody as referred to herein includes naturally-occurring and whole antibodies.
  • a naturally-occurring “antibody” is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds.
  • Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as V H ) and a heavy chain constant region.
  • the heavy chain constant region is comprised of three domains, CHI, CH2 and CH3.
  • Each light chain is comprised of a light chain variable region (abbreviated herein as V L ) and a light chain constant region.
  • the light chain constant region is comprised of one domain, CL.
  • the V H and V L regions can be further subdivided into regions of hypervariability, termed hypervariable regions or complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDR complementarity determining regions
  • FR framework regions
  • Each V H and V L is composed of three CDRs and four FRs arranged from amino-terminus to car boxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
  • the constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
  • Exemplary antibodies include secukinumab (Table 1), CJM112 (Table 2) and ixekizumab (U.S. Patent No.
  • antigen-binding fragment of an antibody, as used herein, refers to fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., IL-17). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full- length antibody.
  • binding fragments encompassed within the term "antigen-binding portion" of an antibody include a Fab fragment, a monovalent fragment consisting of the V L , V3 ⁇ 4 CL and CHI domains; a F(ab)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment consisting of the V H and CHI domains; a Fv fragment consisting of the V L and V H domains of a single arm of an antibody; a dAb fragment (Ward et al., 1989 Nature 341:544-546), which consists of a V H domain; and an isolated CDR.
  • Fab fragment a monovalent fragment consisting of the V L , V3 ⁇ 4 CL and CHI domains
  • F(ab)2 fragment a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region
  • a Fd fragment consisting of the V H and CHI domains
  • Exemplary antigen-binding sites include the CDRs of secukinumab as set forth in SEQ ID NOs: 1-6 and 11-13 (Table 1), preferably the heavy chain CDR3.
  • Exemplary antigen- binding sites include the CDRs of CJM112 as set forth in SEQ ID NOs: 16-21 and 24-30 (Table 2), preferably the heavy chain CDR3.
  • the two domains of the Fv fragment, V L and V H are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the V L and V H regions pair to form monovalent molecules (known as single chain Fv (scFv); see, e.g., Bird et al., 1988 Science 242:423-426; and Huston et al., 1988 Proc. Natl. Acad. Sci. 85:5879-5883).
  • single chain Fv single chain Fv
  • Such single chain antibodies are also intended to be encompassed within the term "antibody”.
  • Single chain antibodies and antigen-binding portions are obtained using conventional techniques known to those of skill in the art
  • an “isolated antibody”, as used herein, refers to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds 1L-17 is substantially free of antibodies that specifically bind antigens other than IL-17).
  • the term “monoclonal antibody” or “monoclonal antibody composition” as used herein refer to a preparation of antibody molecules of single molecular composition.
  • 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 sequences of human origin. A "human antibody” need not be produced by a human, human tissue or human cell.
  • the human antibodies of the disclosure may include amino acid residues not encoded by human sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro, by N-nucleotide addition at junctions in vivo during recombination of antibody genes, or by somatic mutation in vivo).
  • the IL-17 antibody is a human antibody, an isolated antibody, and/or a monoclonal antibody.
  • IL-17 refers to IL-17 A, formerly known as CTLA8, and includes wild-type IL- 17A from various species (e.g., human, mouse, and monkey), polymorphic variants of IL-17A, and functional equivalents of IL-17A.
  • Functional equivalents of IL-17A according to the present disclosure preferably have at least about 65%, 75%, 85%, 95%, 96%, 97%, 98%, or even 99% overall sequence identity with a wild-type IL-17A (e.g., human IL-17A), and substantially retain the ability to induce IL-6 production by human dermal fibroblasts.
  • KD is intended to refer to the dissociation rate of a particular antibody-antigen interaction.
  • KD is intended to refer to the dissociation constant, which is obtained from the ratio of to and is expressed as a molar concentration
  • KD values for antibodies can be determined using methods well established in the art.
  • a method for determining the KD of an antibody is by using surface plasmon resonance, or using a biosensor system such as a Biacore® system.
  • the IL-17 antibody or antigen-binding fragment thereof e.g., secukinumab or CJMl 12, binds human IL-17 with a KD of about 1-250 pM, preferably about 1-10 pM (e.g., about 6 pM) or about 100-200 pM (e.g., about 200 pM).
  • affinity refers to the strength of interaction between antibody and antigen at single antigenic sites. Within each antigenic site, the variable region of the antibody “arm” interacts through weak non-covalent forces with antigen at numerous sites; the more interactions, the stronger the affinity.
  • Standard assays to evaluate the binding affinity of the antibodies toward IL-17 of various species are known in the art, including for example, ELISAs, western blots and RIAs.
  • the binding kinetics (e.g., binding affinity) of the antibodies also can be assessed by standard assays known in the art, such as by Biacore analysis.
  • an antibody that "inhibits" one or more of these IL-17 functional properties will be understood to relate to a statistically significant decrease in the particular activity relative to that seen in the absence of the antibody (or when a control antibody of irrelevant specificity is present).
  • An antibody that inhibits IL-17 activity affects a statistically significant decrease, e.g., by at least about 10% of the measured parameter, by at least 50%, 80% or 90%, and in certain embodiments of the disclosed methods and compositions, the IL-17 antibody used may inhibit greater than 95%, 98% or 99% of IL-17 functional activity.
  • “Inhibit IL-6” as used herein refers to the ability of an IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab or CJM112) to decrease IL-6 production from primary human dermal fibroblasts.
  • the production of IL-6 in primary human (dermal) fibroblasts is dependent on IL-17 (Hwang et al., (2004) Arthritis Res Ther; 6:R120-128).
  • human dermal fibroblasts are stimulated with recombinant IL-17 in the presence of various concentrations of an IL-17 binding molecule or human IL-17 receptor with Fc part.
  • the chimeric anti-CD25 antibody Simulect ® may be conveniently used as a negative control. Supernatant is taken after 16 h stimulation and assayed for IL-6 by ELISA.
  • An IL-17 antibody or antigen-binding fragment thereof e.g., secukinumab or CJM112, typically has an IC50 for inhibition of IL-6 production (in the presence 1 nM human IL-17) of about 50 nM or less (e.g., from about 0.01 to about 50 nM) when tested as above, i.e., said inhibitory activity being measured on IL-6 production induced by hu-IL-17 in human dermal fibroblasts.
  • IL-17 antibodies or antigen-binding fragments thereof e.g., secukinumab or CJM112, and functional derivatives thereof have an IC50 for inhibition of IL-6 production as defined above of about 20 nM or less, more preferably of about 10 nM or less, more preferably of about 5 nM or less, more preferably of about 2 nM or less, more preferably of about 1 nM or less.
  • derivative unless otherwise indicated, is used to define amino acid sequence variants, and covalent modifications (e.g., pegylation, deamidation, hydroxylation, phosphorylation, methylation, etc.) of an IL- 17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112, according to the present disclosure, e.g., of a specified sequence (e.g., a variable domain).
  • a “functional derivative” includes a molecule having a qualitative biological activity in common with the disclosed IL-17 antibodies.
  • a functional derivative includes fragments and peptide analogs of an IL-17 antibody as disclosed herein.
  • Fragments comprise regions within the sequence of a polypeptide according to the present disclosure, e.g., of a specified sequence.
  • Functional derivatives of the IL-17 antibodies disclosed herein preferably comprise V H and/or V L domains that have at least about 65%, 75%, 85%, 95%, 96%, 97%, 98%, or even 99% overall sequence identity with the V H and/or V L sequences of the IL-17 antibodies and antigen-binding fragments thereof disclosed herein, and substantially retain the ability to bind human IL-17 or, e.g., inhibit IL-6 production of IL-17 induced human dermal fibroblasts.
  • substantially identical means that the relevant amino acid or nucleotide sequence (e.g., V H or V L domain) will be identical to or have insubstantial differences (e.g., through conserved amino acid substitutions) in comparison to a particular reference sequence. Insubstantial differences include minor amino acid changes, such as 1 or 2 substitutions in a 5 amino acid sequence of a specified region (e.g., V H or V L domain).
  • the second antibody has the same specificity and has at least 50% of the affinity of the same. Sequences substantially identical (e.g., at least about 85% sequence identity) to the sequences disclosed herein are also part of this application.
  • sequence identity of a derivative IL-17 antibody can be about 90% or greater, e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher relative to the disclosed sequences.
  • Identity with respect to a native polypeptide and its functional derivative is defined herein as the percentage of amino acid residues in the candidate sequence that are identical with the residues of a corresponding native polypeptide, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent identity, and not considering any conservative substitutions as part of the sequence identity. Neither N- or C-terminal extensions nor insertions shall be construed as reducing identity. Methods and computer programs for the alignment are well known. The percent identity can be determined by standard alignment algorithms, for example, the Basic Local Alignment Search Tool (BLAST) described by Altshul et al. ((1990) J. Mol. Biol., 215: 403 410); the algorithm of Needleman et al.
  • BLAST Basic Local Alignment Search Tool
  • a set of parameters may be the Blosum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.
  • the percent identity between two amino acid or nucleotide sequences can also be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4:11-17) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.
  • amino acid(s) refer to all naturally occurring L-a-amino acids, e.g., and include D- amino acids.
  • amino acid sequence variant refers to molecules with some differences in their amino acid sequences as compared to the sequences according to the present disclosure. Amino acid sequence variants of an antibody according to the present disclosure, e.g., of a specified sequence, still have the ability to bind the human IL-17 or, e.g., inhibit IL-6 production of IL-17 induced human dermal fibroblasts.
  • Amino acid sequence variants include substitutional variants (those that have at least one amino acid residue removed and a different amino acid inserted in its place at the same position in a polypeptide according to the present disclosure), insertional variants (those with one or more amino acids inserted immediately adjacent to an amino acid at a particular position in a polypeptide according to the present disclosure) and deletional variants (those with one or more amino acids removed in a polypeptide according to the present disclosure).
  • pharmaceutically acceptable means a nontoxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s).
