WO2017221174A1 - Méthodes de traitement du vitiligo à l'aide d'anticorps de l'interleukine-17 (il -17) - Google Patents

Méthodes de traitement du vitiligo à l'aide d'anticorps de l'interleukine-17 (il -17) Download PDF

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WO2017221174A1
WO2017221174A1 PCT/IB2017/053701 IB2017053701W WO2017221174A1 WO 2017221174 A1 WO2017221174 A1 WO 2017221174A1 IB 2017053701 W IB2017053701 W IB 2017053701W WO 2017221174 A1 WO2017221174 A1 WO 2017221174A1
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antibody
antigen
patient
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Joel Gelfand
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Novartis Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • 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
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Definitions

  • the present disclosure relates to methods for treating vitiligo, using IL-17 antagonists, e.g., an IL-17 antibody or antigen-binding fragment thereof, such as secukinumab.
  • IL-17 antagonists e.g., an IL-17 antibody or antigen-binding fragment thereof, such as secukinumab.
  • Vitiligo is a relatively common dermatological disorder, affecting about 1% of the population. (Kotobuki et al. (2012) Pigment Cell Melanoma Res. 25; 219-230). It is progressive, characterized by destruction of melanocytes within the epidermis, hair follicles, and possibly other organs, resulting in skin de-pigmentation. Vitiligo is officially categorized by location, i.e., segmental (occurring on one side of the body, typically as a single patch), non- segmental (occurring bilaterally), mixed, and unclassified. Non-segmental vitiligo tends to occur at sites sensitive to pressure or friction, and accounts for up to 90% of overall cases.
  • vitiligo treatments are typically unsatisfactory to patients.
  • Various creams and ointments prescribed for vitiligo patients can cause pimples, ingrown hairs, burning, itching and allergic reactions.
  • Steroids and immunosuppressants can cause thinning of the skin, blood vessel formation, steroid-induced acne, atrophy, etc.
  • Phototheraphy can cause sunburn, redness, blistering, and inflammation.
  • vitiligo can be cosmetically very disabling to patients, particularly in individuals with darker skin. Indeed, recent reports indicate that the chronic nature of vitiligo, length of treatment, and lack of effective therapy are demoralizing for patients, leading to poor self-image and increased incidence of depression. (Al- Harbi (2013) Skinmed 11(6): 327-30). Hence, there is a long-felt need for safe, effective, and non-invasive treatments for vitiligo. SUMMARY OF THE DISCLOSURE
  • Thl7 cells identified a significant number of Thl7 cells infiltrating vitiligo skin, and demonstrated an inhibitory effect of Thl7 cell-related proinflammatory cytokines on melanocyte activity.
  • IL-17 antagonists e.g., IL-17 antibodies, e.g., secukinumab, can be used systemically to treat vitiligo and resolve the skin de-pigmentation associated therewith.
  • an IL-17 antagonist e.g., an anti-IL-17 antibody or antigen-binding fragment thereof
  • 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 selected from the group consisting of: a) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of IL-17 between residues Arg 55 and Trp 67; b) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of IL-17 comprising Arg 55, Glu 57, and Trp 67; c) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of IL-17 comprising: Arg 55, Glu 57, Trp 67, Tyr 62, and Arg 101 ; d) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of IL-17 comprising Arg 55, Glu 57, Trp 67, Tyr 62, Arg 101, Pro 59, Ser 64, and Val 65; e) an IL-17 antibody or antigen-bind
  • 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:25, SEQ ID NO: 27 and SEQ ID NO: 29; vii) 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; vih) 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
  • the IL-17 antibody or antigen-binding fragment thereof is secukinumab (AIN457).
  • Secukinumab is a high-affinity recombinant, fully human monoclonal anti-human interleukin-17A antibodies of the IgGl/ ⁇ - class. Secukinumab binds to human IL-17A and neutralize the bioactivity of this cytokine.
  • vitiligo refers to all forms of vitiligo, e.g., generalized (vitiligo vulgaris); acral, acrofacial and localized vitiligo (frequently referred to collectively as focal vitiligo); universal; segmental; non-segmental; unspecified; mixed; koebnerised; trichome; poliosis; and mucosal, unless otherwise stated.
  • the patient has moderate to extensive vitiligo.
