Treatment method using anti il-17a / f antibody

Abstract

To provide a pharmaceutical composition for treating hidradenitis suppurativa.SOLUTION: There is provided a pharmaceutical composition for treating hidradenitis suppurativa in a human being, the pharmaceutical composition including a neutralization antibody coupling to human IL-17A and human IL-17F. The antibody comprises: a light chain variable domain; and a heavy chain variable domain. The light chain variable domain and the heavy chain variable domain include respectively a specific sequence. The pharmaceutical composition is (i) administered for every two weeks, in a dose of 320 mg of the antibody, or (ii) administered for every four weeks in a dose of the antibody of 320 mg.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present application relates to antibody molecules having specificity for antigenic determinants of both IL-17A and IL-17F, and therapeutic uses of said antibody molecules. [Background technology]

[0002] Interleukin 17 (IL-17), also known as CTLA-8 or IL-17A, is a proinflammatory cytokine that stimulates the secretion of a wide range of other cytokines from various non-immune cells. IL-17A can induce secretion of IL-6, IL-8, PGE2, MCP-1 and G-CSF by adherent cells such as fibroblasts, keratinocytes, epithelial cells and endothelial cells, and can also induce ICAM-1 surface expression, proliferation of T cells, proliferation and differentiation of CD34+ human progenitor cells into neutrophils when co-cultured in the presence of irradiated fibroblasts (Fossiez et al., 1998, Int. Rev. Immunol. 16, 541-551). IL-17A is produced primarily by activated memory T cells and acts by binding to a ubiquitously distributed cell surface receptor (IL-17R) (Yao et al., 1997, Cytokine, 9, 794-800). IL-17A may act by binding to a complex of IL-17RA and IL-17RC (Toy et al., 2006, J. Immunol. 177(11);36-39). IL-17-producing T cells, termed "TH17 cells", have been implicated in the pathogenesis of certain cancers (Weaver et al., 2006, Immunity, 24, 677-688; Langowski et al., 2006, 442, 461-465; Iwakura and Ishigame, 2006, J. Clin. Invest. 116, 5, 1218-1222).

[0003] A number of IL-17 homologues have been identified that have similar but distinct roles in regulating inflammatory responses. For a review of the IL-17 cytokine / receptor family, see Dumont, 2003, Expert Opin. Ther. Patents, 13, 287-303. One such homologue is IL-17F, also known as IL-24 and ML-1, which has been reported to be approximately 55% identical to IL-17A and is thought to share the same receptor as IL-17A (Kolls and Linden 2004, Immunity, 21, 467-476; Hymowitz et al., 2001, EMBO J. 20(19), 5332-5341; Kuestner et al., 2007, Journal of Immunology, 179, 5462-5473). Although individual signaling molecules of IL-17A are more potent than those of IL-17F, IL-17F has a greater effect in cooperation with other molecules. For example, when IL-17F is added together with TNFα to RA synovial cells, the induction of strong inflammatory pathways is similar to the response observed with IL-17A and TNFα (Hot et al., 2011, Ann. Rheumatic Dis., 70, 341-348).

[0004] IL-17A and IL-17F are expressed as homodimers, but may also be expressed as IL-17A / F heterodimers (Wright et al., 2008, J. Immunol. 181:2799-2805). IL-17A and F signal through the receptors IL-17R, IL-17RC, or the IL-17RA / RC receptor complex (Gaffen 2008, Cytokine. 43:402-407).

[0005] IL-17A and IL-17F are related to skin conditions and rheumatic conditions.Such skin conditions include, but are not limited to, psoriasis, atopic dermatitis, discoid lupus erythematosus, alopecia areata, autoimmune urticaria, bullous pemphigoid, dermatitis herpetiformis, hidradenitis, linear IgA dermatitis, morphea, pemphigus vulgaris and pyoderma.Such rheumatic conditions include psoriatic arthritis, axial spondyloarthritis including ankylosing spondylitis, systemic lupus erythematosus (SLE), rheumatoid arthritis, vasculitis, Sjogren's syndrome (extraglandular), juvenile idiopathic arthritis, granulomatosis, Behcet's disease (mucocutaneous), antiphospholipid syndrome, giant cell arteritis, scleroderma, polyarteritis nodosa, Behcet's disease (thrombosis) and Takayasu's disease.

[0006] Psoriatic arthritis is an inflammatory condition that affects both the joints and the skin. Psoriatic arthritis can cause significant joint damage and disability over time, and can be accompanied by both the skin and nail abnormalities seen in psoriasis. (Schett et al., 2011, Arthritis Research and Therapy, 13 Suppl.1:S4.) Psoriatic arthritis can be difficult to distinguish from other forms of arthritis, especially when skin changes are minimal or absent. Patients with psoriatic arthritis often experience many other diseases at a higher frequency than the general population, including iritis / uveitis (eye swelling and inflammation) and inflammatory bowel disease (IBD), as well as autoimmune conditions such as cardiovascular disease and osteoporosis.

[0007] Psoriatic arthritis can negatively impact many aspects of patients' lives, causing pain, physical function and fatigue burden, and reducing psychological, emotional and social health and overall health-related quality of life. (Husted et al., 2001, Arthritis Care and Research, 45:151-8; Picchianti-Diamani et al., 2010, Qual.Life Res., 19:821-6.) Research suggests that many aspects of health-related quality of life (HRQol) are affected to the same extent in patients with psoriatic arthritis and rheumatoid arthritis (Husted et al., 2001, Arthritis Care and Research, 45:151-8). Psoriatic arthritis carries a significant economic burden, both in terms of direct costs (costs spent on medications, hospital treatment, informal care and over-the-counter medications) and indirect costs (associated with lost productivity at work) (Ackermann & Kavanaugh, 2008, Pharmacoeconomics, 26(2):121-9).

[0008] Psoriatic arthritis is an inflammatory disorder of the skin that can develop in individuals with psoriasis (Shbeeb et al., 2000, J Rheumatol., 27:1247-50). Psoriatic arthritis typically develops in patients after the onset of psoriasis (Gladman et al., 2006, Annals of the Rheumatic Diseases, 65(Suppl.III):iii12-iii24). The average age of patients diagnosed with psoriatic arthritis is 41 years, with men (20-39 years) being diagnosed at a younger age than women (40-59 years) (Shbeed et al., 2000, J Rheumatol., 27:1247-50). Each year, 3 to 8 new cases of psoriatic arthritis are diagnosed per 100,000 people (Gladman et al., 2005, Annals of the Rheumatic Diseases, 64(Suppl II):ii14-ii17).

[0009] Certain genes have been linked to psoriatic arthritis, particularly the HLA-B27 (human leukocyte antigen) gene, which is present in approximately 50% of psoriatic arthritis patients and only 3-18% of the general Western population (Gladman et al., 2005, Annals of the Rheumatic Diseases, 64(Suppl II):ii14-ii17; Salvarani & Fries, 2009, World J. Gastroenterol., 15(20):2449-55).

[0010] However, environmental factors may also precipitate disease onset.Risk factors associated with psoriatic arthritis include psoriasis involving the scalp, buttocks area, more than three affected areas, nail dystrophy, recent oral ulcers, and trauma requiring treatment (Ogdie & Gelfand, 2010, Arch. Dermatol. 146(7):785-8; Pattison et al., 2008, Ann. Rheum. Dis., 67(5):672-6).

[0011] There is a strong association between psoriasis, psoriatic arthritis and obesity. (Russolillo et al., 2013, J. Rheumatol., 52:62-67.) In 80% of cases of psoriatic arthritis, the arthritis develops after the appearance of psoriasis.

[0012] Symptoms of psoriatic arthritis include, but are not limited to, stiffness, pain, tenderness, swelling and tingling, usually in hands or feet, but sometimes in one or more joints of wrists, ankles, knees or hips; swelling of fingers or toes (dactylitis), which may cause a "sausage" appearance; reduced ability to move; nail changes, such as pitting or separation from the nail bed, which causes dysfunction, pain and emotional stress; redness and pain in eyes (uveitis); fatigue and morning stiffness (in affected joints); tenderness, pain and swelling of tendons (enthesis).Psoriatic arthritis may affect a few joints (oligoarthritis) or a large number of joints (polyarthritis) and / or spine.

[0013] People with symptoms of psoriatic arthritis, especially those with psoriasis or a family history of psoriatic arthritis, should see a specialist (e.g., a rheumatologist) as the symptoms may resemble those seen in other forms of joint disease (e.g., rheumatoid arthritis, gout, reactive arthritis) (Conaghan & Coates, 2009, The Practioner, 253(1724):15-18). Diagnosis is based on symptoms, medical history, physical exam, blood test results, and x-ray results (Conaghan & Coates, 2009, The Practioner, 253(1724);15-18).

[0014] Mild cases of psoriatic arthritis are usually treated with nonsteroidal anti-inflammatory drugs (NSAIDs), low doses of oral steroids or steroid injections into painful joints. (Mease, 2011, Ann. Rheum. Dis., 70(Suppl 1):i77-i84.) More severe psoriatic arthritis is often treated with disease-modifying antirheumatic drugs (DMARDs). (Weger, 2010, British Journal of Pharmacology, 160:810-20.) More recently, biologic agents have become available, including anti-tumor necrosis factor alpha antibodies (TNFα blockers). (Weger, 2010, British Journal of Pharmacology, 160:810-20.) Clinical evidence has shown that minimal disease activity was achieved in 64% of patients treated with TNF inhibitors. This means that a significant proportion of patients (36%) did not achieve this goal. (Haddad A et al. Arthritis Care Res.2015;67, 842-7).

[0015] Some subjects do not respond to previously known therapies, do not maintain a clinical response (defined as reaching the American College of Rheumatology 20% response criteria (ACR20)), or are contraindicated or intolerant to these drugs. The availability of effective drugs for psoriatic arthritis with alternative mechanisms of action would improve treatment for patients, especially those who have not benefited from, lost efficacy, or could not use TNF inhibitors for safety or tolerability reasons (Mease P, Curr Opin Rheumatol. 2015, 27:127-33). The ACR score is a scale that measures symptoms such as joint effects associated with psoriatic arthritis and rheumatoid arthritis, so improvement in the ACR score is relevant for the treatment of both psoriatic arthritis and rheumatoid arthritis.

[0016] Breakthroughs in understanding the immunopathogenesis of psoriatic arthritis have led to novel therapies beyond TNF inhibitors. These therapies are summarized in Sritheran and Ying Leung, Ther. Adv. Musculoskel. Dis, 2015, 7(5), 173-186. Table 1 in this paper shows the ACR and PASI scores of the various treatments.

[0017] Drugs that inhibit IL-17 and IL-23 have shown significant benefit in psoriasis, and emerging studies have also shown benefit in psoriatic arthritis and ankylosing spondylitis (Mease P, Curr Opin Rheumatol 2015, 27:127-33). Biological therapies targeting IL-17A have been developed, including the anti-IL-17A antibodies, secukinumab and ixekizumab, which are currently in phase III clinical trials for psoriatic arthritis. Results of a phase II clinical trial of secukinumab in psoriatic arthritis are described in Mease et al., 2015, N Engl J Med, 373, 14, 1329-1339, and in ankylosing spondylitis, Baeten et al., N.Engl.J.Med, 2015, 373(26), 2534-48. The results of a phase III clinical trial of ixekizumab in psoriatic arthritis are described in Mease et al., 2015, ACR Abstract number 977. Brodalumab is an anti-IL-17RA monoclonal antibody that blocks the activity of IL-17A, IL-17F and IL-17E (IL-25) by targeting IL-17RA. The results of a phase II clinical trial of brodalumab in psoriatic arthritis are described in Mease et al., 2015, N Engl J Med, 370, 24, 2295-2306. The efficacy of current therapy at week 24 is about 60%, about 40% and about 20% for ACR20, ACR50 and ACR70, respectively, with PASI75 being about 65% (Table 1 in Sritheran and Ying Leung, Ther. Adv. Musculoskel. Dis., 2015, 7(5), 173-186). [Prior art documents] [Non-patent literature]

[0018] [Non-Patent Document 1] Fossiez et al., 1998, Int.Rev.Immunol.16,541-551 [Non-Patent Document 2] Yao et al., 1997, Cytokine, 9, 794-800 [Non-Patent Document 3] Toy et al., 2006, J. Immunol. 177(11);36-39 [Non-Patent Document 4] Weaver et al., 2006, Immunity, 24, 677-688 [Non-Patent Document 5] Langowsik et al., 2006, 442, 461-465 [Non-Patent Document 6] Iwakura and Ishigame, 2006, J. Clin. Invest. 116, 5, 1218-1222 [Non-Patent Document 7] Dumont, 2003, Expert Opin.Ther.Patents, 13,287-303 [Non-Patent Document 8] Kolls and Linden 2004, Immunity, 21, 467-476 [Non-Patent Document 9] Hymowitz et al., 2001, EMBO J.20(19), 5332-5341 [Non-Patent Document 10] Kuestner et al., 2007, Journal of Immunology, 179, 5462-5473 [Non-Patent Document 11] Hot et al., 2011, Ann. Rheumatic Dis., 70, 341-348 [Non-Patent Document 12] Wright et al., 2008, J. Immunol. 181:2799-2805 [Non-Patent Document 13] Gaffen 2008, Cytokine.43:402-407 [Non-Patent Document 14] Schett et al., 2011, Arthritis Research and Therapy, 13 Suppl.1:S4 [Non-Patent Document 15] Husted et al., 2001, Arthritis Care and Research, 45:151-8 [Non-Patent Document 16] Picchianti-Diamaniら, 2010, Qual. Life Res., 19:821-6

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[0019] The present invention relates to antibody molecules having specificity for antigenic determinants of both IL-17A and IL-17F, their therapeutic use in the treatment of skin and rheumatic diseases (e.g. psoriatic arthritis), and methods for producing the antibody molecules. In one example, the antibodies of the invention may be used to treat skin conditions (e.g., but not limited to, psoriasis, atopic dermatitis, discoid lupus erythematosus, alopecia areata, autoimmune urticaria, bullous pemphigoid, dermatitis herpetiformis, hidradenitis suppurativa, linear IgA bullous dermatosis, morphea, pemphigus vulgaris, pyoderma gangrenosum) and / or rheumatic conditions (e.g., but not limited to, psoriatic arthritis, axial spondyloarthritis including non-radiographically evident axial spondyloarthritis and ankylosing spondylitis, systemic lupus erythematosus (SLE), rheumatoid arthritis, vasculitis, Sjogren's syndrome (extraglandular), juvenile idiopathic arthritis, granulomatosis, Behcet's disease (mucocutaneous), antiphospholipid syndrome, giant cell arteritis, scleroderma, polyarteritis nodosa, Behcet's disease (thrombosis), and Takayasu's disease). In one example, the antibodies of the present invention may be used to treat psoriatic arthritis. Neutralizing antibodies that bind both IL-17A and IL-17F (e.g., bimekizumab) may provide significant improvements in both the speed and magnitude of clinical benefit compared to existing psoriatic arthritis treatments. For example, they may produce comparable or even improved clinical scores by week 8. Suitable clinical scores include American College of Rheumatology (ACR) 20 / 50 / 70 responses for joints, skin, clinical features of psoriasis, and Psoriasis Area and Severity Index ("PASI") 50 / 75 / 90 responses. For example, these antibodies may increase the number of patients who reach ACR20, ACR50, ACR70 and PASI75 by more than 60%, 40%, 20% and 65%, respectively (average response rate). It may even increase by 60-95%, 40-60%, 20-40% and 80-100% the number of patients achieving ACR20, ACR50, ACR70 and PASI75 at week 8 or week 12. For example, these may be close to 80%, 60%, 40%, 90% or close to 100%, respectively.The speed of achieving a beneficial response in subjects administered the antibodies described herein is also remarkable. For example, in various embodiments, subjects reach ACR20 or ACR50 (or PASI20 or PASI50) within 4 weeks (e.g., within 3 weeks or within 2 weeks) of the first administration. Furthermore, in various embodiments, the beneficial response to the methods described herein can be sustained for a significant period of time. For example, a subject administered three doses of an anti-IL-17A / F antibody described herein (e.g., on days 0, 21, and 42) showed a near maximal response at week 20. Thus, in various aspects, the methods described herein can achieve a biological response in subjects at week 8 or 12 that declines to 10% or less, 20% or less, 30% or less, 40% or less, 50% or less at week 20. In one example, the antibodies of the invention can be used to treat any of the symptoms of psoriatic arthritis, including, but not limited to, dactylitis, enthesitis, nail dystrophy, skin conditions, signs and symptoms of peripheral arthritis, axial disease and the structural progression of the disease. In one example, the antibodies of the invention may be used to prevent the onset of psoriatic arthritis or other conditions in patients with psoriasis.

[0020] The present invention further provides the use of an antibody molecule of the present invention in the manufacture of a medicament for the treatment or prevention of a pathological disorder mediated by IL-17A and / or IL-17F or associated with increased levels of IL-17A and / or IL-17F. Preferably, the pathological disorder may be one of the medical indications described herein. In one embodiment, the pathological disorder may comprise psoriatic arthritis. In other embodiments, the pathological disorder may comprise psoriasis, rheumatoid arthritis, and / or arthritis. In various embodiments, the pathological disorder is ankylosing spondylitis. In various embodiments, the pathological disorder is axial spondyloarthritis or radiographically silent axial spondyloarthritis.

[0021] The antibody molecules of the present invention may be utilized in any therapy in which it is desirable to reduce the effect of IL-17A and / or IL-17F in the human or animal body. IL-17A and / or IL-17F may be circulating in the body or may be localized to particular sites in the body, for example sites of inflammation, and present at undesirably high levels.

[0022] In one embodiment, the invention provides a method of treating a human or animal subject suffering from, or at risk of, an IL-17A and / or IL-17F mediated disorder, the method comprising administering to the subject an effective amount of an antibody molecule of the invention.

[0023] In one embodiment, the present invention further provides an antibody molecule of the present invention, in particular a neutralizing antibody that binds human IL-17A and human IL-17F, for use in the treatment of a human or animal subject suffering from or at risk of a disorder mediated by IL-17A and / or IL-17F. Preferably, the pathological disorder may be one of the medical indications described herein. In one embodiment, the pathological disorder may comprise psoriatic arthritis. In other embodiments, the pathological disorder may comprise psoriasis, rheumatoid arthritis, and / or arthritis. In one embodiment, the pathological disorder may comprise ankylosing spondylitis. In one embodiment, the pathological disorder may comprise axial spondyloarthritis or radiographically silent axial spondyloarthritis.

[0024] Thus, in one embodiment, the invention provides an antibody molecule of the invention, in particular a neutralizing antibody that binds human IL-17A and human IL-17F, for use in the treatment of psoriatic arthritis, psoriasis, rheumatoid arthritis, arthritis, axial spondyloarthritis, ankylosing spondylitis or non-radiographically evident axial spondyloarthritis.

[0025] "Psoriasis" encompasses the skin-related components (i.e., symptoms) of the disorder, including, but not limited to, plaque psoriasis, pustular psoriasis, generalized pustular psoriasis, palmoplantar psoriasis, scalp psoriasis, guttate psoriasis, erythrodermic psoriasis, inverse psoriasis, acrodermatitis continua, SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome, hidradenitis suppurativa, and DITRA (deficiency of IL-36 receptor [IL-36R] antagonist) / DIRA (deficiency of interleukin 1 (IL-1) receptor antagonist). The severity of psoriasis may vary, and may be selected, for example, from mild, mild-to-moderate, moderate, severe, and moderate-to-severe psoriasis.

[0026] The antibody molecules of the present invention may be used diagnostically, for example for the in vivo diagnosis and imaging of disease states in which IL-17A and / or IL-17F is involved.

[0027] The present invention provides a method of treating psoriatic arthritis in a human comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F. In one embodiment, the antibody specifically binds to an epitope of human IL-17F, the epitope comprising one or more residues selected from ARG47, ARG73, LEU75 and ILE86 of SEQ ID NO: 27. In the same or a different embodiment, the antibody specifically binds to an epitope of human IL-17A, the epitope comprising one or more residues selected from TYR44, ASN45, ARG46, TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO: 28. In various embodiments, the antibody binds to the same epitope of human IL-17A, human IL-17F or human IL-17A / F heterodimer as a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10. Optionally, the antibody is a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10, and cross-blocks neutralizing antibodies that bind human IL-17A and human IL-17F. In various embodiments, the antibody comprises a light chain variable domain and a heavy chain variable domain, and the light chain variable domain comprises the sequence given in SEQ ID NO: 10. In one aspect, the antibody is bimekizumab. Optionally, the antibody is administered as a pharmaceutical composition. In various embodiments, the antibody is administered subcutaneously or intravenously.

[0028] In any of the embodiments of the method of treating psoriatic arthritis in a human, comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F, the human optionally has a diagnosis of adult-onset psoriatic arthritis. Optionally, the human is at least 18 years old and / or has been diagnosed at least 6 months prior to administration of the antibody. Also, optionally, the human has been diagnosed based on CASPAR criteria. In any of the above-mentioned embodiments, the human has active arthritis. This is typically defined as 3 or more tender joints and 3 or more swollen joints. The patient may have concurrent or coexisting psoriasis and / or a history of psoriasis. For example, the human optionally has active psoriatic lesions or a history of psoriatic lesions.

[0029] In any of the embodiments of the methods of treating psoriatic arthritis, psoriasis, rheumatoid arthritis, or axial spondylitis, including ankylosing spondylitis and non-radiographically evident spondylitis in a human comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F described herein, the antibody may be administered as a monotherapy.

[0030] In any of the embodiments of the methods of treating psoriatic arthritis, psoriasis, rheumatoid arthritis, or axial spondylitis, including ankylosing spondylitis and non-radiographically evident spondylitis in a human comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F as described herein, the human is optionally biologically naive, i.e., has not been previously treated with a biological agent, e.g., a TNFα inhibitor, e.g., an anti-TNF antibody.

[0031] In any embodiment of the method of treating psoriatic arthritis in a human comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F as described herein, the human is optionally inadequately responsive to at least one non-biologic disease-modifying antirheumatic drug ("DMARD") and / or one or more approved biologic DMARDs (e.g., a TNF inhibitor, e.g., an anti-TNF antibody, e.g., infliximab or adalimumab, or a soluble TNF receptor, e.g., etanercept). Examples of non-biologic DMARDs include sulfasalazine, methotrexate, cyclosporine, hydorzychloroquine, azathioprine, and leflunomide. Optionally, the human is inadequately responsive to at least one nonsteroidal anti-inflammatory drug (NSAID). Examples of suitable NSAIDs include, but are not limited to, propionic acid derivatives, acetic acid derivatives, enolic acid derivatives, fenamic acid derivatives, Cox inhibitors, ibuprofen, fenoprofen, and aspirin.

[0032] The present invention also provides a method of treating psoriatic arthritis in a human being concomitantly treated with methotrexate or other non-biologic DMARDs (e.g., leflunomide) or nonsteroidal anti-inflammatory drugs (NSAIDs) and / or steroids, comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F. In various embodiments, the antibody specifically binds to an epitope of human IL-17F, the epitope comprising one or more residues selected from ARG47, ARG73, LEU75, and ILE86 of SEQ ID NO:27. In the same or different embodiment, the antibody specifically binds to an epitope of human IL-17A, the epitope comprising one or more residues selected from TYR44, ASN45, ARG46, TRP51, ASN52, HIS54, and ASP84 of SEQ ID NO:28. Optionally, the antibody binds to the same epitope of human IL-17A, human IL-17F, or human IL-17A / F heterodimer as a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10. Also, optionally, the antibody cross-blocks a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10 that binds to human IL-17A and human IL-17F. In various aspects of the method, the antibody comprises a light chain variable domain and a heavy chain variable domain, the light chain variable domain comprising the sequence given in SEQ ID NO: 10. In a preferred embodiment, the antibody is bimekizumab. The antibody may be administered as a pharmaceutical composition. The antibody is optionally administered subcutaneously or intravenously.

[0033] The invention includes a method of treating psoriatic arthritis in a human, comprising administering to the human a therapeutically effective amount of a neutralizing antibody that binds human IL-17A and human IL-17F. In various embodiments, the antibody specifically binds to an epitope of human IL-17F, the epitope comprising one or more residues selected from ARG47, ARG73, LEU75 and ILE86 of SEQ ID NO: 27. In the same or different embodiments, the antibody specifically binds to an epitope of human IL-17A, the epitope comprising one or more residues selected from TYR44, ASN45, ARG46, TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO: 28. Optionally, the antibody binds to the same epitope of human IL-17A, human IL-17F or human IL-17A / F heterodimer as a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10. In various embodiments, the antibody is a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10, and cross-blocks neutralizing antibodies that bind human IL-17A and human IL-17F. In various embodiments, the antibody comprises a light chain variable domain and a heavy chain variable domain, the light chain variable domain comprising the sequence given in SEQ ID NO: 10. In a preferred embodiment, the antibody is bimekizumab. The antibody is optionally administered as a pharmaceutical composition. The antibody can be administered subcutaneously or intravenously.

[0034] An embodiment of the present invention includes a method of treating psoriatic arthritis in a human patient, comprising administering to the patient a neutralizing antibody that binds human IL-17A and human IL-17F in an amount effective to provide an ACR20 response at week 8 or week 12, an ACR50 response at week 8 or week 12, or an ACR70 response at week 8 or week 12 in a population of patients in need of treatment. For example, the amount administered is an amount effective to provide an ACR50 response at week 8 or week 12, or an ACR70 response at week 8 or week 12 in a population of patients. In a preferred embodiment, the amount is an amount effective to provide an ACR70 response at week 8 or week 12 in a population of patients. Alternatively, or in addition, the neutralizing antibody is administered in an amount effective to provide a PASI50 response at week 8 or 12, a PASI75 response at week 8 or 12, or a PASI90 response at week 8 or 12 in a patient population, e.g., a PASI75 response at week 8 or 12, or a PASI90 response at week 8 or 12. In a preferred embodiment, the neutralizing antibody is administered in an amount effective to provide a PASI90 response or a PASI100 response at week 8 or 12 in a patient population. Typically, the response is sustained such that the ACR50, ACR70 and / or PASI response may be maintained until week 16, week 20, week 24 or later. In various embodiments, the antibody specifically binds to an epitope of IL-17F comprising one or more residues selected from ARG47, ARG73, LEU75, and ILE86 of SEQ ID NO: 27, and / or specifically binds to an epitope of human IL-17A comprising one or more residues selected from TYR44, ASN45, ARG46, TRP51, ASN52, HIS54, and ASP84 of SEQ ID NO: 28. In various embodiments, the antibody binds to the same epitope of human IL-17A, human IL-17F, or human IL-17A / F heterodimer as a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10.In various embodiments, the antibody is a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10, and cross-blocks neutralizing antibodies that bind human IL-17A and human IL-17F. Optionally, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises the sequence given in SEQ ID NO: 10. In a preferred embodiment, the antibody is bimekizumab. The antibody is optionally administered as a pharmaceutical composition. The antibody can be administered subcutaneously or intravenously.

