WO2019171267A1

WO2019171267A1 - Antibodies and pharmaceutical compositions thereof for the treatment of autoimmune skin diseases

Info

Publication number: WO2019171267A1
Application number: PCT/IB2019/051761
Authority: WO
Inventors: Nick Ernest René Vandeghinste; Kilian Georg EYERICH; Felix Josef LAUFFER
Original assignee: Galapagos NV; Morphosys AG
Current assignee: Galapagos NV; Morphosys AG
Priority date: 2018-03-06
Filing date: 2019-03-05
Publication date: 2019-09-12
Anticipated expiration: 2020-09-06
Also published as: GB201803563D0

Abstract

The present invention relates to the use of an antibody or antibody fragment specific for IL-17C in the prophylaxis and/or treatment of autoimmune skin diseases. In one embodiment, the antibody or antibody fragment specific for IL-17C 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. In another embodiment, the 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. In some embodiments the autoimmune skin disease is selected from pemphigus vulgaris, bullous pemphigoid, vasculitis, pyoderma gangrenosum and Sweet's disease.

Description

ANTIBODIES AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE

TREATMENT OF AUTOIMMUNE SKIN DISEASES

FIELD OF THE INVENTION

[0001] 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.

BACKGROUND OF THE INVENTION

[0002] 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. Depending on the stimulus, 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). In case of bacterial infections, pathogen-associated-molecular-pattems bound to keratinocytes via toll-like-receptors induce a strong immune response mediated by epithelial cytokines and anti-microbial peptides. In the context of inflammatory skin diseases, however, these mechanisms can lead to exaggerated and self-amplifying immune reactions resulting in a disturbance of the skin barrier and systemic inflammation (Yazdi AS, Rocken M, and Ghoreschi K. Seminars in immunopathology. 20l6;38(l):3-l0; Eyerich K, and Eyerich S. Journal of the European Academy of Dermatology and Venereology : JEADV. 2017).

[0003] Interleukin- 17C (IL-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, Hackney 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.). 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.

[0004] The present inventors have identified that enhanced numbers of IL-17C expressing cells can be detected in almost all autoimmune, infectious, and inflammatory skin diseases. Additionally, they have shown that 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. [0005] Antibodies that antagonize IL-17C were disclosed (e.g. in WO1999/060127, WO

2013/057241, W02017/060289, W02017/140831) and it was demonstrated that antagonists of IL-17C are effective in the treatment of (auto-)inflammatory disorders, such as rheumatoid arthritis, psoriasis or atopic dermatitis.

[0006] 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.

[0007] 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.

SUMMARY OF THE INVENTION

[0008] The present invention provides antibody or antibody fragments specific for IL-17C, in particular MOR106, for use in the treatment of autoimmune skin diseases. In particular 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.

[0009] Furthermore, 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. In particular, 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.

[0010] Accordingly, in a particular aspect of the invention, 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.

[0011] 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.

[0012] In a further particular aspect, the pharmaceutical compositions may additionally comprise further therapeutically active ingredients suitable for use in combination with the antibody or antibody fragments of the invention. In a more particular aspect, the further therapeutically active ingredient is an agent for the treatment of autoimmune skin diseases.

[0013] In one aspect of the invention, 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.

[0014] In one aspect, 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.

[0015] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description.

[0016] Moreover, the 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.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0017] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.

[0018] When describing the invention, which may include antibodies, antibody fragments, pharmaceutical compositions comprising such antibodies or antibody fragments, and methods of using such antibodies, antibody fragments and compositions, the following terms, if present, have the following meanings unless otherwise indicated.

[0019] 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. By way of example‘an analogue’ means one analogue or more than one analogue.

[0020] The term“IL-17C” refers to a protein known as interleukin 17C (identified in HUGO

Gene Nomenclature Committee (HGNC) by ID 5983 and in Mouse genome Informatics (MGI) database by ID 2446486). 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.