  • the patient has active vitiligo. In some embodiments, the patient has moderate to extensive active vitiligo. In some embodiments, the patient has > 3% BSA involvement. In some embodiments, the patient has > 15% BSA involvement. In some embodiments, the patient has moderate to severe vitiligo by the Physicians Global Assessment Scoring system, based on it being chronic, affecting multiple sites and having > 15% BSA involvement.
  • 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.
  • 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 carboxy-terminus in the following order: FRl, CDRl, 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) and ixekizumab (U.S. Patent No. 7,838,638).
  • 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 , V H , 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.
  • 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.
  • 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).
  • 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 IL-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-17A, 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-17 A.
  • 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.
  • K D is intended to refer to the dissociation rate of a particular antibody-antigen interaction.
  • K D is intended to refer to the dissociation constant, which is obtained from the ratio of K d to K a (i.e., 3 ⁇ 4/ ⁇ 3 ) and is expressed as a molar concentration (M).
  • K D values for antibodies can be determined using methods well established in the art. A method for determining the K D 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 binds human IL-17 with a K D of about 1- 250 pM, preferably 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) 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 ® (basiliximab) may be conveniently used as a negative control.
  • An IL-17 antibody or antigen-binding fragment thereof typically has an IC 50 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, and functional derivatives thereof have an IC 50 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, 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 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.
  • IL-17 antagonist e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 antibody or antigen- binding fragment thereof) that is effective, upon single or multiple
  • an active ingredient e.g., an IL-17 antagonist, e.g., secukinumab
  • the term refers to that ingredient alone.
  • the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.
  • treatment or “treat” is herein defined as the application or administration of an IL-17 antibody according to the disclosure, for example, secukinumab or ixekizumab, or a pharmaceutical composition comprising said anti-IL-17 antibody, to a subject or to an isolated tissue or cell line from a subject, where the subject has a particular disease (e.g., vitiligo), a symptom associated with the disease (e.g., vitiligo), or a predisposition towards development of the disease (e.g., vitiligo), where the purpose is to cure (if applicable), delay the onset of, reduce the severity of, alleviate, ameliorate one or more symptoms of the disease, improve the disease, reduce or improve any associated symptoms of the disease or the predisposition toward the development of the disease.
  • treatment or “treat” includes treating a patient suspected to have the disease as well as patients who are ill or who have been diagnosed as suffering from the disease or medical condition, and includes suppression of clinical relapse.
  • 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.
  • selectively treating 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
  • selectively 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.
  • selectively treating and selectively administering it is meant that 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.
  • 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) 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, which is incorporated by reference herein in its entirety.
  • Secukinumab is a recombinant high-affinity, fully human monoclonal anti-human interleukin- 17A (IL-17A, IL-17) antibody of the IgGi /kappa isotype.
  • Secukinumab has a high affinity for IL-17, i.e., a K D of about 100-200 pM (e.g., about 200 pM), an IC 50 for in vitro neutralization of the biological activity of about 0.67 nM human IL-17A of about 0.4 nM, and a half-life of about 4 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, is provided in Table 1, below.
  • Table 1 Amino acid sequences of the hypervariable regions of secukinumab.
  • the DNA encoding the V L of secukinumab is set forth in SEQ ID NO:9.
  • the DNA encoding the V H of secukinumab is set forth in SEQ ID NO:7.
  • the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin heavy chain variable domain (VH) comprising hypervariable regions CDRl, CDR2 and CDR3, said CDRl 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.
  • VH immunoglobulin heavy chain variable domain
  • the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin light chain variable domain (1 ⁇ 4 ) comprising hypervariable regions CDRl ', CDR2' and CDR3 ', said CDRl ' 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.
  • 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: l, 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 CDR1
  • 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 S
  • 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 CDRl, CDR2 and CDR3 and the constant part or fragment thereof of a human heavy chain; said CDRl 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 CDRl ', CDR2', and CDR3' and the constant part or fragment thereof of a human light chain, said CDRl ' 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 CDRl, CDR2 and CDR3, said CDRl 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) a second domain comprising, in sequence, the hypervariable regions CDRl', CDR2' and CDR3', said CDRl ' 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 extrem
  • 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).
  • 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: 15 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 VH or VL 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, Vail 24, Thrl25, Prol26, Ilel27, Vail 28, 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 Q 16552.
  • the IL-17 antibody has a KD of about 100-200 pM.
  • the IL-17 antibody has an IC 50 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 Tmax of about 7-8 days.