[0035] The present invention further provides a method for reducing psoriasis in a human, comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F. In various embodiments, the psoriasis is plaque psoriasis. In various embodiments, the psoriasis is mild to moderate plaque psoriasis. In various embodiments, the psoriasis is moderate to severe plaque psoriasis. Optionally, the reduction of plaque psoriasis is measured by PASI criteria. In various embodiments, the antibody specifically binds to an epitope of human IL-17F, the epitope comprising one or more residues selected from ARG47, ARG73, LEU75 and ILE86 of SEQ ID NO:27. Alternatively or additionally, the antibody specifically binds to an epitope of human IL-17A, which epitope comprises one or more residues selected from TYR44, ASN45, ARG46, TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO:28. In various aspects, the antibody binds to the same epitope of human IL-17A, human IL-17F or human IL-17A / F heterodimer as a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO:11 and a light chain comprising the sequence given in SEQ ID NO:10. Optionally, the antibody cross-blocks a neutralizing antibody that binds human IL-17A and human IL-17F, the neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO:11 and a light chain comprising the sequence given in SEQ ID NO:10. In various embodiments, the antibody comprises a light chain variable domain and a heavy chain variable domain, the light chain variable domain comprising the sequence given in SEQ ID NO:10. In a preferred embodiment, the antibody is bimekizumab.The antibody may be administered as a pharmaceutical composition.The antibody may be administered subcutaneously or intravenously.In one or more embodiments, the psoriasis treated by the method of the present invention may be selected from psoriasis vulgaris, pustular psoriasis, generalized pustular psoriasis, palmoplantar psoriasis, nail psoriasis, scalp psoriasis, guttate psoriasis, erythrodermic psoriasis, and inverse psoriasis.

[0036] The invention also includes a method of treating psoriasis in a human comprising administering to the human a therapeutically effective amount of a neutralizing antibody that binds human IL-17A and human IL-17F.

[0037] The invention further provides a method of treating psoriasis in a human patient comprising administering to the patient a neutralizing antibody that binds human IL-17A and human IL-17F in an amount effective to provide a PASI75 response at week 8 or 12, or an amount effective to provide a PASI90 response at week 8 or 12. In a preferred embodiment, the neutralizing antibody is administered in an amount effective to provide a PASI75 response or a PASI90 response at week 8 or 12 in a population of patients. In various embodiments, the antibody specifically binds to an epitope of IL-17F comprising one or more residues selected from ARG47, ARG73, LEU75, and ILE86 of SEQ ID NO: 27, and / or specifically binds to an epitope of human IL-17A comprising one or more residues selected from TYR44, ASN45, ARG46, TRP51, ASN52, HIS54, and ASP84 of SEQ ID NO: 28. In various embodiments, the antibody binds to the same epitope of human IL-17A, human IL-17F, or human IL-17A / F heterodimer as a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10. In various embodiments, the antibody is a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10, and cross-blocks neutralizing antibodies that bind human IL-17A and human IL-17F. Optionally, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises the sequence given in SEQ ID NO: 10. In a preferred embodiment, the antibody is bimekizumab. The antibody is optionally administered as a pharmaceutical composition. The antibody can be administered subcutaneously or intravenously.

[0038] The method of treating psoriasis optionally includes administering to a human a loading dose of a neutralizing antibody followed by at least one maintenance dose of the antibody. In various embodiments, the loading dose is 80-560 mg and at least one maintenance dose is 40-320 mg. In one aspect of the method, the loading dose is 80 mg and at least one maintenance dose is 40 mg. In another aspect of the method, the loading dose is 160 mg and at least one maintenance dose is 80 mg. In a further aspect, the loading dose is 240 mg and at least one maintenance dose is 160 mg. In a further aspect, the loading dose is 320 mg and at least one maintenance dose is 160 mg. In another aspect, the loading dose is 560 mg and at least one maintenance dose is 320 mg. In various embodiments, the loading dose is administered followed by two maintenance doses. Optionally, a loading dose is administered followed by at least one maintenance dose at three week or four week intervals.

[0039] In any embodiment of the method of treating psoriasis in a human comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F as described herein, the human is optionally inadequately responsive to at least one non-biologic disease-modifying antirheumatic drug ("DMARD") and / or one or more approved biologic DMARDs (e.g., TNF inhibitors, e.g., anti-TNF antibodies, e.g., infliximab or adalimumab, or soluble TNF receptors, e.g., etanercept). Examples of non-biologic DMARDs include sulfasalazine, methotrexate, cyclosporine, hydorzychloroquine, azathioprine, and leflunomide. Optionally, the human is inadequately responsive to at least one nonsteroidal anti-inflammatory drug (NSAID). Examples of suitable NSAIDs include, but are not limited to, propionic acid derivatives, acetic acid derivatives, enolic acid derivatives, fenamic acid derivatives, Cox inhibitors, ibuprofen, fenoprofen, and aspirin.

[0040] The invention also provides a method of treating psoriasis in a human who is being concomitantly treated with methotrexate or other non-biologic DMARDs (e.g., leflunomide) or nonsteroidal anti-inflammatory drugs (NSAIDs) and / or steroids, comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F.

[0041] The present invention further provides a method for reducing joint involvement in a human, comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F. Optionally, the reduction in joint involvement is measured by ACR criteria. In various embodiments, the antibody specifically binds to an epitope of human IL-17F, the epitope comprising one or more residues selected from ARG47, ARG73, LEU75 and ILE86 of SEQ ID NO:27. Alternatively or in addition, the antibody specifically binds to an epitope of human IL-17A, the epitope comprising one or more residues selected from TYR44, ASN45, ARG46, TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO:28. In various embodiments, the antibody binds to the same epitope of human IL-17A, human IL-17F, or human IL-17A / F heterodimer as a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10. In various embodiments, the antibody cross-blocks a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10 that binds to human IL-17A and human IL-17F. Optionally, the antibody comprises a light chain variable domain and a heavy chain variable domain, the light chain variable domain comprising the sequence given in SEQ ID NO: 10. In a preferred embodiment, the antibody is bimekizumab. The antibody may be administered as a pharmaceutical composition. The antibody is optionally administered subcutaneously or intravenously. Such joint effects may also include peripheral joint involvement, including synovitis, enthesitis, and / or dactylitis.

[0042] The present invention provides a method of reducing psoriasis and reducing joint involvement in a human, comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F. In various embodiments, the psoriasis is plaque psoriasis. The reduction in plaque psoriasis is optionally measured by PASI criteria, and / or the reduction in joint involvement is optionally measured by ACR criteria. Alternatively or additionally, the reduction in joint involvement, such as structural progression, may be measured by modified total Sharp score (mTSS). When measured, the reduction in enthesitis or dactylitis may be measured by a decrease in Leeds Enthesitis Index (LEI) and Leeds Dactylitis Index (LDI) scores, respectively. In various aspects, the antibody specifically binds to an epitope of human IL-17F, the epitope comprising one or more residues selected from ARG47, ARG73, LEU75, and ILE86 of SEQ ID NO:27. Alternatively or additionally, the antibody specifically binds to an epitope of human IL-17A, which epitope comprises one or more residues selected from TYR44, ASN45, ARG46, TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO:28. In various embodiments, the antibody binds to the same epitope of human IL-17A, human IL-17F or human IL-17A / F heterodimer as a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO:11 and a light chain comprising the sequence given in SEQ ID NO:10. In various embodiments, the antibody cross-blocks a neutralizing antibody that binds human IL-17A and human IL-17F, the neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO:11 and a light chain comprising the sequence given in SEQ ID NO:10. Optionally, the antibody comprises a light chain variable domain and a heavy chain variable domain, the light chain variable domain comprising the sequence given in SEQ ID NO:10. In a preferred embodiment, the antibody is bimekizumab. The antibody may be administered as a pharmaceutical composition. The antibody is optionally administered subcutaneously or intravenously.

[0043] The invention further provides a method of treating psoriatic arthritis in a human, comprising administering to the human a loading dose of a neutralizing antibody that binds human IL-17A and human IL-17F, followed by at least one maintenance dose of the antibody. Optionally, the loading dose is 80-560 mg and at least one maintenance dose is 40-320 mg. In one aspect of this method, the loading dose is 80 mg and at least one maintenance dose is 40 mg. In another aspect of this method, the loading dose is 160 mg and at least one maintenance dose is 80 mg. In a further aspect, the loading dose is 240 mg and at least one maintenance dose is 160 mg. In a further aspect, the loading dose is 320 mg and at least one maintenance dose is 160 mg. In another aspect, the loading dose is 560 mg and at least one maintenance dose is 320 mg. In various embodiments, the loading dose is administered followed by two maintenance doses. Optionally, after the loading dose is administered, at least one maintenance dose is administered at three week intervals or four week intervals. In various embodiments, the antibody specifically binds to an epitope of human IL-17F, which epitope comprises one or more residues selected from ARG47, ARG73, LEU75 and ILE86 of SEQ ID NO: 27. Alternatively or additionally, the antibody specifically binds to an epitope of human IL-17A, which epitope comprises one or more residues selected from TYR44, ASN45, ARG46, TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO: 28. In various aspects, the antibody binds to the same epitope of human IL-17A, human IL-17F or human IL-17A / F heterodimer as a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10. In various embodiments, the antibody is a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10, and cross-blocks neutralizing antibodies that bind human IL-17A and human IL-17F. In various embodiments, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises the sequence given in SEQ ID NO: 10. In a preferred embodiment, the antibody is bimekizumab.The antibody may be administered as a pharmaceutical composition. The antibody is optionally administered subcutaneously or intravenously.

[0044] One embodiment of the present invention may include a method of treating psoriatic arthritis in a human comprising administering to the human at least one dose of a neutralizing antibody that binds human IL-17A and human IL-17F. In various embodiments, at least one dose is between 40 and 640 mg of antibody. For example, in various aspects, at least one dose is 40 mg of antibody. In various aspects, at least one dose is 80 mg of antibody. In various aspects, at least one dose is 160 mg of antibody. In various aspects, at least one dose is 240 mg of antibody. In various aspects, at least one dose is 320 mg of antibody. In various aspects, at least one dose is 480 mg of antibody. In various aspects, at least one dose is 560 mg of antibody. In various aspects, at least one dose is 640 mg of antibody. In any aspect, the doses are administered at 3 week intervals or 4 week intervals. In any embodiment, the doses are administered at 8 week intervals or 12 week intervals. In any embodiment, the antibody specifically binds to an epitope of human IL-17F, which epitope comprises one or more residues selected from ARG47, ARG73, LEU75 and ILE86 of SEQ ID NO: 27. Alternatively or additionally, the antibody specifically binds to an epitope of human IL-17A, which epitope comprises one or more residues selected from TYR44, ASN45, ARG46, TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO: 28. In various embodiments, the antibody binds to the same epitope of human IL-17A, human IL-17F or human IL-17A / F heterodimer as a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10. In various embodiments, the antibody is a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10, and cross-blocks neutralizing antibodies that bind human IL-17A and human IL-17F. Optionally, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises the sequence given in SEQ ID NO: 10. In a preferred embodiment, the antibody is bimekizumab.The antibody may be administered as a pharmaceutical composition. The antibody is optionally administered subcutaneously or intravenously.

[0045] The present invention further provides a method of treating rheumatoid arthritis in a human comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F. In various aspects, the antibody specifically binds to an epitope of human IL-17F, the epitope comprising one or more residues selected from ARG47, ARG73, LEU75 and ILE86 of SEQ ID NO: 27. Alternatively or additionally, the antibody specifically binds to an epitope of human IL-17A, the epitope comprising one or more residues selected from TYR44, ASN45, ARG46, TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO: 28. In various embodiments, the antibody binds to the same epitope of human IL-17A, human IL-17F or human IL-17A / F heterodimer as a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10. Optionally, the antibody is a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10, and cross-blocks neutralizing antibodies that bind human IL-17A and human IL-17F. In various embodiments, the antibody comprises a light chain variable domain and a heavy chain variable domain, and the light chain variable domain comprises the sequence given in SEQ ID NO: 10. In a preferred aspect, the antibody is bimekizumab. The antibody may be administered as a pharmaceutical composition. The antibody is optionally administered subcutaneously or intravenously.

[0046] In various embodiments of the method of treating rheumatoid arthritis in a human, the human has a diagnosis of adult-onset chronic rheumatoid arthritis, and optionally the human is at least 18 years old. Also, optionally the human has been diagnosed at least 6 months prior to administration of the antibody. In various embodiments, the human has been classified according to the ACR / EULAR 2010 criteria. In various embodiments of the method of treating rheumatoid arthritis in a human, the human has active arthritis. In various aspects of the method of treating rheumatoid arthritis in a human, the human has an inadequate response to at least one non-biologic disease-modifying antirheumatic drug ("DMARD") and / or at least one approved biologic DMARD. Alternatively or additionally, the human may have an inadequate response to at least one nonsteroidal anti-inflammatory drug (NSAID).

[0047] The present invention provides a method of treating rheumatoid arthritis in a human being concomitantly treated with methotrexate or other non-biologic DMARDs (e.g., leflunomide) or nonsteroidal anti-inflammatory drugs (NSAIDs) and / or steroids, comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F. In various embodiments, the antibody specifically binds to an epitope of human IL-17F, the epitope comprising one or more residues selected from ARG47, ARG73, LEU75, and ILE86 of SEQ ID NO:27. Alternatively, or in addition, the antibody specifically binds to an epitope of human IL-17A, the epitope comprising one or more residues selected from TYR44, ASN45, ARG46, TRP51, ASN52, HIS54, and ASP84 of SEQ ID NO:28. Optionally, the antibody binds to the same epitope of human IL-17A, human IL-17F, or human IL-17A / F heterodimer as a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10. In various embodiments, the antibody cross-blocks a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10 that binds to human IL-17A and human IL-17F. In various embodiments, the antibody comprises a light chain variable domain and a heavy chain variable domain, the light chain variable domain comprising the sequence given in SEQ ID NO: 10. In a preferred embodiment, the antibody is bimekizumab. The antibody may be administered as a pharmaceutical composition. The antibody is optionally administered subcutaneously or intravenously.

[0048] The present invention includes a method of treating rheumatoid arthritis in a human comprising administering to the human a therapeutically effective amount of a neutralizing antibody that binds human IL-17A and human IL-17F. In various embodiments, the antibody specifically binds to an epitope of human IL-17F, the epitope comprising one or more residues selected from ARG47, ARG73, LEU75, and ILE86 of SEQ ID NO: 27. Alternatively, or in addition, the antibody specifically binds to an epitope of human IL-17A, the epitope comprising one or more residues selected from TYR44, ASN45, ARG46, TRP51, ASN52, HIS54, and ASP84 of SEQ ID NO: 28. In various embodiments, the antibody binds to the same epitope of human IL-17A, human IL-17F, or human IL-17A / F heterodimer as a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10. In various embodiments, the antibody cross-blocks a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10 that binds human IL-17A and human IL-17F. Optionally, the antibody comprises a light chain variable domain and a heavy chain variable domain, the light chain variable domain comprising the sequence given in SEQ ID NO: 10. In a preferred embodiment, the antibody is bimekizumab. The antibody may be administered as a pharmaceutical composition. The antibody is optionally administered subcutaneously or intravenously.

[0049] The present invention further includes a method of treating rheumatoid arthritis in a human patient comprising administering to the patient a neutralizing antibody that binds human IL-17A and human IL-17F in an amount effective to provide an ACR20 response at week 8 or week 12, an ACR50 response at week 8 or week 12, or an ACR70 response at week 8 or week 12 in a population of patients in need of treatment. For example, in various embodiments, the amount administered is an amount effective to provide an ACR50 response at week 8 or week 12, or an ACR70 response at week 8 or week 12 in a population of patients in need of treatment. In preferred embodiments, the amount is an amount effective to provide an ACR70 response at week 8 or week 12 in a population of patients in need of treatment. In various aspects, the antibody specifically binds to an epitope of human IL-17F, which epitope comprises one or more residues selected from ARG47, ARG73, LEU75, and ILE86 of SEQ ID NO: 27. Alternatively, or in addition, the antibody specifically binds to an epitope of human IL-17A, which epitope comprises one or more residues selected from TYR44, ASN45, ARG46, TRP51, ASN52, HIS54, and ASP84 of SEQ ID NO: 28. In various embodiments, the antibody binds to the same epitope of human IL-17A, human IL-17F, or human IL-17A / F heterodimer as a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10. In various embodiments, the antibody is a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10, and cross-blocks neutralizing antibodies that bind human IL-17A and human IL-17F. Optionally, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises the sequence given in SEQ ID NO: 10. In a preferred aspect of the invention, the antibody is bimekizumab. The antibody may be administered as a pharmaceutical composition. The antibody is optionally administered subcutaneously or intravenously.

[0050] The invention further provides a method of treating rheumatoid arthritis in a human, comprising administering to the human a loading dose of a neutralizing antibody that binds human IL-17A and human IL-17F, followed by at least one maintenance dose of the antibody. In various aspects, the loading dose is 80-560 mg and at least one maintenance dose is 40-320 mg. For example, in various embodiments, the loading dose is 80 mg and at least one maintenance dose is 40 mg, the loading dose is 160 mg, at least one maintenance dose is 80 mg, the loading dose is 240 mg, at least one maintenance dose is 160 mg, the loading dose is 320 mg, at least one maintenance dose is 160 mg, or the loading dose is 560 mg and at least one maintenance dose is 320 mg. Optionally, after the loading dose is administered, two maintenance doses are administered. Optionally, the loading dose is followed by at least one maintenance dose at three week intervals or four week intervals. In various embodiments, the antibody specifically binds to an epitope of human IL-17F, the epitope comprising one or more residues selected from ARG47, ARG73, LEU75 and ILE86 of SEQ ID NO: 27. Alternatively or additionally, the antibody specifically binds to an epitope of human IL-17A, the epitope comprising one or more residues selected from TYR44, ASN45, ARG46, TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO: 28. In various aspects, the antibody binds to the same epitope of human IL-17A, human IL-17F or human IL-17A / F heterodimer as a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10. In various embodiments, the antibody is a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10, and cross-blocks neutralizing antibodies that bind human IL-17A and human IL-17F. Optionally, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises the sequence given in SEQ ID NO: 10. In a preferred embodiment, the antibody is bimekizumab. The antibody may be administered as a pharmaceutical composition.The antibody is optionally administered subcutaneously or intravenously.

[0051] The invention further provides a method of treating rheumatoid arthritis in a human, comprising administering to the human at least one dose of a neutralizing antibody that binds human IL-17A and human IL-17F. Optionally, the at least one dose is 40-640 mg of antibody. For example, the at least one dose is 40 mg of antibody, or 80 mg of antibody, or 160 mg of antibody, or 240 mg of antibody, or 320 mg of antibody, or 480 mg of antibody, or 560 mg of antibody, or 640 mg of antibody. Optionally, the doses are administered at intervals of 3 or 4 weeks. In various embodiments, the antibody specifically binds to an epitope of human IL-17F, the epitope comprising one or more residues selected from ARG47, ARG73, LEU75, and ILE86 of SEQ ID NO:27. Alternatively or additionally, the antibody specifically binds to an epitope of human IL-17A, which epitope comprises one or more residues selected from TYR44, ASN45, ARG46, TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO:28. In various embodiments, the antibody binds to the same epitope of human IL-17A, human IL-17F or human IL-17A / F heterodimer as a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO:11 and a light chain comprising the sequence given in SEQ ID NO:10. In various embodiments, the antibody cross-blocks a neutralizing antibody that binds human IL-17A and human IL-17F, the neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO:11 and a light chain comprising the sequence given in SEQ ID NO:10. Optionally, the antibody comprises a light chain variable domain and a heavy chain variable domain, the light chain variable domain comprising the sequence given in SEQ ID NO:10. In a preferred embodiment, the antibody is bimekizumab. The antibody may be administered as a pharmaceutical composition. The antibody is optionally administered subcutaneously or intravenously.

[0052] The present invention further provides a method for treating axial spondyloarthritis (e.g., ankylosing spondylitis), comprising administering to a human a neutralizing antibody that binds human IL-17A and human IL-17F. Axial spondyloarthritis refers to a group of inflammatory arthritic diseases that primarily affect the spine and other joints, causing inflammation and chronic pain in the spinal cord and sacral tubers, ultimately resulting in syndrome formation, and includes ankylosing spondylitis and non-radiographic spondylitis. Thus, the present invention provides a method for treating (e.g., ameliorating symptoms, reducing progression of) ankylosing spondylitis and / or non-radiographic axial spondyloarthritis (nr-axSpA). In various embodiments, the antibody specifically binds to an epitope of human IL-17F, the epitope comprising one or more residues selected from ARG47, ARG73, LEU75, and ILE86 of SEQ ID NO:27. Alternatively or additionally, the antibody specifically binds to an epitope of human IL-17A, which epitope comprises one or more residues selected from TYR44, ASN45, ARG46, TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO:28. In various embodiments, the antibody binds to the same epitope of human IL-17A, human IL-17F or human IL-17A / F heterodimer as a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO:11 and a light chain comprising the sequence given in SEQ ID NO:10. In various embodiments, the antibody cross-blocks a neutralizing antibody that binds human IL-17A and human IL-17F, the neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO:11 and a light chain comprising the sequence given in SEQ ID NO:10. Optionally, the antibody comprises a light chain variable domain and a heavy chain variable domain, the light chain variable domain comprising the sequence given in SEQ ID NO:10. In a preferred embodiment, the antibody is bimekizumab. The antibody may be administered as a pharmaceutical composition. The antibody is optionally administered subcutaneously or intravenously. Preferably, the antibody is administered in a therapeutically effective amount. Any of the administration regimens described herein are suitable for use in the context of this method.For example, in various embodiments, the method includes administering 16 mg, 64 mg, 160 mg, or 320 mg of the antibody to the subject every 4 weeks, optionally for a treatment period of 12 weeks, 36 weeks, 48 ​​weeks, or 52 days. The amount and timing of administration is preferably sufficient to achieve at least an ASAS20 response (e.g., ASAS40) at week 2, 4, 8, or 12 of treatment. Methods for ASAS scoring and assessing the severity of axial spondylitis are further described in Ann Rheum Dis 2009;68;ii1-ii44. In one example, the amount and timing of administration is preferably sufficient to achieve an ASAS40 at week 12 of treatment. In one example, the amount and timing of administration is preferably sufficient to achieve at least 30%, or at least 40%, or at least 45%, or at least 50% of the subjects reach an ASAS40 response at week 12 of treatment. In various embodiments, the invention provides methods of inhibiting (e.g., slowing the progression of) periosteal bone formation in a human, e.g., a human suffering from spondylitis (e.g., ankylosing spondylitis), by administering a neutralizing antibody that binds human IL-17A and human IL-17F as described herein. Periosteal bone formation is assessed, e.g., by radiography.

[0053] In any of the embodiments of the method of treating axial spondyloarthritis, including ankylosing spondylitis and nr-axSpA, in a human, comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F, the human optionally has a diagnosis of adult-onset ankylosing spondylitis or nr-axSpA. Optionally, the human is at least 18 years old and / or was diagnosed at least 6 months prior to administration of the antibody. Also, optionally, the human has been classified according to the modified New York criteria or ASAS criteria. In any of the above embodiments, the human has active axial arthritis.

[0054] In any of the embodiments of the methods of treating ankylosing spondylitis and / or axial spondyloarthritis, including nr-axSpA, in a human comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F described herein, the human optionally has an inadequate response to at least one nonsteroidal anti-inflammatory drug ("NSAID") and / or one or more approved biologic DMARDs (e.g., a TNF inhibitor, e.g., an anti-TNF antibody, examples of which include infliximab or adalimumab, or a soluble TNF receptor, e.g., etanercept).

[0055] The invention also provides a method of treating ankylosing spondylitis and / or axial spondyloarthritis, including nr-axSpA, in a human being concomitantly treated with a nonsteroidal anti-inflammatory drug (NSAID), comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F.