  • administering in relation to a compound, e.g., an IL-17 binding molecule or another agent, is used to refer to delivery of that compound to a patient by any route.
  • a "therapeutically effective amount” refers to an amount of an IL-17 antagonist, e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112) or IL-17 receptor binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof) that is effective, upon single or multiple dose administration to a patient (such as a human) for treating, preventing, preventing the onset of, curing, delaying, reducing the severity of, ameliorating at least one symptom of a disorder or recurring disorder, or prolonging the survival of the patient beyond that expected in the absence of such treatment
  • an individual active ingredient e.g., an IL-17 antagonist, e.g., secukinumab or CJM112
  • the term refers to that ingredient alone.
  • the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether
  • treatment refers to curative or disease modifying treatment, including treatment of a patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a patient having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a patient beyond that expected absent such treatment
  • prevent refers to prophylactic or preventative treatment; it is concerned about delaying the onset of, or preventing the onset of the disease, disorders and/or symptoms associated thereto.
  • selecting and “selected” in reference to a patient is used to mean that a particular patient is specifically chosen from a larger group of patients on the basis of (due to) the particular patient having a predetermined criteria.
  • selecting refers to providing treatment to a patient having a particular disease, where that patient is specifically chosen from a larger group of patients on the basis of the particular patient having a predetermined criterion.
  • selective administering refers to administering a drug to a patient that is specifically chosen from a larger group of patients on the basis of (due to) the particular patient having a predetermined criterion.
  • a patient is delivered a personalized therapy based on the patient's personal history (e.g., prior therapeutic interventions, e.g., prior treatment with biologies), biology (e.g., particular genetic markers), and/or manifestation (e.g., not fulfilling particular diagnostic criteria), rather than being delivered a standard treatment regimen based solely on the patient's membership in a larger group.
  • Selecting, in reference to a method of treatment as used herein does not refer to fortuitous treatment of a patient having a particular criterion, but rather refers to the deliberate choice to administer treatment to a patient based on the patient having a particular criterion.
  • selective treatment/administration differs from standard treatment/administration, which delivers a particular drug to all patients having a particular disease, regardless of their personal history, manifestations of disease, and/or biology.
  • Acne vulgaris is a chronic skin disease involving blockage and/or inflammation of pilosebaceous units (hair follicles and their accompanying sebaceous gland). It can present as noninflammatory lesions, inflammatory lesions, or a mixture of both, affecting mostly the face but also the back and chest
  • the phrase "moderate to severe acne” means acne vulgaris with an Investigator's Global assessment (IGA) score of at least moderate (3) acne severity.
  • “moderate to severe inflammatory acne” means acne vulgaris with inflammatory lesions (papules, pustules and nodules) and presence of non-inflammatory lesions (open and closed comedones) and an Investigator's Global assessment (IGA) score of at least moderate (3) acne severity " refers to inflammatory lesions (papules, pustules and nodules), and/or presence of non-inflammatory lesions (open and closed comedones).
  • acne includes all forms of acne, e.g., P. acnes, A. nodulocycstic, A. conglabata, A.
  • fitlminans pyoderma faciale
  • induced forms e.g., chloracne or bromidacne and steroidacne, medication- induced acne rashes [e.g., observed with some cancer therapy]
  • other diseases with acne e.g., Synovitis-Acne-Pustulosis Hyperostosis-Osteitis (SAPHO), acne tetrad and follicular triad.
  • SAPHO Synovitis-Acne-Pustulosis Hyperostosis-Osteitis
  • acne tetrad follicular triad.
  • IL- 17 antagonists include small molecules and biological molecules that are capable of blocking, reducing and/or inhibiting IL-17 signal, activity and/or transduction.
  • IL-17 antagonists include e.g., IL-17 binding molecules (e.g., soluble IL-17 receptors, IL-17 antibodies or antigen-binding fragments thereof, e.g., secukinumab or CJM112) and IL-17 receptor binding molecules (e.g., IL-17 receptor antibodies or antigen-binding fragments thereof).
  • the IL-17 antagonist is an IL-17 binding molecule, preferably an IL-17 antibody or antigen-binding fragment thereof.
  • IL-17 antibodies and antigen-binding fragment thereof as used herein can be fully-human, CDR-grafted, or chimeric. It is preferable that the constant region domains of an antibody or antigen-binding fragment thereof for use in the disclosed methods, uses, kits, etc. preferably comprise suitable human constant region domains, for instance as described in "Sequences of Proteins of Immunological Interest", Kabat E.A. et al, US Department of Health and Human Services, Public Health Service, National Institute of Health.
  • IL-17 antibodies or antigen-binding fragments thereof used in the disclosed methods are human antibodies, especially secukinumab as described in Examples 1 and 2 of WO 2006/013107 and CJM112 as described in US Patent No 9,193,788, both of which are incorporated by reference herein in their entirety.
  • Secukinumab and CJM112 are recombinant high-affinity, fully human monoclonal anti-human interleukin-17A (IL-17 A, IL-17) antibodies of the IgGl /kappa isotype.
  • Secukinumab has a high affinity for IL-17, i.e., a 3 ⁇ 4 of about 100-200 pM (e.g., about 200 pM), an IC50 of about 0.4 nM for in vitro neutralization of the biological activity of about 0.67 nM human IL-17A, and a half-life of about 4 weeks.
  • CJM112 has a very high affinity for human IL-17A, i.e., about 1-10 pM (e.g., about 6 pM), and an in vivo half-life of about 2-4 weeks, e.g., about 3 weeks.
  • amino acid sequences of the hypervariable regions of the secukinumab monoclonal antibody based on the Kabat definition and as determined by the X- ray analysis and using the approach of Chothia and coworkers, as well as the V L and V H domains and full heavy and light chains, is provided in Table 1, below.
  • the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin heavy chain variable domain (V H ) comprising hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:l, said CDR2 having the amino acid sequence SEQ ID NO:2, and said CDR3 having the amino acid sequence SEQ ID NO:3.
  • V H immunoglobulin heavy chain variable domain
  • the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin light chain variable domain (V L ) comprising hypervariable regions CDR1', CDR2' and CDR3', said CDR1' having the amino acid sequence SEQ ID NO:4, said CDR2' having the amino acid sequence SEQ ID NO: 5 and said CDR3' having the amino acid sequence SEQ ID NO:6.
  • V L immunoglobulin light chain variable domain
  • the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin heavy chain variable domain (V H ) comprising hypervariable regions CDRl-x, CDR2-X and CDR3-X, said CDRl-x having the amino acid sequence SEQ ID NO: 11, said CDR2-X having the amino acid sequence SEQ ID NO:12, and said CDR3-X having the amino acid sequence SEQ ID NO:13.
  • V H immunoglobulin heavy chain variable domain
  • the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin V H domain and at least one immunoglobulin V L domain
  • the immunoglobulin V H domain comprises (e.g., in sequence): i) hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO: 1, said CDR2 having the amino acid sequence SEQ ID NO:2, and said CDR3 having the amino acid sequence SEQ ID NO:3; or ii) hypervariable regions CDRl-x, CDR2-X and CDR3-X, said CDRl-x having the amino acid sequence SEQ ID NO: 11, said CDR2-X having the amino acid sequence SEQ ID NO: 12, and said CDR3-X having the amino acid sequence SEQ ID NO: 13; and b) the immunoglobulin V L domain comprises (e.g., in sequence) hypervariable regions CDR1', CDR2' and CDR3', said CDRl' having the
  • the IL-17 antibody or antigen-binding fragment thereof comprises: a) an immunoglobulin heavy chain variable domain (V H ) comprising the amino acid sequence set forth as SEQ ID NO:8; b) an immunoglobulin light chain variable domain (V L ) comprising the amino acid sequence set forth as SEQ ID NO: 10; c) an immunoglobulin V H domain comprising the amino acid sequence set forth as SEQ ID NO: 8 and an immunoglobulin V L domain comprising the amino acid sequence set forth as SEQ ID NO: 10; d) an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO:l, SEQ ID NO:2, and SEQ ID NO:3; e) an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6; f) an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO: 11, SEQ ID NO: 12 and SEQ
  • the IL-17 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 10. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 8. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 10 and the three CDRs of SEQ ID NO:8. CDRs of SEQ ID NO:8 and SEQ ID NO: 10 may be found in Table 1. The free cysteine in the light chain (CysL97) may be seen in SEQ ID NO:6.
  • IL-17 antibody or antigen-binding fragment thereof comprises the light chain of SEQ ID NO: 14. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises the heavy chain of SEQ ID NO: 15. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises the light chain of SEQ ID NO: 14 and the heavy domain of SEQ ID NO: 15. In some embodiments, the IL-17 antibody or antigen- binding fragment thereof comprises the three CDRs of SEQ ID NO: 14. In other embodiments, IL-17 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 15.
  • the IL-17 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 14 and the three CDRs of SEQ ID NO: 15.
  • CDRs of SEQ ID NO: 14 and SEQ ID NO: 15 may be found in Table 1.
  • Hypervariable regions may be associated with any kind of framework regions, though preferably are of human origin. Suitable framework regions are described in Kabat E.A. et al, ibid.
  • the preferred heavy chain framework is a human heavy chain framework, for instance that of the secukinumab antibody. It consists in sequence, e.g. of FR1 (amino acid 1 to 30 of SEQ ID NO: 8), FR2 (amino acid 36 to 49 of SEQ ID NO: 8), FR3 (amino acid 67 to 98 of SEQ ID NO: 8) and FR4 (amino acid 117 to 127 of SEQ ID NO: 8) regions.
  • another preferred heavy chain framework consists in sequence of FRl-x (amino acid 1 to 25 of SEQ ID NO: 8), FR2-x (amino acid 36 to 49 of SEQ ID NO:8), FR3-x (amino acid 61 to 95 of SEQ ID NO:8) and FR4 (amino acid 119 to 127 of SEQ ID NO: 8) regions.