  • IL-17 antagonists e.g., IL-17 binding molecules (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) 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 vitiligo (e.g., human patients having vitiligo).
  • vitiligo e.g., human patients having vitiligo
  • vitiligo scoring means e.g., the Vitiligo Area Scoring Index (VASI), the Vitiligo European Task Force (VETF) system, Vitiligo Extent Tensity Index (VETI) (Feily (2014) Dermatol Pract Concept 4(4)81-4), Vitiligo Disease Activity Score (VIDA), Potential Repigmentation Index (PRI) (Benzekri et al (2013) Br J Dermatol.
  • VASI Vitiligo Area Scoring Index
  • VETF Vitiligo European Task Force
  • VETI Vitiligo Extent Tensity Index
  • VIDA Vitiligo Disease Activity Score
  • PRI Potential Repigmentation Index
  • vitiligo may be treated using the disclosed uses, compositions, methods and kits, e.g., generalized (vitiligo vulgaris); acral, acrofacial and localized vitiligo (frequently referred to collectively as focal vitiligo); universal; segmental; non-segmental; unspecified; mixed;
  • 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 anti-inflammatory 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 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
  • 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
  • Suitable lyophilisate formulations can be reconstituted in a small liquid volume (e.g., 2ml or less) to allow subcutaneous administration and can provide solutions with low levels of antibody aggregation.
  • the use of antibodies as the active ingredient of pharmaceuticals is now widespread, including the products HERCEPTINTM (trastuzumab), RITUXANTM (ntuximab), SYNAGISTM
  • IL-17 antagonist e.g., IL-17 binding molecules (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) 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, on the particular IL-17 antagonists employed, e.g., IL-17 binding molecules (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or IL-17 receptor binding molecules (e.g., IL-17 antibody or antigen-binding fragment thereof) , 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 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).
  • a mammal e.g., a human
  • IL-17 antagonist e.g., secukinumab
  • 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 e.g., secukinumab
  • 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 (e.g., phototherapy, such as whole-body or localized broadband or narrow band UVB; excimer laser UVB; targeted UVB; and/or oral, topical or bathwater photochemotherapy (PUVA) for treating vitiligo patients, e.g., in combination with at least one additional vitiligo agent, such as a topical or systemic steroid, e.g., a cortiocosteroid cream; an immunosuppressive agent (e.g., a calcineurin inhibitor, e.g., pipmecrolimus and tacrolimus (e.g., ointments or creams, e.g., ELIDELTM)); an antibiotic (e.g., tetracycline antibiotics,
  • a topical or systemic steroid
  • an IL-17 antagonist may be administered either simultaneously with the other agent, or sequentially.
  • an IL-17 antagonist e.g., IL-17 binding molecule (e.g., IL- 17 antibody or antigen-binding fragment thereof, e.g., secukinumab) 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.
  • parenterally e.g., intravenously (e.g., into the antecubital or other peripheral vein), intramuscularly, or subcutaneously.
  • IV therapy using a pharmaceutical composition of the present disclosure will vary, depending on the severity of the disease being treated and the condition and personal response of each individual patient.
  • SC therapy using a pharmaceutical composition of the present disclosure.
  • 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 treatment regimens including both induction and maintenance regimens
  • secukinumab which may be employed in treating vitiligo patients, are provided in PCT
  • the IL-17 antagonist e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen- binding fragment thereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 receptor antibody or antigen-binding fragment thereof) may be administered to the vitiligo patient intravenously (IV) at about 10 mg/kg every other week during week 0, 2, and 4 and thereafter administered to the patient subcutaneously (SC) at about 75 mg - about 300 mg (e.g., about 75 mg, about 150 mg, about 300 mg) monthly, beginning during week 8.
  • IV intravenously
  • SC subcutaneously
  • the patient is dosed IV with about 10 mg/kg during week 0, 2, 4, and then the patient is dosed SC with about 75 mg - about 300 mg (e.g., about 75 mg, about 150 mg, about 300 mg) of the IL-17 antagonist (e.g., secukinumab) during week 8, 12, 16, 20, etc.
  • the IL-17 antagonist e.g., secukinumab
  • the IL-17 antagonist e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen- binding fragment thereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 receptor antibody or antigen-binding fragment thereof) may be administered to the patient SC at about 75 mg - about 300 mg (e.g., about 75 mg, about 150 mg, about 300 mg) weekly during weeks 0, 1, 2, and 3, and thereafter administered to the patient SC at about 75 mg - about 300 mg (e.g., about 75 mg, about 150 mg, about 300 mg) monthly, beginning during week 4.