[0056] The invention also includes a method of treating psoriatic arthritis comprising administering to a human an amount of a neutralizing antibody that binds human IL-17A and human IL-17F effective to cause at least 50% of the subjects to achieve an ACR20 response at week 8 or week 12. For example, the amount is effective to cause at least 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64 or 65% of the subjects to achieve an ACR20 response at week 8 or week 12. In one example, the amount is effective to cause at least 50-90%, or 60-90%, or 63-91% of the subjects to achieve an ACR20 response at week 8 or week 12. In one example, the amount is effective for at least 40%, at least 45%, at least 50% or at least 55% of the subjects to reach an ACR50 response at week 8 or week 12 or week 20. Alternatively or additionally, the amount of neutralizing antibody is effective for at least 80% of the subjects to reach PASI75 at week 8 or week 12. For example, the amount is effective for 80-100% of the subjects to reach PASI75 at week 8 or week 12, e.g., at least 80%, 85%, 90%, 95% or 99% of the subjects to reach PASI75 at week 8 or week 12. In various embodiments, the amount of neutralizing antibody is an amount effective to cause at least 60% of subjects to achieve a PASI90 or PASI100 response at week 8 or week 12, e.g., an amount effective to cause 60-100% or 62-96% of subjects to achieve a PASI90 response at week 8 or week 12 (e.g., an amount effective to cause at least 60, 65, 70, 75, 80, 85, 90, 95 or 96% of subjects to achieve a PASI90 response at week 8 or week 12). [Brief description of the drawings]

[0057] [Figure 1] Nucleotide and amino acid sequences. [Diagram 2] CASPAR criteria [Figure 3a] PASI50 / 75 / 90 response at week 8 for cohorts 1-4 as described in Example 1. [Figure 3b]Time course of PASI90 response (PA0007) from the first dose (Day 0) to Day 140 (Week 20) ​​of Example 1. [Figure 4] Secukinumab Future 1 results: PASI. [Figure 5a] ACR20 / 50 / 70 response at week 8 for cohorts 1-4 as described in Example 1. [Figure 5b-d] Summary plot of ACR20 / 50 / 70 response rates from PA0007 from study start (Day 0) to Day 140 (Week 20) ​​(Example 1). [Figure 6] Secukinumab Future 1 results and Cimzia RAPID PSA results: ACR20. [Figure 7] Table summarizing the Bayesian analysis. [Figure 8]Table summarizing ACR20 response at week 8 in psoriatic arthritis for enrolled anti-TNF or phase III results. References 1.Mease PJ, Gladman DD, Ritchlin CT, Ruderman EM, Steinfeld SD, Choy EH et al. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trial.Arthritis and rheumatism.2005;52(10):3279-89.2. Kavanaugh A, McInnes I, Mease P, Krueger GG, Gladman D, Gomez-Reino J, et al. Golimumab, a new human tumor necrosis factor alpha antibody, administered every four weeks as a subcutaneous injection in psoriatic arthritis: Twenty-four-week efficacy and safety results of a randomized, placebo-controlled study. Arthritis and rheumatism. 2009;60(4):976-86. 3.Mease PJ, Fleischmann R, Deodhar AA, Wollenhaupt J, Khraishi M, Kielar D, et al. Effect of certolizumab pegol on signs and symptoms in patients with psoriatic arthritis:24-week results of a Phase 3 double-blind randomized placebo-controlled study (RAPID-PsA).Annals of the rheumatic diseases.2014;73(1):48-55.4.McInnes IB, Mease PJ, Kirkham B, Kavanaugh A, Ritchlin CT, Rahman P, et al. Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis(FUTURE 2): a randomized, double-blind, placebo-controlled, phase 3 trial.Lancet.2015;386(9999):1137-46.5.McInnes IB, Kavanaugh A, Gottlieb AB, Puig L, Rahman P, Ritchlin C, et al. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis:1 year results of the phase 3,multicentre,double-blind,placebo-controlled PSUMMIT 1 trial.Lancet.2013;382(9894):780-9. [Figure 9] Targeted CA028_0496.g3 PK concentrations. [Figure 10] Summary PK plots for predicted SC dosing showing that after a loading dose of 320, 160 mg Q4W or ≥160 mg Q4W dosing can reach plasma concentrations tested with PA0007 at the top 3 doses. [Figure 11] Percentage change from baseline in Lesion Severity Score in Study UP0008. [Figure 12] Percent change from baseline in PASI in Study UP0008 [Figure 13] Table summarizing PASI90 responses in study UP0008 [Figure 14a-c]Mean percent change from baseline in (a) LSS, (b) PASI, and (c) PGA in placebo and bimekizumab cohorts. Filled circles = placebo; diamonds = 8 mg bimekizumab; filled squares = 40 mg bimekizumab; open squares = 160 mg bimekizumab; open diamonds = 480 mg bimekizumab; open triangles = 640 mg bimekizumab. [Fig. 15A-G]15A-E are bar graphs showing osteogenic gene expression in hPDSCs following treatment with GFC (growth factor cocktail; first bar from the left), GFC(-IL-6) (growth factor cocktail without IL-6; second bar), TH-17SN (TH-17 supernatant in (GFC-IL-6), third bar), TH-17SN+IL-17A mAb (TH-17 supernatant in (GFC-IL-6) with IL-17A monoclonal antibody treatment, fourth bar), or IL-17F mAb (TH-17 supernatant in (GFC-IL-6) with IL-17F monoclonal antibody treatment, fifth bar), or IL-17A / F mAb (TH-17 supernatant in (GFC-IL-6) with IL-17A / F monoclonal antibody treatment, sixth bar). FIG. 15F is a bar graph showing in vitro calcification (y-axis = absorbance at 595 nm; bars from left to right: control, GFC, GFC-IL-6, TH-17SN, IL-17A mAb, IL-17F mAb, IL-17A / F mAb). FIG. 15G is a bar graph showing IL-6 gene expression following treatment with GFC (growth factor cocktail; first bar from the left), GFC(-IL-6) (growth factor cocktail without IL-6; second bar), TH-17SN (TH-17 supernatant in (GFC-IL-6), third bar), TH-17SN+IL-17A mAb (TH-17 supernatant in (GFC-IL-6) with IL-17A monoclonal antibody treatment, fourth bar), or IL-17F mAb (TH-17 supernatant in (GFC-IL-6) with IL-17F monoclonal antibody treatment, fifth bar), or IL-17A / F mAb (TH-17 supernatant in (GFC-IL-6) with IL-17A / F monoclonal antibody treatment, sixth bar). Results are expressed as the mean fold change in expression compared to GM±SEM. ***p<0.001; **p<0.01; *p<0.05 compared to one-way ANOVA (n=3) between all treatment groups. [Figure 16A-B]Bar graphs showing the reduction of IL-6 (FIG. 16A) and RUNX2 (FIG. 16B) expression in three patient samples (SRSC04, SRSCO6, and SRSCO7) in hPDSCs treated with 10% AS patient serum (CTRL, first bar from the left) or with AS patient serum containing IgG mAb control (second bar), IL-17A mAb (third bar), IL-17F mAb (fourth bar), IL-17A / F mAb (fifth bar) before incubation. Results are expressed as mean relative expression ± SEM (***p<0.001; **p<0.01; *p<0.05) §§§p<0.01 (in all cases comparison between neutralizing groups compared with one-way ANOVA (n=3)). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0058] antibody In one embodiment, the antibody of the present invention specifically binds to IL-17A. By specifically binds, it is meant that the antibody has greater affinity for an IL-17A polypeptide than for other polypeptides.

[0059] In one embodiment, the antibody of the present invention specifically binds to IL-17F. By specifically binds, it is meant that the antibody has greater affinity for an IL-17F polypeptide than for other polypeptides.

[0060] In a preferred embodiment, the antibody of the present invention specifically binds to IL-17A and IL-17F. By specifically bind, we mean that the antibody has greater affinity for IL-17A and IL-17F polypeptides (including IL-17A / IL-17F heterodimers) than for other polypeptides.

[0061] Preferably, the IL-17A and IL-17F polypeptides are human. In one embodiment, the antibody also binds to cynomolgus monkey IL-17A and / or IL-17F.

[0062] It will be appreciated that antibodies of the invention which neutralize both IL-17A and IL-17F may be made as cross-reactive antibodies as described herein below, or by combining both IL-17A and IL-17F binding domains in a bispecific antibody.

[0063] In one embodiment, the antibodies of the invention capable of binding to both IL-17A and IL-17F are capable of neutralizing the activity of both isoforms of IL-17. Preferably, the antibodies of the invention neutralize the activity of both IL-17A and IL-17F. In one embodiment, the antibodies of the invention also neutralize the activity of the IL-17A / IL-17F heterodimer. Thus, the antibodies provided by this aspect of the invention have the advantageous property of being able to inhibit the biological activity of both IL-17A and IL-17F. Thus, the invention also provides the use of such antibodies in the treatment and / or prevention of diseases mediated by either or both of IL-17A and IL-17F, such as autoimmune or inflammatory diseases.

[0064] As used herein, the term "neutralizing antibody" describes an antibody that can neutralize the biological signaling activity of IL-17A and / or IL-17F and / or IL-17A / F heterodimer, for example, by blocking the binding of IL-17A and / or IL-17F to one or more receptors and by blocking the binding of IL-17A / IL-17F heterodimer to one or more receptors. It will be understood that the term "neutralizing" as used herein refers to a reduction in biological signaling activity. This reduction in biological signaling activity may be a partial reduction or a complete reduction. Furthermore, it will be understood that the degree of neutralization of IL-17A activity and IL-17F activity by an antibody that binds both IL-17A and IL-17F may be the same or different. In one embodiment, the degree of neutralization of the activity of IL-17A / IL-17F heterodimer may be the same or different from the degree of neutralization of IL-17A activity or IL-17F activity.

[0065] IL-17A or IL-17F polypeptides, or a mixture of the two, or cells expressing either or both of the aforementioned polypeptides can be used to produce antibodies that specifically recognize either or both polypeptides. IL-17 polypeptides (IL-17A and IL-17F) can be "mature" polypeptides or biologically active fragments or derivatives thereof, preferably including receptor binding sites. Preferably, IL-17 polypeptides are the mature polypeptides provided in SEQ ID NOs: 27 and 28 for IL-17A and IL-17F, respectively. IL-17 polypeptides can be prepared by methods well known in the art from genetically engineered host cells containing expression systems, or can be recovered from natural biological sources.

[0066] In this application, the term "polypeptide" includes peptides, polypeptides, and proteins, which terms are used interchangeably unless otherwise specified.

[0067] IL-17 polypeptides may in some cases be part of a larger protein, such as a fusion protein fused to an affinity tag. Antibodies generated against these polypeptides can be obtained by administering the polypeptide to animals, preferably non-human animals, using well-known conventional protocols, if immunization of animals is required (e.g., Handbook of Experimental Immunology, DM Weir (ed.), Vol. 4, Blackwell Scientific Publishers, Oxford, England, 1986). Many warm-blooded animals can be immunized, such as rabbits, mice, rats, sheep, cattle or pigs. Mice, rabbits, pigs and rats would be preferred.

[0068] Antibodies for use in the present invention include whole antibodies and functionally active fragments or derivatives thereof, including, but not limited to, monoclonal antibodies, multivalent antibodies, multispecific antibodies, bispecific antibodies, fully human antibodies, humanized or chimeric antibodies, domain antibodies, such as VH, VL, VHH, single chain antibodies, Fab fragments, Fab' and F(ab')2 fragments, and epitope-binding fragments of any of the above. Other antibody fragments include those described in WO2005003169, WO2005003170, WO2005003171, WO2009040562, and WO2010035012. Antibody fragments and methods for producing them are well known in the art. See, e.g., Verma et al., 1998, Journal of Immunological Methods, 216, 165-181; Adair and Lawson, 2005. Therapeutic antibodies. Drug Design Reviews-Online 2(3):209-217.

[0069] Antibodies for use in the present invention include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that specifically binds an antigen. The immunoglobulin molecules of the present invention may be of any class (e.g., IgG, IgE, IgM, IgD and IgA) or subclass of immunoglobulin molecule.

[0070] Monoclonal antibodies may be prepared by any method known in the art, such as the hybridoma technique (Kohler & Milstein, 1975, Nature, 256:495-497), the trioma technique, the human B-cell hybridoma technique (Kozbor et al., 1983, Immunology Today, 4:72) and the EBV-hybridoma technique (Cole et al., Monoclonal Antibodies and Cancer Therapy, pp77-96, Alan R Liss, Inc., 1985).

[0071] Antibodies for use in the present invention may be made using the single lymphocyte antibody technique by cloning and expressing immunoglobulin variable region cDNA generated from a single lymphocyte selected to produce a specific antibody, for example by the methods described in Babcook, J et al., 1996, Proc. Natl. Acad. Sci. USA 93(15):7843-78481; WO 92 / 02551; WO 2004 / 051268 and WO 2004 / 106377.

[0072] Humanized antibodies are antibody molecules from non-human species having one or more complementarity determining regions (CDRs) from the non-human species and a framework region from a human immunoglobulin molecule (see, e.g., U.S. Pat. No. 5,585,089; WO 91 / 09967).

[0073] Chimeric antibodies are antibodies that are encoded by genetically engineered immunoglobulin genes, such that the light and heavy chain genes are composed of immunoglobulin gene segments that belong to different species. These chimeric antibodies are likely to have low antigenicity. Bivalent antibodies can be produced by methods known in the art (Milstein et al., 1983, Nature 305:537-539; WO 93 / 08829; Traunecker et al., 1991, EMBO J. 10:3655-3659). Multivalent antibodies may contain multiple specificities or may be monospecific (see, for example, WO 92 / 22853 and WO 05 / 113605).

[0074] In one embodiment, the antibody provided by the present invention is a monoclonal antibody. In one embodiment, the antibody provided by the present invention is a humanized antibody. In one embodiment, the antibody provided by the present invention is a chimeric antibody. The antibody molecule of the present invention preferably comprises a complementary light chain or a complementary heavy chain, respectively.

[0075] Antibodies for use in the present invention can also be generated using various phage display methods known in the art, such as those disclosed by Brinkman et al. (J. Immunol. Methods, 1995, 182:41-50), Ames et al. (J. Immunol. Methods, 1995, 184:177-186), Kettleborough et al. (Eur. J. Immunol. 1994, 24:952-958), Persic et al. (Gene, 1997 187 9-18), Burton et al. (Advances in Immunology, 1994, 57:191-280), and WO 90 / 02809; WO 91 / 10737; WO 92 / 01047; WO 92 / 18619; WO 93 / 11236; WO 95 / 15982; WO 95 / 20401; and U.S. Pat. No. 5,698,426; 223,409; 5,403,484; 5,580,717; 5,427,908; 5,750,753; 5,821,047; 5,571,698; 5,427,908; 5,516,637; 5,780,225; 5,658,727; 5,733,743 and 5,969,108. Techniques for producing single chain antibodies, such as those described in U.S. Pat. No. 4,946,778, can also be adapted to produce single chain antibodies that bind to IL-17A and IL-17F. Transgenic mice or other organisms, including other mammals, can also be used to express humanized antibodies, including those within the scope of the present invention.

[0076] In one embodiment, the antibody provided by the present invention is a CDR-grafted antibody molecule. As used herein, the term "CDR-grafted antibody molecule" refers to an antibody molecule whose heavy and / or light chains comprise one or more CDRs (including one or more modified CDRs, if desired) from a donor antibody (e.g., a murine monoclonal antibody) grafted onto the variable region framework of the heavy and / or light chains of an acceptor antibody (e.g., a human antibody). For a review, see Vaughan et al., Nature Biotechnology, 16, 535-539, 1998. In one embodiment, instead of transferring the entire CDR, only the specificity-determining residues of any one or more of the above-mentioned CDRs are transferred to the human antibody framework (e.g., Kashmiri et al., 2005, Methods, 36, 25-34). In one embodiment, only the specificity-determining residues from one or more CDRs described herein above are transferred to the human antibody framework. In another embodiment, only the specificity-determining residues from each CDR described herein above are transferred to the human antibody framework.

[0077] When CDRs or specificity determining residues are grafted, appropriate acceptor variable region framework sequences may be used for the class / type of donor antibody from which the CDRs are derived, including mouse, primate and human framework regions. Preferably, the CDR-grafted antibodies of the invention comprise variable domains comprising human acceptor framework regions and one or more CDRs or specificity determining residues as described above. Thus, in one embodiment, a CDR-grafted neutralizing antibody is provided, the variable domains comprising human acceptor framework regions and non-human donor CDRs.

[0078] Examples of human frameworks that can be used in the present invention are KOL, NEWM, REI, EU, TUR, TEI, LAY and POM (Kabat et al., supra). For example, KOL and NEWM can be used for the heavy chain, REI for the light chain, and EU, LAY and POM for both the heavy and light chains. Alternatively, human germline sequences can be used. These are available, for example, at http: / / vbase.mrc-cpe.cam.ac.uk / . In the CDR-grafted antibodies of the present invention, the acceptor heavy and light chains do not necessarily have to be derived from the same antibody, and may, if desired, include composite chains with framework regions derived from different chains.

[0079] As mentioned above, the antibody molecules of the present invention may include whole antibody molecules having full-length heavy and light chains or fragments thereof, such as domain antibodies, such as VH, VL, VHH, Fab, modified Fab, Fab', F(ab')2, Fv or scFv fragments.

[0080] It will be appreciated that the antibodies of the invention, in particular the antibody fragments described above, can be incorporated into other antibody formats, in particular multispecific antibodies such as bispecific or trispecific antibodies, with the specificity (in particular specificity for IL-17A and IL-17F (including IL-17A / F heterodimer)) being provided by the antibodies of the invention. Thus, in one embodiment, the invention provides a multispecific antibody comprising one or more of the antibody fragments described herein above. Such a multispecific antibody may comprise one or more further antibody fragments having binding specificity for another antigen (e.g. serum albumin such as human serum albumin) in order to extend the half-life of the multispecific antibody. For example, the antibody fragments described in WO 2012 / 156219 and combinations or variants thereof comprising both an anti-IL-17A / F VHH binding domain and a serum albumin VHH binding domain.

[0081] Examples of multispecific antibodies include bivalent, trivalent or tetravalent antibodies, Bis-scFv, diabodies, triabodies, tetrabodies, bibodies and tribodies (see, e.g., Holliger and Hudson, 2005, Nature Biotech 23(9):1126-1136; Schoonjans et al., 2001, Biomolecular Engineering, 17(6), 193-202). Other multispecific antibodies include Fab-Fv, Fab-dsFv, Fab-Fv-Fv. Fab-Fv-Fc and Fab-dsFv-PEG fragments as described in WO2009040562, WO2010035012, WO2011 / 08609, WO2011 / 030107 and WO2011 / 061492, respectively.

[0082] If present, the constant region domain of the antibody molecule of the present invention can be selected taking into account the proposed function of the antibody molecule, in particular the effector function that may be required. For example, the constant region domain may be a human IgA, IgD, IgE, IgG or IgM domain. In particular, when the antibody molecule is intended for therapeutic use and antibody effector function is required, human IgG constant region domains, in particular of the IgG1 and IgG3 isotypes, can be used. Alternatively, when the antibody molecule is intended for therapeutic purposes and antibody effector function is not required, for example to simply block IL-17 activity, IgG2 and IgG4 isotypes can be used. For example, an IgG4 molecule can be used in which the serine at position 241 has been changed to a proline, as described in Angal et al., Molecular Immunology, 1993, 30(1), 105-108. IgG4 constant domains containing this change are particularly preferred.

[0083] Those skilled in the art will also understand that antibodies may undergo various post-translational modifications. The type and extent of these modifications often depend on the host cell line and culture conditions used to express the antibody. Such modifications may include changes in glycosylation, methionine oxidation, diketopiperazine formation, aspartic acid isomerization and asparagine deamidation. Frequent modifications result in the loss of a basic residue (such as lysine or arginine) at the carboxy terminus due to the action of carboxypeptidase (as described in Harris, R J. Journal of Chromatography 705:129-134,1995). Thus, for example, the C-terminal lysine of the heavy chain of an antibody as shown in SEQ ID NO:16 in FIG. 1 may not be present.

[0084] In one embodiment, the heavy chain of the antibody comprises a CH1 domain and the light chain of the antibody comprises a CL domain, either kappa or lambda.

[0085] A fully human antibody is one in which the variable and constant regions (if present) of both the heavy and light chains are all of human origin or are substantially identical to sequences of human origin, although not necessarily from the same antibody. Examples of fully human antibodies would include, for example, antibodies produced by the phage display method described above, and antibodies made from mice by replacing murine immunoglobulin variable and constant region genes with their human counterparts, such as those described in EP 0546073, U.S. Patent No. 5,545,806, U.S. Patent No. 5,569,825, U.S. Patent No. 5,625,126, U.S. Patent No. 5,633,425, U.S. Patent No. 5,661,016, U.S. Patent No. 5,770,429, EP 0438474 and EP 0463151.

[0086] The above mentioned antibodies are provided for the purposes of reference and example and are not intended to limit the scope of the invention.

[0087] The inhibitor of IL-17A activity and IL-17F activity is known in the art, for example, the inhibitor described herein.Antibody that binds both IL-17A and IL-17F is described in WO2007 / 106769, WO2008 / 047134, WO2009 / 136286, WO2010 / 025400 and WO2012 / 156219.IL-17A and IL-17F activity can also be antagonized by using anti-IL-17RC antibody or IL-17RC fusion protein, as described in US2007196371A.

[0088] US Patent No. 8,303,953 (priority date October 18, 2006) describes a high affinity antibody CA028_00496 that binds to human IL-17A, IL-17F and IL-17A / F heterodimers, the sequence of which is given in Figure [1] herein. CA028_0496 is a humanized neutralizing antibody that includes grafted variable regions gL7 and gH9, the sequence of which is given in US Patent No. 8,303,953 (priority date October 18, 2006) and in Figure [1] herein. The heavy chain acceptor framework is the human germline sequence VH3 1-3 3-07 with framework 4 coming from this portion of the human JH region germline JH4. The light chain acceptor framework is the human germline sequence VK1 2-1-(1)L4 with framework 4 coming from this portion of the human JK region germline JK1. Examples 2-4 of U.S. Pat. No. 8,303,953, and the DNA Engineering and General Methods sections therein, describe the characterization and testing of the neutralizing activity and affinity of CA028_0496.

[0089] US Patent No. 8,580,265 (priority date January 14, 2011) describes a second high affinity antibody CA028_00496.g3 (also known as UCB4940 or bimekizumab) that binds human IL-17A, IL-17F and the IL-17A / F heterodimer, the sequence of which is provided herein in Figure [1]. As described in US Patent No. 8,580,265, the antibody CA028_0496 was affinity matured to improve the affinity of the antibody for IL-17F while retaining its affinity for IL-17A. This affinity matured antibody CA028_0496.g3 (also known as UCB4940 or bimekizumab) was expressed as an IgG1. The final sequence of the affinity matured variable region of CA028_0496.g3 is provided in Figures 1a and 1b of U.S. Patent No. 8,580,265, Figure [1] herein. U.S. Patent No. 8,679,494 (priority date April 23, 2008) provides novel neutralizing epitopes on IL-17A and IL-17F and antibodies that bind and / or interact with those epitopes, the sequences of which are provided in Figure [1] herein. The aforementioned patents are incorporated by reference as if fully set forth herein.

[0090] In antibody CA028_0496.g3, the sequence of the heavy chain variable region is the same as that of the parent antibody CA028_0496. In contrast, the light chain variable region differs by five amino acids. The five residues that differ between the light chains of antibody CA028_0496 and antibody CA028_0496.g3 are underlined in FIG. 1a of U.S. Pat. No. 8,580,265. Three residues were in the CDRs and two residues were in the framework. Thus, in one embodiment, the light chain variable domain comprises an arginine residue at position 30, a serine residue at position 54, an isoleucine residue at position 56, an aspartic acid residue at position 60, and an arginine residue at position 72.

[0091] Antibody CA028_0496.g3 selectively and potently inhibits the activity of both IL-17A and IL-17F isoforms in vitro. Antibody CA028_0496.g3 binds to IL-17A, IL-17F and the IL-17A / F heterodimer, neutralizing the biological activity of each cytokine by blocking the cytokines from signaling through the IL-17RA / RC complex.

[0092] Characterization of CA028_0496.g3 and CA028_0496 and their properties are described in Examples 2 and 3 of U.S. Patent No. 8,580,265 as if fully set forth herein. Biomolecular analysis of antibody CA028_0496.g3 was performed using a Biacore 3000 (Biacore AB) as detailed in U.S. Patent No. 8,580,265. The assay format was capture of antibody CA028_0496.g3 with immobilized anti-human IgG Fc specific antibody followed by titration of recombinant human IL-17A or human IL-17F on the captured surface. Further details regarding the surface plasmon resonance (Biacore) assay are provided below. Details are described with reference to specific antibodies, but the parameters described herein are suitable for use in characterizing any of the antibodies described herein. The assay was performed at 25°C. Affinipure F(ab')2 fragment goat anti-human IgG Fc specific antibody (Jackson ImmunoResearch) was immobilized on a CM5 sensor chip (Biacore AB) via amine coupling chemistry to a level of approximately 6000 response units (RU). HBS-EP buffer (10 mM HEPES pH 7.4, 0.15 M NaCl, 3 mM EDTA, 0.005% Surfactant P20, Biacore AB) was used as running buffer with a flow rate of 10 μL / min (min). A 10 μL injection of CA028_00496.g3 at 0.5 μg / mL was used for capture by immobilized anti-human IgG Fc. Human IL-17A was titrated onto the captured CA028_00496.g3 from 5 nM at a flow rate of 30 μL / min for 3 min, followed by dissociation for 20 min. Human IL-17F (R&D systems) was titrated from 10 nM onto the captured CA028_00496.g3 at a flow rate of 30 μL / min for 3 min, followed by 5 min of dissociation. The surface was regenerated at a flow rate of 10 μL / min by injection of 10 μL of 40 mM HCl followed by 5 μL of 5 mM NaOH. Double-referenced background-subtracted binding curves were analyzed using BIAevaluation software (version 4.1) following standard procedures. Kinetic parameters were determined from the fitting algorithm.

[0093] The data are detailed in Table 1, with mean values ​​highlighted in grey.

[0094] [Table 1]

[0095] As described in US Patent No. 8,580,265, the preferred framework region of the heavy chain of CA028_0496.g3 is derived from the human subgroup VH3 sequence 1-3 3-07 together with JH4, as previously described in WO 2008 / 047134. Thus, an embodiment of the present invention may be a CDR-grafted neutralizing antibody, the heavy chain framework region of which comprises at least one non-human donor CDR derived from the human subgroup sequence 1-3 3-07 together with JH4. The sequence of human JH4 is (YFDY)WGQGTLVTVSS. The YFDY motif is part of CDR-H3 and not part of framework 4 (Ravetch, J V. et al., 1981, Cell, 27, 583-591).