  • the light chain framework consists, in sequence, of FR1' (amino acid 1 to 23 of SEQ ID NO: 10), FR2' (amino acid 36 to 50 of SEQ ID NO: 10), FR3' (amino acid 58 to 89 of SEQ ID NO: 10) and FR4' (amino acid 99 to 109 of SEQ ID NO: 10) regions.
  • the IL-17 antibody or antigen-binding fragment thereof is selected from a human IL-17 antibody that comprises at least: a) an immunoglobulin heavy chain or fragment thereof which comprises a variable domain comprising, in sequence, the hypervariable regions CDR1, CDR2 and CDR3 and the constant part or fragment thereof of a human heavy chain; said CDR1 having the amino acid sequence SEQ ID NO:l, said CDR2 having the amino acid sequence SEQ ID NO:2, and said CDR3 having the amino acid sequence SEQ ID NO:3; and b) an immunoglobulin light chain or fragment thereof which comprises a variable domain comprising, in sequence, the hypervariable regions CDR1', CDR2', and CDR3' and the constant part or fragment thereof of a human light chain, said CDR1' having the amino acid sequence SEQ ID NO:4, said CDR2' having the amino acid sequence SEQ ID NO: 5, and said CDR3' having the amino acid sequence SEQ ID NO:
  • the IL-17 antibody or antigen-binding fragment thereof is selected from a single chain antibody or antigen-binding fragment thereof that comprises an antigen- binding site comprising: a) a first domain comprising, in sequence, the hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO: 1, said CDR2 having the amino acid sequence SEQ ID NO:2, and said CDR3 having the amino acid sequence SEQ ID NO:3; and b) a second domain comprising, in sequence, the hypervariable regions CDR1', CDR2' and CDR3', said CDR1' having the amino acid sequence SEQ ID NO:4, said CDR2' having the amino acid sequence SEQ ID NO: 5, and said CDR3' having the amino acid sequence SEQ ID NO: 6; and c) a peptide linker which is bound either to the N-terminal extremity of the first domain and to the C -terminal extremity of the second domain or to the C-terminal extremity of the
  • an IL-17 antibody or antigen-binding fragment thereof as used in the disclosed methods may comprise a derivative of the IL-17 antibodies set forth herein by sequence (e.g., a pegylated version of secukinumab or CJM112).
  • the V H or V L domain of an IL-17 antibody or antigen-binding fragment thereof used in the disclosed methods may have V H or V L domains that are substantially identical to the V H or V L domains set forth in SEQ ID NO:8 and 10.
  • a human IL-17 antibody disclosed herein may comprise a heavy chain that is substantially identical to that set forth as SEQ ID NO: IS and/or a light chain that is substantially identical to that set forth as SEQ ID NO: 14.
  • a human IL-17 antibody disclosed herein may comprise a heavy chain that comprises SEQ ID NO: 15 and a light chain that comprises SEQ ID NO: 14.
  • a human IL-17 antibody disclosed herein may comprise: a) one heavy chain, comprising a variable domain having an amino acid sequence substantially identical to that shown in SEQ ID NO: 8 and the constant part of a human heavy chain; and b) one light chain, comprising a variable domain having an amino acid sequence substantially identical to that shown in SEQ ID NO: 10 and the constant part of a human light chain.
  • an IL-17 antibody or antigen-binding fragment thereof used in the disclosed methods may be an amino acid sequence variant of the reference IL-17 antibodies set forth herein, as long as it contains CysL97.
  • the disclosure also includes IL-17 antibodies or antigen-binding fragments thereof (e.g., secukinumab) in which one or more of the amino acid residues of the V H or V L domain of secukinumab (but not CysL97), typically only a few (e.g., 1- 10), are changed; for instance by mutation, e.g., site directed mutagenesis of the corresponding DNA sequences.
  • the IL-17 antibodies or antigen-binding fragments thereof bind to an epitope of mature human IL-17 comprising Leu74, Tyr85, His86, Met87, Asn88, Vall24, Thrl25, Prol26, Ilel27, Vall28, Hisl29.
  • the IL- 17 antibody e.g., secukinumab, binds to an epitope of mature human IL-17 comprising Tyr43, Tyr44, Arg46, Ala79, Asp80.
  • the IL-17 antibody e.g., secukinumab
  • the residue numbering scheme used to define these epitopes is based on residue one being the first amino acid of the mature protein (i.e., IL-17A lacking the 23 amino acid N-terminal signal peptide and beginning with Glycine).
  • the sequence for immature IL-17A is set forth in the Swiss-Prot entry Q16552.
  • the IL-17 antibody has a KD of about 100-200 pM.
  • the IL-17 antibody has an IC50 of about 0.4 nM for in vitro neutralization of the biological activity of about 0.67 nM human IL-17A.
  • the absolute bioavailability of subcutaneously (SC) administered IL-17 antibody has a range of about 60 - about 80%, e.g., about 76%.
  • the IL-17 antibody such as secukinumab
  • the IL-17 antibody (such as secukinumab) has a T m ax of about 7-8 days.
  • amino acid sequences of the hypervariable regions of the CJM112 monoclonal antibody based on the Kabat definition and the Chothia definition, as well as the V L and V H domains and full heavy and light chains are provided in Table 2, below.
  • the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin heavy chain variable domain (V H ) comprising hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:24, said CDR2 having the amino acid sequence SEQ ID NO:26, and said CDR3 having the amino acid sequence SEQ ID NO:28.
  • V H immunoglobulin heavy chain variable domain
  • the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin heavy chain variable domain (V H ) comprising hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:25, said CDR2 having the amino acid sequence SEQ ID NO:27, and said CDR3 having the amino acid sequence SEQ ID NO:29.
  • V H immunoglobulin heavy chain variable domain
  • the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin light chain variable domain (V L ⁇ ) comprising hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO: 16, said CDR2 having the amino acid sequence SEQ ID NO: 18 and said CDR3 having the amino acid sequence SEQ ID NO:20.
  • V L ⁇ immunoglobulin light chain variable domain
  • the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin light chain variable domain (V L ) comprising hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO: 17, said CDR2 having the amino acid sequence SEQ ID NO: 19 and said CDR3 having the amino acid sequence SEQ ID NO:21.
  • V L immunoglobulin light chain variable domain
  • the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin V H domain and at least one immunoglobulin V L domain
  • the immunoglobulin V H domain comprises (e.g., in sequence): i) hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:24, said CDR2 having the amino acid sequence SEQ ID NO: 26, and said CDR3 having the amino acid sequence SEQ ID NO:28; or ii) hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:25, said CDR2 having the amino acid sequence SEQ ID NO:27, and said CDR3 having the amino acid sequence SEQ ID NO:29; and b) the immunoglobulin V L domain comprises (e.g., in sequence): i) hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO: 16, said C
  • the IL- 17 antibody or antigen-binding fragment thereof comprises: a) an immunoglobulin heavy chain variable domain (V H ) comprising the amino acid sequence set forth as SEQ ID NO:30; b) an immunoglobulin light chain variable domain (V L ) comprising the amino acid sequence set forth as SEQ ID NO:22; c) an immunoglobulin V H domain comprising the amino acid sequence set forth as SEQ ID NO:30 and an immunoglobulin V L domain comprising the amino acid sequence set forth as SEQ ID NO:22; d) an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO:24, SEQ ID NO:26, and SEQ ID NO:28; e) an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO: 16, SEQ ID NO: 18 and SEQ ID NO:20; f) an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO:25, SEQ ID NO:27
  • the IL-17 antibody or antigen-binding fragment thereof (e.g., CJM112) comprises the three CDRs of SEQ ID NO:22. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO:30. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO:22 and the three CDRs of SEQ ID NO:30. In some embodiments, the IL- 17 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO:23. In other embodiments, IL-17 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO:31. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO:23 and the three CDRs of SEQ ID NO: 31.
  • the IL-17 antibody or antigen-binding fragment thereof is selected from a human IL-17 antibody that comprises at least: a) an immunoglobulin heavy chain or fragment thereof which comprises a variable domain comprising, in sequence, the hypervariable regions CDR1, CDR2 and CDR3 and the constant part or fragment thereof of a human heavy chain; said CDR1 having the amino acid sequence SEQ ID NO:24, said CDR2 having the amino acid sequence SEQ ID NO: 26, and said CDR3 having the amino acid sequence SEQ ID NO:28; and b) an immunoglobulin light chain or fragment thereof which comprises a variable domain comprising, in sequence, the hypervariable regions CDR1, CDR2, and CDR3 and the constant part or fragment thereof of a human light chain, said CDR1 having the amino acid sequence SEQ ID NO: 16, said CDR2 having the amino acid sequence SEQ ID NO: 18, and said CDR3 having the amino acid sequence SEQ ID NO:20.
  • a human IL-17 antibody that comprises at least: a) an immunoglobulin
  • the IL-17 antibody or antigen-binding fragment thereof is selected from a human IL-17 antibody that comprises at least: a) an immunoglobulin heavy chain or fragment thereof which comprises a variable domain comprising, in sequence, the hypervariable regions CDR1, CDR2 and CDR3 and the constant part or fragment thereof of a human heavy chain; said CDR1 having the amino acid sequence SEQ ID NO:2S, said CDR2 having the amino acid sequence SEQ ID NO:27 and said CDR3 having the amino acid sequence SEQ ID NO: 29; and b) an immunoglobulin light chain or fragment thereof which comprises a variable domain comprising, in sequence, the hypervariable regions CDR1, CDR2, and CDR3 and the constant part or fragment thereof of a human light chain, said CDR1 having the amino acid sequence SEQ ID NO: 17, said CDR2 having the amino acid sequence SEQ ID NO: 19, and said CDR3 having the amino acid sequence SEQ ID NO:21.
