WO2019171267A1 - Anticorps et compositions pharmaceutiques associées pour le traitement de maladies cutanées auto-immunes - Google Patents

Anticorps et compositions pharmaceutiques associées pour le traitement de maladies cutanées auto-immunes Download PDF

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WO2019171267A1
WO2019171267A1 PCT/IB2019/051761 IB2019051761W WO2019171267A1 WO 2019171267 A1 WO2019171267 A1 WO 2019171267A1 IB 2019051761 W IB2019051761 W IB 2019051761W WO 2019171267 A1 WO2019171267 A1 WO 2019171267A1
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antibody
seq
region
antibody fragment
amino acid
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PCT/IB2019/051761
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English (en)
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Nick Ernest René Vandeghinste
Kilian Georg EYERICH
Felix Josef LAUFFER
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Galapagos Nv
Morphosys 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
    • C07K2317/70—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 invention relates to an antibody or antibody fragment specific to IL-17C useful in the prophylaxis and/or treatment of autoimmune skin diseases, in particular T-cell mediated autoimmune skin diseases, B-cell mediated autoimmune skin diseases, granulomatous autoimmune skin diseases or neutrophilic skin diseases.
  • the skin immune system is a finely tuned interplay of different cell types ensuring host defence against pathogenic organisms and tolerance towards commensal skin microbes.
  • skin resident immune cells and keratinocytes initiate a quick and directing immune response towards innate, adaptive or tolerogenic inflammation (Belkaid Y, and Tamoutounour S. Nature reviews Immunology. 20l6;l6(6):353-66).
  • pathogen-associated-molecular-pattems bound to keratinocytes via toll-like-receptors induce a strong immune response mediated by epithelial cytokines and anti-microbial peptides.
  • Interleukin- 17C is a member of the IL-17 cytokine family and is produced by epithelial cells of barrier organs. IL-17C regulates the production of anti-microbial peptides via its specific receptor dimer IL-17RA/IL-17RE (Ramirez-Carrozzi V, Sambandam A, Luis E, Lin Z, Jeet S, Lesch J, Ralphney J, Kim J, Zhou M, Lai J, et al. Nature immunology. 2011 ; 12(12): 1159-66; Song X, Zhu S, Shi P, Liu Y, Shi Y, Levin SD, and Qian Y. Nature immunology. 2011; 12(12): 1151-8.).
  • IL-17C While overexpression of IL-17C in keratinocytes leads to a psoriasis-like inflammation in murine models, IL- 17C is required for the sufficient control of pathogenic intestinal infections (5, 6). The role of IL-17C for barrier associated immune reactions under physiological and chronic inflammatory conditions, however, remains poorly investigated.
  • IL-17C is a key driver of a barrier associated NF-kB dependent innate circuit (BANDIC) of the skin, which is induced by specific extrinsic and intrinsic alarmins. Namely, flagellin (FLG), tumour-necrosis-factor-a (TNF-a) and IE-1b initiate an NF-kB dependent, pro-inflammatory feedback loop consisting of IL-17C and TNF-a in keratinocytes, which directly activates mast cells and recruits neutrophil granulocytes to the site of inflammation.
  • FLG flagellin
  • TNF-a tumour-necrosis-factor-a
  • IE-1b initiate an NF-kB dependent, pro-inflammatory feedback loop consisting of IL-17C and TNF-a in keratinocytes, which directly activates mast cells and recruits neutrophil granulocytes to the site of inflammation.
  • MOR106 (W02017/140831) is a fully human antibody that binds IL-17C and inhibits binding of IL-17C to its receptor throughout relevant species (e.g. human, mouse and cynomolgus monkey) with an IC50 concentration of 80 pM or less. MOR106 proved to be effective in various in vivo mouse models for atopic dermatitis and psoriasis.
  • the present invention demonstrates that IL-17C is elevated not only in inflammatory skin conditions supporting the utility of antibodies specific for IL-17C in the treatment of conditions such as atopic dermatitis, but also in autoimmune skin diseases, which had not previously been demonstrated. Therefore antagonists of IL-17C, specifically antibodies (e.g. MOR106) or antibody fragments may be useful in the prophylaxis and or treatment of autoimmune skin diseases.
  • antagonists of IL-17C specifically antibodies (e.g. MOR106) or antibody fragments may be useful in the prophylaxis and or treatment of autoimmune skin diseases.
  • the present invention provides antibody or antibody fragments specific for IL-17C, in particular MOR106, for use in the treatment of autoimmune skin diseases.
  • the antibody or antibody fragment is for use in the treatment of T-cell mediated autoimmune skin diseases, B-cell mediated autoimmune skin diseases, granulomatous autoimmune skin diseases or neutrophilic skin diseases.
  • the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of an antibody or antibody fragment specific for IL-17C, in particular MOR106, for use in the treatment of autoimmune skin diseases.
  • the antibody or antibody fragment is for use in the treatment of T-cell mediated autoimmune skin diseases, B-cell mediated autoimmune skin diseases, granulomatous autoimmune skin diseases or neutrophilic autoimmune skin diseases.