[0096] As described in US Patent No. 8,580,265, the preferred framework region of the light chain of CA028_0496.g3 is derived from the human subgroup VK1 sequence 2-1-(1)L4 with JK1 as previously described in WO 2008 / 047134. Thus, an embodiment of the present invention may be a CDR-grafted neutralizing antibody, the light chain framework region of which comprises at least one non-human donor CDR derived from the human subgroup sequence VK1 2-1-(1)L4 with JK1. The JK1 sequence is (WT)FGQGTKVEIK. The WT motif is part of CDR-L3 and not part of framework 4 (Hieter, P A. et al., 1982, J. Biol. Chem., 257, 1516-1522).

[0097] Also, in CA028_0496.g3, the framework regions do not have to have exactly the same sequence as the acceptor antibody. For example, unusual residues may be changed to residues that occur more frequently in that class or type of acceptor chain. Alternatively, selected residues in the acceptor framework regions may be altered so that they correspond to residues found at the same positions in the donor antibody (see Reichmann et al., 1998, Nature, 332, 323-324). Such changes should be kept to the minimum necessary to restore the affinity of the donor antibody. Protocols for selecting acceptor framework region residues that may need to be altered are described in WO 91 / 09967.

[0098] In one embodiment, in CA028_0496.g3, where the acceptor heavy chain has the human VH3 sequence 1-3 3-07 with JH4, the acceptor framework region of the heavy chain comprises, in addition to one or more donor CDRs, a donor residue at least at position 94 (according to Kabat et al., supra). Thus, an embodiment of the invention may be a CDR-grafted antibody in which at least one residue at position 94 of the variable domain of the heavy chain is a donor residue.

[0099] In one embodiment, in CA028_0496.g3, where the acceptor light chain has the human subgroup VK1 sequence 2-1-(1)L4 with JK1, no donor residues are transferred, i.e. only the CDRs are transferred. Thus, an embodiment of the invention may be a CDR-grafted antibody, where only the CDRs are transferred to the donor framework.

[0100] The donor residues are those residues from the donor antibody, i.e. the antibody from which the CDRs are originally derived.

[0101] Antibody CA028_0496.g3 does not bind to either IL-17A or IL-17F in rats or mice and is therefore not pharmacologically active in rodents. Antibody CA028_0496.g3 has been shown to bind to IL-17A and IL-17F in cynomolgus monkeys and non-clinical evaluations have demonstrated that the antibody is pharmacologically active in vivo in cynomolgus monkeys. In humans, antibody CA028_0496.g3 exhibits a long half-life in a dose-proportional manner, with PK for doses of 8 mg to 640 mg ranging from 17.00 days to 25.55 days (e.g., 23.6 days) across multiple treatment groups.

[0102] The above-mentioned antibodies are described for reference and example purposes, and do not limit the scope of the present invention. For example, as described herein, it will be understood that the affinity of the antibody provided by the present invention can be modified using any suitable method known in the art. Thus, the present invention also relates to variants of the antibody molecule of the present invention, which have improved affinity for IL-17A and / or IL-17F. Such variants can be obtained by a number of affinity-altering protocols, including mutating the CDRs (Yang et al., J. Mol. Biol., 254, 392-403, 1995), chain shuffling (Marks et al., Bio / Technology, 10, 779-783, 1992), use of mutator strains of E. coli (Low et al., J. Mol. Biol., 250, 359-368, 1996), DNA shuffling (Patten et al., Curr. Opin. Biotechnol., 8, 724-733, 1997), phage display (Thompson et al., J. Mol. Biol., 256, 77-88, 1996) and sexual PCR (Crameri et al., Nature, 391, 288-291, 1998). Vaughan et al., supra, discuss these affinity maturation methods.

[0103] Antibodies can be screened using an assay that measures binding to human IL-17A and human IL-17F, such as a BIAcore™ assay. BIAcore™ (i.e., a surface plasmon resonance assay) is described herein. Suitable neutralization assays are known in the art, see, for example, WO 2008 / 047134. An exemplary cell-based neutralization assay utilizes HeLa cells. For example, HeLa cells are grown in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum, penicillin, gentamicin, and glutamine. 1×10 4 Cells are seeded into 96-well flat-bottom tissue culture plates. Cells are incubated overnight and washed once with assay buffer. HeLa cells are stimulated for 48 hours with recombinant human IL-17F (125 ng / ml) or human IL-17A (25 ng / ml) in combination with tumor necrosis factor-α (TNF-α) (1 ng / ml) in the presence of various concentrations of candidate antibodies. In HeLa cell lines, IL-17A or IL-17F synergize with TNF-α to induce the production of IL-6, which can be quantified using a specific MSD assay kit. The resulting amount of secreted IL-6 is measured using Meso Scale Discovery (MSD) assay technology and IC50 values ​​are calculated. Antibody activity is measured as the dose required to inhibit 50% of IL-17A or IL-17F activity (IC 50 )

[0104] "Identity" as used herein indicates that at any particular position in the aligned sequences, the amino acid residue is the same between the sequences. "Similarity" as used herein indicates that at any particular position in the aligned sequences, the amino acid residue is of similar species between the sequences. For example, leucine may be used instead of isoleucine or valine. Other amino acids that can often be substituted for one another include, but are not limited to, phenylalanine, tyrosine and tryptophan (amino acids with aromatic side chains); lysine, arginine and histidine (amino acids with basic side chains); aspartic acid and glutamic acid (amino acids with acidic side chains); asparagine and glutamine (amino acids with amide side chains); cysteine ​​and methionine (amino acids with sulfur-containing side chains).

[0105] The degree of identity and similarity can be readily calculated (Computational Molecular Biology, edited by Lesk, AM, Oxford University Press, New York, 1988; Biocomputing. Informatics and Genome Projects, edited by Smith, DW, Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part 1, edited by Griffin, AM and Griffin, HG, Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; and Sequence Analysis Primer, edited by Gribskov, M. and Devereux, J., M Stockton Press, New York, 1991).

[0106] Residues in antibody variable domains are conventionally numbered according to a system devised by Kabat et al., 1987, Sequences of Proteins of Immunological Interest, US Department of Health and Human Services, NIH, USA (hereinafter "Kabat et al.", supra). This numbering system is used herein unless otherwise indicated.

[0107] The Kabat residue nomenclature does not necessarily correspond directly to the linear numbering of the amino acid residues. The actual linear amino acid sequence may contain fewer or additional amino acids than the strict Kabat numbering corresponding to the shortening or insertion of structural components, whether framework or complementarity determining regions (CDRs) of the basic variable domain structure. The correct Kabat numbering of residues may be determined for a given antibody by alignment of the "standard" Kabat numbered sequence with the homologous residues in the antibody sequence.

[0108] The CDRs of the heavy chain variable domain are located at residues 31-35 (CDR-H1), residues 50-65 (CDR-H2) and residues 95-102 (CDR-H3) according to the Kabat numbering system. However, according to Chothia (Chothia, C. and Lesk, AM J Mol. Biol, 196, 901-917 (1987)), the loop corresponding to CDR-H1 extends from residue 26 to residue 32. Thus, "CDR-H1", as used herein, includes residues 26-35 as described by a combination of the Kabat numbering system and Chothia's topological loop definition.

[0109] The CDRs of the light chain variable domain are located at residues 24-34 (CDR-L1), residues 50-56 (CDR-L2) and residues 89-97 (CDR-L3) according to the Kabat numbering system.

[0110] In one embodiment, the antibody provided by the present invention is a CDR-grafted antibody molecule comprising one or more of the CDRs provided in SEQ ID NOs: 1-8.

[0111] In one embodiment, the invention provides a neutralizing antibody having specificity for human IL-17A and human IL-17F comprising a heavy chain, the variable domain of the heavy chain comprising the sequence set forth in SEQ ID NO:1 for CDR-H1, the sequence set forth in SEQ ID NO:2 for CDR-H2, and the sequence set forth in SEQ ID NO:3 for CDR-H3.

[0112] In one embodiment, the invention provides a neutralizing antibody having specificity for human IL-17A and human IL-17F comprising a light chain, the variable domain of the light chain comprising the sequence set forth in SEQ ID NO:4 or SEQ ID NO:7 for CDR-L1, the sequence set forth in SEQ ID NO:5 or SEQ ID NO:8 for CDR-L2, and the sequence set forth in SEQ ID NO:6 for CDR-L3.

[0113] It will also be understood that one or more amino acid substitutions may be made in the CDRs provided by the present invention without significantly altering the ability of the antibody to bind IL-17A and IL-17F and neutralize IL-17A and IL-17F activity. The effect of any amino acid substitution on binding and neutralization can be easily tested by one of skill in the art, for example, by using the methods described herein. Thus, the present invention provides antibodies comprising one or more CDRs selected from CDR-H1 (SEQ ID NO:1), CDR-H2 (SEQ ID NO:2), CDR-H3 (SEQ ID NO:3), CDR-L1 (SEQ ID NO:4 or SEQ ID NO:7), CDR-L2 (SEQ ID NO:5 or SEQ ID NO:8) and CDR-L3 (SEQ ID NO:6), in which one or more amino acids in one or more CDRs are replaced with another amino acid. It will also be understood that the length of one or more CDRs may be altered without significantly altering the ability of the antibody to bind IL-17A and IL-17F and neutralize IL-17A and IL-17F activity.

[0114] In one embodiment, the invention provides a neutralizing antibody having specificity for human IL-17A and human IL-17F comprising a heavy chain, wherein at least two of the variable domains CDR-H1, CDR-H2 and CDR-H3 of the heavy chain are selected from the sequence set forth in SEQ ID NO: 1 for CDR-H1, the sequence set forth in SEQ ID NO: 2 for CDR-H2 and the sequence set forth in SEQ ID NO: 3 for CDR-H3. For example, the antibody may comprise a heavy chain in which CDR-H1 has the sequence set forth in SEQ ID NO: 1 and CDR-H2 has the sequence set forth in SEQ ID NO: 2. Alternatively, the antibody may comprise a heavy chain in which CDR-H1 has the sequence set forth in SEQ ID NO: 1 and CDR-H3 has the sequence set forth in SEQ ID NO: 3, or the antibody may comprise a heavy chain in which CDR-H2 has the sequence set forth in SEQ ID NO: 2 and CDR-H3 has the sequence set forth in SEQ ID NO: 3. For the avoidance of doubt, it is understood that all permutations are included.

[0115] In another embodiment, the present invention provides a neutralizing antibody having specificity for human IL-17A and human IL-17F, comprising a light chain, wherein at least two of the variable domains CDR-L1, CDR-L2 and CDR-L3 of the light chain are selected from the sequence set forth in SEQ ID NO: 4 or SEQ ID NO: 7 for CDR-L1, the sequence set forth in SEQ ID NO: 5 or SEQ ID NO: 8 for CDR-L2 and the sequence set forth in SEQ ID NO: 6 for CDR-L3. For example, the antibody may comprise a light chain in which CDR-L1 has the sequence set forth in SEQ ID NO: 4 and CDR-L2 has the sequence set forth in SEQ ID NO: 5. Alternatively, the antibody may comprise a light chain in which CDR-L1 has the sequence set forth in SEQ ID NO: 4 and CDR-L3 has the sequence set forth in SEQ ID NO: 6, or the antibody may comprise a light chain in which CDR-L2 has the sequence set forth in SEQ ID NO: 5 and CDR-L3 has the sequence set forth in SEQ ID NO: 6. For the avoidance of doubt, it is understood that all permutations are included.

[0116] In one embodiment, an antibody of the invention comprises a heavy chain, the variable domain of which comprises the sequence set forth in SEQ ID NO:1 for CDR-H1, the sequence set forth in SEQ ID NO:2 for CDR-H2, and the sequence set forth in SEQ ID NO:3 for CDR-H3, and a light chain, the variable domain of which comprises the sequence set forth in SEQ ID NO:4 for CDR-L1, the sequence set forth in SEQ ID NO:5 for CDR-L2, and the sequence set forth in SEQ ID NO:6 for CDR-L3.

[0117] In one embodiment, an antibody of the invention comprises a heavy chain, the variable domain of which comprises the sequence set forth in SEQ ID NO:1 for CDR-H1, the sequence set forth in SEQ ID NO:2 for CDR-H2, and the sequence set forth in SEQ ID NO:3 for CDR-H3, and a light chain, the variable domain of which comprises the sequence set forth in SEQ ID NO:7 for CDR-L1, the sequence set forth in SEQ ID NO:8 for CDR-L2, and the sequence set forth in SEQ ID NO:6 for CDR-L3.

[0118] In one embodiment, an antibody of the invention comprises a heavy chain, the variable domain of the heavy chain comprising three CDRs, wherein the sequence of CDR-H1 has at least 60% identity or similarity to the sequence set forth in SEQ ID NO:1, CDR-H2 has at least 60% identity or similarity to the sequence set forth in SEQ ID NO:2, and / or CDR-H3 has at least 60% identity or similarity to the sequence set forth in SEQ ID NO:3. In another embodiment, an antibody of the invention comprises a heavy chain, wherein the variable domain of the heavy chain comprises three CDRs, wherein the sequence of CDR-H1 has at least 70%, 80%, 90%, 95% or 98% identity or similarity to the sequence set forth in SEQ ID NO:1, CDR-H2 has at least 70%, 80%, 90%, 95% or 98% identity or similarity to the sequence set forth in SEQ ID NO:2, and / or CDR-H3 has at least 70%, 80%, 90%, 95% or 98% identity or similarity to the sequence set forth in SEQ ID NO:3.

[0119] In another embodiment, an antibody of the invention comprises a light chain, wherein the variable domain of the light chain comprises three CDRs, wherein the sequence of CDR-L1 has at least 60% identity or similarity to the sequence set forth in SEQ ID NO:4, CDR-L2 has at least 60% identity or similarity to the sequence set forth in SEQ ID NO:5, and / or CDR-L3 has at least 60% identity or similarity to the sequence set forth in SEQ ID NO:6. In another embodiment, an antibody of the invention comprises a light chain, wherein the variable domain of the light chain comprises three CDRs, wherein the sequence of CDR-L1 has at least 70%, 80%, 90%, 95% or 98% identity or similarity to the sequence set forth in SEQ ID NO:4, CDR-L2 has at least 70%, 80%, 90%, 95% or 98% identity or similarity to the sequence set forth in SEQ ID NO:5, and / or CDR-L3 has at least 70%, 80%, 90%, 95% or 98% identity or similarity to the sequence set forth in SEQ ID NO:6.

[0120] In another embodiment, an antibody of the invention comprises a light chain, wherein the variable domain of the light chain comprises three CDRs, wherein the sequence of CDR-L1 has at least 60% identity or similarity to the sequence set forth in SEQ ID NO:4, CDR-L2 has at least 60% identity or similarity to the sequence set forth in SEQ ID NO:5, and / or CDR-L3 has at least 60% identity or similarity to the sequence set forth in SEQ ID NO:6. In another embodiment, an antibody of the invention comprises a light chain, wherein the variable domain of the light chain comprises three CDRs, wherein the sequence of CDR-L1 has at least 70%, 80%, 90%, 95% or 98% identity or similarity to the sequence set forth in SEQ ID NO:7, CDR-L2 has at least 70%, 80%, 90%, 95% or 98% identity or similarity to the sequence set forth in SEQ ID NO:8, and / or CDR-L3 has at least 70%, 80%, 90%, 95% or 98% identity or similarity to the sequence set forth in SEQ ID NO:6.

[0121] In one embodiment, an antibody of the invention comprises a light chain, the variable domain of which comprises the sequence shown in SEQ ID NO:9 (gL7).

[0122] In another embodiment, an antibody of the invention comprises a light chain, the variable domain of which comprises a sequence having at least 60% identity or similarity to the sequence set forth in SEQ ID NO: 9. In one embodiment, an antibody of the invention comprises a light chain, the variable domain of which comprises a sequence having at least 70%, 80%, 90%, 95% or 98% identity or similarity to the sequence set forth in SEQ ID NO: 9.

[0123] In one embodiment, an antibody of the invention comprises a light chain, the variable domain of which comprises the sequence shown in SEQ ID NO: 10 (gL57).

[0124] In another embodiment, an antibody of the invention comprises a light chain, the variable domain of which comprises a sequence having at least 60% identity or similarity to the sequence set forth in SEQ ID NO: 10. In one embodiment, an antibody of the invention comprises a light chain, the variable domain of which comprises a sequence having at least 70%, 80%, 90%, 95% or 98% identity or similarity to the sequence set forth in SEQ ID NO: 10.

[0125] In one embodiment, an antibody of the invention comprises a heavy chain, the variable domain of which comprises the sequence shown in SEQ ID NO:11 (gH9).

[0126] In another embodiment, an antibody of the invention comprises a heavy chain, the variable domain of which comprises a sequence having at least 60% identity or similarity to the sequence set forth in SEQ ID NO: 11. In one embodiment, an antibody of the invention comprises a heavy chain, the variable domain of which comprises a sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identity or similarity to the sequence set forth in SEQ ID NO:11.

[0127] In one embodiment, an antibody of the invention comprises a heavy chain and a light chain, wherein the variable domain of the heavy chain comprises the sequence set forth in SEQ ID NO:11 and the variable domain of the light chain comprises the sequence set forth in SEQ ID NO:9.

[0128] In another embodiment of the invention, the antibody comprises a heavy chain and a light chain, wherein the variable domain of the heavy chain comprises a sequence having at least 60% identity or similarity to the sequence set forth in SEQ ID NO: 11, and the variable domain of the light chain comprises a sequence having at least 60% identity or similarity to the sequence set forth in SEQ ID NO: 9. Preferably, the antibody comprises a heavy chain and a light chain, wherein the variable domain of the heavy chain comprises a sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identity or similarity to the sequence set forth in SEQ ID NO: 11, and the variable domain of the light chain comprises a sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identity or similarity to the sequence set forth in SEQ ID NO: 9.

[0129] In one embodiment, an antibody of the invention comprises a heavy chain and a light chain, wherein the variable domain of the heavy chain comprises the sequence set forth in SEQ ID NO:11 and the variable domain of the light chain comprises the sequence set forth in SEQ ID NO:10.

[0130] In another embodiment of the invention, the antibody comprises a heavy chain and a light chain, wherein the variable domain of the heavy chain comprises a sequence having at least 60% identity or similarity to the sequence set forth in SEQ ID NO:11, and the variable domain of the light chain comprises a sequence having at least 60% identity or similarity to the sequence set forth in SEQ ID NO:10. Preferably, the antibody comprises a heavy chain and a light chain, wherein the variable domain of the heavy chain comprises a sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identity or similarity to the sequence set forth in SEQ ID NO:11, and the variable domain of the light chain comprises a sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identity or similarity to the sequence set forth in SEQ ID NO:10.

[0131] In a preferred embodiment, the antibody provided by the present invention is a neutralizing antibody having specificity for human IL-17A and human IL-17F, the heavy chain constant region of which comprises a human IgG1 constant region. Thus, the present invention provides an antibody whose heavy chain comprises or consists of the sequence shown in SEQ ID NO:15.

[0132] In one embodiment of the invention, the antibody comprises a heavy chain, which comprises a sequence having at least 60% identity or similarity to the sequence set forth in SEQ ID NO: 15. Preferably, the antibody comprises a heavy chain, which comprises a sequence having at least 70%, 80%, 90%, 95%, 97%, 98% or 99% identity or similarity to the sequence set forth in SEQ ID NO: 15.

[0133] In one embodiment, the antibody molecule of the invention comprises a light chain comprising the sequence given in SEQ ID NO:12.

[0134] In one embodiment of the invention, the antibody comprises a light chain, which comprises a sequence having at least 60% identity or similarity to the sequence set forth in SEQ ID NO: 12. Preferably, the antibody comprises a light chain, which comprises a sequence having at least 70%, 80%, 90%, 95% or 98% identity or similarity to the sequence set forth in SEQ ID NO: 12.

[0135] In one embodiment, the invention provides an antibody wherein the heavy chain comprises or consists of the sequence set forth in SEQ ID NO: 15 and the light chain comprises or consists of the sequence set forth in SEQ ID NO: 12.

[0136] In one embodiment of the invention, the antibody comprises a heavy chain comprising a sequence having at least 60% identity or similarity to the sequence set forth in SEQ ID NO: 15, and a light chain comprising a sequence having at least 60% identity or similarity to the sequence set forth in SEQ ID NO: 12. Preferably, the antibody comprises a heavy chain comprising a sequence having at least 70%, 80%, 90%, 95% or 98% identity or similarity to the sequence set forth in SEQ ID NO: 15, and a light chain comprising a sequence having at least 70%, 80%, 90%, 95% or 98% identity or similarity to the sequence set forth in SEQ ID NO: 12.

[0137] In a preferred embodiment, the antibody provided by the present invention is a neutralizing antibody having specificity for human IL-17A and human IL-17F, the heavy chain constant region of which comprises a human IgG1 constant region. Thus, the present invention provides an antibody whose heavy chain comprises or consists of the sequence shown in SEQ ID NO:16.

[0138] In one embodiment of the invention, the antibody comprises a heavy chain comprising a sequence having at least 60% identity or similarity to the sequence set forth in SEQ ID NO: 16. Preferably, the antibody comprises a heavy chain comprising a sequence having at least 70%, 80%, 90%, 95%, 97%, 98% or 99% identity or similarity to the sequence set forth in SEQ ID NO: 16.

[0139] In one embodiment, the antibody molecule of the invention comprises a light chain comprising the sequence given in SEQ ID NO:13.

[0140] In one embodiment of the invention, the antibody comprises a light chain comprising a sequence having at least 60% identity or similarity to the sequence set forth in SEQ ID NO: 13. Preferably, the antibody comprises a light chain comprising a sequence having at least 70%, 80%, 90%, 95% or 98% identity or similarity to the sequence set forth in SEQ ID NO: 13.

[0141] In one embodiment, the invention provides an antibody wherein the heavy chain comprises or consists of the sequence set forth in SEQ ID NO: 16 and the light chain comprises or consists of the sequence set forth in SEQ ID NO: 13.

[0142] In one embodiment of the invention, the antibody comprises a heavy chain comprising a sequence having at least 60% identity or similarity to the sequence set forth in SEQ ID NO: 16, and a light chain comprising a sequence having at least 60% identity or similarity to the sequence set forth in SEQ ID NO: 13. Preferably, the antibody comprises a heavy chain comprising a sequence having at least 70%, 80%, 90%, 95% or 98% identity or similarity to the sequence set forth in SEQ ID NO: 16, and a light chain comprising a sequence having at least 70%, 80%, 90%, 95% or 98% identity or similarity to the sequence set forth in SEQ ID NO: 13.

[0143] In one embodiment, the invention provides an antibody wherein the heavy chain comprises or consists of the sequence set forth in SEQ ID NO: 15 and the light chain comprises or consists of the sequence set forth in SEQ ID NO: 13.

[0144] In one embodiment of the invention, the antibody comprises a heavy chain comprising a sequence having at least 60% identity or similarity to the sequence set forth in SEQ ID NO: 15, and a light chain comprising a sequence having at least 60% identity or similarity to the sequence set forth in SEQ ID NO: 13. Preferably, the antibody comprises a heavy chain comprising a sequence having at least 70%, 80%, 90%, 95% or 98% identity or similarity to the sequence set forth in SEQ ID NO: 15, and a light chain comprising a sequence having at least 70%, 80%, 90%, 95% or 98% identity or similarity to the sequence set forth in SEQ ID NO: 13.

[0145] In one embodiment, the invention provides an antibody wherein the heavy chain comprises or consists of the sequence set forth in SEQ ID NO: 16 and the light chain comprises or consists of the sequence set forth in SEQ ID NO: 12.

[0146] In one embodiment of the invention, the antibody comprises a heavy chain comprising a sequence having at least 60% identity or similarity to the sequence set forth in SEQ ID NO: 16, and a light chain comprising a sequence having at least 60% identity or similarity to the sequence set forth in SEQ ID NO: 12. Preferably, the antibody comprises a heavy chain comprising a sequence having at least 70%, 80%, 90%, 95% or 98% identity or similarity to the sequence set forth in SEQ ID NO: 16, and a light chain comprising a sequence having at least 70%, 80%, 90%, 95% or 98% identity or similarity to the sequence set forth in SEQ ID NO: 12. binding affinity

[0147] The neutralizing antibody molecule of any embodiment of the present invention preferably has high binding affinity, preferably nanomolar, and even more preferably picomolar binding affinity. It will be understood that the binding affinity of an antibody of the present invention to human IL-17A may differ from the binding affinity of the same antibody to human IL-17F and / or the IL-17A / F heterodimer.

[0148] In one example, the antibody molecule of the present invention has a greater affinity for IL-17A than for IL-17F. In one example, the antibody molecule of the present invention has an affinity for IL-17A that is at least 10 times greater than its binding affinity for IL-17F. In one example, the antibody molecule of the present invention has an affinity for IL-17A that is at least 50 times greater than its binding affinity for IL-17F. In one example, the antibody molecule of the present invention has an affinity for IL-17A that is at least 100 times greater than its binding affinity for IL-17F. In one example, the antibody molecule of the present invention has a nanomolar affinity for IL-17F and a picomolar affinity for IL-17A.

[0149] In one example, the antibody molecule of the present invention has a greater affinity for IL-17F than it has binding affinity for IL-17A. In one example, the antibody molecule of the present invention has an affinity for IL-17F that is at least 10 times greater than its binding affinity for IL-17A. In one example, the antibody molecule of the present invention has an affinity for IL-17F that is at least 50 times greater than its binding affinity for IL-17A. In one example, the antibody molecule of the present invention has an affinity for IL-17F that is at least 100 times greater than its binding affinity for IL-17A. In one example, the antibody molecule of the present invention has picomolar affinity for IL-17A and nanomolar affinity for IL-17F.

[0150] In one example, the antibody molecule of the present invention has the same affinity for IL-17A as it has for IL-17F. In one example, the antibody molecule of the present invention has nanomolar affinity for both IL-17A and IL-17F. In one example, the antibody molecule of the present invention has picomolar affinity for both IL-17A and IL-17F.

[0151] Affinity may be measured using any suitable method known in the art, including BIAcore™, using isolated native or recombinant IL-17A and IL-17F, both of which exist as homodimers.