  • IL-17 binding molecule e.g., IL-17 antibody or antigen- binding fragment thereof, e.g., secukinumab
  • IL-17 receptor binding molecule e.g., IL-17 receptor antibody or antigen-binding fragment thereof
  • the patient is dosed SC with about 75 mg - about 300 mg (e.g., about 75 mg, about 150 mg, about 300 mg) of the IL-17 antagonist (e.g., secukinumab) during weeks 0, 1, 2, 3, 4, 8, 12, 16, 20, etc.
  • the IL-17 antagonist e.g., secukinumab
  • the IL-17 antagonist e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 receptor antibody or antigen-binding fragment thereof) may be administered to the patient without a loading regimen, e.g., the antagonist may be administered to the patient SC at about 75 mg - about 300 mg (e.g., about 75 mg, about 150 mg, about 300 mg) every 4 weeks (monthly).
  • IL-17 binding molecule e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab
  • 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 about 75 mg - about 300 mg (e.g., about 75 mg, about 150 mg, about 300 mg) every 4 weeks (monthly).
  • the patient is dosed SC with about 75 mg - about 300 mg (e.g., about 75 mg, about 150 mg, about 300 mg) of the IL-17 antagonist (e.g., secukinumab) during weeks 0, 4, 8, 12, 16, 20, etc.
  • dosing may be weekly, bimonthly (every 2 weeks), monthly (every 4 weeks), every other month, quarterly (every three months), biyearly (every 6 months), or yearly.
  • Preferred S.C. doses are 150 mg - 300 mg, preferably 150 mg or 300 mg.
  • dose escalation may be required (e.g., during an induction and/or maintenance phase) for certain 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) 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
  • IL-17 receptor binding molecules e.g., IL-17 receptor antibody or antigen-binding fragment thereof.
  • SC dosages of secukinumab may be greater than about 150 mg to about 300 mg SC, e.g., about 175 mg, about 200 mg, about 250 mg, about 350 mg, about 400 mg, about 600 mg, etc.; similarly, IV 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.
  • dose reduction may also be required (e.g., during the induction and/or maintenance phase) for certain patients, e.g., patients that display adverse events or an adverse response to treatment with the IL-17 antagonist (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab).
  • IL-17 antagonist e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab.
  • dosages of the IL-17 antagonist may be less than about 150 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, about 250 mg, about 275 mg, etc.; similarly, IV dosages may be less than about 10 mg/kg, e.g., about 9 mg/kg, 8 mg/kg, 5 mg/kg, 4 mg/kg, 3 mg/kg, 2 mg/kg, 1 mg/kg, 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 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 (or doses) of 150 mg delivered SC, and the dose is then escalated to about 300 mg if needed, as determined by a physician.
  • an initial dose or doses
  • the timing of dosing is generally measured from the day of the first dose of secukinumab (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 2.
  • Table 2 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.
  • weekly dosing is the provision of a weekly dose of the IL-17 antibody regardless of whether the physician refers to a particular week as "week 1" or "week 2".
  • the antibody is administered monthly during week 0, 4, 8, 12, 16, etc.
  • the antibody is administered during week 0, 1, 2, 3, 4, 8, 12, 16, 20, etc.
  • Some providers may refer to this regimen as weekly for five weeks and then monthly (or every 4 weeks) thereafter, beginning during week 8, while others may refer to this regimen as weekly for four weeks and then monthly (or every 4 weeks) thereafter, beginning during week 4.
  • administering a patient an injection at weeks 0, 1, 2 and 3, followed by once monthly dosing starting at week 4 is the same as: 1) administering the patient an injection at weeks 0, 1, 2, 3, and 4, followed by once monthly dosing starting at week 8; 2) administering the patient an injection at weeks 0, 1, 2, 3 and 4 followed by dosing every 4 weeks; and 3) administering the patient an injection at weeks 0, 1, 2, 3 and 4 followed by monthly administration.
  • an 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, 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 4 weeks.
  • IL-17 antagonists e.g., IL-17 antibody or antigen- binding fragment thereof, e.g., secukinumab
  • the IL-17 antagonist e.g., IL-17 antibody or antigen-binding fragment thereof, e.g.,
  • secukinumab 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, 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 4 weeks.