  • the antibody or antibody fragment comprises a HCDR1 region of amino acid sequence SEQ ID NO: 7, a HCDR2 region of amino acid sequence SEQ ID NO: 8, a HCDR3 region of amino acid sequence of SEQ ID NO: 9, a LCDR1 region of amino acid sequence SEQ ID NO: 13, a LCDR2 region of amino acid sequence of SEQ ID NO: 14 and a LCDR3 region of amino acid sequence SEQ ID NO: 15 for use in the treatment of autoimmune skin diseases.
  • the present invention also provides pharmaceutical compositions comprising an antibody or antibody fragment specific for IL-17C, and a suitable pharmaceutical carrier, excipient or diluent for use in the prophylaxis and/or treatment of autoimmune skin diseases.
  • compositions may additionally comprise further therapeutically active ingredients suitable for use in combination with the antibody or antibody fragments of the invention.
  • the further therapeutically active ingredient is an agent for the treatment of autoimmune skin diseases.
  • this invention provides a method for the prophylaxis and/or treatment of autoimmune skin diseases in a mammal in need thereof, in particular humans, which method comprises administering an effective amount of a pharmaceutical composition, antibody or antibody fragment of the invention as described herein.
  • this invention provides an antibody, or antibody fragment, specific for IL-
  • 17C for use in the prophylaxis and/or treatment of autoimmune skin diseases in a mammal, in particular humans, afflicted with said autoimmune skin disease.
  • antibodies or antibody fragments, specific for IL-17C, useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.
  • the articles‘a’ and‘an’ may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article.
  • an analogue means one analogue or more than one analogue.
  • IL-17C refers to a protein known as interleukin 17C (identified in HUGO
  • HGNC Gene Nomenclature Committee
  • MMI Mouse genome Informatics
  • IL-17C is in some older publications referred to as CX2 or IL-21, however, it should not be confused with IL-21 cytokine, which is specifically expressed in activated CD4 + T cells, but not most of other tissues (Parrish-Novak et al (2000). Nature 408 (6808): 57-63).
  • Human IL-21 is located on Chromosome 4 and is identified in HGNC database by ID 6005.
  • Human IL-17C is located on Chromosome 16 and has the amino acid sequence of (UniProt Q9P0M4):
  • Mouse IL-17C has the amino acid sequence of (UniProt Q8K4C5):
  • Cynomolgus monkey IL-17C has the amino acid sequence of (XP_005592825.1):
  • IL-17RA refers to a protein known as interleukin 17 receptor A.
  • IL-17RA has the amino acid sequence of (UniProt Q96F46):
  • IL-17RE refers to a protein known as interleukin 17 receptor E.
  • IL-17RE has the amino acid sequence of (UniProt Q8NFR9):
  • Murine IL17RE has the amino acid sequence of (UniProt Q8BH06):
  • the term“antibody” as used herein refers to a protein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds which interacts with an antigen.
  • Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region.
  • the heavy chain constant region is comprised of three domains, CH1, CH2 and CH3.
  • Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region.
  • the light chain constant region is comprised of one domain, CL.
  • VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDR complementarity determining regions
  • FR framework regions
  • Each VH and VL is composed of three CDRs and four FR’s arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and 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.
  • antibody includes for example, monoclonal antibodies, human antibodies, humanized antibodies, camelised antibodies and chimeric antibodies.
  • the antibodies can be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclass. Both the light and heavy chains are divided into regions of structural and functional homology.
  • antibody fragment refers to one or more portions of an antibody that retain the ability to specifically interact with (e.g., by binding, steric hindrance, stabilizing spatial distribution) an antigen.
  • binding fragments include, but are not limited to, a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; a F(ab)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment consisting of the VH and CH1 domains; a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a dAb fragment (Ward et al., (1989) Nature 341:544-546), which consists of a VH domain; and an isolated complementarity determining region (CDR).
  • a Fab fragment a monovalent fragment consisting of the VL, VH, CL and CH1 domains
  • F(ab)2 fragment a bivalent
  • the two domains of the Fv fragment, VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al, (1988) Science 242:423-426; and Huston et al, (1988) Proc. Natl. Acad. Sci. 85:5879- 5883).
  • single chain Fv single chain Fv
  • Such single chain antibodies are also intended to be encompassed within the term“antibody fragment”.
  • Antibody fragments are obtained using conventional techniques known to those of skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies.
  • Antibody fragments can also be incorporated into single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, (2005) Nature Biotechnology 23: 1126-1136).
  • Antibody fragments can be grafted into scaffolds based on polypeptides such as Fibronectin type III (Fn3) (see U.S. Pat. No. 6,703,199, which describes fibronectin polypeptide monobodies).
  • Fn3 Fibronectin type III
  • Antibody fragments can be incorporated into single chain molecules comprising a pair of tandem Fv segments (VH-CH1-VH-CH1) which, together with complementary light chain polypeptides, form a pair of antigen-binding sites (Zapata et al, (1995) Protein Eng. 8: 1057-1062; and U.S. Pat. No. 5,641,870).