  • a human IL-17 antibody that comprises at least: a) an immunoglobul
  • the IL-17 antibody or antigen-binding fragment thereof is selected from a single chain antibody or antigen-binding fragment thereof that comprises an antigen- binding site comprising: a) a first domain comprising, in sequence, the hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:24, said CDR2 having the amino acid sequence SEQ ID NO:26, and said CDR3 having the amino acid sequence SEQ ID NO:28; and b) a second domain comprising, in sequence, the hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO: 16, said CDR2 having the amino acid sequence SEQ ID NO: 18, and said CDR3 having the amino acid sequence SEQ ID NO: 20; and c) a peptide linker which is bound either to the N-terminal extremity of the first domain and to the C-terminal extremity of the second domain or to the C-terminal extremity of the first domain and to the N
  • the IL-17 antibody or antigen-binding fragment thereof is selected from a single chain antibody or antigen-binding fragment thereof that comprises an antigen-binding site comprising: a) a first domain comprising, in sequence, the hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:25, said CDR2 having the amino acid sequence SEQ ID NO:27, and said CDR3 having the amino acid sequence SEQ ID NO:29; and b) a second domain comprising, in sequence, the hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO: 17, said CDR2 having the amino acid sequence SEQ ID NO: 19, and said CDR3 having the amino acid sequence SEQ ID NO:21; and c) a peptide linker which is bound either to the N-terminal extremity of the first domain and to the C-terminal extremity of the second domain or to the C-termin
  • the V H or V L domain of an IL-17 antibody or antigen-binding fragment thereof used in the disclosed methods may have V H and/or V L domains that are substantially identical to the V H or V L domains set forth in SEQ ID NO:22 and 30.
  • a human IL-17 antibody disclosed herein may comprise a heavy chain that is substantially identical to that set forth as SEQ ID NO: 31 and/or a light chain that is substantially identical to that set forth as SEQ ID NO:23.
  • a human IL-17 antibody disclosed herein may comprise a heavy chain that comprises SEQ ID NO:31 and a light chain that comprises SEQ ID NO:23.
  • a human IL-17 antibody disclosed herein may comprise: a) one heavy chain, comprising a variable domain having an amino acid sequence substantially identical to that shown in SEQ ID NO:30 and the constant part of a human heavy chain; and b) one light chain, comprising a variable domain having an amino acid sequence substantially identical to that shown in SEQ ID NO:22 and the constant part of a human light chain.
  • the IL-17 antibody or antigen-binding fragment thereof binds to an epitope of IL-17 between residues Arg 55 and Trp 67, e.g., an epitope comprising Arg 55, Glu 57, and Trp 67.
  • the IL-17 antibody or antigen-binding fragment thereof binds to an epitope comprising: Arg 55, Glu 57, Trp 67, Tyr 62, and Arg 101; Arg 55, Glu 57, Trp 67, Tyr 62, Arg 101, Pro 59, Ser 64, and Val 65; Arg 55, Glu 57, Trp 67, Tyr 62, Arg 101, Pro 59, Ser 64, Val 65, Val 22*, Leu 26, Asp 58, Glu 60, Pro 63, Pro 107, Phe 110, and Lys 114*, where amino acids marked with (*) designate residue contributed by the second IL-17 subunit of the homodimer IL-17 A.
  • residue numbering scheme used to define these epitopes is based on residue one being the first amino acid of the mature protein (i.e., IL-17A lacking the 23 amino acid N-terminal signal peptide and beginning with Glycine).
  • the sequence for immature IL-17 A is set forth in the Swiss-Prot entry Q 16552.
  • the IL-17 antibody or antigen-binding fragment thereof has a KD for human IL-17 of about 1-10 pM (e.g., about 6 pM). In some embodiments, the IL-17 antibody or antigen-binding fragment thereof has an in vivo half-life of about 2-4 weeks, e.g., about 3 weeks.
  • IL-17 antagonists for use in the disclosed methods, kits and regimens are those set forth in US Patent Nos: 8,057,794; 7,767,206; 8,003,099; 8,110,191; and 7,838,638 and US Published Patent Application Nos: 20120034656 and 20110027290, which are incorporated by reference herein in their entirety.
  • IL-17 antagonists e.g., IL-17 binding molecules (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112) or IL-17 receptor binding molecules (e.g., IL-17 receptor antibody or antigen-binding fragment thereof), may be used in vitro, ex vivo, or incorporated into pharmaceutical compositions and administered in vivo to treat acne, e.g., moderate to severe inflammatory acne (e.g., human patients having acne).
  • acne e.g., moderate to severe inflammatory acne (e.g., human patients having acne).
  • the IL-17 antagonists may be used as a pharmaceutical composition when combined with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier may contain, in addition to an IL-17 antagonist, carriers, various diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The characteristics of the carrier will depend on the route of administration.
  • the pharmaceutical compositions for use in the disclosed methods may also contain additional therapeutic agents for treatment of the particular targeted disorder.
  • a pharmaceutical composition may also include antiinflammatory agents.
  • additional factors and/or agents may be included in the pharmaceutical composition to produce a synergistic effect with the IL-17 binding molecules, or to minimize side effects caused by the IL-17 antagonists, e.g., IL-17 binding molecules (e.g., IL- 17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112) or IL-17 receptor binding molecules (e.g., IL-17 antibody or antigen-binding fragment thereof).
  • IL-17 binding molecules e.g., IL- 17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112
  • IL-17 receptor binding molecules e.g., IL-17 antibody or antigen-binding fragment thereof.
  • compositions for use in the disclosed methods may be manufactured in conventional manner.
  • the pharmaceutical composition is provided in lyophilized form.
  • a suitable aqueous carrier for example sterile water for injection or sterile buffered physiological saline.
  • a suitable aqueous carrier for example sterile water for injection or sterile buffered physiological saline.
  • a suitable aqueous carrier for example sterile water for injection or sterile buffered physiological saline.
  • a suitable aqueous carrier for example sterile water for injection or sterile buffered physiological saline.
  • albumin a suitable concentration is from 0.5 to 4.5% by weight of the saline solution.
  • Other formulations comprise liquid or lyophilized formulation.
  • Antibodies e.g., antibodies to IL-17
  • the IL-17 antagonist e.g., IL-17 antibody, e.g., secukinumab or CJM112
  • Suitable lyophilisate formulations can be reconstituted in a small liquid volume (e.g., 2 ml or less) to allow subcutaneous administration and can provide solutions with low levels of antibody aggregation.
  • antibodies as the active ingredient of pharmaceuticals is now widespread, including the products HERCEPTINTM (trastuzumab), RITUXANTM (rituximab), SYNAGISTM (palivizumab), etc.
  • Techniques for purification of antibodies to a pharmaceutical grade are well known in the art.
  • an IL-17 antagonist e.g., IL-17 binding molecules (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112) or IL-17 receptor binding molecules (e.g., IL-17 antibody or antigen- binding fragment thereof)
  • the IL-17 antagonist will be in the form of a pyrogen-free, parenterally acceptable solution.
  • a pharmaceutical composition for intravenous, cutaneous, or subcutaneous injection may contain, in addition to the IL-17 antagonist, an isotonic vehicle such as sodium chloride, Ringer's solution, dextrose, dextrose and sodium chloride, lactated Ringer's solution, or other vehicle as known in the art.
  • an isotonic vehicle such as sodium chloride, Ringer's solution, dextrose, dextrose and sodium chloride, lactated Ringer's solution, or other vehicle as known in the art.
  • the appropriate dosage will vary depending upon, for example, the particular IL-17 antagonists, e.g., IL-17 binding molecules (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112) or IL-17 receptor binding molecules (e.g., IL-17 antibody or antigen-binding fragment thereof) to be employed, the host, the mode of administration and the nature and severity of the condition being treated, and on the nature of prior treatments that the patient has undergone.
  • the attending health care provider will decide the amount of the IL-17 antagonist with which to treat each individual patient.
  • the attending health care provider may administer low doses of the IL-17 antagonist and observe the patient's response.
  • the initial dose(s) of IL-17 antagonist administered to a patient are high, and then are titrated downward until signs of relapse occur. Larger doses of the IL-17 antagonist may be administered until the optimal therapeutic effect is obtained for the patient, and the dosage is not generally increased further.
  • a therapeutically effective amount of an IL-17 antagonist e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112) or IL-17 receptor binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof) is administered to a patient, e.g., a mammal (e.g., a human).
  • IL-17 antagonist e.g., secukinumab or CJMl 12
  • this does not preclude that, if the patient is to be ultimately treated with an IL-17 antagonist, such IL-17 antagonist therapy is necessarily a monotherapy.
  • the IL-17 antagonist may be administered in accordance with the methods of the disclosure either alone or in combination with other agents and therapies for treating acne patients, e.g., in combination with at least one additional acne agent or acne treatment, such as a topical acne agent, e.g., medicated (anti-acne) creams, medicated cleansers or medicated soaps; an oral/systemic acne agent, e.g., antibiotics (such as doxycycline, tetracycline, lymecycline, minocycline, sarecycline or erythromycin), dapsone, oral zinc, oral retinoids (in particular isotretinoin); a systemic or lesional injected anti acne agent; systemic hormonal treatments, e.g., combined estrogen products and anti-androgens, such as spironolactone, finasteride and
  • a topical acne agent e.g., medicated (anti-acne) creams, medicated cleansers or medicated soaps
  • IL-17 antagonists e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112) or IL-17 receptor binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof)
  • IL-17 antagonists include tretinoin, adapalene, MBI 226, Retin-A Micro 0.04% facial acne treatment, M22-IPL, benzoyl peroxide, clindamycin, salicylic acid, JNJ 10229570- AAA, CB-03-01, ASC-J9, ARK-E021, aminolevulinic acid, BAY39-6251, RA-18C3, BLI1100, aminolevulinic acid HCL, SB204, tazarotene, lemuteporfin, CD0271, CD1579, S6G5T-3, -5, -7, F
  • an IL-17 antagonist When co-administered with one or more additional acne agents, an IL-17 antagonist may be administered either simultaneously with the other agent, or sequentially. If administered sequentially, the attending physician will decide on the appropriate sequence of administering the IL-17 antagonist in combination with other agents and the appropriate dosages for co- delivery.