  • IL-17 antagonists e.g., IL-17 antibody or antigen- binding fragment thereof, e.g., secukinumab
  • the IL-17 antagonist e.g., IL-17 antibody or antigen- binding fragment thereof, e.g., secukinumab
  • 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
  • IL-17 antagonists e.g., IL-17 antibody or antigen- binding fragment thereof, e.g., secukinumab
  • 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) to allow subcutaneous delivery of at least about 75 mg - about 300 mg (e.g., about 75 mg, about 150 mg, about 300 mg) of the IL-17 antagonist (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) per unit dose, and further wherein the IL-17 antagonist (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) binds to an epitope of an IL-17 homodimer having two mature
  • 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, via a designated route of administration (e.g., SC or IV).
  • an IL-17 antagonist e.g., an IL-17 antibody, e.g., secukinumab
  • SC or IV designated route of administration
  • 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 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.
  • 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. In each such case, these containers have a sufficient amount of the IL-17 antagonist to allow delivery of the desired 150 mg dose.
  • the patient has a concomitant autoimmune disease, e.g., myasthenia gravis, thyoma, polymyositis and giant cell myocarditis, alopecia areata, scleroderma, inflammatory bowel disease (ulcerative colitis or Crohn's), ankylosing spondylitis, psoriatic arthritis, Sjogren's syndrome, rheumatoid arthritis (RA), primary biliary cirrhosis (PBC), scleroderma, autoimmune thyroid disease, multiple sclerosis, uveitis, type 1 diabetes mellitus, morphoea, discoid lupus erythematosus, pemphigus erythematosus, Grave's disease, systemic (or cutaneous) lupus, pernicious anemia, idiopathic thrombopenic purpura (ITP), Addison
  • the patient is additionally administered a steroid, an antibiotic or a TNF-alpha antagonist.
  • the patient is administered about 75 mg - about 300 mg (e.g., about 150 mg - about 300 mg) of the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab) by subcutaneous injection at weeks 0, 1, 2 and 3, followed by once monthly dosing starting at week 4.
  • the patient is administered 150 mg or 300 mg of the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab) by subcutaneous injection at weeks 0, 1, 2 and 3, followed by once monthly dosing starting at week 4.
  • the patient is monthly administered about 75 mg - about 300 mg (e.g., about 150 mg - about 300 mg) of the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab) by subcutaneous injection.
  • the patient is monthly administered 150 mg or 300 mg of the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab) by subcutaneous injection.
  • 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 ID NO:
  • kits for treating a vitiligo patient 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 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).
  • 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 vitiligo, 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.
  • IL-17 antagonist e.g., IL-17 antibody, e.g., secukinumab
  • kits may also comprise instructions for administration of the IL-17 antagonist (e.g., IL-17 antibody, e.g., secukinumab) to treat the vitiligo patient.
  • Such instructions may provide the dose (e.g., 10 mg/kg, 75 mg, 150 mg, 300 mg), route of administration (e.g., IV, SC), and dosing regimen (e.g., about 10 mg/kg given IV, every other week during weeks 0, 2, and 4, and thereafter at about 75 mg, about 150 mg, or about 300 mg given SC monthly, beginning during week 8; about 75 mg, about 150 mg, or about 300 mg given SC weekly during week 0, 1, 2, and 3 and thereafter at about 75 mg, about 150 mg, or about 300 mg given SC monthly, beginning during week 4; about 75 mg, about 150 mg, or about 300 mg given SC monthly, etc.) for use with the enclosed IL-17 antagonist, e.g., IL-17 binding molecule, e.g., IL-17 antibody, e.g., secukinumab.
  • IL-17 antagonist e.g., IL-17 binding molecule, e.g., IL-17 antibody, e.g., secukinumab.
  • 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.
  • kits for use in treating a patient having vitiligo comprising an IL-17 antagonist (e.g., IL-17 binding molecule, e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab).
  • an IL-17 antagonist e.g., IL-17 binding molecule, e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab.
  • 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) is to be administered to the patient intravenously (IV) at about 10 mg/kg every other week during week 0, 2, and 4 and thereafter is to be administered to the patient subcutaneously (SC) at about 75 mg - about 300 mg (e.g., about 75 mg, about 150 mg, or about 300 mg) monthly, beginning during week 8.