[0021] Human IL-17C is located on Chromosome 16 and has the amino acid sequence of (UniProt Q9P0M4):

MTLLPGLLFLTWLHTCLAHHDPSLRGHPHSHGTPHCYSAEELPLGQAPPHLLARGAKWGQALPVA

LVS SLEAASHRGRHERPSATTQCPVLRPEEVLEADTHQRS I S PWRYRVDTDEDRY PQKLAFAECL

CRGCI DARTGRETAALNSVRLLQSLLVLRRRPCSRDGSGLPT PGAFAFHTE FI HVPVGCTCVLPR

SV (SEQ ID NO: 1) [0022] Mouse IL-17C has the amino acid sequence of (UniProt Q8K4C5):

MSLLLLGWLPTGMTHQDPPSWGKPRSHRTLRCYSAEELSHGQAPPHLLTRSARWEQALPVALVAS

LEATGHRRQHEGPLAGTQCPVLRPEEVLEADTHERSISPWRYRIDTDENRYPQKLAVAECLCRGC

INAKTGRETAALNSVQLLQSLLVLRRQPCSRDGTADPTPGSFAFHTEFIRVPVGCTCVLPRSTQ

(SEQ ID NO: 4)

[0023] Cynomolgus monkey IL-17C has the amino acid sequence of (XP_005592825.1):

MTLLPGLLFLTWLHACLAHQDPFLRGHPHTHGTPRCYSAEELPLGQAPPHLLARGAKWGQALPVA

LVSSLEAAGHRRRHDRPSAATQCPVLRPEEVLEADTHQRSISPWRYRVDTDEDRYPQKLAFAECL

CRGCIDPRTGRETAALNSVRLLQSLLVLRRRPCSRDGSGLPTPGAFAFHTEFIRVPVGCTCVLPR

SV (SEQ ID NO: 5)

[0024] The term“IL-17RA” refers to a protein known as interleukin 17 receptor A. Human

IL-17RA has the amino acid sequence of (UniProt Q96F46):

MGAARSPPSAVPGPLLGLLLLLLGVLAPGGASLRLLDHRALVCSQPGLNCTVKNSTCLDDSWIHP RNLTPSSPKDLQIQLHFAHTQQGDLFPVAHIEWTLQTDASILYLEGAELSVLQLNTNERLCVRFE FLSKLRHHHRRWRFTFSHFVVDPDQEYEVTVHHLPKPIPDGDPNHQSKNFLVPDCEHARMKVTTP CMSSGSLWDPNITVETLEAHQLRVSFTLWNESTHYQILLTSFPHMENHSCFEHMHHIPAPRPEEF HQRSNVTLTLRNLKGCCRHQVQIQPFFSSCLNDCLRHSATVSCPEMPDTPEPIPDYMPLWVYWFI TGISILLVGSVILLIVCMTWRLAGPGSEKYSDDTKYTDGLPAADLIPPPLKPRKVWI IYSADHPL YVDVVLKFAQFLLTACGTEVALDLLEEQAISEAGVMTWVGRQKQEMVESNSKI IVLCSRGTRAKW QALLGRGAPVRLRCDHGKPVGDLFTAAMNMILPDFKRPACFGTYVVCYFSEVSCDGDVPDLFGAA PRYPLMDRFEEVYFRIQDLEMFQPGRMHRVGELSGDNYLRSPGGRQLRAALDRFRDWQVRCPDWF ECENLYSADDQDAPSLDEEVFEEPLLPPGTGIVKRAPLVREPGSQACLAIDPLVGEEGGAAVAKL EPHLQPRGQPAPQPLHTLVLAAEEGALVAAVEPGPLADGAAVRLALAGEGEACPLLGSPGAGRNS VLFLPVDPEDSPLGSSTPMASPDLLPEDVREHLEGLMLSLFEQSLSCQAQGGCSRPAMVLTDPHT PYEEEQRQSVQSDQGYISRSSPQPPEGLTEMEEEEEEEQDPGKPALPLSPEDLESLRSLQRQLLF RQLQKNSGWDTMGSESEGPSA (SEQ ID NO: 2)

[0025] The term“IL-17RE” refers to a protein known as interleukin 17 receptor E. Human

IL-17RE has the amino acid sequence of (UniProt Q8NFR9):