  • A“human antibody” or“human antibody fragment”, as used herein, includes antibodies and antibody fragments having variable regions in which both the framework and CDR regions are derived from sequences of human origin.
  • Human antibodies can also be isolated from synthetic libraries or from transgenic mice (e.g. xenomouse) provided the respective system yield in antibodies having variable regions in which both the framework and CDR regions are derived from sequences of human origin.
  • the constant region also is derived from such sequences.
  • Human origin includes, e.g., human germline sequences, or mutated versions of human germline sequences or antibody containing consensus framework sequences derived from human framework sequences analysis, for example, as described in Knappik et al, (2000) J Mol Biol 296:57-86).
  • immunoglobulin variable domains e.g., CDRs
  • CDRs may be defined using well known numbering schemes, e.g., the Rabat numbering scheme, the Chothia numbering scheme, or a combination of Rabat and Chothia (see, e.g., Sequences of Proteins of Immunological Interest, U.S. Department of Health and Human Services (1991), eds. Rabat et al., ⁇ Uazikani et al, (1997) J. Mol. Bio. 273:927-948); Rabat et al, (1991) Sequences of Proteins of Immunological Interest, 5th edit., NIH Publication no. 91-3242 U.S.
  • A“humanized antibody” or“humanized antibody fragment” is defined herein as an antibody molecule which has constant antibody regions derived from sequences of human origin and the variable antibody regions or parts thereof or only the CDRs are derived from another species.
  • a humanized antibody can be CDR-grafted, wherein the CDRs of the variable domain are from a non-human origin, while one or more frameworks of the variable domain are of human origin and the constant domain (if any) is of human origin.
  • chimeric antibody or“chimeric antibody fragment” is defined herein as an antibody molecule which has constant antibody regions derived from, or corresponding to, sequences found in one species and variable antibody regions derived from another species.
  • the constant antibody regions are derived from, or corresponding to, sequences found in humans
  • the variable antibody regions are derived from sequences found in a non-human animal, e.g. a mouse, rat, rabbit or hamster.
  • isolated antibody refers to an antibody or antibody fragment, that is substantially free of other antibodies or antibody fragments having different antigenic specificities. Moreover, an isolated antibody or antibody fragment may be substantially free of other cellular material and/or chemicals. Thus, in some aspects, antibodies provided are isolated antibodies which have been separated from antibodies with a different specificity. An isolated antibody may be a monoclonal antibody. An isolated antibody may be a recombinant monoclonal antibody. An isolated antibody that specifically binds to an epitope, isoform or variant of a target may, however, have cross-reactivity to other related antigens, e.g., from other species (e.g., species homologs).
  • recombinant antibody includes all antibodies that are prepared, expressed, created or segregated by means not existing in nature. For example antibodies isolated from a host cell transformed to express the antibody, antibodies selected and isolated from a recombinant, combinatorial human antibody library, and antibodies prepared, expressed, created or isolated by any other means that involve splicing of all or a portion of a human immunoglobulin gene, sequences to other DNA sequences or antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom.
  • an animal e.g., a mouse
  • such recombinant antibodies have variable regions in which the framework and CDR regions are derived from human germline immunoglobulin sequences.
  • such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.
  • a recombinant antibody may be a monoclonal antibody.
  • the antibodies and antibody fragment disclosed herein are isolated from the Ylanthia® antibody library as disclosed in US 13/321,564 or US 13/299,367, which both herein are incorporated by reference.
  • monoclonal antibody refers to a preparation of antibody molecules of single molecular composition.
  • a monoclonal antibody composition displays a unique binding site having a unique binding specificity and affinity for particular epitopes.
  • IL-17C antagonist refers to any molecule which inhibits the activity or function of IL 17C.
  • IL 17C antagonist includes, but is not limited to, antibodies or antibody fragments specifically binding to IL-17C.
  • an IL-17C antagonist in the present disclosure is an antibody specific for human IL-17C.
  • Such an antibody may be of any type, such as a murine, a rat, a chimeric, a humanized or a human antibody.
  • antagonistic antibody specific for IL _ 17C or antagonistic antibodies specific for IL-17C refers to antibodies or antibody fragments specifically binding to IL-17C. More preferably an IL-17C antagonist is an antibody or antibody fragment, such as a monoclonal antibody, specifically binding to IL-17C and blocks the binding of IL-17C to receptors of IL-17C, wherein the receptors of IL-17C include IL-17RE and IL-17RA.
  • an antibody may be of any type, such as a murine, a rat, a chimeric, a humanized or a human antibody.
  • an antibody“binds specifically to”,“specifically binds to”, is“specific to/for” or“specifically recognizes” an antigen or epitope if such antibody is able to discriminate between such antigen or epitope and one or more reference antigen(s) or epitope(s), since binding specificity is not an absolute, but a relative property.
  • a standard ELISA assay can be carried out.