  • the IL-17 antagonist e.g., IL-17 binding molecule, e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab
  • SC subcutaneously
  • 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) is to be administered to the patient SC with or without a loading regimen, e.g., at about 75 mg - about 300 mg (e.g., about 75 mg, about 150 mg, or about 300 mg): a) weekly during weeks 0, 1, 2, and 3, and thereafter SC at about 75 mg - about 300 mg (e.g., about 75 mg, about 150 mg, or about 300 mg) monthly, beginning during week 4; or b) every month (every 4 weeks).
  • the instructions will provide for dose escalation (e.g., from a dose of about 75 mg to a higher dose of about 150 mg or about 300 mg as needed, to be determined by a physician).
  • 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) is to be administered to the patient SC at about 75 mg - about 300 mg (e.g., about 75 mg, about 150 mg, or about 300 mg): a) weekly during weeks 0, 1, 2, and 3, and thereafter is to be administered to the patient SC at about 75 mg - about 300 mg (e.g., about 75 mg, about 150 mg, or about 300 mg) monthly, beginning during week 4; or b) every month (every 4 weeks).
  • the IL-17 antagonist e.g., IL-17 binding molecule, e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab
  • the IL-17 antagonist e.g., IL-17 binding molecule, e.g.,
  • the instructions will provide for dose escalation (e.g., from a dose of about 75 mg to a higher dose of about 150 mg or about 300 mg as needed, to be determined by a physician).
  • dose escalation e.g., from a dose of about 75 mg to a higher dose of about 150 mg or about 300 mg as needed, to be determined by a physician.
  • 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 IgGi isotype.
  • the antibody or antigen-binding fragment thereof is secukinumab.
  • vitiligo There are two main clinical variants of vitiligo: generalized (non- segmental) vitiligo, characterized by symmetrical patchy white areas that may spread to any part of the body; and segmental vitiligo, defined by unilateral depigmented macules. There are several subtypes of vitiligo applicable to both variants.
  • Focal vitiligo is characterized by one or few small macules; periorificial vitiligo involves skin around the eyes, nose, ears, mouth, and anus; acrofacial vitiligo affects periorificial facial areas and distal extremities; mucosal vitiligo affects the oral and/or genital mucosa; and vitiligo universalis refers to generalized vitiligo with complete or almost complete depigmentation. Guidelines for vitiligo trial design and results reporting may be found in Gonzalez et al. (2011) Arch. Dermatol. 147(12): 1428-36.
  • All study subjects receive either placebo or SC secukinumab at a dose of either 150 mg or 300 mg in one of the following regimens: weekly during week 0, 1, 2, 3 and then monthly beginning during week 4; or monthly (no induction regimen).
  • the primary outcome percent change in repigmentation with therapy as measured using the Vitiligo Area and Severity Index (VASI) score, is assessed at 24 weeks.
  • Secondary outcome measures include percentage repigmentation with secukinumab therapy as measured using the physician's global assessment, effect on disease-related quality of life as measured using the validated Vitiligo Quality of Life (VitiQOL) tool, maintenance of repigmentation after stopping therapy, and initial time to repigmentation.
  • VitiQOL Vitiligo Quality of Life
  • Some patients may continue in an extension study, receiving the same dose of secukinumab at monthly intervals, with reassessment of skin involvement at week 52.
  • Subjects completing the primary study who do not enter the extension study are monitored at a week 32 follow-up visit to evaluate maintenance of response (repigmentation).
  • Subjects completing the extension study are monitored at a week 60 follow-up visit to evaluate maintenance of response (repigmentation).
  • a dose escalation to 300 mg may be implemented if, after, e.g., 12 weeks of dosing at 150 mg, a subject has not experienced repigmentation or escalation is warranted based on persistent signs and/or symptoms of disease. Following any dose escalation, subjects will be observed for 4 weeks; if criteria for dose escalation are still met, the dose may be raised again, e.g., to 350 mg SC or 450 mg once- monthly.

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Abstract

La présente invention concerne des méthodes de traitement du vitiligo à l'aide d'antagonistes de l'IL -17, par exemple, le secukinumab. L'invention concerne également des utilisations d'antagonistes d'IL-17, par exemple, des anticorps contre IL-17, tels que le sécukinumab, pour traiter des patients atteints de vitiligo, ainsi que des médicaments, des schémas de traitement, des formulations pharmaceutiques, des formes pharmaceutiques et des trousses destinées à être utilisées dans les applications et les procédés de l'invention.