  • An IL-17 antagonist e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen- binding fragment thereof, e.g., secukinumab or CJM112) or IL-17 receptor binding molecule (e.g., IL-17 receptor antibody or antigen-binding fragment thereof) is conveniently administered parenterally, e.g., intravenously (e.g., into the antecubital or other peripheral vein), intramuscularly, or subcutaneously.
  • IV intravenous
  • SC subcutaneous
  • the health care provider will decide on the appropriate duration of IV or SC therapy and the timing of administration of the therapy, using the pharmaceutical composition of the present disclosure.
  • Preferred dosing and treatment regimens for treating acne patients using secukinumab are provided in PCT Application No. PCT/US2011/064307, which is incorporated by reference herein in its entirety.
  • the IL-17 antagonist e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen- binding fragment thereof, e.g., secukinumab or CJM112) or IL-17 receptor binding molecule (e.g., IL-17 receptor antibody or antigen-binding fragment thereof) may be administered to the acne patient as part of a loading regimen (an initial regimen designed to deliver drug quickly to target tissue - typically using more frequent dosing than employed for maintenance, but also sometimes using higher doses than employed for maintenance).
  • a loading regimen an initial regimen designed to deliver drug quickly to target tissue - typically using more frequent dosing than employed for maintenance, but also sometimes using higher doses than employed for maintenance.
  • a loading regimen may employ unit subcutaneous (SC) dosing of about 75 mg to about 600 mg (e.g., about 75 mg, about 150 mg, about 300 mg, about 350 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg) of the IL-17 antibody (e.g., CJM112, Secukinumab (or a functional derivatives or biosimilar thereof, e.g. secukinumab or CJM112)).
  • SC unit subcutaneous
  • the loading regimen employs unit intraveneous (IV) dosing of about 10mg/kg of the IL-17 antibody (e.g., CJMl 12, Secukinumab (or a functional derivatives or biosimilar thereof, e.g. secukinumab or CJMl 12))
  • IV unit intraveneous
  • the loading dose may be administered weekly or biweekly (every two weeks), e.g weekly.
  • the loading dose may be administered during 1 to 8 weeks, e.g during 1 to 4 weeks, e.g 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks.
  • the loading dose is administered weekly at weeks 0, 1, 2, 3, and 4.
  • the IL-17 antibody or antigen-binding fragment thereof e.g., secukinumab or CJMl 12 (or a functional derivatives or biosimilar thereof, e.g. secukinumab or CJM112)
  • an unit dose of about 75 mg to about 600 mg, during 2 to 8 weeks, e.g. during 4 to 8 weeks, e.g. during 4 or 5 weeks, e.g. at weeks 0, 1, 2, 3, and 4.
  • Such an unit dose is for example administered weekly.
  • the unit dose may also be administered every two weeks, or twice a week, or monthly.
  • the IL-17 antibody or antigen-binding fragment thereof e.g., secukinumab or CJM112 (or a functional derivatives or biosimilar thereof, e.g. secukinumab or CJM112)
  • an unit dose of about 150 mg to about 600 mg, during 2 to 8 weeks, e.g. during 4 to 8 weeks, e.g. during 4 or 5 weeks, e.g. at weeks 0, 1, 2, 3, and 4.
  • Such an unit dose is for example administered weekly.
  • the unit dose may also be administered every two weeks, or twice a week, or monthly.
  • the IL-17 antibody or antigen-binding fragment thereof e.g., secukinumab or CJM112 (or a functional derivatives or biosimilar thereof, e.g. secukinumab or CJM112)
  • an unit dose of about 300 mg to about 600 mg, during 2 to 8 weeks, e.g. during 4 to 8 weeks, e.g. during 4 or 5 weeks, e.g. at weeks 0, 1, 2, 3, and 4.
  • Such an unit dose is for example administered weekly.
  • the unit dose may also be administered every two weeks, or twice a week.
  • the IL-17 antibody or antigen-binding fragment thereof e.g., secukinumab or CJM112 (or a functional derivatives or biosimilar thereof, e.g. secukinumab or CJM112)
  • an unit dose of about 450 mg to about 600 mg, during 2 to 8 weeks, e.g. during 4 to 8 weeks, e.g. during 4 or 5 weeks, e.g. at weeks 0, 1, 2, 3, and 4.
  • Such a dose is preferably administered weekly.
  • the dose may also be administered every two weeks, or twice a week.
  • the IL-17 antibody or antigen-binding fragment thereof e.g., secukinumab or CJM112 (or a functional derivatives or biosimilar thereof, e.g. secukinumab or CJM112)
  • Such a dose is preferably administered weekly.
  • the dose may also be administered every two weeks, or twice a week.
  • a maintenance regimen is employed, and the patient is administered the IL-17 antibody, e.g.
  • secukinumab or CJM112 (or a functional derivatives or biosimilar thereof, e.g. secukinumab or CJM112), subcutaneously at dose of about, subcutaneously at about 75 mg - about 600 mg (e.g., about 75 mg, about 150 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg).
  • the maintenance regimen may be administered monthy, e.g. a dose of 75 mg - about 600 mg (e.g., about 75 mg, about 150 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg) is administered monthly.
  • the patient may be dosed subcutaneously with about 75 mg - about 600 mg (e.g., about 75 mg, about 150 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg) of the IL-17 antagonist (e.g., secukinumab or CJM112 (or a functional derivatives or biosimilar thereof, e.g. secukinumab or CJM112)) during weeks 0, 1, 2, 3, 4, 8, 12, 16, 20, etc.
  • the IL-17 antagonist e.g., secukinumab or CJM112 (or a functional derivatives or biosimilar thereof, e.g. secukinumab or CJM112)
  • Maintenance dosing may be less frequent than monthly, e.g., every other month, quarterly, bi-yearly, etc., which typically accompanies a higher of drug, e.g., 450 mg, 600 mg, etc.
  • the IL-17 antagonist e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112) or IL-17 receptor binding molecule (e.g., IL-17 receptor antibody or antigen-binding fragment thereof) may be administered to the acne patient without a loading regimen, e.g., the antagonist may be administered to the patient SC at about 75 mg to about 600 mg (e.g., about 75 mg, about 150 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg), e.g. every 4 weeks (monthly).
  • IL-17 binding molecule e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112
  • IL-17 receptor binding molecule e.g., IL-17 receptor antibody or antigen-binding fragment thereof
  • the antagonist may be administered
  • the patient is dosed SC with about 75 mg to about 600 mg (e.g., about 75 mg, about 150 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg) of the IL-17 antagonist (e.g., secukinumab or CJM112) during weeks 0, 4, 8, 12, 16, 20, etc.
  • the IL-17 antagonist e.g., secukinumab or CJM112
  • Dosing may be less frequent than monthly, e.g., every other month, quarterly, bi-yearly, etc., which typically (but not necessarily) accompanies a higher of drug, e.g., 450 mg, 600 mg, etc.
  • the IL-17 antagonist is CJM112, which is administered without a loading regimen; preferably CJMl 12 is administered to the patient SC at about 75 mg to about 600 mg (e.g., about 75 mg, about 150 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg) every 4 weeks (monthly).
  • a typical duration of treatment is about of 6 months or less, e.g. about 12 to about 24 weeks, although both shoreter and longer courses of treatment may be employed, depending on a patient's response to therapy.
  • the IL-17 antagonist e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJMl 12 (or a functional derivatives or biosimilar thereof, e.g. secukinumab or CJMl 12)) or IL-17 receptor binding molecule (e.g., IL- 17 receptor antibody or antigen-binding fragment thereof) may be administered to the acne patient as a single dose.
  • IL-17 binding molecule e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJMl 12 (or a functional derivatives or biosimilar thereof, e.g. secukinumab or CJMl 12)
  • IL-17 receptor binding molecule e.g., IL- 17 receptor antibody or antigen-binding fragment thereof
  • the antagonist may be administered to the patient SC at a single dose of about 150 mg to about 600 mg (e.g., about 150 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg) once.
  • the patient is dosed SC with about 150 mg to about 600 mg (e.g., about 150 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg) of the IL-17 antagonist (e.g., secukinumab or CJMl 12) only one time.
  • the patient is dosed IV with about 10mg/kg. The patient would then be dosed again only when acne symptoms recur.
  • unit dose refers to a SC dose that can be comprised between about 75mg to 600 mg, e.g. about 150mg to about 600mg, e.g. about 150 mg to about 450 mg, e.g. about 300 mg to about 450 mg, or a e.g. about 75 mg to about 300 mg.
  • an unit SC dose is about 75 mg, about 150 mg, about 300 mg, about 350 mg, about 400 mg, about 450mg, about 500 mg, about 550 mg, about 600 mg.
  • dose escalation may be appropriate for certain acne patients, e.g., patients that display inadequate response to treatment with the IL-17 antagonists, e.g., IL-17 binding molecules (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab and CJM112) or IL-17 receptor binding molecules (e.g., IL-17 receptor antibody or antigen- binding fragment thereof).
  • IL-17 binding molecules e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab and CJM112
  • IL-17 receptor binding molecules e.g., IL-17 receptor antibody or antigen- binding fragment thereof.
  • SC dosages may be greater than about 75 mg to about 300 mg SC, e.g., about 80 mg, about 100 mg, about 125 mg, about 175 mg, about 200 mg, about 250 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, etc.; similarly, IV (intraveneous) dosages may be greater than about 10 mg/kg, e.g., about 11 mg/kg, 12 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, etc.
  • dosages of the IL-17 antagonist may be less than about 75 mg to about 300 mg SC, e.g., about 25 mg, about 50 mg, about 80 mg, about 100 mg, about 125 mg, about 175 mg, about 200 mg, 250 mg, etc.
  • the IL-17 antagonist e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112) or IL-17 receptor binding molecule (e.g., IL-17 receptor antibody or antigen-binding fragment thereof) may be administered to the patient at an initial dose of 75 mg delivered SC, and the dose may be then escalated to 150 mg or 300 mg if needed, as determined by a physician.