  • the scoring may be carried out by standard color development (e.g. secondary antibody with horseradish peroxide and tetramethyl benzidine with hydrogen peroxide).
  • the reaction in certain wells is scored by the optical density, for example, at 450 nm.
  • determination of binding specificity is performed by using not a single reference antigen, but a set of about three to five unrelated antigens, such as milk powder, BSA, transferrin or the like.
  • compositions of the present disclosure may be used for therapeutic or prophylactic applications.
  • the present disclosure therefore, includes a pharmaceutical composition containing an antibody (or functional antibody fragment) as disclosed herein and a pharmaceutically acceptable carrier or excipient therefor.
  • the present disclosure provides a method for treating autoimmune skin diseases, such method contains the steps of administering to a subject in need thereof an effective amount of the pharmaceutical composition that contains an antibody (or functional antibody fragment) as described or contemplated herein.
  • the present disclosure provides therapeutic methods comprising the administration of a therapeutically effective amount of an IL-17C antibody as disclosed to a subject in need of such treatment.
  • a “therapeutically effective amount” or“effective amount”, as used herein, refers to the amount of an antibody specific for IL-17C, necessary to elicit the desired biological response.
  • the therapeutic effective amount is the amount of an antibody specific for IL-17C necessary to treat and/or prevent autoimmune skin diseases and symptoms associated with autoimmune skin diseases.
  • treat means to alleviate symptoms, eliminate the causation of symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.
  • Preventing refers to a reduction in risk of acquiring or developing a disease or disorder (/. e. causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
  • prophylacticaxis is related to‘prevention’, and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease.
  • prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.
  • the terms“subject”,“a subject in need thereof’ or the like mean a human or non-human animal that exhibits one or more symptoms or indicia of an autoimmune skin disease, and/or who has been diagnosed with an autoimmune skin disease.
  • the subject is a patient who has been diagnosed with an autoimmune skin disease.
  • “Subject” or“species”, as used in this context refers to any mammal, including rodents, such as mouse or rat, and primates, such as cynomolgus monkey ( Macaca fascicularis), rhesus monkey ( Macaca mulatto) or humans ⁇ Homo sapiens).
  • the subject is a primate, most preferably a human.
  • autoimmune skin diseases refers to a group of diseases including T-cell mediated autoimmune skin diseases (e.g. lupus erythematosus, alopecia areata, lichen sclerosus et atrophicus and morphea), B-cell mediated autoimmune skin diseases (e.g. pemphigus vulgaris and bullous pemphigoid), granulomatous autoimmune skin diseases (e.g. granuloma anulare, sarcoidosis, rosacea and acrodermatitis chronica atrophicans) or neutrophilic skin diseases (e.g.
  • T-cell mediated autoimmune skin diseases e.g. lupus erythematosus, alopecia areata, lichen sclerosus et atrophicus and morphea
  • B-cell mediated autoimmune skin diseases e.g. pemphigus vulgaris and bullous pemphigoid
  • B-cell mediate autoimmune skin diseases e.g. pemphigus vulgaris and bullous pemphigoid
  • neutrophilic skin diseases e.g. drug eruption, vasculitis, pyoderma gangrenosum and Sweet’s disease.
  • the term“about” when used in reference to a particular recited numerical value means that the value may vary from the recited value by no more than 1 %.
  • the expression “about 100” includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
  • PK Pharmacokinetics
  • ‘Pharmaceutically acceptable’ means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which an antibody or antibody fragment is administered.
  • the present invention relates to an antibody, or antibody fragment, specific for IL-17C useful in the prophylaxis and/or treatment of autoimmune skin conditions.
  • the antibody is MOR106.
  • the present invention also provides methods for the prophylaxis and/or treatment of autoimmune skin conditions comprising administering an antibody or antibody fragment, specific for IL- 17C to a subject in need thereof.
  • the present invention also provides pharmaceutical compositions comprising said antibody, or antibody fragment, specific for IL-17C and methods for the prophylaxis and/or treatment of autoimmune skin conditions by administering said antibody, or antibody fragment, specific for IL-17C.
  • compositions can be prepared in a manner well known in the pharmaceutical art and comprise the antibody, or antibody fragment, specific for IL-17C, e.g. MOR106.
  • the antibody, or antibody fragment, specific for IL-17C is administered in an effective amount.
  • the amount of the antibody, or antibody fragment, specific for IL- 17C actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual an antibody, or antibody fragment, administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.
  • compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal.
  • the antibody, or antibody fragment, specific for IL-17C is preferably formulated as either injectable compositions (e.g. intravenous) or as salves, as lotions or as patches all for transdermal administration.
  • compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the an antibody, or antibody fragment is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • Liquid forms suitable for oral administration may include a suitable aqueous or non- aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any of the following ingredients, or a compound of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch
  • Injectable compositions are typically based upon injectable sterile saline or phosphate- buffered saline or other injectable carriers known in the art.
  • the antibody, or antibody fragment, specific for IL-17C in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
  • Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • the active ingredients When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base.
  • Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.
  • transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
  • the antibody, or antibody fragment, specific for IL-17C can also be administered in sustained release forms or from sustained release drug delivery systems.
  • sustained release materials can be found in Remington’s Pharmaceutical Sciences.
  • the present invention provides the antibody, or antibody fragment, specific for IL-17C, or pharmaceutical compositions comprising an antibody, or antibody fragment, specific for IL-17C, for use in the prophylaxis and/or treatment of autoimmune skin diseases.
  • the present invention provides the antibody, or antibody fragment, specific for IL-17C and another therapeutic agent or pharmaceutical compositions comprising the antibody, or antibody fragment, specific for IL-17C and another therapeutic agent, for use in the prophylaxis and/or treatment of autoimmune skin diseases.
  • said another therapeutic agent is an autoimmune skin disease treatment agent.
  • said another agent is selected from steroids (such as clobetasol propionate, desoximetasone, hydrocortisone, methylprednisolone, prednisone, prednisolone, budesonide, or dexamethasone), topical immunotherapy (Dinitrochlorobenzene, squaric acid dibutylester (SADBE), diphenylcyclopropenone (DPCP)), topical minoxidil, anthralin, psoralen and immunosuppressants (eg, cyclosporin, azathioprine, methotrexate).
  • steroids such as clobetasol propionate, desoximetasone, hydrocortisone, methylprednisolone, prednisone, prednisolone, budesonide, or dexamethasone
  • topical immunotherapy Dinitrochlorobenzene, squaric acid dibutylester (SADBE), diphen
  • the present invention provides the antibody, or antibody fragment, specific for IL-17C, or pharmaceutical compositions comprising the antibody, or antibody fragment, specific for IL-17C for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of autoimmune skin diseases.
  • the present invention provides the antibody, or antibody fragment, specific for IL-17C and another therapeutic agent, or pharmaceutical compositions comprising the antibody, or antibody fragment, specific for IL-17C and another therapeutic agent for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of autoimmune skin diseases.
  • said another therapeutic agent is an autoimmune skin disease treatment agent.
  • said another agent is selected from steroids (such as clobetasol propionate, desoximetasone, hydrocortisone, methylprednisolone, prednisone, prednisolone, budesonide, or dexamethasone), topical immunotherapy (Dinitrochlorobenzene, squaric acid dibutylester (SADBE), diphenylcyclopropenone (DPCP)), topical minoxidil, anthralin, psoralen and immunosuppressants (eg, cyclosporin, azathioprine, methotrexate).
  • steroids such as clobetasol propionate, desoximetasone, hydrocortisone, methylprednisolone, prednisone, prednisolone, budesonide, or dexamethasone
  • topical immunotherapy Dinitrochlorobenzene, squaric acid dibutylester (SADBE), diphen
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with an autoimmune skin disease, which methods comprise the administration of an effective amount of the antibody, or antibody fragment, specific for IL-17C or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • the present invention provides methods of prophylaxis and/or treatment of a mammal afflicted with an autoimmune skin disease, wherein said methods comprise an administration of another therapeutic agent with the antibody, or antibody fragment, specific for IL-17C.
  • said another therapeutic agent is an autoimmune skin disease treatment agent.
  • said another agent is selected from steroids (such as clobetasol propionate, desoximetasone, hydrocortisone, methylprednisolone, prednisone, prednisolone, budesonide, or dexamethasone), topical immunotherapy (Dinitrochlorobenzene, squaric acid dibutylester (SADBE), diphenylcyclopropenone (DPCP)), topical minoxidil, anthralin, psoralen and immunosuppressants (eg, cyclosporin, azathioprine, methotrexate).
  • steroids such as clobetasol propionate, desoximetasone, hydrocortisone, methylprednisolone, prednisone, prednisolone, budesonide, or dexamethasone
  • topical immunotherapy Dinitrochlorobenzene, squaric acid dibutylester (SADBE), diphen
  • the autoimmune skin disease is particularly a T-cell mediated autoimmune skin diseases (e.g. lupus erythematosus, alopecia areata, lichen sclerosus et atrophicus and morphea), a B-cell mediated autoimmune skin diseases (e.g. pemphigus vulgaris and bullous pemphigoid), a granulomatous autoimmune skin diseases (e.g. granuloma anulare, sarcoidosis, rosacea and acrodermatitis chronica atrophicans) or a neutrophilic autoimmune skin diseases (e.g.
  • T-cell mediated autoimmune skin diseases e.g. lupus erythematosus, alopecia areata, lichen sclerosus et atrophicus and morphea
  • B-cell mediated autoimmune skin diseases e.g. pemphigus vulgaris and bullous pemphigoid
  • the autoimmune skin disease is a B-cell mediated autoimmune skin disease (e.g. pemphigus vulgaris and bullous pemphigoid) or a neutrophilic autoimmune skin diseases (e.g. drug eruption, vasculitis, pyoderma gangrenosum and Sweet’s disease).