[0152] Preferably, the antibody molecule of the present invention has a binding affinity to IL-17A of less than 10 nM. In one embodiment, the antibody molecule of the present invention has a binding affinity to IL-17A of less than 500 pM. In one embodiment, the antibody molecule of the present invention has a binding affinity to IL-17A of 100 pM or less. In one embodiment, the antibody molecule of the present invention has a binding affinity to IL-17A of 20 pM or less. In one embodiment, the antibody of the present invention has an affinity to IL-17A of 16 pM. In one embodiment, the antibody molecule of the present invention has a binding affinity to IL-17A of 10 pM or less. In one embodiment, the antibody molecule of the present invention has a binding affinity to IL-17A of 5 pM or less. In one embodiment, the antibody of the present invention has an affinity to IL-17A of 3.2 pM.

[0153] Preferably, the antibody molecule of the present invention has a binding affinity to IL-17F of less than 10 nM. In one embodiment, the antibody of the present invention has an affinity to IL-17F of less than 2 nM. In one embodiment, the antibody of the present invention has an affinity to IL-17F of 1.75 nM. In one embodiment, the antibody of the present invention has an affinity to IL-17F of less than 500 pM. In one embodiment, the antibody molecule of the present invention has a binding affinity to IL-17F of 100 pM or less. In one embodiment, the antibody of the present invention has an affinity to IL-17F of 50 pM or less. In one embodiment, the antibody of the present invention has an affinity to IL-17F of 23 pM. In one embodiment, the antibody molecule of the present invention has a binding affinity to IL-17F of 10 pM or less. In one embodiment, the antibody molecule of the present invention has a binding affinity to IL-17F of 5 pM or less.

[0154] Preferably, the antibody molecule of the present invention has a binding affinity to the IL-17A / F heterodimer of 10 nM or less. In one embodiment, the antibody molecule of the present invention has a binding affinity to the IL-17A / F heterodimer of 500 pM or less. In one embodiment, the antibody molecule of the present invention has a binding affinity to the IL-17A / F heterodimer of 150 pM or less. In one embodiment, the antibody molecule of the present invention has a binding affinity to the IL-17A / F heterodimer of 116 pM. In one embodiment, the antibody molecule of the present invention has a binding affinity to the IL-17A / F heterodimer that is better than 100 pM. In one embodiment, the antibody molecule of the present invention has a binding affinity to the IL-17A / F heterodimer of 10 pM or less. In one embodiment, the antibody molecule of the present invention has a binding affinity to the IL-17A / F heterodimer of 5 pM or less.

[0155] In one embodiment, the antibody molecule of the invention has a binding affinity for cynomolgus IL-17F of less than 2 nM. In one embodiment, the antibody molecule of the invention has a binding affinity for cynomolgus IL-17F of 1.03 nM. Cross-blocking antibodies

[0156] Antibodies that cross-block the binding of the antibodies of the invention, particularly those that comprise the heavy chain sequence gH9 (SEQ ID NO: 11) and the light chain sequence gL57 (SEQ ID NO: 10) or the light chain sequence gL7 (SEQ ID NO: 9), are useful for neutralizing IL-17A and IL-17F activity. Thus, the present invention also provides neutralizing antibodies that bind human IL-17A and / or human IL-17F and cross-block the binding of any one of the above-mentioned antibodies to human IL-17A and / or human IL-17F / and / or human IL-17A / F heterodimers and / or cross-block the binding of IL-17A and / or IL-17F / and / or human IL-17A / F heterodimers by any one of these antibodies. In one embodiment, such antibodies bind to the same epitope as the antibodies described herein above. In another embodiment, the cross-blocking neutralizing antibodies bind to epitopes adjacent and / or overlapping with the epitopes bound by the above-mentioned antibodies. In another embodiment, a cross-blocking neutralising antibody according to this aspect of the invention does not bind to the same epitope as an antibody of the invention or to an epitope adjacent and / or overlapping said epitope.

[0157] Cross-blocking antibodies can be identified using any suitable method in the art, for example, competitive ELISA or BIAcore, where binding of the cross-blocking antibody to human IL-17A and / or human IL-17F prevents binding of the antibody of the invention, or vice versa. In surface plasmon resonance (BIAcore), the target molecule is immobilized on a solid phase and exposed to a ligand in a mobile phase that moves along a flow cell. Ligand binding to the immobilized target changes the local refractive index, resulting in a change in the SPR angle, which can be monitored in real time by detecting changes in the intensity of the reflected light. The rate of change of the SPR signal can be analyzed to obtain the apparent rate constants of the association and dissociation phases of the binding reaction. The ratio of these values ​​gives the apparent equilibrium constant (affinity) (see, for example, Wolff et al., Cancer Res. 53:2560 65 (1993)). Conditions suitable for surface plasmon resonance (BIAcore) assays are known in the art and are described elsewhere herein.

[0158] ELISA-derived methods for determining cross-blocking are also well known in the art. A non-limiting exemplary assay format suitable for both IL-17A and IL-17F is as follows, and is illustrated using IL-17A. Anti-IL-17A / F antibody (Ab-1) is coated (e.g., 50 μL per 1 μg / ml) on a 96-well ELISA plate (e.g., Corning 96 Well EIA / RIA Flat Bottom Microplate (product number 3590), Corning Inc., Acton, Mass.) for at least 1 hour. After this coating step, the antibody solution is removed, and the plate is washed once or twice with a washing solution (e.g., PBS and 0.05% Tween20), and then blocked using an appropriate blocking solution (e.g., PBS, 1% BSA, 1% goat serum, and 0.5% Tween20) and procedures known in the art. The blocking solution is then removed from the ELISA plate, and a second anti-IL17A / F antibody (Ab-2), which is being tested for its ability to cross-block the coated antibody, is added in excess (e.g., 50 μl per 10 μg / ml) to the appropriate wells of the ELISA plate. A limited amount of IL-17A in blocking solution (e.g., 50 μl per 10 ng / ml) is then added to the appropriate wells, and the plate is incubated at room temperature for at least 1 hour with shaking. The plate is then washed 2-4 times with washing solution. An appropriate amount of IL-17A detection reagent [e.g., biotinylated anti-IL-17 polyclonal antibody precomplexed with an appropriate amount of streptavidin-horseradish peroxidase (HRP) conjugate] in blocking solution is added to the ELISA plate and incubated at room temperature for at least 1 hour. The plate is then washed with washing solution and developed with an appropriate reagent [e.g., HRP substrate such as TMB (colorimetric) or various HRP luminescent substrates]. The background signal of the assay is defined as the signal obtained in wells containing the coated antibody (in this case Ab-1), the second solution phase antibody (in this case Ab-2), IL-17A buffer only (i.e., no IL-17A) and the IL-17A detection reagent.The positive control signal of the assay is defined as the signal obtained in wells containing coated antibody (in this case Ab-1), second solution phase antibody buffer only (i.e., no second solution phase antibody), IL-17A and IL-17A detection reagent. Preferably, the ELISA assay is performed in such a manner that the positive control signal is at least 6-fold the background signal.

[0159] In one embodiment, a neutralizing antibody is provided that binds to human IL-17A and human IL-17F and cross-blocks an antibody whose heavy chain comprises the sequence gH9 (SEQ ID NO:11) and whose light chain comprises the sequence gL57 (SEQ ID NO:10) from binding to human IL-17A and human IL-17F. In one embodiment, the cross-blocking antibody provided by the invention inhibits binding of an antibody comprising the heavy chain sequence gH9 (SEQ ID NO:11) and the light chain sequence gL57 (SEQ ID NO:10) to IL-17A by greater than 80%, preferably greater than 85%, more preferably greater than 90%, and even more preferably greater than 95%, and inhibits binding to IL-17F by greater than 80%, preferably greater than 85%, more preferably greater than 90%, and even more preferably greater than 95%.

[0160] In one embodiment, a neutralizing antibody is provided that binds to human IL-17A and human IL-17F and cross-blocks an antibody whose heavy chain comprises the sequence gH9 (SEQ ID NO:11) and whose light chain comprises the sequence gL7 (SEQ ID NO:9) from binding to human IL-17A and human IL-17F. In one embodiment, the cross-blocking antibody provided by the invention inhibits binding of an antibody comprising the heavy chain sequence gH9 (SEQ ID NO:11) and the light chain sequence gL7 (SEQ ID NO:9) to IL-17A by greater than 80%, preferably greater than 85%, more preferably greater than 90%, and even more preferably greater than 95%, and inhibits binding to IL-17F by greater than 80%, preferably greater than 85%, more preferably greater than 90%, and even more preferably greater than 95%.

[0161] In one embodiment, a neutralizing antibody is provided that binds to human IL-17A and human IL-17F and cross-blocks the binding of an antibody whose heavy chain comprises the sequence gH9 (SEQ ID NO:11) and whose light chain comprises the sequence gL57 (SEQ ID NO:10) to human IL-17A and human IL-17F and to the human IL-17A / F heterodimer. In one embodiment, a cross-blocking antibody provided by the present invention inhibits binding of an antibody comprising the heavy chain sequence gH9 (SEQ ID NO:11) and the light chain sequence gL57 (SEQ ID NO:10) to IL-17A by greater than 80%, preferably greater than 85%, more preferably greater than 90%, and even more preferably greater than 95%; inhibits binding to IL-17F by greater than 80%, preferably greater than 85%, more preferably greater than 90%, and even more preferably greater than 95%; and inhibits binding to IL-17A / F heterodimer to IL-17F by greater than 80%, preferably greater than 85%, more preferably greater than 90%, and even more preferably greater than 95%.

[0162] In one embodiment, a neutralizing antibody is provided that binds to human IL-17A and human IL-17F and cross-blocks an antibody whose heavy chain comprises the sequence gH9 (SEQ ID NO:11) and whose light chain comprises the sequence gL7 (SEQ ID NO:9) from binding to human IL-17A and human IL-17F and human IL-17A / F heterodimer. In one embodiment, the cross-blocking antibody provided by the present invention inhibits the binding of an antibody comprising the heavy chain sequence gH9 (SEQ ID NO:11) and the light chain sequence gL7 (SEQ ID NO:9) to IL-17A by greater than 80%, preferably greater than 85%, more preferably greater than 90%, and even more preferably greater than 95%, inhibits the binding of IL-17F by greater than 80%, preferably greater than 85%, more preferably greater than 90%, and even more preferably greater than 95%, and inhibits the binding of IL-17F to IL-17A / F heterodimer by greater than 80%, preferably greater than 85%, more preferably greater than 90%, and even more preferably greater than 95%.

[0163] In one embodiment, a neutralizing antibody is provided that binds human IL-17A and human IL-17F and cross-blocks an antibody whose heavy chain comprises the sequence gH9 (SEQ ID NO:11) and whose light chain comprises the sequence gL57 (SEQ ID NO:10) from binding to human IL-17A or human IL-17F or human IL-17A / F heterodimer. In one embodiment, the cross-blocking antibody provided by the invention inhibits binding of an antibody comprising the heavy chain sequence gH9 (SEQ ID NO:11) and the light chain sequence gL57 (SEQ ID NO:10) to IL-17A or IL-17F or IL-17A / F by greater than 80%, preferably greater than 85%, more preferably greater than 90%, and even more preferably greater than 95%.

[0164] In one embodiment, a neutralizing antibody is provided that binds human IL-17A and human IL-17F and cross-blocks an antibody whose heavy chain comprises the sequence gH9 (SEQ ID NO:11) and whose light chain comprises the sequence gL7 (SEQ ID NO:9) from binding to human IL-17A or human IL-17F or human IL-17A / F heterodimer. In one embodiment, the cross-blocking antibody provided by the present invention inhibits binding of an antibody comprising the heavy chain sequence gH9 (SEQ ID NO:11) and the light chain sequence gL7 (SEQ ID NO:9) to IL-17A or IL-17F or IL-17A / F by greater than 80%, preferably greater than 85%, more preferably greater than 90%, and even more preferably greater than 95%.

[0165] Alternatively or additionally, the neutralizing antibody of this aspect of the invention may be cross-blocked from binding to human IL-17A and human IL-17F by an antibody comprising the heavy chain sequence gH9 (SEQ ID NO:11) and the light chain sequence gL57 (SEQ ID NO:10). Thus, there is also provided a neutralizing antibody molecule that binds to human IL-17A and human IL-17F that is cross-blocked from binding to human IL-17A and human IL-17F by an antibody comprising the heavy chain sequence gH9 (SEQ ID NO:11) and the light chain sequence gL57 (SEQ ID NO:10). In one embodiment, the neutralizing antibody provided by this aspect of the invention inhibits binding of an antibody comprising the heavy chain sequence gH9 (SEQ ID NO:11) and the light chain sequence gL57 (SEQ ID NO:10) to human IL-17A and human IL-17F by greater than 80%, preferably greater than 85%, more preferably greater than 90%, and even more preferably greater than 95%.

[0166] Alternatively or additionally, the neutralizing antibody of this aspect of the invention may be cross-blocked from binding to human IL-17A and human IL-17F by an antibody comprising the heavy chain sequence gH9 (SEQ ID NO:11) and the light chain sequence gL7 (SEQ ID NO:9). Thus, there is also provided a neutralizing antibody molecule that binds to human IL-17A and human IL-17F that is cross-blocked from binding to human IL-17A and human IL-17F by an antibody comprising the heavy chain sequence gH9 (SEQ ID NO:11) and the light chain sequence gL7 (SEQ ID NO:9). In one embodiment, the neutralizing antibody provided by this aspect of the invention inhibits binding of an antibody comprising the heavy chain sequence gH9 (SEQ ID NO:11) and the light chain sequence gL7 (SEQ ID NO:9) to IL-17A and IL-17F by greater than 80%, preferably greater than 85%, more preferably greater than 90%, and even more preferably greater than 95%.

[0167] In another embodiment, a neutralizing antibody molecule is provided that binds human IL-17A and human IL-17F, which is cross-blocked from binding to human IL-17A and human IL-17F and human IL-17A / F heterodimers by an antibody comprising the heavy chain sequence gH9 (SEQ ID NO:11) and the light chain sequence gL57 (SEQ ID NO:10). In one embodiment, the neutralizing antibody provided by this aspect of the invention has binding of an antibody comprising the heavy chain sequence gH9 (SEQ ID NO:11) and the light chain sequence gL57 (SEQ ID NO:10) to human IL-17A and human IL-17F and human IL-17A / F heterodimers by greater than 80%, preferably greater than 85%, more preferably greater than 90%, and even more preferably greater than 95%.

[0168] In another embodiment, a neutralizing antibody molecule is provided that binds human IL-17A and human IL-17F, which is cross-blocked from binding to human IL-17A and human IL-17F and human IL-17A / F heterodimers by an antibody comprising the heavy chain sequence gH9 (SEQ ID NO:11) and the light chain sequence gL7 (SEQ ID NO:9). In one embodiment, the neutralizing antibody provided by this aspect of the invention has binding of an antibody comprising the heavy chain sequence gH9 (SEQ ID NO:11) and the light chain sequence gL7 (SEQ ID NO:9) to human IL-17A and human IL-17F and human IL-17A / F heterodimers by greater than 80%, preferably greater than 85%, more preferably greater than 90%, and even more preferably greater than 95%.

[0169] Thus, there is also provided a neutralizing antibody molecule that binds human IL-17A and human IL-17F that is cross-blocked from binding to human IL-17A or human IL-17F or human IL-17A / F by an antibody comprising the heavy chain sequence gH9 (SEQ ID NO:11) and the light chain sequence gL57 (SEQ ID NO:10). In one embodiment, the neutralizing antibody provided by this aspect of the invention has binding of an antibody comprising the heavy chain sequence gH9 (SEQ ID NO:11) and the light chain sequence gL57 (SEQ ID NO:10) to IL-17A or IL-17F or IL-17A / F inhibited by greater than 80%, preferably greater than 85%, more preferably greater than 90%, and even more preferably greater than 95%.

[0170] Thus, there is also provided a neutralizing antibody molecule that binds human IL-17A and human IL-17F that is cross-blocked from binding to human IL-17A or human IL-17F or human IL-17A / F by an antibody comprising the heavy chain sequence gH9 (SEQ ID NO:11) and the light chain sequence gL7 (SEQ ID NO:9). In one embodiment, the neutralizing antibody provided by this aspect of the invention has binding of an antibody comprising the heavy chain sequence gH9 (SEQ ID NO:11) and the light chain sequence gL7 (SEQ ID NO:9) to IL-17A or IL-17F or IL-17A / F inhibited by greater than 80%, preferably greater than 85%, more preferably greater than 90%, and even more preferably greater than 95%. Epitopes of IL-17A / 17-F

[0171] The present invention also provides specific regions or epitopes of human IL-17A and / or human IL-17F and / or specific regions or epitopes of the human IL-17A / F heterodimer bound by the antibodies provided by the present invention, in particular those bound by antibodies comprising the heavy chain sequence gH9 (SEQ ID NO: 11) and / or the light chain sequence gL7 (SEQ ID NO: 9) and / or the light chain sequence gL57 (SEQ ID NO: 10). The sequences of human IL-17A and human IL-17F are shown in Figure [1] (SEQ ID NOs: 27 and 28) herein.

[0172] Examples of epitopes of the present invention and methods for determining those epitopes are provided in Examples 5-7 of US Pat. No. 8,679,494 (priority date April 23, 2008).

[0173] Any suitable method known in the art (e.g., hydrogen-deuterium exchange, site-directed mutagenesis, mass spectrometry, NMR and X-ray crystallography) can be used to determine the residues bound by the antibodies provided by the present invention. See, for example, the methods described in WO 2007 / 149032.

[0174] Specific regions or epitopes of human IL-17A polypeptide and / or human IL-17F polypeptide and / or human IL-17A / F heterodimer can be identified by any suitable epitope mapping method known in the art in combination with any one of the antibodies provided by the present invention. An example of such a method includes screening peptides of various lengths derived from IL-17A and IL-17F for binding to the antibody of the present invention using the smallest fragment capable of specifically binding to the antibody that contains the sequence of the epitope recognized by the antibody. IL-17 peptides can be made synthetically or by proteolytic digestion of the appropriate IL-17 polypeptide. Peptides that bind to the antibody can be identified, for example, by mass spectrometry. In another example, NMR spectroscopy can be used to identify the epitope to which the antibody of the present invention binds. In another example, NMR spectroscopy can be used to identify residues that interact with the antibody of the present invention. Once identified, the epitopic fragment that binds an antibody of the invention can be used, if necessary, as an immunogen to obtain additional neutralizing antibodies that bind the same epitope.

[0175] In one embodiment, the invention provides a neutralizing epitope of IL-17A comprising or consisting of one or more residues selected from the group consisting of TYR44, ASN45, TRP51, ASN52 and ASP84 of human IL-17A (SEQ ID NO:27).

[0176] In one embodiment, the invention provides a neutralizing epitope of IL-17A comprising or consisting of one or more residues selected from the group consisting of SER41, TYR44, ASN45, TRP51, ASN52, HIS54, ARG72, HIS73 and ASP84 of human IL-17A (SEQ ID NO:27).

[0177] In one embodiment, the invention provides a neutralizing epitope of IL-17A comprising or consisting of one or more residues selected from the group consisting of SER41, TYR44, ASN45, ARG46, TRP51, ASN52, HIS54, ARG72, HIS73, ASP84, HIS86, VAL128, HIS129 and VAL131 (SEQ ID NO: 27) of human IL-17A.

[0178] In one embodiment, the invention provides a neutralizing epitope of IL-17A comprising one or more residues selected from the group consisting of TYR44, ASN45, TRP51, ASN52 and ASP84 of human IL-17A (SEQ ID NO: 27), and optionally comprising one or more residues selected from the group consisting of SER41, ARG46, HIS54, ARG72, HIS73, HIS86, VAL128, HIS129 and VAL131 of human IL-17A (SEQ ID NO: 27).

[0179] In one embodiment, the invention provides a neutralizing epitope of IL-17A comprising amino acid residues TYR44, ASN45, TRP51, ASN52 and ASP84 of human IL-17A (SEQ ID NO: 27), and optionally one or more residues selected from the group consisting of SER41, ARG46, HIS54, ARG72, HIS73, HIS86, VAL128, HIS129 and VAL131 of human IL-17A (SEQ ID NO: 27).

[0180] IL-17A is a dimer, and in various embodiments, the epitope bound by the antibody comprises one or more residues selected from the group consisting of ARG72, HIS73, ASP80, GLY81, ASN82, ASP84, HIS86, VAL128, HIS129 and VAL131 (of SEQ ID NO:27) from the first chain of the dimer, and one or more residues selected from the group consisting of SER41, TYR44, ASN45, ARG46, TRP51, ASN52 and HIS54 (of SEQ ID NO:27) from the second chain of the dimer (e.g., selected from the group consisting of SER41, TYR44, ASN45 and ARG46).

[0181] In various embodiments, the neutralizing antibody specifically binds to an epitope of human IL-17A that comprises or consists of one or more of residues L74, Y85, H73, N82 and R72 of SEQ ID NO:27, preferably L74 and Y85.

[0182] In various embodiments, the neutralizing antibody specifically binds to an epitope of human IL-17A (eg, the sequence of which is set forth in GenBank Accession No. Q16552) that comprises or consists of one or more of L74 and G75.

[0183] The present invention further provides novel neutralizing epitopes of human IL-17F (SEQ ID NO: 28) comprising or consisting of one or more of the following residues: SER39, MET40, SER41, ARG42, ARG47, ASN53, ARG73, ASN74, LEU75, LYS83, GLU84, ASP85, ILE86, SER87, MET88, ASN89, VAL91, PRO92, GLN94, THR126, PRO127, VAL128.

[0184] The present invention further provides novel neutralizing epitopes of human IL-17F (SEQ ID NO: 28) comprising or consisting of one or more of the following residues: SER39, MET40, SER41, ARG42, ARG47, ASN53, CYS72, ARG73, ASN74, LEU75, LYS83, GLU84, ASP85, ILE86, SER87, MET88, ASN89, SER90, VAL91, PRO92, GLN94, THR119, CYS122, VAL125, THR126, PRO127, VAL128.

[0185] In one embodiment, the neutralizing epitope of human IL-17F (SEQ ID NO: 28) comprises or consists of one or more of the following residues: SER39, MET40, SER41, ARG42, ARG47, ASN53, ARG73, ASN74, LEU75, LYS83, GLU84, ASP85, ILE86, SER87, MET88, ASN89, VAL91, PRO92, GLN94, THR126, PRO127, VAL128.

[0186] In one embodiment, a neutralizing epitope of human IL-17F (SEQ ID NO: 28) comprises or consists of (or further comprises or further consists of) one or more of the following residues from the first chain of the IL17F dimer: GLN71, CYS72, ILE86, ASN89, SER90 and VAL128.

[0187] In one embodiment, a neutralizing epitope of human IL-17F (SEQ ID NO:28) comprises or consists of (or further comprises or further consists of) one or more of the residues ARG47, e.g., from the second chain of the IL17F dimer.

[0188] In one embodiment, a neutralizing epitope of human IL-17F (SEQ ID NO: 28) comprises or consists of one or more of the following residues from the first chain of the IL17F dimer: GLN71, CYS72, ASN74, LEU75, ILE86, ASN89, SER90, PRO92, VAL128, HIS131 and GLN133.

[0189] In one embodiment, a neutralizing epitope of human IL-17F (SEQ ID NO: 28) comprises or consists of (or further comprises or further consists of) one or more of residues ARG37, SER39, SER41 and ARG47, e.g., from the second chain of the IL17F dimer.

[0190] In one embodiment, a neutralizing epitope of human IL-17F (SEQ ID NO:28) comprises or consists of one or more of the following residues from the first chain of the IL17F dimer: GLN71, CYS72, ARG73, ASN74, LEU75, ILE86, SER87 ASN89, SER90, VAL91, PRO92, VAL128, HIS131 and GLN133.

[0191] In one embodiment, a neutralizing epitope of human IL-17F (SEQ ID NO: 28) comprises or consists of (or further comprises or further consists of) one or more of residues ASN33, GLN36, ARG37, SER39, SER41, ARG42, ILE44 and ARG47, e.g., from the second chain of the IL17F dimer.

[0192] In one embodiment, the neutralizing epitope of human IL-17F (SEQ ID NO: 28) comprises or consists of one or more of the following residues: GLN12, LYS13, SER24, ISO32, ASN33, GLU34, ASN35, GLN36, VAL38, SER46, ASN53, TYR54, GLN69, ISO78, ASP85, SER87, MET88, ASM89, GLN94, LYS103 and THR126.

[0193] In one embodiment, the neutralizing epitope of human IL-17F (SEQ ID NO:28) comprises or consists of one or more of residues GLN12, SER24, ASN33, GLU34, GLN36, VAL38, ASN53, TYR54, ASP85, MET88, ASM89 and THR126.

[0194] In one embodiment, the neutralizing epitope of human IL-17F (SEQ ID NO:28) comprises or consists of one or more of residues GLN12, SER24, ASN33, GLU34, ASP85 and MET88.

[0195] In one embodiment, the neutralizing epitope of human IL-17F (SEQ ID NO: 28) comprises or consists of amino acids V33 to V38.

[0196] In one embodiment, the neutralizing epitope of human IL-17F (SEQ ID NO: 28) comprises or consists of amino acids V87 to Q94.

[0197] In one embodiment, the neutralizing epitope of IL-17F (SEQ ID NO:28) further comprises one or more of the following residues: ILE129, HIS130, H131, V132, Q133.

[0198] In one embodiment, one or more neutralizing epitopes of human IL-17F (SEQ ID NO: 28) are provided that independently comprise or consist of amino acids V33 to V38 and / or V87 to Q94.

[0199] In various embodiments, the antibody specifically binds to an epitope of human IL-17F comprising or consisting of R73, I86, N89 and R47 of SEQ ID NO:28.

[0200] In various embodiments, the neutralizing antibody specifically binds to an epitope of human IL-17F (eg, the sequence of which is set forth in GenBank Accession No. Q96PD4) that comprises or consists of one or more of L75 and G76.