MGSSRLAALLLPLLLIVIDLSDSAGIGFRHLPHWNTRCPLASHTDDSFTGSSAYIPCRTWWALFS

TKPWCVRVWHCSRCLCQHLLSGGSGLQRGLFHLLVQKSKKSSTFKFYRRHKMPAPAQRKLLPRRH

LSEKSHHISIPSPDISHKGLRSKRTQPSDPETWESLPRLDSQRHGGPEFSFDLLPEARAIRVTIS

SGPEVSVRLCHQWALECEELSSPYDVQKIVSGGHTVELPYEFLLPCLCIEASYLQEDTVRRKKCP

FQSWPEAYGSDFWKSVHFTDYSQHTQMVMALTLRCPLKLEAALCQRHDWHTLCKDLPNATARESD

GWYVLEKVDLHPQLCFKFSFGNSSHVECPHQTGSLTSWNVSMDTQAQQLILHFSSRMHATFSAAW

SLPGLGQDTLVPPVYTVSQARGSSPVSLDLIIPFLRPGCCVLVWRSDVQFAWKHLLCPDVSYRHL

GLLILALLALLTLLGVVLALTCRRPQSGPGPARPVLLLHAADSEAQRRLVGALAELLRAALGGGR

DVIVDLWEGRHVARVGPLPWLWAARTRVAREQGTVLLLWSGADLRPVSGPDPRAAPLLALLHAAP RPLLLLAY FSRLCAKGDI PPPLRALPRY RLLRDLPRLLRALDARP FAEATSWGRLGARQRRQSRL ELCSRLEREAARLADLG (SEQ ID NO: 3)

[0026] Murine IL17RE has the amino acid sequence of (UniProt Q8BH06):

MGS PRLAALLLSLPLLL IGLAVSARVACPCLRSWTSHCLLAYRVDKRFAGLQWGWFPLLVRKSKS PPKFEDYWRHRTPAS FQRKLLGSPSLSEESHRI S I PSSAI SHRGQRT KRAQPSAAEGREHLPEAG SQKCGGPE FS FDLLPEVQAVRVT I PAGPKASVRLCYQWALECEDLSS PFDTQKIVSGGHTVDLPY E FLLPCMCI EASYLQEDTVRRKKCPFQSWPEAYGSDFWQS IRFTDYSQHNQMVMALTLRCPLKLE ASLCWRQDPLT PCETLPNATAQESEGWY ILENVDLHPQLC FKFS FENS SHVECPHQSGSLP SWT V SMDTQAQQLTLHFSSRTYAT FSAAWSDPGLGPDT PMPPVY S I SQTQGSVPVTLDL I I PFLRQENC ILVWRSDVH FAWKHVLCPDVSHRHLGLL ILALLALTALVGVVLVLLGRRLLPGSGRTRPVLLLHA ADSEAQRRLVGALAELLRTALGGGRDVIVDLWEGTHVARIGPLPWLWAARERVAREQGTVLLLWN CAGPSTACSGDPQAASLRTLLCAAPRPLLLAY FSRLCAKGDI PRPLRALPRYRLLRDLPRLLRAL DAQPATLAS SWSHLGAKRCLKNRLEQCHLLELEAAKDDYQGSTNS PCGFSCL (SEQ ID NO: 6)

[0027] 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. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). 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. The term“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.

[0028] The phrase“antibody fragment”, as used herein, 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. Examples of 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). Furthermore, although 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). Such single chain antibodies are also intended to be encompassed within the term“antibody fragment”. These 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). 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).

[0029] 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.

[0030] Furthermore, if the antibody contains a constant region, 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).

[0031] The structures and locations of immunoglobulin variable domains, e.g., 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. Department of Health and Human Services; Chothia et al, (1987) J. Mol. Biol. 196:901-917; Chothia et al, (1989) Nature 342:877-883; and Al-Uazikani et al, (1997) J. Mol. Biol. 273:927-948.

[0032] 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. For example 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.

[0033] The term "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. Preferably, the constant antibody regions are derived from, or corresponding to, sequences found in humans, and the variable antibody regions (e.g. VH, VL, CDR or FR regions) are derived from sequences found in a non-human animal, e.g. a mouse, rat, rabbit or hamster.

[0034] The term "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).