  • a B-cell mediated autoimmune skin disease e.g. pemphigus vulgaris and bullous pemphigoid
  • a neutrophilic autoimmune skin diseases e.g. drug eruption, vasculitis, pyoderma gangrenosum and Sweet’s disease.
  • pemphigus vulgaris, bullous pemphigoid, vasculitis, pyoderma gangrenosum or Sweet’s disease is pemphigus vulgaris, bullous pemphigoid, vasculitis, pyoderma gangrenosum or Sweet’s disease.
  • Injection dose levels range from about 0.1 mg/kg/h to at least 10 mg/kg/h, all for from about 1 to about 120 h and especially 24 to 96 h.
  • a preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels.
  • the maximum total dose is not expected to exceed about 1 g/day for a 40 to 80 kg human patient.
  • the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance.
  • one to four (1-4) regular doses daily especially one to three (1-3) regular doses daily, typically one to two (1-2) regular doses daily, and most typically one (1) regular dose daily are representative regimens.
  • dosage regimen can be every 1-14 days, more particularly 1-10 days, even more particularly 1-7 days, and most particularly 1-3 days.
  • each dose provides from about 1 to about 1000 mg of an antibody, or antibody fragment, specific for IL-17C, with particular doses each providing from about 10 to about 500 mg and especially about 30 to about 250 mg.
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
  • the antibody, or antibody fragment, specific for IL-17C When used to prevent the onset of a condition, the antibody, or antibody fragment, specific for IL-17C will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above.
  • Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
  • the antibody, or antibody fragment, specific for IL-17C can be administered as the sole active agent or it can be administered in combination with other therapeutic agents.
  • co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.
  • the antibody, or antibody fragment, specific for IL-17C or a pharmaceutical composition comprising the antibody, or antibody fragment, specific for IL-17C is administered as a medicament.
  • said pharmaceutical composition additionally comprises a further active ingredient.
  • any means of delivering two or more therapeutic agents to the patient as part of the same treatment regimen is included any means of delivering two or more therapeutic agents to the patient as part of the same treatment regimen, as will be apparent to the skilled person.
  • the two or more agents may be administered simultaneously in a single formulation, i.e. as a single pharmaceutical composition, this is not essential.
  • the agents may be administered in different formulations and at different times.
  • the antibody or antibody fragment specific for IL-17C comprises a variable heavy chain variable region, a variable light chain region, heavy chain, light chain and/or CDRs comprising any of the amino acid sequences of the IL-17C specific antibodies as set forth in W02017/140831.
  • said antibody or antibody fragment specific for IL-17C comprises a
  • HCDR1 region comprising the amino acid sequence of SEQ ID NO: 7
  • a HCDR2 region comprising the amino acid sequence of SEQ ID NO: 8
  • a HCDR3 region comprising the amino acid sequence of SEQ ID NO: 9
  • a LCDR1 region comprising the amino acid sequence of SEQ ID NO: 13
  • a LCDR2 region comprising the amino acid sequence of SEQ ID NO: 14
  • a LCDR3 region comprising the amino acid sequence of SEQ ID NO: 15.
  • said antibody or antibody fragment specific for IL-17C comprises the HCDR1 region of SEQ ID NO: 7, the HCDR2 region of SEQ ID NO: 8, the HCDR3 region of SEQ ID NO: 9, the LCDR1 region of SEQ ID NO: 13, the LCDR2 region of SEQ ID NO: 14 and the LCDR3 region of SEQ ID NO: 15.
  • said antibody or antibody fragment specific for IL-17C comprises a
  • HCDR1 region comprising the amino acid sequence of SEQ ID NO: 10
  • a HCDR2 region comprising the amino acid sequence of SEQ ID NO: 11
  • a HCDR3 region comprising the amino acid sequence of SEQ ID NO: 12
  • a LCDR1 region comprising the amino acid sequence of SEQ ID NO: 13
  • a LCDR2 region comprising the amino acid sequence of SEQ ID NO: 14
  • a LCDR3 region comprising the amino acid sequence of SEQ ID NO: 15.
  • said antibody or antibody fragment specific for IL-17C comprises the
  • HCDR1 region of SEQ ID NO: 10 the HCDR2 region of SEQ ID NO: 11, the HCDR3 region of SEQ ID NO: 12, the LCDR1 region of SEQ ID NO: 13, the LCDR2 region of SEQ ID NO: 14 and the LCDR3 region of SEQ ID NO: 15.
  • said antibody or antibody fragment specific for IL-17C comprises • a HCDR1 region comprising the amino acid sequence of SEQ ID NO: 7, a HCDR2 region comprising the amino acid sequence of SEQ ID NO: 8, a HCDR3 region comprising the amino acid sequence of SEQ ID NO: 9, a LCDR1 region comprising the amino acid sequence of SEQ ID NO: 13, a LCDR2 region comprising the amino acid sequence of SEQ ID NO: 14 and a LCDR3 region comprising the amino acid sequence of SEQ ID NO: 15, or
  • a HCDR1 region comprising the amino acid sequence of SEQ ID NO: 10
  • a HCDR2 region comprising the amino acid sequence of SEQ ID NO: 11
  • a HCDR3 region comprising the amino acid sequence of SEQ ID NO: 12
  • a LCDR1 region comprising the amino acid sequence of SEQ ID NO: 13
  • a LCDR2 region comprising the amino acid sequence of SEQ ID NO: 14
  • a LCDR3 region comprising the amino acid sequence of SEQ ID NO: 15.