PCT/IB2017/053701 2016-06-22 2017-06-21 Méthodes de traitement du vitiligo à l'aide d'anticorps de l'interleukine-17 (il -17) WO2017221174A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3689907A1 (fr) * 2019-01-31 2020-08-05 Numab Therapeutics AG Anticorps dirigés contre il-17a et leurs procédés d'utilisation
CN112424224A (zh) * 2018-05-30 2021-02-26 中山康方生物医药有限公司 抗白细胞介素-17a抗体、其药物组合物及其用途
US20220064280A1 (en) * 2018-09-11 2022-03-03 Eli Lilly And Company Methods of treating psoriasis

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006013107A1 (fr) 2004-08-05 2006-02-09 Novartis Ag Anticorps antagonistes de il-17
US7767206B2 (en) 2006-10-02 2010-08-03 Amgen Inc. Neutralizing determinants of IL-17 Receptor A and antibodies that bind thereto
US7838638B2 (en) 2005-12-13 2010-11-23 Eli Lilly And Company Anti-IL-17 antibodies
US8003099B2 (en) 2008-09-29 2011-08-23 Roche Palo Alto Llc Antibodies against human IL17 and uses thereof
US8057794B2 (en) 2006-06-29 2011-11-15 Ucb Pharma S.A. Antibody molecules which bind to human IL-17
US20120034656A1 (en) 2004-11-19 2012-02-09 Ucb Pharma S.A. Neutralising Antibody Molecules Having Specificity for Human IL-17
WO2012101263A1 (fr) * 2011-01-28 2012-08-02 4Sc Discovery Gmbh Inhibition de l'il17 et de l'ifn-gamma dans le traitement d'une inflammation autoimmune
WO2014155278A2 (fr) * 2013-03-26 2014-10-02 Novartis Ag Méthodes de traitement de maladies auto-immunes à l'aide d'antagonistes de l'il -17
US9193788B2 (en) 2013-02-08 2015-11-24 Novartis Ag Anti-IL-17A antibodies and their uses

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006013107A1 (fr) 2004-08-05 2006-02-09 Novartis Ag Anticorps antagonistes de il-17
US20120034656A1 (en) 2004-11-19 2012-02-09 Ucb Pharma S.A. Neutralising Antibody Molecules Having Specificity for Human IL-17
US7838638B2 (en) 2005-12-13 2010-11-23 Eli Lilly And Company Anti-IL-17 antibodies
US20110027290A1 (en) 2005-12-13 2011-02-03 Eli Lilly And Company Anti-il-17 antibodies
US8110191B2 (en) 2005-12-13 2012-02-07 Eli Lilly And Company Anti-IL-17 antibodies
US8057794B2 (en) 2006-06-29 2011-11-15 Ucb Pharma S.A. Antibody molecules which bind to human IL-17
US7767206B2 (en) 2006-10-02 2010-08-03 Amgen Inc. Neutralizing determinants of IL-17 Receptor A and antibodies that bind thereto
US8003099B2 (en) 2008-09-29 2011-08-23 Roche Palo Alto Llc Antibodies against human IL17 and uses thereof
WO2012101263A1 (fr) * 2011-01-28 2012-08-02 4Sc Discovery Gmbh Inhibition de l'il17 et de l'ifn-gamma dans le traitement d'une inflammation autoimmune
US9193788B2 (en) 2013-02-08 2015-11-24 Novartis Ag Anti-IL-17A antibodies and their uses
WO2014155278A2 (fr) * 2013-03-26 2014-10-02 Novartis Ag Méthodes de traitement de maladies auto-immunes à l'aide d'antagonistes de l'il -17

Non-Patent Citations (27)

* Cited by examiner, † Cited by third party
Title
AL-HARBI, SKINMED, vol. 11, no. 6, 2013, pages 327 - 30
ALTSHUL ET AL., J. MOL. BIOL., vol. 215, 1990, pages 403 - 410
BASAK ET AL., J. AM. ACAD. DERMATOL., vol. 60, 2009, pages 256 - 60