[0201] In various embodiments, the antibody specifically binds to an epitope of human IL-17F comprising or consisting of S39, S41, N89, C72, N74, L75, S90, V91, P92, V198 of SEQ ID NO:28.

[0202] In various embodiments, the epitope bound by the antibody comprises one or more residues selected from the group consisting of GLN71, CYS72, ARG73, ASN74, LEU75, ILE86, SER87, ASN89, SER90, VAL91, PRO92, VAL128, HIS131 and GLN133 (of SEQ ID NO:28) from the first chain of the dimer, and one or more residues selected from the group consisting of ASN33, GLN36, ARG37, SER39, SER41, ARG42, ILE44, ARG47 (of SEQ ID NO:28) from the second chain of the dimer.

[0203] In one embodiment, an epitope is defined as amino acid residues located within 4 angstroms, within 3.5 angstroms, or within 3.0 angstroms of a binding entity, such as an antibody or fragment.

[0204] The present invention also provides, if necessary, an epitope fragment of IL-17A that can be used as an immunogen to obtain a neutralizing antibody that binds to a neutralizing epitope of IL-17A. For example, an epitope fragment containing one or more of the above-mentioned amino acid residues of IL-17A may be used as an immunogen.

[0205] The present invention also provides, if necessary, epitope fragments of IL-17F that can be used as immunogens to obtain neutralizing antibodies that bind to neutralizing epitopes of IL-17F. For example, epitope fragments containing one or more of the above-mentioned amino acid residues of IL-17F may be used as immunogens.

[0206] The present invention also provides antibodies that bind and / or interact with the neutralizing epitopes provided by the present invention. It will be understood that the antibodies can interact with the epitopes of the present invention directly or indirectly, for example, by direct binding or allosteric interactions.

[0207] In one embodiment, the present invention provides antibodies that bind to and / or interact with a neutralizing epitope of IL-17A provided by the present invention.

[0208] Thus, in one embodiment, the invention provides a neutralizing antibody that binds to human IL-17A and human IL-17F, binds to and / or interacts with an epitope of human IL-17A that comprises or consists of one or more residues selected from the group consisting of TYR44, ASN45, TRP51, ASN52 and ASP84 of human IL-17A (SEQ ID NO:27).

[0209] In one embodiment, the invention provides a neutralizing antibody that binds to human IL-17A and human IL-17F that binds to an epitope of human IL-17A, including ASN52 of human IL-17A (SEQ ID NO:27).

[0210] In one embodiment, the invention provides neutralizing antibodies that bind to human IL-17A and human IL-17F that bind to epitopes of human IL-17A, including ASN52 and ASP84 of human IL-17A (SEQ ID NO:27).

[0211] In one embodiment, the invention provides neutralizing antibodies that bind to human IL-17A and human IL-17F that bind to an epitope of human IL-17A, including ARG46 and HIS54 of human IL-17A (SEQ ID NO:27).

[0212] In one embodiment, the invention provides a neutralizing antibody that binds to human IL-17A and human IL-17F, which binds to an epitope of human IL-17A that comprises or consists of one or more residues selected from the group consisting of SER41, ASN52, ARG72, HIS73 and ASP84 of human IL-17A (SEQ ID NO:27).

[0213] In one embodiment, the invention provides a neutralizing antibody that binds to human IL-17A and human IL-17F that binds to an epitope in human IL-17A that comprises or consists of one or more residues selected from the group consisting of SER41, TYR44, ASN45, ARG46, TRP51, ASN52, HIS54, ARG72, HIS73, ASP84, HIS86, VAL128, HIS129 and VAL131 of human IL-17A (SEQ ID NO:27).

[0214] In one embodiment, the present invention provides antibodies that bind to and / or interact with a neutralizing epitope of IL-17F provided by the present invention.

[0215] Thus, in one embodiment, the invention provides a neutralizing antibody that binds to human IL-17F that binds to an epitope of human IL-17F that includes one or more of residues SER39, MET40, SER41, ARG42, ARG47, ASN53, ARG73, ASN74, LEU75, LYS83, GLU84, ASP85, ILE86, SER87, MET88, ASN89, SER90, VAL91, PRO92, GLN94, THR126, PRO127, VAL128 of human IL-17F (SEQ ID NO: 28).

[0216] In one embodiment, the invention provides a neutralizing antibody that binds to human IL-17F that binds to an epitope of human IL-17F within one or more of the following regions: (i) 39-42 (SER39, MET40, SER41, ARG42), (ii) 47 (ARG47), (iii) 53 (ASN53), (iv) 72-75 (CYS72, ARG73, ASN74, LEU75), (v) 83-92 (LYS83, GLU84, ASP85, ILE86, SER87, MET88, ASN89, SER90, VAL91, PRO92), (vi) 94 (GLN94), (vii) 119 (THR119), (viii) 122 (CYS122), (ix) 125-128 (VAL125, THR126, PRO127, VAL128).

[0217] In one embodiment, an antibody of the invention binds to human IL-17A and human IL-17F. In one embodiment, an antibody of the invention binds to human IL-17A / F heterodimers. In one embodiment, an antibody of the invention binds to human IL-17A and human IL-17A / F heterodimers. In one embodiment, an antibody of the invention binds to human IL-17F and human IL-17A / F heterodimers. In a preferred embodiment, an antibody of the invention binds to human IL-17A, human IL-17F and human IL-17A / F heterodimers.

[0218] In one embodiment, the present invention provides a neutralizing antibody that binds to human IL-17A and IL-17F, which binds to an epitope of human IL-17F within one or more of the following regions: (i) 39-42 (SER39, MET40, SER41, ARG42), (ii) 47 (ARG47), (iii) 53 (ASN53), (iv) 72-75 (CYS72, ARG73, ASN7 4, LEU75), (v)83~92(LYS83, GLU84, ASP85, ILE86, SER87, MET88, ASN89, SER90, VAL91, PRO92), (vi)9 4(GLN94), (vii)119(THR119), (viii)122(CYS122), (ix)125~128(VAL125, THR126, PRO127, VAL128).

[0219] Accordingly, in one embodiment, the invention provides a neutralising antibody that binds to human IL-17A and human IL-17F, that binds to and / or interacts with an epitope of human IL-17F, and that comprises or consists of one or more residues selected from the group consisting of SER39, MET40, SER41, ARG42, ARG47, ASN53, ARG73, ASN74, LEU75, LYS83, GLU84, ASP85, ILE86, SER87, MET88, ASN89, SER90, VAL91, PRO92, GLN94, THR126, PRO127, VAL128 of SEQ ID NO:28 (IL-17F).

[0220] In one embodiment, the present invention provides an antibody that binds to and / or interacts with an epitope of human IL-17A that comprises or consists of one or more residues selected from the group consisting of SER41, TYR44, ASN45, ARG46, TRP51, ASN52, HIS54, ARG72, HIS73, ASP84, HIS86, VAL128, HIS129 and VAL131 of human IL-17A (SEQ ID NO:27) and is also capable of binding to and / or interacting with an epitope of human IL-17A that comprises or consists of one or more residues selected from the group consisting of SER39, MET40, SER41, MET50, MET60, MET70, MET80, MET90, MET100, MET110, MET120, MET130, MET140, MET150, MET160, MET170, MET180, MET190, MET200, MET210, MET220, MET230, MET240, MET250, MET260, MET270, MET280, MET290, MET300, MET310, MET400, MET410, MET510, MET320, MET420, MET520, MET330, MET430, MET530, MET340, MET440, MET540, MET350, MET450, MET550, MET360, MET460, MET560, MET370, MET470, MET570, MET380, MET480, MET580, MET390, MET490, MET59 Provided is a neutralising antibody that binds to human IL-17A and human IL-17F, that binds to and / or interacts with an epitope of human IL-17F, and that comprises or consists of one or more residues selected from the group consisting of ARG42, ARG47, ASN53, ARG73, ASN74, LEU75, LYS83, GLU84, ASP85, ILE86, SER87, MET88, ASN89, SER90, VAL91, PRO92, GLN94, THR126, PRO127, VAL128.

[0221] In one embodiment, the invention provides a neutralizing antibody that binds to human IL-17A and human IL-17F, binds to and / or interacts with an epitope of human IL-17F, and comprises or consists of one or more residues selected from the group consisting of SER39, SER41, ASN74, LEU75, ASN89, SER90, VAL91, PRO92 and VAL128 of SEQ ID NO:28 (IL-17F).

[0222] Thus, in one embodiment, the invention provides a neutralizing antibody that binds to human IL-17A and human IL-17F, binds to and / or interacts with an epitope of human IL-17F, and comprises or consists of one or more residues selected from the group consisting of ARG47, ARG73, LEU75 and ILE86 of SEQ ID NO:28 (IL-17F).

[0223] Thus, in one embodiment, the invention provides a neutralizing antibody that binds to human IL-17A and human IL-17F, which binds to and / or interacts with an epitope of human IL-17F comprising LEU75 of SEQ ID NO:28 (IL-17F). DNA sequence of isolated antibodies

[0224] The present invention also provides an isolated DNA comprising a nucleic acid sequence encoding the heavy and / or light chain of the antibody molecule of the present invention. Preferably, the DNA sequence encodes the heavy or light chain of the antibody molecule of the present invention. The DNA of the present invention may comprise synthetic DNA, e.g., produced by chemical processing, cDNA, genomic DNA, or any combination thereof.

[0225] DNA containing a nucleic acid sequence encoding the antibody molecule of the present invention can be obtained by methods well known to those skilled in the art. For example, DNA containing a nucleic acid sequence encoding a part or all of the heavy and light chains of an antibody can be synthesized as desired from a determined DNA sequence or based on the corresponding amino acid sequence.

[0226] DNA encoding acceptor framework sequences is widely available to those skilled in the art and can be readily synthesized based on their known amino acid sequences.

[0227] Standard techniques of molecular biology can be used to prepare DNA sequences encoding the antibody molecules of the present invention. The desired DNA sequence can be fully or partially synthesized using oligonucleotide synthesis techniques. Where appropriate, site-directed mutagenesis and polymerase chain reaction (PCR) techniques can be used.

[0228] Examples of suitable sequences are provided in SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25 and SEQ ID NO:26. The present invention also relates to a cloning or expression vector comprising one or more DNA sequences of the present invention. Thus, the present invention provides a cloning or expression vector comprising one or more DNA sequences encoding an antibody of the present invention. Preferably, the cloning or expression vector comprises two DNA sequences encoding the light and heavy chains, respectively, of the antibody molecule of the present invention, together with a suitable signal sequence. Preferably, the vector of the present invention comprises the sequences shown in SEQ ID NO:21 and SEQ ID NO:24. In one embodiment, the vector of the present invention comprises the sequences shown in SEQ ID NO:21 and SEQ ID NO:24.

[0229] The general methods by which vectors can be constructed, transfection methods and culture methods are well known to those skilled in the art. In this regard, see the Maniatis Manual, "Current Protocols in Molecular Biology", 1999, edited by FMAusubel, Wiley Interscience, New York and Cold Spring Harbor Publishing.

[0230] The present invention also provides host cells comprising one or more cloning or expression vectors comprising one or more DNA sequences encoding an antibody of the present invention. Any suitable host cell / vector system can be used for the expression of DNA sequences encoding the antibody molecules of the present invention. Bacterial (e.g., E. coli) and other microbial systems may be used, or eukaryotic, e.g., mammalian, host cell expression systems may be used. Suitable mammalian host cells include CHO, myeloma or hybridoma cells.

[0231] The invention also provides a process for producing an antibody molecule of the invention comprising culturing a host cell containing a vector of the invention under conditions suitable for expression of a protein from DNA encoding the antibody molecule of the invention and isolating the antibody molecule.

[0232] An antibody molecule may contain only heavy or light chain polypeptides, in which case it is necessary to use only sequences encoding heavy or light chain polypeptides to transfect host cells. For the production of products containing both heavy and light chains, a cell line may be transfected with two vectors, a first vector encoding a light chain polypeptide and a second vector encoding a heavy chain polypeptide. Alternatively, a single vector may be used that contains sequences encoding light and heavy chain polypeptides. Conjugation with effector molecules

[0233] If desired, the antibody for use in the present invention may be conjugated to one or more effector molecules. It will be understood that the effector molecule may comprise a single effector molecule, or may comprise two or more such molecules linked to form a single moiety that can be connected to the antibody of the present invention. If it is desired to obtain an antibody fragment linked to an effector molecule, it may be prepared by standard chemical or recombinant DNA procedures, in which the antibody fragment is linked to the effector molecule directly or via a coupling agent. Such techniques for binding effector molecules to antibodies are well known in the art (see Hellstrom et al., Controlled Drug Delivery, 2nd Edition, Robinson et al., eds., 1987, pp.623-53; Thorpe et al., 1982, Immunol.Rev., 62:119-58 and Dubowchik et al., 1999, Pharmacology and Therapeutics, 83, 67-123). Particular chemical procedures include, for example, those described in WO 93 / 06231, WO 92 / 22583, WO 89 / 00195, WO 89 / 01476 and WO 03031581. Alternatively, where the effector molecule is a protein or polypeptide, linkage can be achieved using recombinant DNA procedures, for example as described in WO 86 / 01533 and EP 0392745.

[0234] The term effector molecule as used herein includes, for example, anti-tumor agents, drugs, toxins, biologically active proteins, such as enzymes, other antibodies or antibody fragments, synthetic or naturally occurring polymers, nucleic acids and fragments thereof, such as DNA, RNA and fragments thereof, radioisotopes, in particular radioactive iodine, radioisotopes, chelated metals, nanoparticles, and reporter groups, such as fluorescent compounds or compounds that can be detected by NMR or ESR spectroscopy.

[0235] Examples of effector molecules may include cytotoxic agents, including cytotoxins or any agent that is detrimental to (e.g., kills) cells. Examples include combrestatins, dolastatins, epothilones, staurosporines, maytansinoids, spongiostatins, rhizoxins, halichondrins, roridin, hemiasterin, taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyantheracindione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin, and analogs or congeners thereof.

[0236] Effector molecules include, but are not limited to, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thiopeachlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C and cis-dichlorodiamineplatinum(II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, anthramycin (AMC), calicheamicin or duocarmycin), and antimitotic agents (e.g., vincristine and vinblastine).

[0237] Other effector molecules include radionuclides, e.g. 111 In and 90 Y.,Lu 177 , Bismuth 213 , Californium 252 ,iridium 192 and tungsten 188 / ruthenium188 or drugs, which may include, but are not limited to, alkylphosphocholines, topoisomerase I inhibitors, taxoids and suramin.

[0238] Other effector molecules include proteins, peptides and enzymes. Enzymes of interest include, but are not limited to, proteases, hydrolases, lyases, isomerases, transferases. Proteins, polypeptides and peptides of interest include, but are not limited to, immunoglobulins, toxins such as abrin, lysine A, Pseudomonas exotoxin, or diphtheria toxin, proteins such as insulin, tumor necrosis factor, alpha-interferon, beta-interferon, nerve growth factor, platelet-derived growth factor or tissue plasminogen activator, thrombotic agents or angiogenesis inhibitors such as angiostatin or endostatin, or biological response modifiers such as lymphokines, interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), granulocyte macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), nerve growth factor (NGF) or other growth factors and immunoglobulins.

[0239] Other effector molecules may include detectable substances useful, for example, in diagnosis. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent substances, luminescent substances, bioluminescent substances, radionuclides, positron-emitting metals (for use in positron emission tomography), and non-radioactive paramagnetic metal ions. For metal ions that can be conjugated to antibodies for use as diagnostic agents, see generally U.S. Pat. No. 4,741,900. Suitable enzymes include horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase. Suitable prosthetic groups include streptavidin, avidin, and biotin. Suitable fluorescent substances include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride, and phycoerythrin. Suitable luminescent substances include luminol. Suitable bioluminescent materials include luciferase, luciferin and aequorin. Suitable radionuclides include: 125 I, 131 I, 111 In and 99 Contains Tc.

[0240] In another example, the effector molecule may increase the half-life of the antibody in vivo and / or reduce the immunogenicity of the antibody and / or enhance delivery of the antibody across an epithelial barrier to the immune system. Examples of suitable effector molecules of this type include polymers, albumin, albumin binding proteins, or albumin binding compounds such as those described in WO 05 / 117984.

[0241] When the effector molecule is a polymer, it may generally be a synthetic or naturally occurring polymer, such as an optionally substituted linear or branched polyalkylene, polyalkenylene or polyoxyalkylene polymer or a branched or unbranched polysaccharide, such as a homopolysaccharide or heteropolysaccharide.

[0242] Particular optional substituents which may be present on the above-mentioned synthetic polymers include one or more hydroxy, methyl or methoxy groups.

[0243] Particular examples of synthetic polymers include optionally substituted linear or branched poly(ethylene glycol), poly(propylene glycol), poly(vinyl alcohol) or derivatives thereof, in particular optionally substituted poly(ethylene glycol), such as methoxypoly(ethylene glycol), or derivatives thereof.

[0244] Specific naturally occurring polymers include lactose, amylose, dextran, glycogen or derivatives thereof.

[0245] As used herein, "derivative" is intended to include reactive derivatives, e.g., thiol-selective reactive groups such as maleimides and the like. The reactive group may be directly attached to the polymer or may be attached via a linker segment of the polymer. It will be understood that the residue of such a group will, in some cases, form part of the product as the linking group between the antibody fragment and the polymer.

[0246] The size of the polymer may be varied as desired, but will generally range from 500 Da to 50,000 Da, preferably 5,000 to 40,000 Da, more preferably 20,000 to 40,000 Da, in average molecular weight. The size of the polymer may be selected based on, among other things, the intended use of the product (e.g., the ability to localize to a particular tissue, such as a tumor, or to extend blood half-life) (for review, see Chapman, 2002, Advanced Drug Delivery Reviews, 54, 531-545). Thus, for example, when the product is intended to leave the circulation and penetrate into tissues, for example, for use in treating tumors, it may be advantageous to use a low molecular weight polymer (e.g., a molecular weight of about 5,000 Da). For applications in which the product will remain in the blood, it may be advantageous to use a higher molecular weight polymer (e.g., 20,000 Da to 40,000 Da).

[0247] Particularly preferred polymers include polyalkylene polymers such as poly(ethylene glycol), or especially methoxypoly(ethylene glycol), or derivatives thereof, especially those having a molecular weight in the range of about 15,000 Da to about 40,000 Da.

[0248] In one example, the antibody used in the present invention is attached to a poly(ethylene glycol) (PEG) moiety. In one particular example, the antibody is an antibody fragment, and the PEG molecule may be attached via any available amino acid side chain or terminal amino acid functional group located in the antibody fragment, such as any free amino, imino, thiol, hydroxyl or carboxyl group. Such amino acids may be naturally present in the antibody fragment or may be engineered into the fragment using recombinant DNA methods (see, for example, U.S. Pat. No. 5,219,996; U.S. Pat. No. 5,667,425; WO 98 / 25971). In one example, the antibody molecule of the present invention is a modified Fab fragment modified to add one or more amino acids to the C-terminus of its heavy chain to allow for the attachment of an effector molecule. Preferably, the additional amino acids form a modified hinge region containing one or more cysteine ​​residues to which an effector molecule may be attached. Multiple sites may be used to attach two or more PEG molecules.

[0249] Preferably, the PEG molecule is covalently attached via a thiol group of at least one cysteine ​​residue located in the antibody fragment. Each polymer molecule connected to the modified antibody fragment may be covalently attached to the sulfur atom of a cysteine ​​residue located in the fragment. The covalent bond will generally be a disulfide bond, or in particular a sulfur-carbon bond. When a thiol group is used as the attachment point, an appropriately activated effector molecule (e.g., thiol-selective derivatives such as maleimides and cysteine ​​derivatives) may be used. The activated polymer may be used as a starting material in the preparation of the polymer-modified antibody fragments described above. The activated polymer may be any polymer containing a thiol-reactive group, such as an α-halo carboxylic acid or ester, e.g., iodoacetamide, imide, e.g., maleimide, vinyl sulfone, or disulfide. Such starting materials can be commercially available (e.g., from Nektar, formerly Shearwater Polymers Inc., Huntsville, Ala, USA) or can be prepared using conventional chemical procedures from commercially available starting materials. Particular PEG molecules include 20K methoxy-PEG-amine (available from Nektar, formerly Shearwater; Rapp Polymere; and SunBio) and M-PEG-SPA (available from Nektar, formerly Shearwater).

[0250] In one embodiment, the antibody is a modified Fab fragment that is PEGylated, i.e., has PEG (poly(ethylene glycol)) covalently attached thereto, for example according to the methods disclosed in EP 0948544. [see also "Poly(ethyleneglycol)Chemistry, Biotechnical and Biomedical Applications", 1992, J. Milton Harris (ed.), Plenum Press, New York, "Poly(ethyleneglycol)Chemistry and Biological Applications", 1997, J. Milton Harris and S. Zalipsky (eds.), American Chemical Society, Washington DC, and "Bioconjugation Protein Coupling Techniques for the Biomedical Sciences", 1998, M. Aslam and A. Dent, Grove Publishers, New York; Chapman, A. 2002, Advanced Drug Delivery Reviews 2002, 54:531-545]. In one example, PEG is attached to a cysteine ​​in the hinge region. In one example, the PEG-modified Fab fragment has a maleimide group covalently attached to one thiol group in the modified hinge region. A lysine residue may be covalently attached to this maleimide group, and a methoxypoly(ethylene glycol) polymer with a molecular weight of about 20,000 Da may be attached to each amine group on the lysine residue. Thus, the total molecular weight of the PEG attached to the Fab fragment may be about 40,000 Da.

[0251] In one embodiment, the neutralizing antibody molecule of the invention is a modified Fab fragment having a modified hinge region comprising at least one cysteine ​​residue at the C-terminus of the heavy chain, to which an effector molecule is attached. In one embodiment, the invention provides a neutralizing antibody molecule having specificity for human IL-17A and human IL-17F, which is a modified Fab fragment having a heavy chain comprising the sequence shown in SEQ ID NO: 11 and a light chain comprising the sequence shown in SEQ ID NO: 9 or the sequence shown in SEQ ID NO: 10, and having a modified hinge region comprising at least one cysteine ​​residue at the C-terminus of the heavy chain to which an effector molecule is attached. The effector molecule is preferably PEG, in which a lysyl-maleimide group is attached to the cysteine ​​residue at the C-terminus of the heavy chain, and each amino group of the lysyl residue is covalently bound to a methoxypoly(ethylene glycol) residue having a molecular weight of about 20,000 Da, by attachment using the methods described in (WO 98 / 25971 and WO 2004072116). Thus, the total molecular weight of the PEG attached to the antibody is approximately 40,000 Da.

[0252] In another example, effector molecules may be attached to antibody fragments using the methods described in International Patent Applications Nos. 2005 / 003169, 2005 / 003170 and 2005 / 003171. Pharmaceutical Compositions, Dosage Regimens

[0253] Since the antibody of the present invention is useful for the treatment and / or prevention of pathological conditions, the present invention also provides a pharmaceutical or diagnostic composition comprising the antibody molecule of the present invention together with one or more pharma- ceutically acceptable excipients, diluents or carriers. Accordingly, there is provided the use of the antibody of the present invention for the manufacture of a medicament. The composition will usually be supplied as part of a sterile pharmaceutical composition, which may usually include a pharma- ceutically acceptable carrier. The pharmaceutical composition of the present invention may further include a pharma- ceutically acceptable adjuvant.

[0254] The present invention also provides a process for the preparation of a pharmaceutical or diagnostic composition which comprises adding and mixing an antibody molecule of the invention with one or more pharma- ceutically acceptable excipients, diluents or carriers.

[0255] The antibody molecule may be the sole active ingredient in a pharmaceutical or diagnostic composition or may be associated with other active ingredients including other antibody components such as, for example, anti-TNF, anti-IL-1β, anti-T cell, anti-IFNγ, anti-LPS antibodies, or non-antibody components such as xanthines or small molecule inhibitors.

[0256] The pharmaceutical composition preferably comprises a therapeutically effective amount of the antibody of the invention. As used herein, the term "therapeutically effective amount" refers to the amount of a therapeutic agent required to treat, ameliorate or prevent a targeted disease or condition, or to exhibit a detectable therapeutic or prophylactic effect.

[0257] The exact therapeutically effective amount for a human subject will vary depending on the severity of the disease state, the subject's overall health, the subject's age, weight and sex, diet, time and frequency of administration, drug combinations, reaction sensitivities and tolerance / response to treatment. This amount can be determined by routine experimentation and is within the judgement of the clinician. In general, a therapeutically effective amount will be 0.01 mg / kg to 50 mg / kg, preferably 0.1 mg / kg to 20 mg / kg (e.g., 5 mg / kg to 10 mg / kg, e.g., about 8 mg / kg). Pharmaceutical compositions can be conveniently provided in unit dosage forms containing a predetermined amount of the active agent of the invention per dosage. The unit dose may be from 10 mg to 1000 mg (e.g., 80 mg to 720 mg, 100 mg to 680 mg, or 160 mg to 640 mg), preferably 8 mg, 16 mg, 32 mg, 40 mg, 80 mg, 160 mg, 240 mg, 320 mg, 480 mg, 560 mg, and 640 mg.