  • said antibody or antibody fragment specific for IL-17C comprises
  • said antibody or antibody fragment specific for IL-17C comprises
  • said antibody or antibody fragment specific for IL-17C comprises a variable heavy chain of SEQ ID NO: 17 and a variable light chain of SEQ ID NO: 16.
  • said antibody or antibody fragment specific for IL-17C comprises a heavy chain of SEQ ID NO: 30 and a light chain of SEQ ID NO: 29.
  • the present disclosure refers to a nucleic acid composition
  • a nucleic acid composition comprising a nucleic acid sequence or a plurality of nucleic acid sequences encoding said antibody or antibody fragment specific for IL-17C, wherein said antibody or antibody fragment comprises
  • said antibody or antibody fragment comprises a variable heavy chain of SEQ ID NO: 17 and a variable light chain of SEQ ID NO: 16 or a variable heavy chain and a variable light chain that has at least 60%, at least 70 %, at least 80%, at least 90% or at least 95% identity to the a variable heavy chain of SEQ ID NO: 17 and to the variable light chain of SEQ ID NO: 16.
  • the disclosure refers to an isolated nucleic acid encoding a heavy chain sequence and/or light chain sequence of said antibody or antibody fragment that binds to IL-17C, the nucleic acid comprising
  • a HCDR1 region of SEQ ID NO: 20 the HCDR2 region of SEQ ID NO: 21, the HCDR3 region of SEQ ID NO: 22, the LCDR1 region of SEQ ID NO: 26, the LCDR2 region of SEQ ID NO: 27 and the LCDR3 region of SEQ ID NO: 28, or
  • the disclosure refers to a nucleic acid encoding an isolated monoclonal antibody or antibody fragment specific for IL-17C, wherein the nucleic acid comprises a VH region of SEQ ID NO: 19 and a VL region of SEQ ID NO: 18, or a VH region and a VL region that has at least 60%, at least 70 %, at least 80%, at least 90% or at least 95% identity to the VH region of SEQ ID NO: 19 and/or the VL region of SEQ ID NO: 18.
  • the disclosure refers to a nucleic acid encoding an isolated monoclonal antibody or antibody fragment specific for IL-17C, wherein the nucleic acid comprises a VH region of SEQ ID NO: 43 and a VL region of SEQ ID NO: 42, or a VH region and a VL region that has at least 60%, at least 70 %, at least 80%, at least 90% or at least 95% identity to the VH region of SEQ ID NO: 43 and/or the VL region of SEQ ID NO: 42.
  • the disclosure refers to a nucleic acid encoding an isolated monoclonal antibody or antibody fragment specific for IL-17C wherein the nucleic acid comprises a Heavy chain (IgGl) of SEQ ID NO: 32 and a Light chain of SEQ ID NO: 31.
  • the nucleic acid comprises a Heavy chain (IgGl) of SEQ ID NO: 32 and a Light chain of SEQ ID NO: 31.
  • the disclosure refers to a nucleic acid encoding an isolated monoclonal antibody or antibody fragment specific for IL-17C wherein the nucleic acid comprises a Heavy chain (IgGl) of SEQ ID NO: 45 and a Light chain of SEQ ID NO: 44.
  • the disclosure refers to a nucleic acid encoding an isolated monoclonal antibody or antibody fragment specific for IL-17C wherein the nucleic acid comprises a VH and a VL of any of the antibodies in Table 1.
  • the disclosure refers to a nucleic acid encoding an isolated monoclonal antibody or antibody fragment specific for IL-17C wherein the nucleic acid comprises a Heavy chain (IgGl) and a Light chain of any of the antibodies in Table 1.
  • the nucleic acid comprises a Heavy chain (IgGl) and a Light chain of any of the antibodies in Table 1.
  • the present disclosure refers to a pharmaceutical composition
  • a pharmaceutical composition comprising an antibody or antibody fragment specific for IL-17C as disclosed in Table 1 and a pharmaceutically acceptable carrier or excipient.
  • An exemplary antibody or antibody fragment comprising a heavy chain comprising the variable heavy chain sequence of SEQ ID NO: 17 and a variable light chain comprising the amino acid sequence of SEQ ID NO: 16 is the fully human anti-IL-l7C antibody known as MOR106.
  • said antibody or antibody fragment is an antagonistic antibody or antibody fragment.
  • said antagonistic antibody or antibody fragment blocks the binding of IL-17C to IL 17RE.