  • IL-17 binding molecule e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112
  • IL-17 receptor binding molecule e.g., IL-17 receptor antibody or antigen-binding fragment thereof
  • the IL-17 antagonist e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112) or IL-17 receptor binding molecule (e.g., IL-17 receptor antibody or antigen-binding fragment thereof) may be administered to the patient at an initial dose of 150 mg delivered SC, and the dose may be then escalated to 450 mg or 600 mg if needed, as determined by a physician.
  • IL-17 binding molecule e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112
  • IL-17 receptor binding molecule e.g., IL-17 receptor antibody or antigen-binding fragment thereof
  • the IL-17 antagonist e.g., IL-17 binding molecule (e.g., IL- 17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112) or IL-17 receptor binding molecule (e.g., IL-17 receptor antibody or antigen-binding fragment thereof) may be administered to the patient at an initial dose of 300 mg delivered SC, and the dose may be then escalated to 450 mg or 600 mg if needed, as determined by a physician.
  • IL-17 binding molecule e.g., IL- 17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112
  • IL-17 receptor binding molecule e.g., IL-17 receptor antibody or antigen-binding fragment thereof
  • the timing of dosing is generally measured from the day of the first dose of secukinumab or CJM112 (which is also known as "baseline").
  • baseline which is also known as “baseline”.
  • health care providers often use different naming conventions to identify dosing schedules, as shown in Table 3.
  • Table 3 Common naming conventions for dosing regimens. Bolded items refer to the naming convention used herein.
  • week zero may be referred to as week one by some health care providers, while day zero may be referred to as day one by some health care providers.
  • day zero may be referred to as day one by some health care providers.
  • different physicians will designate, e.g., a dose as being given during week 3 / on day 21, during week 3 / on day 22, during week 4 / on day 21, during week 4 / on day 22, while referring to the same dosing schedule.
  • the first week of dosing will be referred to herein as week 0, while the first day of dosing will be referred to as day 1.
  • regimen changes may be appropriate for certain acne patients, e.g., patients that display inadequate response to treatment with the IL-17 antagonists, e.g., IL-17 binding molecules (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab and CJM112) or IL-17 receptor binding molecules (e.g., IL-17 receptor antibody or antigen- binding fragment thereof).
  • IL-17 antagonists e.g., IL-17 binding molecules (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab and CJM112) or IL-17 receptor binding molecules (e.g., IL-17 receptor antibody or antigen- binding fragment thereof).
  • administration e.g for secukinumab or CJM112
  • Some patients may benefit from a loading regimen (e.g., weekly for several weeks [e.g., 1 to 5 weeks, e.g., dosing at weeks 0, 1, 2, 3 and/or 4] or biweekly for several weeks (e.g., 2 to 8 weeks, e.g., dosing at weeks 0, 2, 4, and/or 6) followed by maintenance regimen, e.g. a monthly maintenance regimen.
  • a loading regimen e.g., weekly for several weeks [e.g., 1 to 5 weeks, e.g., dosing at weeks 0, 1, 2, 3 and/or 4] or biweekly for several weeks (e.g., 2 to 8 weeks, e.g., dosing at weeks 0, 2, 4, and/or 6) followed by maintenance regimen, e.g. a monthly maintenance regimen.
  • a loading regimen e.g., weekly for several weeks [e.g., 1 to 5 weeks, e.g., dosing at weeks 0, 1, 2, 3 and/or 4] or biweekly
  • an apropriate regimen for secukinumab or CJM112 is biweekly for several weeks (e.g., 2 to 8 weeks, e.g., dosing at weeks 0, 2, 4, and/or 6) followed by a monthly maintenance regimen.
  • administration may be less frequent than monthly dosing, e.g., dosing every 6 weeks, every 8 weeks (every two months), quarterly (every three months), etc.
  • Patients' responses to treatment may be assessed using patient reported outcomes. For example the Dermatology Life Quality Index (DLQI), Patient global assessment, Patient's satisfaction questionnaire,. Patient's responses to treatment may also be assessed by analyzing the acne severity in different areas of the body (Investigator Global Assessment (IGA) on the face [achievement of clear or almost clear; or 2 grade improvement from baseline] and Comprehensive Acne severity scale (CASS) on the trunk [Tan et al. (2007) J Cutan Med Surg. 11(6): 211-6]) and also the numbers of lesions (inflammatory [papules, pustules, nodules]) and their type in the different anatomical areas.
  • IGA Investigator Global Assessment
  • CASS Comprehensive Acne severity scale
  • a therapeutic effect in inflammatory acne exists when there is a reduction in inflammatory lesions (typically inflammatory facial lesions).
  • IL-17 antagonist is an IL-17 antibody or antigen-binding fragment thereof, e.g. secukinumab or CJM112.
  • a patient having acne e.g., moderate to severe inflammatory acne, e.g. non-inflammatory acne, inflammatory acne or non-inflammatory and inflammatory acne
  • administering an IL-17 antibody or antigen-binding fragment thereof to a patient in need thereof wherein the IL-17 antibody or antigen-binding fragment thereof binds to an epitope of mature IL-17: a) between residues Arg 55 and Trp 67; b) comprising Arg 55, Glu 57, and Trp 67; c) comprising Arg 55, Glu 57, Trp 67, Tyr 62, and Arg 101; d) comprising Arg 55, Glu 57, Trp 67, Tyr 62, Arg 101, Pro 59, Ser 64, and Val 65; or e) comprising Arg 55, Glu 57, Trp 67, Tyr 62, Arg 101, Pro 59, Ser 64, Val 65, Val 22*, Leu 26, As
  • IL-17 antagonists e.g., IL-17 antibody or antigen- binding fragment thereof, e.g., CJM112
  • the IL-17 antibody or antigen-binding fragment thereof binds to an epitope of mature IL-17: a) between residues Arg 55 and Trp 67; b) comprising Arg 55, Glu 57, and Trp 67; c) comprising Arg 55, Glu 57, Trp 67, Tyr 62, and Arg 101; d) comprising Arg 55, Glu 57, Trp 67, Tyr 62, Arg 101, Pro 59, Ser 64, and Val 65; or e) comprising Arg 55, Glu 57, Trp 67, Tyr 62, Arg 101, Pro 59, Ser 64, Val 65, Val 22*, Leu 26, Asp 58, Glu 60, Pro 63, Pro 107, P
  • IL-17 antagonists e.g., IL-17 antibody or antigen- binding fragment thereof, e.g., CJM112
  • the IL-17 antibody or antigen-binding fragment thereof binds to an epitope of mature IL-17: a) between residues Arg 55 and Trp 67; b) comprising Arg 55, Glu 57, and Trp 67; c) comprising Arg 55, Glu 57, Trp 67, Tyr 62, and Arg 101; d) comprising Arg 55, Glu 57, Trp 67, Tyr 62, Arg 101, Pro 59, Ser 64, and Val 65; or e) comprising Arg 55, Glu 57, Trp 67, Tyr 62, Arg 101, Pro 59, Ser 64, Val 65, Val 22*, Leu 26, Asp 58, Glu 60, Pro 59, Ser 64, Val 65, Val 22*, Leu 26, Asp 58, Glu 60, Pro 59, Ser 64, Val 65,
  • 1L-17 antagonists e.g., IL-17 antibody or antigen- binding fragment thereof, e.g., secukinumab or CJM112
  • 1L-17 antagonists for use in the manufacture of a medicament for treating and/or preventing a patient having acne, e.g., moderate to severe inflammatory acne, e.g.
  • the medicament is formulated to comprise containers, each container having a sufficient amount of the IL-17 antagonist (e.g., IL-17 antibody or antigen- binding fragment thereof, e.g., secukinumab or CJM112) to allow subcutaneous delivery of at least about 75 mg - about 600 mg (e.g., about 75 mg, about 150 mg, about 300 mg, about 450 mg, about 600 mg), preferably about 75 mg - about 300 mg, of the IL-17 antagonist (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112) per unit dose, and further wherein the IL-17 antibody or antigen-binding fragment thereof binds to an epitope of mature IL-17: a) between residues Arg 55 and Trp 67; b) comprising Arg 55, Glu 57, and Trp 67; c) comprising Arg 55, Glu
  • a patient having acne e.g., moderate to severe inflammatory acne
  • administering an IL-17 antibody or antigen- binding fragment thereof to a patient in need thereof wherein the IL-17 antibody or antigen- binding fragment thereof binds to an epitope of an IL-17 homodimer having two mature IL-17 protein chains, said epitope comprising Leu74, Tyr85, His86, Met87, Asn88, Val 124, Thrl25, Prol26, Ilel27, Vall28, Hisl29 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain
  • the IL-17 antibody or antigen-binding fragment thereof has a KD for human IL- 17 of about 100-200 pM
  • the IL- 17 antibody or antigen-binding fragment thereof has an in vivo half-life of about 4 weeks.
  • IL-17 antagonists e.g., IL-17 antibody or antigen- binding fragment thereof, e.g., secukinumab or CJM112
  • a patient having acne e.g., moderate to severe acne, e.g.
  • the IL-17 antagonist e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112
  • IL-17 antibody or antigen-binding fragment thereof binds to an epitope of an IL-17 homodimer having two mature IL-17 protein chains, said epitope comprising Leu74, Tyr85, His86, Met87, Asn88, Vall24, Thrl25, Prol26, Ilel27, Vall28, Hisl29 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain
  • the IL-17 antibody or antigen- binding fragment thereof has a K D for human IL-17 of about 100-200 pM
  • the IL-17 antibody or antigen-binding fragment thereof has an in vivo half-life of about 4 weeks.
  • IL-17 antagonists e.g., IL-17 antibody or antigen- binding fragment thereof, e.g., secukinumab or CJM112
  • IL-17 antibody or antigen- binding fragment thereof e.g., secukinumab or CJM112
  • acne e.g., moderate to severe acne, e.g.