BASSIOUNY; SHAKER, CLIN. EXP. DERMATOL., vol. 36, 2011, pages 292 - 97
BENZEKRI ET AL., BR J DERMATOL., vol. 168, 2013, pages 1143 - 6
BIRD ET AL., SCIENCE, vol. 242, 1988, pages 423 - 426
BOSSARD ET AL., ANN RHEUM DIS, vol. 73, no. 2, 2014, pages 237
D. A. BASSIOUNY ET AL: "Role of interleukin-17 in the pathogenesis of vitiligo", CLINICAL AND EXPERIMENTAL DERMATOLOGY, vol. 36, no. 3, 24 December 2010 (2010-12-24), GB, pages 292 - 297, XP055401655, ISSN: 0307-6938, DOI: 10.1111/j.1365-2230.2010.03972.x *
E. MEYERS; W. MILLER, CABIOS, vol. 4, 1989, pages 11 - 17
ESMAEILI ET AL., IRAN J. ALLERGY ASTHMA IMMUNOL., vol. 10, no. 2, 2011, pages 81 - 9
FEILY, DERMATOL PRACT CONCEPT, vol. 4, no. 4, 2014, pages 81 - 4
GONZALEZ ET AL., ARCH. DERMATOL, vol. 147, no. 12, 2011, pages 1428 - 36
HOSSAIN, J AM ACAD DERMATOL, vol. 52, no. 6, 2005, pages 110 - 111
HUSTON ET AL., PROC. NATL. ACAD. SCI., vol. 85, 1988, pages 5879 - 5883
JANDUS ET AL., ARTHRITIS RHEUM, vol. 58, 2008, pages 2307 - 2317
K.A. PAPP ET AL: "Efficacy and safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled phase II dose-ranging study : Secukinumab in the treatment of moderate to severe plaque psoriasis", BRITISH JOURNAL OF DERMATOLOGY, vol. 168, no. 2, 18 January 2013 (2013-01-18), UK, pages 412 - 421, XP055401648, ISSN: 0007-0963, DOI: 10.1111/bjd.12110 *
KABAT E.A. ET AL.: "Sequences of Proteins of Immunological Interest", US DEPARTMENT OF HEALTH AND HUMAN SERVICES
KHAN ET AL., J. AM. ACAD. DERMATOL., 2012, pages 510 - 11
KOTOBUKI ET AL., PIGMENT CELL MELANOMA RES., vol. 25, 2012, pages 219 - 230
MERY-BOSSARD ET AL., J EUR ACAD DERMATOL VENEREOL., vol. 31, no. 1, 2017, pages 181 - 186
MEYERS ET AL., COMPUT. APPL. BIOSCI., vol. 4, 1988, pages 11 - 17
NEEDLEMAN ET AL., J. MOL. BIOL., vol. 48, 1970, pages 444 - 453
SINGH ET AL., AUTOIMMUNITY REVIEWS, 2016, pages 397 - 404
SINGH RASNIK K ET AL: "The role of IL-17 in vitiligo: A review", AUTOIMMUNITY REVIEWS, ELSEVIER, AMSTERDAM, NL, vol. 15, no. 4, 21 January 2016 (2016-01-21), pages 397 - 404, XP029432858, ISSN: 1568-9972, DOI: 10.1016/J.AUTREV.2016.01.004 *
THOMAS MCCORMICK ET AL: "Current knowledge on psoriasis and autoimmune diseases", PSORIASIS: TARGETS AND THERAPY, 1 February 2016 (2016-02-01), pages 7, XP055401640, DOI: 10.2147/PTT.S64950 *
WANG ET AL., PLOS ONE, vol. 6, no. 4, 2011, pages e18907
WARD ET AL., NATURE, vol. 341, 1989, pages 544 - 546

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112424224A (zh) * 2018-05-30 2021-02-26 中山康方生物医药有限公司 抗白细胞介素-17a抗体、其药物组合物及其用途
JP2021526022A (ja) * 2018-05-30 2021-09-30 アケソ バイオファーマ カンパニー，リミティド 抗インターロイキン１７ａ抗体、医薬組成物、およびその使用
JP7538721B2 (ja) 2018-05-30 2024-08-22 アケソ バイオファーマ カンパニー，リミティド 抗インターロイキン１７ａ抗体、医薬組成物、およびその使用
US20220064280A1 (en) * 2018-09-11 2022-03-03 Eli Lilly And Company Methods of treating psoriasis
EP3689907A1 (fr) * 2019-01-31 2020-08-05 Numab Therapeutics AG Anticorps dirigés contre il-17a et leurs procédés d'utilisation

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