  • said antagonistic antibody or antibody fragment specific for IL comprises:
  • the antibody or antibody fragment specific for IL-17C is an antibody or antibody fragment that specifically binds IL-17C.
  • said antibody or antibody fragment specific for IL-17C is an antibody or antibody fragment that specifically binds to human IL-17C.
  • said antibody or antibody fragment specific for IL-17C is an isolated monoclonal antibody or antibody fragment that specifically binds to human IL-17C.
  • said antibody or antibody fragment thereof specific for IL-17C is an isolated antibody or antibody fragment specific for IL-17C.
  • said antibody or antibody fragment thereof specific for IL-17C block the binding of IL-17C to IL-17RE.
  • said antibody or antibody fragment thereof specific for IL-17C blocks the binding of IL-17C to the receptor of IL-17C.
  • said antibody or antibody fragment thereof specific for IL-17C blocks the binding of IL-17C to the receptor of IL-17C, wherein said receptor is IL-17RE.
  • said antibody or antibody fragment thereof specific for IL-17C blocks the binding of IL-17C to IL-17RE.
  • said antibody or antibody fragment thereof is an IL-17C antagonist.
  • said antibody or antibody fragment specific for IL-17C blocks the binding of IL-17C to one or more receptors of IL-17C.
  • Other antagonistic anti-IL-l7C antibodies that can be used in the context of the methods of the present invention include any of the IL-17C specific antibodies as set forth in WO1999/060127, WO2013/057241 , WO2017060289, and WO2017140831.
  • the antibody or antibody fragment used in the present invention is an antibody or antibody fragment specific for a polypeptide encoding an amino acid sequence comprising SEQ ID NO: 1.
  • the exemplary antagonistic antibody specific for IL-17C used in the following examples is the human antibody MOR22420, comprising a HCDR1 region of amino acid sequence SEQ ID NO: 46, a HCDR2 region of amino acid sequence SEQ ID NO: 47, a HCDR3 region of amino acid sequence SEQ ID NO: 48, a LCDR1 region of amino acid sequence SEQ ID NO: 49, a LCDR2 region of amino acid sequence SEQ ID NO: 50 and a LCDR3 region of amino acid sequence SEQ ID NO: 51.
  • Example 1 Expression of IL-17C in inflammatory and autoimmune skin diseases
  • IL-17C positive cells were detected in almost all inflammatory and autoimmune skin conditions, regardless if the disease pathology is autoimmune and T cell mediated (e.g. alopecia areata) (Gilhar A, Etzioni A, and Paus R. The New England journal of medicine. 2012;366( 16) : 1515-25), autoimmune and B cell mediated (e.g. pemphigus vulgaris) (Spindler V, Eming R, Schmidt E, Amagai M, Grando S, Jonkman MF, Kowalczyk AP, Muller EJ, Payne AS, Pincelli C, et al. The Journal of investigative dermatology.
  • T cell mediated e.g. alopecia areata
  • autoimmune and B cell mediated e.g. pemphigus vulgaris
  • spindler V Eming R, Schmidt E, Amagai M, Grando S, Jonkman MF, Kowalczyk AP, Muller EJ, Payne AS, Pincelli C,
  • Example 2 In vivo models
  • autoimmune skin diseases In vivo models to evaluate the efficacy of antibodies and small molecules in the autoimmune skin diseases described in the present invention are well known and already described. Where necessary antibodies as described in WO2013/057241 which show higher affinity for murine IL-17C may be used in these models in addition to, or as an alternative to, those described in the present application.
  • exemplary animal models for the autoimmune skin diseases include:

Abstract

La présente invention concerne l'utilisation d'un anticorps ou d'un fragment d'anticorps spécifique de l'IL-17C dans la prophylaxie et/ou le traitement de maladies cutanées auto-immunes. Selon un mode de réalisation de la présente invention, l'anticorps ou le fragment d'anticorps spécifique de l'IL-17C comprend une région HCDR1 de la séquence d'acides aminés SEQ ID NO : 7, une région HCDR2 de séquence d'acides aminés SEQ ID NO : 8, une région HCDR3 de séquence d'acides aminés SEQ ID NO : 9, une région LCDR1 de séquence d'acides aminés SEQ ID NO : 13, une région LCDR2 de séquence d'acides aminés de SEQ ID NO : 14 et une région LCDR3 de séquence d'acides aminés SEQ ID NO : 15. Selon un autre mode de réalisation de l'invention, l'anticorps ou le fragment d'anticorps spécifique de l'IL-17C comprend une chaîne lourde variable de SEQ ID NO : 17 et une chaîne légère variable de SEQ ID NO : 16. Selon certains modes de réalisation de l'invention, la maladie cutanée auto-immune est choisie parmi le pemphigus vulgaire, la pemphigoïde bulleuse, la vasculite, la pyoderma gangrenosum et la maladie de Sweet.
PCT/IB2019/051761 2018-03-06 2019-03-05 Anticorps et compositions pharmaceutiques associées pour le traitement de maladies cutanées auto-immunes WO2019171267A1 (fr)

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