[0035] The term "recombinant antibody", as used herein, 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. Preferably, such recombinant antibodies have variable regions in which the framework and CDR regions are derived from human germline immunoglobulin sequences. In certain embodiments, however, 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. In an embodiment, 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.

[0036] The term "monoclonal antibody" as used herein 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.

[0037] The terms “antagonist of IL-17C” and an “IL-17C antagonist”, are used interchangeably herein and refer to any molecule which inhibits the activity or function of IL 17C. The term“IL 17C antagonist” includes, but is not limited to, antibodies or antibody fragments specifically binding to IL-17C. Preferably, 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.

[0038] The term 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. Such an antibody may be of any type, such as a murine, a rat, a chimeric, a humanized or a human antibody.

[0039] As used herein, 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. For example, 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. Typical background (=negative reaction) may be 0.1 OD; typical positive reaction may be 1 OD. This means the difference positive/negative can be more than lO-fold. Typically, 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.

[0040] 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. In a related aspect, 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.

[0041] 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. In accordance with the subject disclosure, 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.

[0042] As used herein, the terms "treat", "treating", or the like, mean 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.

[0043] ‘Preventing’ or‘prevention’ 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.

[0044] The term‘prophylaxis’ 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. Non-limiting examples of 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.

[0045] As used herein, 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. Preferably 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). Preferably the subject is a primate, most preferably a human.

[0046] As used herein, the term“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. drug eruption, vasculitis, pyoderma gangrenosum and Sweet’s disease). In particular, it refers to B-cell mediate autoimmune skin diseases (e.g. pemphigus vulgaris and bullous pemphigoid) and neutrophilic skin diseases (e.g. drug eruption, vasculitis, pyoderma gangrenosum and Sweet’s disease). Most particularly, it refers to pemphigus vulgaris, bullous pemphigoid, vasculitis, pyoderma gangrenosum and Sweet’s disease.

[0047] As used herein, 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 %. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0048] “Pharmacokinetics” or“PK” as used herein describes how the body affects a specific drug after administration through the mechanisms like absorption and distribution, as well as the metabolic changes of the drug in the body, and the effects and routes of excretion of the metabolites of the drug. Pharmacokinetic properties of drugs may be affected by the route of administration and the dose of administered drug.

[0049] ‘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. [0050] ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which an antibody or antibody fragment is administered.

The Invention

[0051] 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. In particular, 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.

[0052] 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.

Pharmaceutical Compositions

[0053] When employed as a pharmaceutical the antibody, or antibody fragment, specific for IL-

17C is typically administered in a pharmaceutical composition. Such 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. Generally, 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.

[0054] The pharmaceutical compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, 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.

[0055] The 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. The term‘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. In such 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.

[0056] 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.

[0057] Injectable compositions are typically based upon injectable sterile saline or phosphate- buffered saline or other injectable carriers known in the art. As before, 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.

[0058] 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. 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.

[0059] The antibody, or antibody fragment, specific for IL-17C can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0060] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington’s Pharmaceutical Sciences, l7^th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0061] The antibody, or antibody fragment, specific for IL-17C can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.

[0062] The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with this invention. The present invention, however, is not limited to the following pharmaceutical compositions.

Methods of Treatment [0063] In one embodiment, 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.

[0064] In one embodiment, 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. In a particular embodiment, said another therapeutic agent is an autoimmune skin disease treatment agent. In a particular embodiment 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).

[0065] In another embodiment, 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.

[0066] In one embodiment, 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. In a particular embodiment, said another therapeutic agent is an autoimmune skin disease treatment agent. In a particular embodiment 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).

[0067] In additional method of treatment aspects, 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.

[0068] In one embodiment, 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. In a particular embodiment, said another therapeutic agent is an autoimmune skin disease treatment agent. In a particular embodiment 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).

[0069] In the method of treatment or uses described herein 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. drug eruption, vasculitis, pyoderma gangrenosum and Sweet’s disease). In particular 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). In particular it is pemphigus vulgaris, bullous pemphigoid, vasculitis, pyoderma gangrenosum or Sweet’s disease.

[0070] 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.