  • the IL-17 antagonist e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112
  • IL-17 antibody or antigen-binding fragment thereof binds to an epitope of an IL-17 homodimer having two mature IL-17 protein chains, said epitope comprising Leu74, Tyr85, His86, Met87, Asn88, Vall24, Thrl25, Prol26, Ilel27, Vall28, Hisl29 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain
  • the IL-17 antibody or antigen-binding fragment thereof has a KD for human IL-17 of about 100-200 pM
  • the IL-17 antibody or antigen-binding fragment thereof has an in vivo half-life of about 4 weeks.
  • IL-17 antagonists e.g., IL-17 antibody or antigen- binding fragment thereof, e.g., secukinumab or CJM112
  • IL-17 antibody or antigen- binding fragment thereof e.g., secukinumab or CJM112
  • acne e.g., moderate to severe acne, e.g.
  • the medicament is formulated to comprise containers, each container having a sufficient amount of the IL-17 antagonist (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112) to allow subcutaneous delivery of at least about 75 mg - about 300 mg (e.g., about 75 mg, about 150 mg, about 300 mg, about 450 mg, about 600 mg), preferably about 75 mg - about 300 mg, of the IL-17 antagonist (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112) per unit dose, and further wherein the IL-17 antagonist (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112) binds to an epitope of an IL-17 homodimer having two mature IL-17 protein chains, said epitope
  • the IL-17 antagonist e.g., IL-17 antibody or
  • the phrase "formulated at a dosage to allow [route of administration] delivery of [a designated dose]" is used to mean that a given pharmaceutical composition can be used to provide a desired dose of an IL-17 antagonist, e.g., an IL-17 antibody, e.g., secukinumab or CJM112, via a designated route of administration (e.g., SC or IV).
  • an IL-17 antagonist e.g., an IL-17 antibody, e.g., secukinumab or CJM112
  • SC or IV designated route of administration
  • a desired subcutaneous dose is 300 mg
  • a clinician may use 2 ml of an IL-17 antibody formulation having a concentration of 150 mg/ml, 1 ml of an IL-17 antibody formulation having a concentration of 300 mg/ml, 0.5 ml of an IL-17 antibody formulation having a concentration of 600 mg/ml, etc.
  • these IL-17 antibody formulations are at a concentration high enough to allow subcutaneous delivery of the IL-17 antibody.
  • Subcutaneous delivery typically requires delivery of volumes of less than about 2 ml, preferably a volume of about 1 ml or less.
  • Preferred formulations are liquid pharmaceutical compositions comprising: a) about 25 mg/mL to about 150 mg/mL secukinumab, about 10 mM to about 30 mM histidine pH 5.8, about 200 mM to about 225 mM trehalose, about 0.02% polysorbate 80, and about 2.5 mM to about 20 mM methionine; and b) about 150 mg/mL CJM112, 4.8 mM L-histidine, 15.2 mM L-histidine-HCl 220 mM sucrose and 0.04% polysorbate 20, at pH 6.0 ⁇ 0.5.
  • the phrase "container having a sufficient amount of the IL-17 antagonist to allow delivery of [a designated dose]” is used to mean that a given container (e.g., vial, pen, syringe) has disposed therein a volume of an IL-17 antagonist (e.g., as part of a pharmaceutical composition) that can be used to provide a desired dose.
  • a clinician may use 2 ml from a container that contains an IL-17 antibody formulation with a concentration of 75 mg/ml, 1 ml from a container that contains an IL-17 antibody formulation with a concentration of 150 mg/ml, 0.5 ml from a container contains an IL-17 antibody formulation with a concentration of 300 mg/ml, etc.
  • these containers have a sufficient amount of the IL-17 antagonist to allow delivery of the desired 150 mg dose.
  • the patient has moderate to severe acne, e.g. moderate to severe inflammatory acne.
  • the patient was previously treated for acne with a topical anti-acne treatment, an oral/systemic anti-acne treatment, a systemic or lesional injected anti-acne treatment, or surgical, physical, light or laser therapy.
  • the patient is monthly administered about 75 mg - about 600 mg (e.g., about 75 mg, about 150 mg, about 300 mg, about 450 mg, about 600mg), preferably about 75 mg - about 300 mg, of the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab or CJM112) by subcutaneous injection.
  • this regimen can be administered for a period of 1 to 24 weeks, e.g about 12 to about 24 weeks.
  • the patient is monthly administered about 75 mg (e.g., 75 mg) of the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab or CJM112) by subcutaneous injection.
  • this regimen can be administered for a period of 1 to 24 weeks, e.g about 12 to about 24 weeks.
  • the patient is monthly administered about 150 mg (e.g., 150 mg) of the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab or CJM112) by subcutaneous injection.
  • this regimen can be administered for a period of 1 to 24 weeks, e.g about 12 to about 24 weeks.
  • the patient is monthly administered about 300 mg (e.g., 300 mg) of the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab or CJM112) by subcutaneous injection.
  • this regimen can be administered for a period of 1 to 24 weeks, e.g about 12 to about 24 weeks.
  • the patient is monthly administered about 400 mg (e.g., 400 mg) of the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab or CJM112) by subcutaneous injection.
  • this regimen can be administered for a period of 1 to 24 weeks, e.g about 12 to about 24 weeks.
  • the patient is monthly administered about 450 mg (e.g., 450 mg) of the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab or CJM112) by subcutaneous injection.
  • this regimen can be administered for a period of 1 to 24 weeks, e.g about 12 to about 24 weeks.
  • the patient is monthly administered about 500 mg (e.g., 500 mg) of the IL- 17 antibody or antigen-binding fragment thereof (e.g., secukinumab or CJM112) by subcutaneous injection.
  • this regimen can be administered for a period of 1 to 24 weeks, e.g about 12 to about 24 weeks.
  • the patient is monthly administered about 600 mg (e.g., 600 mg) of the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab or CJM112) by subcutaneous injection.
  • this regimen can be administered for a period of 1 to 24 weeks, e.g about 12 to about 24 weeks.
  • the patient is monthly administered about 10mg/kg (e.g., 10mg/kg) of the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab or CJM112) by intraveneous injection.
  • 10mg/kg e.g., 10mg/kg
  • the IL-17 antibody or antigen-binding fragment thereof e.g., secukinumab or CJM112
  • the patient is given a single administration of about 150 mg - about 600 mg (e.g., about 150 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg) of the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab or CJM112) by subcutaneous injection.
  • about 150 mg - about 600 mg e.g., about 150 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg
  • the IL-17 antibody or antigen-binding fragment thereof e.g., secukinumab or CJM112
  • the IL-17 antibody or antigen-binding fragment thereof comprises: i) an immunoglobulin heavy chain variable domain (V H ) comprising the amino acid sequence set forth as SEQ ID NO:30; ii) an immunoglobulin light chain variable domain (V L ) comprising the amino acid sequence set forth as SEQ ID NO:22; iii) an immunoglobulin V H domain comprising the amino acid sequence set forth as SEQ ID NO: 30 and an immunoglobulin V L domain comprising the amino acid sequence set forth as SEQ ID NO:22; iv) an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO:24, SEQ ID NO:26, and SEQ ID NO:28; v) an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO: 16, SEQ ID NO: 18 and SEQ ID NO:20; vi) an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO:
  • the IL-17 antibody or antigen-binding fragment thereof comprises: i) an immunoglobulin heavy chain variable domain (V H ) comprising the amino acid sequence set forth as SEQ ID NO: 8; ii) an immunoglobulin light chain variable domain (V L ) comprising the amino acid sequence set forth as SEQ ID NO: 10; iii) an immunoglobulin V H domain comprising the amino acid sequence set forth as SEQ ID NO: 8 and an immunoglobulin V L domain comprising the amino acid sequence set forth as SEQ ID NO: 10; iv) an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO:l, SEQ ID NO:2, and SEQ ID NO:3; v) an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6; vi) an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ
  • moderate to severe acne e.g. non-inflammatory acne, inflammatory acne or non-inflammatory and inflammatory acne, e.g. moderate to severe inflammatory acne
  • a patient having moderate to severe acne e.g. non-inflammatory acne, inflammatory acne or noninflammatory and inflammatory acne, e.g. moderate to severe inflammatory acne, comprising monthly administering to the patient about 10 mg/kg of CJM112 (or a functional derivatives or biosimilar thereof) by intraveneous injection.
  • moderate to severe acne e.g. non-inflammatory acne, inflammatory acne or noninflammatory and inflammatory acne, e.g. moderate to severe inflammatory acne
  • moderate to severe acne e.g. non-inflammatory acne, inflammatory acne or non-inflammatory and inflammatory acne, e.g. moderate to severe inflammatory acne
  • kits for treating and/or preventing a patient having moderate to severe acne comprising monthly administering to the patient about 10 mg/kg of Secukinumab (or a functional derivatives or biosimilar thereof ⁇ ) by intraveneous injection.
  • kits for treating acne e.g., moderate to severe acne, e.g. non-inflammatory acne, inflammatory acne or non-inflammatory and inflammatory acne, e.g. moderate to severe inflammatory acne.
  • kits comprise an IL-17 antagonist, e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112, or IL-17 receptor binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof) (e.g., in liquid or lyophilized form) or a pharmaceutical composition comprising the IL- 17 antagonist (described supra).
  • IL-17 binding molecule e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112
  • IL-17 receptor binding molecule e.g., IL-17 antibody or antigen-binding fragment thereof
  • a pharmaceutical composition comprising the IL- 17 antagonist
  • kits may comprise means for administering the IL-17 antagonist (e.g., an autoinjector, a syringe and vial, a prefilled syringe, a prefilled pen) and instructions for use.
  • kits may contain additional therapeutic agents (described supra) for treating acne, e.g., for delivery in combination with the enclosed IL-17 antagonist, e.g., IL-17 binding molecule, e.g., IL-17 antibody, e.g., secukinumab or CJM112.
  • kits may also comprise instructions for administration of the IL-17 antagonist (e.g., IL-17 antibody, e.g., secukinumab or CJM112) to treat acne, e.g., moderate to severe inflammatory acne.