[0258] In various embodiments of the method of treating psoriasis, e.g., psoriasis vulgaris, the amount of neutralizing antibody administered to the subject is an amount that achieves at least a 50% change, at least a 60% change, at least a 75% change (e.g., at least an 80% change, at least an 85% change, at least a 90% change, or at least a 95% change) in Lesion Severity Score (LSS) compared to pretreatment (i.e., LSS before administration of the neutralizing antibody) 2 weeks, 4 weeks, 6 weeks, or 8 weeks after administration of the antibody. Alternatively, or in addition, the amount of neutralizing antibody administered is an amount that achieves at least a 50% change, at least a 60% change, at least a 75% change (e.g., at least an 80% change, at least an 85% change, at least a 90% change, or at least a 95% change) in Psoriasis Area and Severity Index (PASI) compared to pretreatment 2 weeks, 4 weeks, 6 weeks, or 8 weeks after administration of the antibody. Alternatively, or in addition, the amount of neutralizing antibody is an amount that achieves at least a 50% change, at least a 60% change, at least a 75% change (e.g., at least an 80% change, at least an 85% change, at least a 90% change, or at least a 95% change) in PASI compared to pre-treatment 2, 4, 6, or 8 weeks after administration of the antibody, and maintains or increases the change in PASI response compared to pre-treatment 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or more weeks after administration of the antibody.In some cases, the amount of neutralizing antibody is an amount that achieves at least a 50% change, at least a 60% change, at least a 75% change (e.g., at least an 80% change, at least an 85% change, at least a 90% change, or at least a 95% change) in PASI compared to pre-treatment 2 weeks, 4 weeks, 6 weeks, or 8 weeks after administration of the antibody, and does not change the PASI score by more than 5%, more than 10%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% relative to baseline (pre-treatment level) compared to pre-treatment 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, or more after administration of the antibody.

[0259] Another method for evaluating the treatment of psoriasis is the Physician's Global Assessment score. The PGA scoring system is based on erythema lesions, induration and scale, usually using a 5-level or 6-level scale, with score allocation from non-applicable to severe.See, for example, Langley et al., J Am Acad Dermatol.2004;51(4):563-569.In various embodiments, the method of treating psoriasis described herein results in a reduction of PGA score from baseline at least 20%, at least 50%, or at least 70% at 2 weeks, 6 weeks, 8 weeks and / or 12 weeks after administration.

[0260] In various embodiments relating to the treatment of psoriatic arthritis, the amount of neutralizing antibody administered to a subject is such that (i) at least a 50% change, at least a 60% change, at least a 75% change (e.g., at least an 80% change, at least an 85% change, at least a 90% change, or at least a 95% change) in Lesion Severity Score (LSS) 2, 4, 6, or 8 weeks after administration of the antibody compared to pre-treatment (i.e., the LSS before administration of the neutralizing antibody), and / or (ii) at least a 50% change, at least a 60% change, at least a 75% change (e.g., at least an 80% change, at least an 85% change, at least a 90% change, or at least a 95% change) in Psoriasis Area and Severity Index (PASI) 2, 4, 6, or 8 weeks after administration of the antibody compared to pre-treatment, and / or (iii) at least a 50% change, at least a 60% change, at least a 75% change (e.g., at least an 80% change, at least an 85% change, at least a 90% change, or at least a 95% change) in Psoriasis Area and Severity Index (PASI) 2, 4, 6, or 8 weeks after administration of the antibody compared to pre-treatment, and / or (iv) at least a 50% change, at least a 60% change, at least a 75% change (e.g., at least a 80% change, at least a 85% change, at least a 90% change, or at least a 95% change) in Psoriasis Area and Severity Index (PASI) 2, 4, 6, or 8 weeks after administration of the antibody compared to pre-treatment, Alternatively, or in addition, the amount of neutralizing antibody is an amount that achieves the above-mentioned changes in LSS, PASI and / or ACR scores 2, 4, 6, or 8 weeks after administration of the antibody, and maintains or increases the changes in LSS, PASI and / or ACR responses 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or more weeks after administration of the antibody.In some cases, the amount of neutralizing antibody is an amount that achieves the above-mentioned changes in LSS, PASI and / or ACR scores 2 weeks, 4 weeks, 6 weeks, or 8 weeks after administration of the antibody, and does not change the LSS, PASI and / or ACR scores by more than 5%, more than 10%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% relative to baseline (pre-treatment levels) relative to baseline (pre-treatment levels) an additional 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, or more after administration of the antibody.

[0261] CA028_0496.g3 has been studied in patients after a single intravenous administration over a dose range of 8 mg to 640 mg. CA028_0496.g3 has also been studied as a repeated dose with different dosing regimens involving a loading dose followed by a maintenance dose of 3 to 6 weeks. Multiple dosing regimens without a loading dose are also envisioned as part of the present invention.

[0262] It is understood that an appropriate dosing regimen for any given anti-IL-17A / F antibody can be designed using PK and PD (efficacy) information determined for the antibody, as described in the Examples herein for CA028_0496.g3 (bimekizumab). Typically, a dosing regimen for use in the present invention will provide an average trough level of about 1-50 μg / ml, for example an average trough level of greater than 10 μg / ml, after a single dose or multiple doses (steady state).

[0263] Potential dose ranges and regimens for any of the embodiments described herein include, but are not limited to, dosing in the range of 10 mg to 1000 mg unit doses (e.g., 8 mg, 16 mg, 32 mg, 40 mg, 64 mg, 80 mg, 160 mg, 240 mg, 320 mg, 480 mg, 560 mg, or 640 mg) given every 1 to 10 weeks (by any route of administration, e.g., either subcutaneous or intravenous). Optionally, doses of neutralizing antibody are administered every 1 to 20 weeks, e.g., every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, or every 8 to 12 weeks (e.g., every 8 weeks, every 9 weeks, every 10 weeks, every 11 weeks, or every 12 weeks). The treatment period (i.e., the period during which one or more doses of antibody are administered to the subject) may include a period of at least 2 weeks, at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 30 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 52 weeks, or more. Any suitable number of doses may be administered within the treatment period (e.g., the doses and the time between administrations as described above). For example, one, two, three, or four doses of antibody are administered to the subject, for example, during a 12-week treatment period (optionally at weeks 0, 4, 8, and 12). In one exemplary embodiment, the method includes administering 320 mg of antibody to the subject every four weeks for at least 12 weeks. In one exemplary embodiment, the method includes administering 160 mg of antibody to the subject every four weeks for at least 12 weeks. In one example, the method includes administering 160 mg, 240 mg, or 320 mg every four weeks. In one example, the method includes a loading dose of 320 mg, followed by a maintenance dose of 160 mg or 240 mg every four weeks.Doses may be given at these intervals during a first treatment period, and then at different intervals during a second treatment period (e.g., administered every 4 or 8 weeks for a period of, e.g., 12, 16 or 20 weeks during a first treatment period, and then every 8, 12 or 16 weeks for a further, e.g., 24 or 36 weeks, or longer, lasting second treatment period).

[0264] In some examples of the invention, the dosing regimen used for an initial treatment period, such as the first 12 or 16 or 24 weeks of treatment, may be considered an "induction period", after which a different regimen, such as a maintenance regimen, may typically use lower dosages or less frequent dosing.

[0265] In some cases, once efficacy reaches a certain level, it is possible to reduce the dosing frequency and / or dose.For example, in the method of treating psoriasis of the present invention, if the subject reaches PASI75 or PASI90 at week 12, week 16, or week 24, the dosing frequency and / or dose can be changed.For example, in the method of treating psoriatic arthritis of the present invention, if the patient reaches ACR50 at week 12, week 16, or week 24, the dosing frequency and / or dose can be changed.For example, in the method of treating ankylosing spondylitis or nr-axSpa of the present invention, if the patient reaches ASAS40 at week 12, week 16, or week 24, the dosing frequency and / or dose can be changed.Similarly in each of these embodiments, if the subject does not reach the desired clinical score at week 12, week 16, or week 20, or week 24, the dose and / or dosing frequency can be increased.

[0266] In various embodiments, including those involving treating psoriasis in a subject, an initial dose of antibody is administered, and then subsequent doses of neutralizing antibody (e.g., CA028_0496.g3) are administered 8-20 weeks (e.g., 8 weeks, 12 weeks, 16 weeks, or 20 weeks) after the initial dose. Subsequent doses may be the same as the initial dose, increased amounts of neutralizing antibody, or decreased amounts of neutralizing antibody (i.e., maintenance doses). Administration of the neutralizing antibodies described herein (e.g., CA028_0496.g3 (bimekizumab)) has shown rapid onset and significant and sustained beneficial effects in humans, e.g., humans with psoriasis and psoriatic arthritis. For example, single doses of 160 mg or greater (e.g., 160 mg, 480 mg, and 640 mg) achieved clinically relevant and statistical significance vs. placebo at week 2 in Lesion Severity Score (LSS) and Psoriasis Area and Severity Index (PASI). Near-maximal improvement was achieved by weeks 4-6 post-dose and was maintained until approximately 16-20 weeks post-dose. In the 480 mg and 640 mg dose groups, on average, 83% of patients experienced a PASI 90 at weeks 6-12 and 90% at week 12. Clinically relevant responses in disease activity measures were observed 20 weeks after the first dose of neutralizing antibody (after two maintenance doses as described in Example 1) in subjects with psoriatic arthritis.

[0267] Exemplary methods of treating psoriatic arthritis provided by the present disclosure include administering to a subject an antibody described herein using any one of the following dosing regimens: 16 mg every 4 weeks, 160 mg every 4 weeks, a loading dose of 320 mg at week 0, followed by a maintenance dose of 160 mg every 4 weeks, and a maintenance dose of 320 mg every 4 weeks. In one example, a method of treating psoriatic arthritis provided by the present disclosure includes administering to a subject an antibody described herein using any one of the following dosing regimens: 160 mg every 4 weeks, 320 mg every 4 weeks, a loading dose of 320 mg at week 0, followed by a maintenance dose of 160 mg every 4 weeks, or a loading dose of 320 mg at week 0, followed by a maintenance dose of 240 mg every 4 weeks. The treatment period may include, for example, 12 weeks (at least 3 or 4 doses of antibody in total), 16 weeks, 24 weeks, or 48 weeks, or more. Doses may be given at these intervals during a first treatment period, and then at different intervals during a second treatment period (e.g., administered every 4 or 8 weeks for a period of, e.g., 12, 16 or 20 weeks during a first treatment period, and then every 8, 12 or 16 weeks for a second treatment period lasting an additional, e.g., 24 or 36 weeks or longer). For example, the dosing regimen (e.g., dosing frequency) may be altered after a given period, such that, in one example, the antibody is administered at 160 mg every 4 weeks until week 12, 16 or 24, and then at 160 mg every 8 weeks starting at week 20, 24 or 32, respectively. In one example, the antibody is administered using a dosing regimen of 320 mg every 4 weeks until week 12, 16, or 24, followed by 320 mg every 8 weeks, respectively, beginning at week 20, 24, or 32. Optionally, the dosing regimen (e.g., dosage) may be altered after a period of time, such that in one example, the antibody is administered using a dosing regimen of 160 mg or 320 mg every 4 weeks until week 12, 16, or 24, followed by a dosing regimen of 320 mg or 160 mg every 4 weeks, respectively.Optionally, the dosage and dosing frequency may be altered such that, in one example, the antibody is administered using a dosage regimen of 160 mg every 4 weeks until week 12 or 16 or 24, and then a dosage regimen of 320 mg every 8 weeks.

[0268] It will be understood that in the case of psoriatic arthritis, the dosage regimen may be different depending on whether the subject has concurrent psoriasis and / or a history of psoriasis.For example, the dosage regimen for the psoriatic arthritis patient with moderate to severe concurrent plaque psoriasis or a history of psoriasis may comprise higher dosage and / or more frequent dosing than the dosage regimen for the subject without concurrent psoriasis and / or a history of psoriasis.

[0269] Exemplary methods of treating psoriasis provided by the present disclosure include administering to a subject an antibody described herein using any one of the following dosing regimens: 64 mg every 4 weeks, 160 mg every 4 weeks or every 8 weeks, 320 mg every 4 weeks or every 8 weeks, a loading dose of 320 mg at week 0, followed by a maintenance dose of 160 mg every 4 weeks or 480 mg every 4 weeks. Doses may be given at these intervals for any suitable treatment period, such as for a period of at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 30 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 52 weeks, or longer. Doses may be given at these intervals during a first treatment period, and then at different intervals during a second treatment period (e.g., every 4 or 8 weeks for a period of, e.g., 12, 16, 20, or 24 weeks during a first treatment period, and then every 8, 12, or 16 weeks for a second treatment period lasting an additional, e.g., 24 or 36 weeks). For example, the dosing regimen (e.g., dosing frequency) may be altered after a given period, such that, in one example, the antibody is administered at 160 mg every 4 weeks until the 8th, 12th, or 16th week, and then at 160 mg every 8 weeks starting at the 16th, 20th, or 24th week, respectively. In one example, the antibody is administered using a dosing regimen of 320 mg every 4 weeks until week 8, 12 or 16, followed by 320 mg every 8 weeks beginning at week 16, 20 or 24, respectively. In one example, the antibody is administered using a dosing regimen of 320 mg or 160 mg every 4 weeks until week 8, 12 or 16, followed by 320 mg or 160 mg every 12 weeks. Optionally, the dosing regimen (e.g., dosing frequency) may be altered after a period of time, such that in one example, the antibody is administered using a dosing regimen of 320 mg every 4 weeks until week 8 or 12, followed by tapering to 160 mg every 4 weeks beginning at week 12 or 16, respectively.

[0270] An exemplary method of treating ankylosing spondylitis or nr-axSpa provided by the present disclosure includes administering to a subject an antibody described herein using any one of the following dosing regimens: 16 mg every 4 weeks, 160 mg every 4 weeks, a loading dose of 320 mg at week 0, followed by a maintenance dose of 160 mg every 4 weeks or 320 mg every 4 weeks. Preferably, the dosing regimen is 160 mg or 320 mg every 4 weeks. The treatment period may include, for example, 12 weeks (at least 3 or 4 doses of antibody in total), 16 weeks, 24 weeks, or 48 weeks, or more. Doses may be given at these intervals during a first treatment period, and then at different intervals during a second treatment period (e.g., every 4 or 8 weeks for a period of, e.g., 12, 16, 20, or 24 weeks during a first treatment period, and then every 8, 12, or 16 weeks for a second treatment period lasting an additional, e.g., 24 or 36 weeks, or longer). For example, the dosing regimen (e.g., dosing frequency) may be altered after a period of time, such that in one example, the antibody is administered using a dosing regimen of 160 mg every 4 weeks until week 12, 16, or 24, and then 160 mg every 8 weeks. In one example, the antibody is administered using a dosing regimen of 320 mg every 4 weeks until week 12, 16, or 24, and then 320 mg every 8 weeks. Optionally, the dosing regimen (e.g., dosage) may be altered after a period of time such that, in one example, the antibody is administered using a dosing regimen of 160 mg or 320 mg every 4 weeks until week 12 or week 16 or week 24, and then a dosing regimen of 320 mg or 160 mg every 4 weeks, respectively. Optionally, the dosage and dosing frequency may be altered such that, in one example, the antibody is administered using a dosing regimen of 160 mg every 4 weeks until week 12 or week 16 or week 24, and then a dosing regimen of 320 mg every 8 weeks.

[0271] Compositions may be administered individually to a patient or may be administered in combination (eg, simultaneously, sequentially or separately) with other agents, drugs or hormones.

[0272] The dosage at which the antibody molecule of the invention is administered will depend on the nature of the condition being treated, the degree of inflammation present, and whether the antibody molecule is being used prophylactically or to treat an existing condition.

[0273] The frequency of dosing will depend on the half-life of the antibody molecule and the duration of its effect. If the antibody molecule has a short half-life (e.g., 2-10 hours), it may be necessary to give one or more doses per day. Alternatively, if the antibody molecule has a long half-life (e.g., 2-15 days), it may only be necessary to administer it once per day, once per week, or once every month or two.

[0274] After the loading dose, it may be necessary to administer one or more maintenance doses.The loading dose and the maintenance dose may be the same dosage or different dosages.In one embodiment, the maintenance dose may be one-quarter, one-third, one-half, two-thirds, three-quarters, the same amount, one-quarter, one-third, one-half, one-two-thirds, one-three-quarters, twice the loading dose, or more.

[0275] In one embodiment, the maintenance doses may be administered at a predetermined interval after the loading dose. The intervals may be the same for each dose or may vary. The intervals may be one day, one week, two weeks, three weeks, four weeks, one month, six weeks, eight weeks, every other month, or any other interval. In one embodiment, after a total of three loading doses, two maintenance doses are administered every three weeks. In one embodiment, the maintenance doses are administered every four weeks.

[0276] Pharmaceutically acceptable carriers should not induce the production of antibodies harmful to the individual receiving the composition, nor should they be toxic. Suitable carriers may be large, slowly metabolized macromolecules such as proteins, polypeptides, liposomes, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive virus particles.

[0277] Pharmaceutically acceptable salts can be used, for example mineral acid salts such as hydrochlorides, hydrobromides, phosphates and sulfates, or organic acid salts such as acetates, propionates, malonates and benzoates.

[0278] The pharma- ceutically acceptable carrier in the therapeutic composition may further contain liquids such as water, saline, glycerol and ethanol.In addition, auxiliary substances, such as wetting agents or emulsifying agents or pH buffering substances, may be present in such compositions.Such carriers allow the pharmaceutical composition to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries and suspensions for ingestion by patients.

[0279] Preferred forms for administration include those suitable for parenteral administration by injection or infusion, for example, by bolus injection or continuous infusion.When the product is for injection or infusion, it may be in the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and may contain formulating agents such as suspending agents, preservatives, stabilizers and / or dispersants.Alternatively, the antibody molecule may be in a dry form for reconstitution before use in a suitable sterile liquid.

[0280] Once formulated, the compositions of the invention can be administered directly to the subject. The subject to be treated may be an animal. However, it is preferred that the compositions are suitable for administration to human subjects.

[0281] The pharmaceutical compositions of the present invention may be administered by any route, including, but not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intraventricular, transdermal, transdermal through the skin (see, for example, WO 98 / 20734), subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, vaginal or rectal. Hypodermic sprays may also be used to administer the pharmaceutical compositions of the present invention. Typically, the therapeutic compositions may be prepared as injectables, either in liquid solutions or suspensions. Solid forms suitable for solution or suspension in liquid vehicles prior to injection may also be prepared.

[0282] Direct delivery of the composition is generally accomplished by injection, subcutaneously, intraperitoneally, intravenously or intramuscularly, or delivered to the interstitial space of a tissue. The composition can also be administered to the site of a lesion. Dosage treatment can be a single dose schedule or a multiple dose schedule. A preferred embodiment of the present invention includes subcutaneous or intravenous administration of the antibody.

[0283] It is understood that the active ingredient in the composition can be an antibody molecule. In this case, the active ingredient may be susceptible to degradation in the gastrointestinal tract. Therefore, when the composition is administered by a route using the gastrointestinal tract, the composition must contain an agent that protects the antibody from degradation, but releases the antibody after being absorbed from the digestive tract.

[0284] A thorough discussion of pharma- ceutical acceptable carriers is available in Remington's Pharmaceutical Sciences (Mack Publishing Company, NJ 1991).

[0285] It is also envisioned that the antibodies of the invention may be administered by the use of gene therapy. To accomplish this, DNA containing nucleic acid sequences encoding the heavy and light chains of the antibody molecule under the control of appropriate DNA elements is introduced into a patient such that the antibody chains are expressed from the DNA sequences and assembled in situ.

[0286] In one embodiment, the formulation is provided as a formulation for topical administration, including inhalation. Suitable inhalable preparations include inhalable powders, metered aerosols with a propellant gas or inhalable solutions without a propellant gas. Inhalable powders according to the present disclosure containing active substances may consist of the above-mentioned active substances alone or in mixtures of the above-mentioned active substances with physiologically acceptable excipients. These inhalable powders may include monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligosaccharides and polysaccharides (e.g. dextran), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures thereof. Monosaccharides or disaccharides are preferably used, in particular, but not exclusively, lactose or glucose in the form of their hydrates.

[0287] Particles for deposition in the lungs should have a particle size of less than 10 microns, for example 1-9 microns, such as 0.1-5 microns, especially 1-5 microns. The particle size of the active ingredient (such as an antibody or fragment) is of utmost importance.

[0288] The propellant gases that can be used to prepare inhalable aerosols are known in the art. Suitable propellant gases are selected from hydrocarbons such as n-propane, n-butane or isobutane, halohydrocarbons such as chlorinated and / or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The above-mentioned propellant gases can be used alone or as mixtures thereof. Particularly suitable propellant gases are halogenated alkane derivatives selected from TG11, TG12, TG134a and TG227. Among the above-mentioned halogenated hydrocarbons, TG134a (1,1,1,2-tetrafluoroethane) and TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof are particularly suitable. The inhalable aerosols containing the propellant gas may also contain other components such as cosolvents, stabilizers, surface active agents (surfactants), antioxidants, lubricants and pH adjusting means. All these components are known in the art.

[0289] Inhalable aerosols containing the propellant gas according to the invention may contain up to 5% by weight of active substance, for example 0.002 to 5% by weight, 0.01 to 3% by weight, 0.015 to 2% by weight, 0.1 to 2% by weight, 0.5 to 2% by weight or 0.5 to 1% by weight of active ingredient.

[0290] Alternatively, local administration to the lung may be by administration of a liquid solution or suspension formulation, for example by use of a device such as a nebulizer (e.g., a Pari LC-Jet Plus® nebulizer connected to a Pari Master® compressor manufactured by Pari Respiratory Equipment, Inc., Richmond, Virginia).

[0291] The antibody of the present invention can be dispersed in a solvent and delivered, for example, in the form of a solution or suspension. The antibody of the present invention can be suspended in an appropriate physiological solution, for example, physiological saline or other pharmacologically acceptable solvent or buffer solution. A buffer solution known in the art may contain, per ml of water, 0.05 mg to 0.15 mg of disodium edetate, 8.0 mg to 9.0 mg of NaCl, 0.15 mg to 0.25 mg of polysorbate, 0.25 mg to 0.30 mg of anhydrous citric acid, and 0.45 mg to 0.55 mg of sodium citrate to achieve a pH of about 4.0 to 5.0. The suspension can use, for example, a lyophilized antibody.

[0292] Therapeutic suspension or solution formulations may also contain one or more excipients. Excipients are well known in the art and include buffers (e.g., citrate buffer, phosphate buffer, acetate buffer and bicarbonate buffer), amino acids, urea, alcohol, ascorbic acid, phospholipids, proteins (e.g., serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol and glycerol. The solution or suspension can be encapsulated in liposomes or biodegradable microspheres. The formulation is generally provided in substantially sterile form using a sterile manufacturing process.

[0293] This may involve manufacturing and sterilization by filtration of a buffered solvent / solution used in the formulation, sterile suspension of the antibody in a sterile buffered solvent solution, and dispensing the formulation into sterile containers by methods well known to those of skill in the art.

[0294] A nebulizable formulation according to the present disclosure may be provided as a single-dose unit (e.g., a sealed plastic container or vial) packaged, for example, in a foil envelope, with each vial containing a unit dose in a predetermined volume (e.g., 2 mL) of solvent / solution buffer.

[0295] The present invention has been described by way of example only and is not meant to be limiting in any way, and may vary in detail within the scope of the following claims. The preferred features of each embodiment of the invention are the same as each other embodiment mutatis mutandis. All publications, including but not limited to patents and patent applications cited in this specification, are incorporated by reference in this specification to the same extent as if each individual publication was specifically and individually indicated to be fully set forth herein. EXAMPLES

[0296] Example 1 - Clinical Trial of CA028_0496.g3 (UCB4940 or Bimekizumab); Loading Dose and Maintenance Dose In one embodiment, an early proof-of-concept, investigator-blinded, placebo-controlled study evaluating the safety, pharmacokinetics, and pharmacodynamics of multiple doses of CA028_0496.g3 in subjects with psoriatic arthritis is being conducted, identified as UCB Study PA0007.

[0297] The study included four active dose arms and placebo administered intravenously, three infusions every three weeks: Cohort 1 (240 mg loading dose at week 0, then 160 mg at weeks 3 and 6 [N=20 (active), 3 placebo]; Cohort 2 (80 mg loading dose at week 0, then 40 mg at weeks 3 and 6) [N=6 (active), 3 placebo]; Cohort 3 (160 mg loading dose at week 0, then 80 mg at weeks 3 and 6; N=6 (active), 3 placebo); Cohort 4 (560 mg loading dose at week 0, then 320 mg at weeks 3 and 6; N=6 (active), 3 placebo).

[0298] The objectives of this study included the safety, tolerability, and pharmacokinetics of multiple doses of CA028_0496.g3 in subjects with psoriatic arthritis. Objectives also included evaluation of the effect of multiple doses of CA028_0496.g3 on the severity of psoriatic arthritis in the joints (American College of Rheumatology (ACR) 20 / 50 / 70 response) and on the skin, on the clinical characteristics of plaque psoriasis (Psoriasis Area and Severity Index ("PASI") 50 / 75 / 90 response). The ACR score is a scale that measures improvement in joint effects associated with psoriatic arthritis and rheumatoid arthritis, and improvement in the ACR score is also associated with the treatment of rheumatoid arthritis.

[0299] Patient population: All eligible subjects were required to be at least 18 years of age and to have a diagnosis of adult-onset psoriatic arthritis made at least 6 months prior to study screening defined by the classification criteria for psoriatic arthritis ("CASPAR") criteria (i.e., inflammatory joint disease (joint, spine or tendon) and a score of ≥3 of 5 CASPAR categories). The CASPAR criteria used can be found in Figure [2]. Subjects were also required to have active psoriatic lesions or a history of psoriatic lesions. In terms of joint involvement, subjects were required to have active arthritis defined by ≥3 tender joints at screening and baseline, ≥3 swollen joints at screening and baseline, and at least one of the following during screening (ESR ≥28 mm / h or CRP ≥3 mg / L). Subjects had an inadequate response to at least one non-biologic disease-modifying antirheumatic drug ("DMARD") and / or one approved biologic DMARD. Subjects must have been taking methotrexate concomitantly for at least 3 months at the time of treatment initiation and had been on a stable dose for at least 4 weeks prior to baseline. Methotrexate-intolerant subjects may have been eligible if they had been taking nonsteroidal anti-inflammatory drugs (NSAIDs) and / or steroids for at least 8 weeks and had been on a stable dose for at least 4 weeks prior to baseline.

[0300] Study Conduct: Fifty subjects completed the full study load. Of these, 38 subjects received at least one dose of study drug (CA028_0496.g3). Two subjects were excluded due to potential in situ unblinding, so a total of 48 subjects, including the subject who received placebo, formed the overall analysis dataset.