[0071] For the prophylaxis and/or treatment of long-term conditions, such as degenerative conditions, the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, 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. Alternatively for long lasting effect drugs, with oral dosing, once every other week, once weekly, and once a day are representative regimens. In particular, 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.

[0072] Using these dosing patterns, 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.

[0073] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.

[0074] 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.

[0075] 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. In a specific embodiment, co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.

[0076] In one embodiment, 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. In a specific embodiment, said pharmaceutical composition additionally comprises a further active ingredient.

[0077] By co-administration 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. Whilst 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.

Antibody

[0078] In certain embodiment of the present disclosure, the antibody or antibody fragment specific for IL-17C according to the present disclosure 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.

[0079] In an embodiment, 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.

[0080] In one embodiment, 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.

[0081] In an embodiment, 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 and a LCDR3 region comprising the amino acid sequence of SEQ ID NO: 15.

[0082] In an embodiment, 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.

[0083] In an embodiment, 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 and a LCDR3 region comprising the amino acid sequence of SEQ ID NO: 15.

[0084] In an embodiment, 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, or

• 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.

[0085] In an embodiment, 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, and further comprises a heavy chain of SEQ ID NO: 17 or a light chain of SEQ ID NO: 16, or

• 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 and further comprises a variable heavy chain of SEQ ID NO: 17 or a variable light chain of SEQ ID NO: 16.

[0086] In an embodiment, 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.

[0087] In a further embodiment, 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.

[0088] In one embodiment, the present disclosure refers to 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

• 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, or • 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,

[0089] In another embodiment 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.

[0090] In another embodiment, 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: 33, the HCDR2 region of SEQ ID NO: 34, the HCDR3 region of SEQ ID NO: 35, the LCDR1 region of SEQ ID NO: 39, the LCDR2 region of SEQ ID NO: 40 and the LCDR3 region of SEQ ID NO: 41, or

• a HCDR1 region of SEQ ID NO: 36, the HCDR2 region of SEQ ID NO: 37, the HCDR3 region of SEQ ID NO: 38, the LCDR1 region of SEQ ID NO: 39, the LCDR2 region of SEQ ID NO: 40 and the LCDR3 region of SEQ ID NO: 41, or

• 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

• a HCDR1 region of SEQ ID NO: 23, the HCDR2 region of SEQ ID No: 24, the HCDR3 region of SEQ ID No: 25, 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.

[0091] In an embodiment, 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.

[0092] In an embodiment, 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.

[0093] In an embodiment, 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.

[0094] In an embodiment, 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. [0095] In an embodiment, 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.

[0096] In an embodiment, 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.

[0097] In an embodiment, the present disclosure refers to 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.

[0098] 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.

[0099] In an embodiments, said antibody or antibody fragment is an antagonistic antibody or antibody fragment.

[0100] In certain embodiments, said antagonistic antibody or antibody fragment blocks the binding of IL-17C to IL 17RE.

[0101] In certain embodiments, said antagonistic antibody or antibody fragment specific for IL

17C antagonize any of the roles of IL-17C in autoimmune skin diseases.

[0102] In certain embodiments, the antibody or antibody fragment specific for IL-17C is an antibody or antibody fragment that specifically binds IL-17C.

[0103] In certain embodiments, said antibody or antibody fragment specific for IL-17C is an antibody or antibody fragment that specifically binds to human IL-17C.

[0104] In certain embodiments, said antibody or antibody fragment specific for IL-17C is an isolated monoclonal antibody or antibody fragment that specifically binds to human IL-17C.

[0105] In certain embodiments, said antibody or antibody fragment thereof specific for IL-17C is an isolated antibody or antibody fragment specific for IL-17C.

[0106] In certain embodiments, said antibody or antibody fragment thereof specific for IL-17C block the binding of IL-17C to IL-17RE.

[0107] In certain embodiments, said antibody or antibody fragment thereof specific for IL-17C blocks the binding of IL-17C to the receptor of IL-17C.

[0108] In certain embodiments, 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.

[0109] In certain embodiments, said antibody or antibody fragment thereof specific for IL-17C blocks the binding of IL-17C to IL-17RE.

[0110] In one embodiment said antibody or antibody fragment thereof is an IL-17C antagonist.