  • IL-17 antagonist e.g., IL-17 antibody, e.g., secukinumab or CJM112
  • Such instructions may provide the dose (e.g., 10 mg/kg, 75 mg, 150 mg, 300 mg, 450 mg, 600 mg), route of administration (e.g., IV, SC), and dosing regimen (e.g., monthly with or without an induction regimen) for use with the enclosed IL-17 antagonist, e.g., IL-17 binding molecule, e.g., IL-17 antibody, e.g., secukinumab or CJM112.
  • phrases "means for administering” is used to indicate any available implement for systemically administering a drug to a patient, including, but not limited to, a pre-filled syringe, a vial and syringe, an injection pen, an autoinjector, an IV drip and bag, a pump, etc.
  • a patient may self-administer the drug (i.e., administer the drug without the assistance of a physican) or a medical practitioner may administer the drug.
  • terapéuticaally effective amount is used to indicate a quantity of drug that can achieve a given stated effect, e.g., treatment of acne.
  • kits for use in treating and/or preventing a patient having acne comprising an IL-17 antagonist (e.g., IL-17 binding molecule, e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112.
  • an IL-17 antagonist e.g., IL-17 binding molecule, e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112.
  • the kit further comprises means for administering the IL-17 antagonist to the patient.
  • the kit further comprises instructions for administration of the IL- 17 antagonist, wherein the instructions indicate that the IL-17 antagonist (e.g., IL-17 binding molecule, e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112, is to be administered to the patient SC with or without a loading regimen, e.g., at about 75 mg - about 600 mg (e.g., about 75 mg, about 150 mg, about 300 mg, about 450 mg, about 600 mg) every 4 weeks (monthly).
  • the IL-17 antagonist e.g., IL-17 binding molecule, e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab or CJM112
  • a loading regimen e.g., at about 75 mg - about 600 mg (e.g., about 75 mg, about 150 mg, about 300 mg, about 450 mg, about 600 mg) every 4 weeks (monthly).
  • the kit further comprises instructions for administration of the IL-17 antagonist, wherein the instructions indicate that the IL-17 antagonist (e.g., IL-17 binding molecule, e.g., IL-17 antibody or antigen- binding fragment thereof, e.g., secukinumab or CJM112, is to be administered a single time (once) to the patient SC with or without a loading regimen, e.g., at about 150 mg - about 600 mg (e.g., about 150 mg, about 300 mg, about 450 mg, about 600 mg).
  • the instructions will provide for dose escalation or dose reduction as needed, to be determined by a physician.
  • IL-17 antagonists e.g., IL-17 binding molecules (e.g., IL-17 antibody or antigen- binding fragment thereof, e.g., Secukinumab, CJM112, or a functional derivatives or biosimilar thereof, e.g.
  • IL-17 binding molecules e.g., IL-17 antibody or antigen- binding fragment thereof, e.g., Secukinumab, CJM112, or a functional derivatives or biosimilar thereof, e.g.
  • IL-17 receptor binding molecules e.g., IL-17 receptor antibody or antigen-binding fragment thereof
  • IL-17 receptor binding molecules may be used in vitro, ex vivo, or incorporated into pharmaceutical compositions and administered in vivo to treat cutaneous lupus erythematosus, skin sarcoidosis, vitiligo, atopic dermatitis, Pityriasis rubra pilaris, entheseal and tendon inflammation (e.g., enthesitis, tendenitis) and injury, keloids, non-melanoma skin cancer (NMSC), aphthous diseases, in particular chronic aphthous stomatitis, lichen planus with its variants, such as oral erosive lichen, alopecia areata, neutrophilic dermatoses, such as Sweet syndrome (acute febrile neutrophilic dermatosis); Pyoderma gangraenosum; Sneddon-
  • lung fibrosis NASH (non-alcoholic steatohepatitis), Guillain- Barre-Syndrome, GVHD, JIA, SLE, Lupus, Lupus Nephritis, Netherton Syndrome, icthyothis, Neuromyelitis Optica, Lichen Planus, Myastenia Gravis, Pyoderma Gangrenosum, Rosacea, Sarcoidosis, Sjoegren's Syndrome, Stroke, Transplantation, Type-1 Diabetes, Wound healing, esophagitis, including Barrett 1 esophagus and esophageal cancer, and cancers of the hypopharynx, Alpha- 1 -antitrypsin deficiency, Septic shock, Injuries and skin wounds, Enteritis of small intestine, Colitis, Inflammatory bowel disease, Appendicitis, Barrett's esophagus, Crohn's disease, Whipple's disease, Gastrointestinal hemorrhage, Polyp of intestin
  • the IL-17 antagonist is an IL-17 binding molecule.
  • the IL-17 binding molecule is an IL-17 antibody or antigen-binding fragment thereof.
  • the IL-17 antibody or antigen-binding fragment thereof is a human antibody of the Igd isotype.
  • the antibody or antigen-binding fragment thereof is Secukinumab, CJM112 or a functional derivatives or biosimilar thereof.
  • the antibody or antigen-binding fragment thereof is secukinumab or CJM112.
  • IL17A signaling signatures were created using various cell types stimulated with the named cytokine.
  • Primary human juvenile foreskin keratinocytes were stimulated with IL17A (200ng/ml) or control for 18h
  • primary human juvenile foreskin fibroblasts stimulated with IL17A (200ng/ml) or control for 18h
  • dermatome sheets from human discard skin were stimulated with IL17A (lOOOng/ml) or control for 18h.
  • Samples were collected and processed for microarray analysis on Affymetrix HG_U133_Plus2 microarrays. RMA normalized samples were quality controlled, filtered for expressed genes.
  • IL17A signaling signatures were identified comparing stimulated and control groups with an unpaired T-test, identifying probesets with a corrected p-value below 0.05 and a fold change above 2.0.
  • the respective signature were used to calculate p- values with a Fisher's exact test which represent the statistical significance of observing an overlap between the signature and the 'disease gene list' (lesional vs non-lesional) of public datasets (Acne NCBI GEO identifiers GSE53795 and Psoriasis skin samples GSE13355).
  • IL17A signaling signatures created in skin or skin derived cell types using the cytokine as a stimulus show significant overlap to a disease gene list (lesional vs non-lesional) from a study with Acne patients, providing evidence that the IL17A pathway is active in this disease.
  • a disease gene list from a psoriasis study was used.
  • the p-values of the three different IL17A signaling signatures are comparable between the two different diseases.
  • the detrimental role of IL17A in Psoriasis is well established and therefore we speculate that inhibiting the cytokine in Acne would be beneficial for the patient.
  • Example 2 IL-17A Production is Diminished by All- Trans-Retinoic Acid (ATRA) in vitro
  • Naive human peripheral blood CD4 positive T cells were purified by negative selection. Cells were cultured in the presence or absence of killed Propionibacterium acnes (P. Acnes). ATRA was added at the indicated concentrations ( ⁇ ) and IL17A production by T cells was assessed by enzyme linked immunosorbent assay (ELISA).
  • ELISA enzyme linked immunosorbent assay
  • P.Acnes induced IL17A production indicative of Thl7 polarization in Donor 1 (Fig. 2A) and Donor 2 (Fig. 2B), while no detectable IL17 production was observed without P. acnes stimulation ("cont"). P. acnes induced IL17A production was suppressed by ATRA at all concentrations tested.
  • IL17A expressing T cells are also located in acne lesions. It is thus possible that ATRA exerts its antiinflammtory effect, in part, by suppression of Thl7 cell priming.
  • Thl7 priming is likely to reduce inflammation in acne lesions and that an IL-17A antagonist, e.g., CJM112, may find use in treateing acne by reducing IL-17A signal and activity.
  • Example 3 A randomized, subject and investigator blinded, placebo-controlled, multi- center study in parallel groups to assess the efficacy and safety of CJM112 in patients with moderate to severe inflammatory acne
  • CJM112 in monthly injections was tested in an ongoing double blind, randomized, multi-center, placebo controlled study with moderate to severe inflammatory acne who failed systemic treatment and had at least 25 facial inflammatory lesions at inclusion.
  • the total facial inflammatory lesion count went down from 33 to 1 after 24 weeks treatment, which may corresponds to a near clearance status.
  • Nodules as a sign of a more severe disease were reduced only by CJM112 and not with placebo, which hints to a clinical activity in nodular or nodulocystic acne.
  • the observed clinical efficacy in reducing inflammatory lesions is superior to what is observed with other systemic treatments such as antibiotics in placebo-controlled studies in somewhat less severe patients (where an efficacy of 46% from baseline was observed, Fleischer 2006).
  • CDR1 hypervariable region 1 of heavy chain of AIN457
  • CDR2 hypervariable region 2 of heavy chain of AIN457
  • CDR3 hypervariable region 3 of heavy chain of AIN457 ⁇ 400> 3
  • tgg atg aac tgg gtc cgc cag get cca ggg aaa ggg ctg gag tgg gtg
  • 35 40 45 lie Tyr Gly Ala Ser Ser Arg Ala Thr GlyIle Pro Asp Arg Phe Ser
  • CDR2-X hypervariable domain of heavy chain x of AIN457 ⁇ 400> 12

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Abstract

La présente invention concerne des méthodes de traitement de l'acné, par exemple, l'acné inflammatoire modérée à sévère, à l'aide d'antagonistes de l'IL -17, par exemple, le secukinumab ou le CJM112. L'invention concerne également des utilisations d'antagonistes d'IL-17, par exemple, des anticorps dirigés contre IL-17, tels que le sécukinumab, pour traiter des patients souffrant d'acné, ainsi que des médicaments, des régimes posologiques, des formules pharmaceutiques, des formes pharmaceutiques et des trousses destinées à être utilisés dans les applications et les méthodes de l'invention.
PCT/IB2017/057330 2016-11-28 2017-11-22 Méthodes de traitement de l'acné à l'aide d'antagonistes de l'interleukine-17 (il -17) Ceased WO2018096467A1 (fr)

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