[0111] In one embodiment, said antibody or antibody fragment specific for IL-17C blocks the binding of IL-17C to one or more receptors of IL-17C. [0112] 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.

[0113] In other embodiments, 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.

Table 1: Antibody sequences

EXAMPLES

Background

[0114] 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

[0115] To assess the impact of IL-17C in pathological inflammation of the skin, we performed an in situ expression analysis of IL-17C in 18 inflammatory and autoimmune skin diseases.

1.1 Study design

[0116] Human skin samples (skin biopsies) derived from the Biobank Biederstein. All patients gave their written informed consent. The study was approved by the local ethics committee and conducted according to ethical principles laid down in the Declaration of Helsinki.

1.2 Punch biopsy specimen, histology and immunohistochemistry

[0117] 4 - 6 mm punch biopsies of lesional skin were obtained under local anaesthesia. For histology skin samples were fixed in 10 % formalin and embedded in paraffin. 2.5 pm sections were cut and dewaxed. After rehydration heat-induced epitope retrieval was performed in boiling EDTA buffer (pH8) for 20 min. After peroxidase and protein block sections were incubated with the primary antibody (biotinylated MOR22420, Morphosys/Galapagos, 1:200) over night. Sections were incubated with Vectastain ABC HRP kit. Colour reaction was performed with diaminobenzidine (DAB, Sigma). Slides were counterstained with haematoxylin. As a negative control isotype-matched monoclonal antibody was used. Positive cells were counted in two visual fields (400x) per condition by two independent investigators in a blinded manner.

1.3 Results

[0118] 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. 2018; l38( l):32-7) or chronic inflammatory and linked to innate immune reactions (e.g. rosacea) (Gallo RL, Granstein RD, Kang S, Mannis M, Steinhoff M, Tan J, and Thiboutot D. Journal of the American Academy of Dermatology. 20l8;78(l): 148-55) (Figure 1). Strikingly, skin conditions with a high number of neutrophils, such as Sweet’s disease, showed the highest numbers of IL- 17C positive cells, while granulomatous skin diseases (morphea, acrodermatitis chronica atrophicans) contained the lowest numbers of IL-17C expressing cells (Figure 1).

Example 2: In vivo models

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:

• Iwata H, et al, (2015, Curr Pharm Des;2l(l8):2422-39) which describes animal models for autoimmune bullous dermatoses, which includes pemphigus vulgaris and bullous pemphigoid.

• Du Y, et al., (2015, Curr Pharm Des. 2015;21(18):2320-49) which describes animal models for lupus.

• Sundberg JP et al., (2015, J Investig Dermatol Symp Proc., l7(2):23-6) which describes animal models available for alopecia areata.

Claims

1. An antibody or antibody fragment specific for IL-17C for use in the treatment of autoimmune skin diseases.

2. The antibody or antibody fragment specific for IL-17C for use according to claim 1, wherein 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.

3. The antibody or antibody fragment specific for IL-17C according to claim 1, wherein 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.

4. The antibody or antibody fragment for use according to any of the preceding claims, wherein the autoimmune skin disease is a T-cell mediated autoimmune skin disease, a B-cell mediated autoimmune skin disease, a granulomatous autoimmune skin disease or a neutrophilic skin disease.

5. The antibody or antibody fragment for use according to any of the preceding claims, wherein the autoimmune skin disease is a B-cell mediated autoimmune skin disease or a neutrophilic skin diseases.

6. The antibody or antibody fragment for use according to any of the preceding claims, wherein the skin disease is selected from pemphigus vulgaris, bullous pemphigoid, vasculitis, pyoderma gangrenosum and Sweet’s disease.

7. The antibody or antibody fragment for use according to any of the preceding claims, in combination with a further therapeutic agent.

8. The antibody or antibody fragment for use according to claim 7 wherein the further therapeutic agent is an agent for the prophylaxis and/or treatment of autoimmune and neutrophilic skin diseases.

9. A pharmaceutical composition comprising an antibody or antibody fragment specific for IL-17C according to any one of the preceding claims for use in the treatment of autoimmune skin diseases.

10. A method of treating autoimmune skin diseases by administering an antibody or antibody fragment specific for IL-17C to a patient in need thereof.