[0301] Clinical Results: Clinically significant effects were observed in both the joints and the skin 8 weeks after the start of treatment.

[0302] Skin effects: 23 subjects had skin involvement at baseline, covering ≥3% of the total body surface area (BSA), with a mean baseline PASI of 15.9 (SD=14.6). Due to one subject dosing failure, only 22 subjects were present in the analysis dataset. Skin effects results are depicted in Figures [3a] and [3b]. Onset of response was rapid in both skin and joints. Among subjects eligible for skin evaluation, 100% PASI75 responses were observed at week 8 of treatment across the top three treatment arms combined, and 87% PASI90 responses were likely maintained through the end of the study at week 20 after treatment initiation. In contrast, in the Future 1 study of secukinumab in psoriatic arthritis, PASI75 responses were observed at week 24 in 64.8% and PASI90 responses were observed at week 24 in 49%. (Glottieb AB et al., Arthritis Rheum. 2014, 66(Suppl 11):S233; Mease P et al., Ann Rheum Dis. 2014;73(1):48-55.) This is further shown in Figure [4].

[0303] Joint Effects: Results for joint effects are shown in Figures [5a]-[5d]. An 80% ACR20 response, a 40% ACR50 response and a 23% ACR70 response were observed 8 weeks after treatment initiation across the top three treatment arms combined. The ACR20 response appeared to be sustained at this level through week 20 (day 140) despite an increase in placebo response (see Figures 5b-5d). After 8 weeks (2 weeks after the last dose), background treatment was uncontrolled.

[0304] The time to maximum ACR50 and ACR70 responses took longer (after 12 weeks) with 56.7% and 36.7% responses by week 20, respectively. In contrast, in the Future1 study of secukinumab in psoriatic arthritis, 50% of patients had an ACR20 response at week 24. Mease P et al., 2014, Arthritis Rheum., 66(Suppl 11):S423-S424; Mease P et al., 2014, Ann Rheum Dis., 73(1):48-55. This is further illustrated in Figure [6].

[0305] Bayesian Analysis: A Bayesian analysis of ACRn(tr) after 8 weeks of treatment was performed using a Gaussian likelihood model with useful prior information for the placebo group. Evaluation of the quantification of the magnitude of the treatment effect and homogeneity of variability was performed, and it was deemed appropriate to pool the top three doses of CA028_0496.g3 together. Data from the previous Cimzia® study in psoriatic arthritis (PsA001, a Phase A 3, multicenter, randomized, double-blind, parallel-group, placebo-controlled study evaluating the efficacy and safety of certolizumab pegol in subjects with adult-onset active and progressive psoriatic arthritis) was used to estimate prior information for ACRn(tr) versus placebo.

[0306] Bayesian analysis showed strong statistical evidence (probability >99%) that CA028_0496.g3 achieved higher ACRn(tr) values ​​compared to placebo. Furthermore, the probability that the median treatment difference in ACRn(tr) compared to placebo was greater than 0.31 (a difference observed in previous Cimzia® studies) was greater than 99% in the top 3 pooled CA028_0496.g3 dose groups.

[0307] For ACR20 response, a Bayesian analysis was performed using a logistic model with prior knowledge for the placebo group at week 8. Data from a previous Cimzia® study (PsA001) was used to estimate prior knowledge for the placebo group on ACR20.

[0308] Bayesian analysis showed that the probability that CA028_0496.g3 would induce a higher ACR20 response rate than placebo was greater than 99% for the top three pooled doses of CA028_0496.g3. Furthermore, the probability that the median ACR20 treatment difference compared to placebo would exceed 25% (the difference observed in PsA001) was greater than 99% for the top three pooled doses of CA028_0496.g3. These results are shown in Figure [7].

[0309] The validity of these results in terms of benchmarks against other biologic therapies in psoriatic arthritis (anti-TNF and IL17A and anti-IL12 / 23) was made by comparison with literature data on ACR20 response at week 8 (adalimumab, golimumab, secukinumab and ustekinumab, see figure [8]), ensuring the overall concordance of the results. In conclusion, the high posterior probability (>99%) of the observed effect on ACR20 response is greater for this PA0007 than for anti-TNF or anti-IL-17A at week 8.

[0310] Pharmacokinetic-pharmacodynamic targeting: Four active dosing arms were selected to achieve pharmacologically active dose levels to achieve the desired clinical effect. The objective was to achieve trough concentrations of approximately 10 μg / mL and 10-fold greater than the Ec50 (derived from the mild psoriatic response in UP0008 described in Example 2) in the first 8 weeks. The results of this study are included in Figure [9]. In UP0008, bimekizumab showed dose-proportional PK (half-life of approximately 22 days).

[0311] Projected subcutaneous administration: A bioavailability study (RA0124) was conducted on CA028_0496.g3 to evaluate the pharmacokinetics of CA028_0496.g3 after subcutaneous administration of doses of 80 mg and 160 mg compared to intravenous administration of 160 mg. The results show that, based on the principle of superposition, it is possible to achieve the target concentrations of CA028_0496.g3 summarized in Figure [9] (achieved in PA0007) by monthly subcutaneous administration of 160 mg or more, e.g., 320 mg, using a Q4W regimen (Figure

[10] ) or a loading dose of 320 mg followed by a Q4W regimen of 160 mg. Example 2 - Clinical Trial of CA028_0496.g3 (UCB4940 or Bimekizumab); Single Dose

[0312] UP0008 is a Phase 1 study (NCT02529956) evaluating the safety of a single escalating dose of CA028_0496.g3 administered intravenously to subjects with mild to moderate psoriasis affecting 5% or less of their body surface area (BSA). Inclusion criteria included, for example, male or female (age ≥18 and ≤70 years), confirmed diagnosis of mild to moderate psoriatic disease for ≥6 months involving ≤5% of body surface area (excluding scalp), and ≥2 psoriatic lesions with ≥1 lesion at an appropriate biopsy site. Exclusion criteria included, for example, systemic non-biologic psoriasis treatment (methotrexate, cyclophosphamide) or psoralen + ultraviolet A / ultraviolet A phototherapy within 4 weeks prior to screening, treatment with a biologic agent within 12 months prior to the study, and use or planned use of a live attenuated vaccine within 6 weeks after screening. A total of 39 patients received a single intravenous dose of bimekizumab (8–640 mg) or placebo (randomized, double-blind). Five doses were used: 8 mg, 40 mg, 160 mg, 480 mg, and 640 mg. After a single dose, bimekizumab (8–640 mg) was well tolerated, with no patient discontinuations due to treatment-emergent AEs. No severe AEs were reported. Indeed, doses up to 640 mg (approximately 8 mg / kg body weight) have been tolerated to date in UP0008.

[0313] After dosing, bimekizumab led to improvements across the assessed clinical features of psoriasis vulgaris, LSS, PASI and PGA (Figure 14). A rapid onset of response was observed in the top two dose cohorts with a greater than 80% reduction from baseline LSS at week 2 of the study. For the 160, 480 and 640 mg doses (N=6 each), clinically relevant and statistically significant differences from placebo (N=13) were observed in Lesion Severity Score (LSS) (Figure

[11] ) and Psoriasis Area and Severity Index (PASI) from week 2 (Figure

[12] ), with near maximal improvements observed by week 4.

[0314] Specifically with regard to LSS, the magnitude of response was reflected by a reduction in the maximum mean change from baseline in LSS of greater than 90% in the 160 mg group. This was achieved by week 8 and demonstrated durability maintained through week 16. In the 480 mg cohort, the maximum response (100%) was achieved as early as week 4. This response was also durable and maintained through week 16. In the 640 mg cohort, the maximum reduction (100%) was achieved by week 8 and was durable and maintained between weeks 12 and 20 (Figure 14A). In addition to the 640 mg cohort, no overlap of CIs was observed between the other bimekizumab cohorts (40–480 mg) versus placebo at week 2, indicating a difference between the two cohorts. Similar results were obtained for the area under the effect curve (weeks 0–4, [AUEC0-4w] variable) (data not shown).

[0315] Regarding PASI, a reduction of >65% from baseline PASI was observed in the top two dose cohorts at week 2. Bayesian analysis revealed that the posterior probability of >60% improvement over placebo at this time point was >80%. For the bimekizumab 160 mg cohort, the magnitude of response was reflected by a maximum reduction in the mean change from baseline in PASI score of >85%, achieved by week 6. This response was durable and maintained through study week 12. A maximum response of >94% was observed in the 480 mg and 640 mg cohorts. This was achieved by week 6 in the 480 mg cohort and by week 4 in the 640 mg cohort. Responses were durable in both cohorts and maintained through week 12 (Figure 5b). Furthermore, the posterior probability of >0% improvement in PASI score over placebo was 99% in the bimekizumab 40–640 mg cohorts at week 2.

[0316] Significant levels of improvement (as indicated by percent change in LSS and percent change in PASI from baseline) were maintained until the final time point (20 weeks) was measured. In the top two dose groups, 83% of patients experienced a PASI 90 (90% improvement in PASI score) between weeks 6 and 12, and 90% by week 12 (Figure

[13] ). In the top three dose groups, 100% of patients achieved PASI 75 and 53% achieved PASI 100.

[0317] Physicians Global Assessment (PGA) was also assessed using a 7-point scale (0 = clear, 6 = severe). See Figure

[14] . A greater than 50% reduction from baseline in PGA was observed when assessed with the highest doses of bimekizumab (480 mg and 640 mg). The greatest reduction in PGA score, with a mean change from baseline of more than 75%, was observed in the bimekizumab 160 mg cohort. This reduction was achieved by week 6, was sustained, and was maintained through week 12. The greatest reduction in mean change from baseline in PGA score was 100% and 94% for the bimekizumab 480 mg and 640 mg cohorts, respectively (Figure 5c). These reductions were achieved by week 8, were sustained, and were maintained through week 12 in the 480 mg cohort, and were achieved by week 4 and were maintained through week 12 in the 640 mg cohort. Example 3 - Anti-IL17A / F antibodies downregulate bone formation processes

[0318] For the combination of peripheral arthritis and psoriasis, a subset of the prototypic spondyloarthritis phenotypes are the axial diseases ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Individual patients often present with multisystem disease. A significant proportion of AS patients present with cutaneous psoriasis, and a significant proportion of PsA patients develop axial disease. AS and PsA have a common genetic background, familial clustering of different subforms, shared histopathological findings, and similar responses to treatment (e.g., the efficacy of TNF blockade and IL-17A blockade in both AS and PsA, and the failure of B cell depletion therapy and IL-6 blockade in AS and PsA). Thus, the results described herein for psoriatic arthritis suggest that anti-IL-17A / F antibodies may also be effective in treating ankylosing spondylitis.

[0319] Pathologic bone formation associated with spondyloarthropathy (SpA) is the primary cause of structural tissue damage that leads to permanent disability in patients. AS patients experience excessive bone formation on periosteal surfaces near joints and intervertebral discs, resulting in the formation of osteophytes that can cause joint fusion, strain tendon and ligament insertion sites, and cause the pain and limited range of motion associated with the disease. Previous studies with recombinant IL-17A and IL-17F revealed differential effects on bone differentiation. Osta et al., Frontiers in Immunology 5 (2014) demonstrate that IL-17 positively influences bone differentiation in human mesenchymal stem cells (hMSCs). Consistent with this, Huang et al., Cell Death Differ. 16, 1332-43 (2009) report that IL-17 stimulates the proliferation and osteogenic differentiation of hMSCs. Additionally, Croes et al., Bone 84, 262-270 (2016) demonstrated osteogenic stimulation of hMSCs with IL-17A and IL-17F over a range of concentrations. Conversely, others have shown that IL-17 inhibits osteogenic differentiation of rat calvarial cells, mouse MSCs and adult human MSCs, suggesting that IL-17 is pro-osteogenic. See, e.g., Chang et al., Proc. Natl. Acad. Sci. USA 110, 9469-74 (2013); Nam et al., PLoS One 7, e40044 (2012).

[0320] This example shows that an anti-IL-17A / F monoclonal antibody (CA028_0496.g3 (bimekizumab)) reduces biomarkers associated with periosteal stem cell bone differentiation in vitro, reduces matrix mineralization, and reduces bone nodule formation in vitro, indicating that an anti-IL-17A / F monoclonal antibody (CA028_0496.g3 (bimekizumab)) is likely to be effective in treating AS (e.g., slowing the progression of symptoms, alleviating symptoms).

[0321] Methodology: Because the periosteum gives rise to repair tissue for fracture repair, we used a human periosteal stem cell model (Eyckmans et al., Biomaterials 34, 4612-21 (2013)) to probe the IL-17 axis in the context of pathological bone formation. Periosteum was collected from patients undergoing lower limb orthopedic surgery as previously described (Roberts et al., Biomaterials 32, 4393-4405 (2011); Roberts et al., Stem Cell Res. 7, 137-144 (2011). Adherent human periosteum-derived stem cells (hPDSCs) were enzymatically released from the matrix and expanded in growth medium (DMEM medium supplemented with 10% fetal bovine serum, 1% sodium pyruvate, 1% antibiotics and antimycotics). For in vitro bone differentiation assays, hPDSCs at passage 6 were plated at 3000 cells / cm in 24-well plates. 2 These cultures were seeded at 100 nmol / well for 24 h at 4°C, allowing for quantification of gene expression and mineralization in response to exposure to TH-17 supernatant. These cultures were supplemented with osteogenic growth factor cocktail (GFC); 10 ng / ml TGF-β1 (Peprotech), 20 ng / ml EGF (Invitrogen), 10 ng / ml IL-6 (Peprotech), 3 mM Ca, 0.5 mM Hb, 0.5 mM Hb, 0.5 mM NaCl ... 2+ ions and 2mM PO4 -(prepared in HEPES-buffered saline) and incubated with vehicle (PBS) or TH-17 supernatant (1:50 dilution) containing anti-IL-17A, anti-IL-17F, or anti-IL-17A / F antibodies (10 μg / ml). Chai et al., Tissue Eng. Part A 17, 1083-1097 (2011). IL-6 was exchanged for TH-17 supernatant under the test conditions (GFC-IL-6) to serve as an inflammatory inducer for differentiation. The mixture was incubated at 37°C for 1 h in a shaking water bath, effectively neutralizing IL-17 isoforms. Each condition was applied to relevant hPDSC monolayers every other day until the end of the culture period on day 8. Monolayers were fixed in 10% neutral buffered formalin or stained with 1% alizarin red to measure mineral deposits or lysed to isolate total RNA for osteogenic marker gene expression analysis. Prior to fixation, the monolayer was visualized using standard microscopic techniques and the appearance of bone nodules was visually assessed.

[0322] To investigate the effect of human serum from AS patients on hPDSC IL-17-mediated signaling, 10,000 cells / cm 2 Cells were seeded in 24-well plates. The next day, the medium was removed and the monolayers were washed with warmed sterile PBS, after which the medium was replaced with DMEM supplemented with 10% healthy human serum (HS) or AS patient serum (SRSC01, SRSC03, SRSC04, SRSC05, SRSC06 and SRSC07) supplemented with 1% sodium pyruvate and 1% antibiotic / antimycotic. The monolayers were incubated for 48 h, after which the medium was discarded and the monolayers were arrested for total RNA isolation. Subsequently, the expression of the downstream target gene IL-6 and the osteogenic marker RUNX2 was evaluated.

[0323] Total RNA extraction, cDNA synthesis and qPCR: Monolayers were lysed using RNeasy mini kit according to kit instructions (Qiagen). Complementary DNA (cDNA) was synthesized by reverse transcription of 500 ng of total RNA using High Capacity cDNA Reverse Transcription Kit (Applied Biosciences) under thermal cycling conditions of 25°C for 10 min, 37°C for 120 min, and 85°C for 5 min. To quantify the levels of gene transcripts in each sample, primers (Primer3 Plus, designed using NCBI) were combined with iTaq universal SYBR green supermix (Biorad) and 10 ng of cDNA, followed by application of 10 μL aliquots to Hard-Shell® 96-well PCR plates (Biorad). Thermal cycling conditions were 95°C for 10 min, 40 cycles of 95°C for 15 s, 60°C for 30 s, and 72°C for 20 s on a Bio-Rad CFX1000 real-time system. Each experiment consisted of melting curve analysis and no template controls to confirm the amplification of a specific single product. All primer pairs produced a single amplicon and reactions were of similar efficiency (95-100%) as established by standard dilution curves and analysis. Quantification of the target genes was achieved using the 2-ΔΔCT method described by Livak et al. in comparison to HPRT1.

[0324] Measurement of IL-17A and IL-17F by ELISA: IL-17A and IL-17F proteins were measured in patient serum from AS patients using a sandwich ELISA (Peprotech, London, UK). Blood from AS patients was isolated in BD Vacutainer SST tubes at the Rheumatology Clinic of the Royal National Orthopaedic Hospital (Stanmore, UK). The NHS Research Ethics Committee approved all procedures. After collection, blood was centrifuged at 1000g for 10 min at room temperature. The separated serum was then filtered through a 0.2 μm membrane. An aliquot of serum was stored at -80°C prior to analysis. Prior to analysis, a 1:2 dilution of each AS patient serum was performed in the dilution buffer provided in the human IL-17A and IL-17F ABTS kit (Peprotech, London, UK) to reduce the effect of the serum matrix. Measurement of IL-17A and IL-17F was performed according to the kit instructions.

[0325] Results: Utilizing a biomimetic bone formation assay (described in International Patent Publication No. 2013189975), TH-17 supernatants (TH-17SN) were treated with or without monoclonal antibodies directed against IL-17A, IL-17F or IL-17A / F. In addition to assessing the degree of mineralization by Alizarin Red staining and the appearance of bone nodules, osteogenic transcripts such as RUNX2, SP7 and BMP2 were analyzed along with markers of bone matrix formation (BGLAP) and mineralization (PHOSPHO1). TH-17 cell supernatants potently enhanced hPDSC bone differentiation and mineralization (p<0.01). Neutralization of IL-17A, IL-17F and IL-17A / F in an inflammatory environment blocked both IL-6 expression and bone formation in vitro, with neutralization of IL-17A / F showing the greatest effect. Figures 15A-G. Additionally, there was a visibly reduced appearance of bone nodules in samples treated with anti-IL-17A / F compared with treatment with anti-IL-17A alone or anti-IL-17F alone.

[0326] The presence of IL-17A and IL-17F in the serum of patients suffering from AS was quantified by ELISA. In six patients, both IL-17A and IL-17F proteins were measured and compared to the levels in healthy human serum (HS). Varying levels of IL-17A and IL-17F were identifiable between the different patients, with both levels of IL-17A and IL-17F being significantly higher (P<0.01) in three patients compared to the healthy human serum control group. Serum derived from patient samples from the remaining three patients appeared to show similar IL-17A, but one patient showed greater IL-17F expression compared to HAS controls. To examine the relevance of this, hPDSCs were treated with serum from AS patients and incubated for 48 hours. The downstream target IL-6 and the osteogenic marker RUNX2 were elevated. To define the importance of IL-17A and IL-17F in the expression of these markers, hPDSCs were treated with serum from AS patients (serum samples that showed significantly higher levels of both IL-17A and IL-17F, stimulating IL-6 and RUNX2 mRNA expression) after pre-incubation with either a control IgG antibody or antibodies specific for IL-17A, IL-17F or IL-17A / F. The results showed that blocking both IL-17A and IL-17F strongly and significantly reduced the expression of IL-6 and RUNX2 mRNA. This effect was greatest when an antibody with high affinity for IL-17A / F was used. Figures 16A and 16B.

[0327] Discussion: Inflammatory and degenerative joint diseases frequently induce a periosteal bone proliferative response, leading to the formation of osteophytes (osteophytes). In inflammatory diseases such as AS, entheseal outgrowths arise at the peripheral joints and at the tendon insertion sites (tendons) of the vertebral bodies. It has been hypothesized that progenitor cells within the periosteum are intimately involved in this bone formation process and may lead to ankylosis with impaired movement and joint function. The results described herein demonstrate that both IL-17A and IL-17F enhance in vitro bone differentiation and bone formation from hPDSCs. Neutralization of IL-17A and IL-17F via a monoclonal antibody that binds both IL-17A / F (CA028_0496.g3 (bimekizumab)) inhibited IL-6 gene expression and suppressed the expression of osteogenic genes (RUNX2, SP7 and BMP2). CA028_0496.g3 also significantly mediated bone matrix mineralization effectors (BGLAP and PHOSPHO1), resulting in an observable decrease in matrix mineralization and bone nodule formation. Neutralization of IL-17A / F maximally inhibited bone differentiation markers and matrix mineralization compared to neutralization of IL-17A or IL-17F alone. Current therapeutic agents show limited efficacy in preventing enthesis outgrowth formation. Thus, the materials and methods described herein offer significant technical advantages for preventing this debilitating tissue disease. [Sequence List Free Text]

[0328] Sequence Listing 1 <223> Synthetic Peptides Sequence Listing 2 <223> Synthetic Peptides Sequence Listing 3 <223> Synthetic Peptides Sequence Listing 4 <223> Synthetic Peptides Sequence Listing 5 <223> Synthetic Peptides Sequence Listing 6 <223> Synthetic Peptides Sequence Listing 7 <223> Synthetic Peptides <223> CDRL1 for CA028_496.g3 Sequence Listing 8 <223> Synthetic Peptides <223> CDRL2 for CA028_496.g3 Sequence Listing 9 <223> Synthetic Peptides <223> Light chain variable region-CA028_496(gL7) Sequence Listing 10 <223> Synthetic Peptides <223> Light chain variable region - CA028_496.g3(gL57) Sequence Listing 11 <223> Synthetic Peptides <223> Heavy chain variable region - CA028_496 and CA028_496.g3 (gH9) Sequence Listing 12 <223> Synthetic Peptides <223> Light chain-CA028_496 (w / o signal) Sequence Listing 13 <223> Synthetic Peptides <223> Light chain - CA028_496.g3 (w / o signal) Sequence Listing 14 <223> Synthetic Peptides <223> Light chain - CA028_496.g3 (w / signal) Sequence Listing 15 <223> Synthetic Peptides <223> Heavy chain - CA028_496 Sequence Listing 16 <223> Synthetic Peptides <223> Heavy chain CA028_496.g3 (w / o signal) Sequence Listing 17 <223> Synthetic Peptides <223> Heavy chain - CA8_496.g3 (w / signal) Sequence Listing 18 <223> Synthetic Peptides <223> Light chain variable region - CA028_496.g3 Sequence Listing 19 <223> Synthetic Peptides <223> Heavy chain variable region - CA028_496.g3 Sequence Listing 20 <223> Synthetic Peptides <223> Light chain-CA028_496(w / signal) Sequence Listing 21 <223> Synthetic Peptides <223> Light chain - CA028_496.g3 (w / o signal) Sequence Listing 22 <223> Synthetic Peptides <223> Light chain - CA028_496.g3 (w / signal) Sequence Listing 23 <223> Synthetic Polynucleotides <223> Heavy chain CA028_496 (w / signal) Sequence Listing 24 <223> Synthetic Polynucleotides <223> Heavy chain - CA028_496.g3 (w / exon, w / o signal) Sequence Listing 25 <223> Synthetic Polynucleotides <223> Heavy chain - CA028_496.g3 (w / signal and exon) Sequence Listing 26 <223> Synthetic Polynucleotides <223> Heavy chain - CA028_496.g3 (w / signal)

Claims

1. A method of treating psoriatic arthritis in a human comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F.

2. 2. The method of claim 1, wherein the antibody specifically binds to an epitope of human IL-17F, the epitope comprising one or more residues selected from ARG47, ARG73, LEU75 and ILE86 of SEQ ID NO:

27.

3. 2. The method of claim 1, wherein the antibody specifically binds to an epitope of human IL-17A, the epitope comprising one or more residues selected from TYR44, ASN45, ARG46, TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO:

28.

4. 2. The method of claim 1, wherein the antibody binds to the same epitope of human IL-17A, human IL-17F, or human IL-17A / F heterodimer as a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO:11 and a light chain comprising the sequence given in SEQ ID NO:

10.

5. 2. The method of claim 1, wherein the antibody is a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO:11 and a light chain comprising the sequence given in SEQ ID NO:10, and cross-blocks neutralizing antibodies that bind human IL-17A and human IL-17F.

6. The method of claim 1 , wherein the antibody comprises a light chain variable domain and a heavy chain variable domain, and the light chain variable domain comprises the sequence given in SEQ ID NO:

10.

7. The method of claim 1 , wherein the antibody is bimekizumab.

8. The method of any one of claims 1 to 7, wherein the antibody is administered as a pharmaceutical composition.

9. The method of any one of claims 1 to 8, wherein the antibody is administered subcutaneously.

10. The method of any one of claims 1 to 8, wherein the antibody is administered intravenously.

11. A method of treating psoriatic arthritis in a human, comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F, wherein the human has a diagnosis of adult-onset psoriatic arthritis.

12. The method of claim 11 , wherein the human is at least 18 years of age.

13. The method of claim 11 , wherein the human was diagnosed at least 6 months prior to administration of the antibody.

14. The method of claim 11 , wherein the human has been diagnosed based on CASPAR criteria.

15. A method of treating psoriatic arthritis in a human comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F, wherein the human has active arthritis.

16. A method of treating psoriatic arthritis in a human, comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F, wherein the human has an active psoriatic lesion or a history of psoriatic lesions.

17. A method of treating psoriatic arthritis in a human, comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F, wherein the human is a poor responder to at least one non-biologic disease-modifying antirheumatic drug ("DMARD") and / or one approved biologic DMARD.

18. A method of treating psoriatic arthritis in a human currently being treated with methotrexate comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F.

19. A method of treating psoriatic arthritis in a human comprising administering to the human a therapeutically effective amount of a neutralizing antibody that binds human IL-17A and human IL-17F.

20. 1. A method of treating psoriatic arthritis in a human patient, comprising administering to a population of patients in need of treatment a neutralizing antibody that binds human IL-17A and human IL-17F in an amount effective to provide an ACR20 response at week 8, an amount effective to provide an ACR50 response at week 8, or an ACR70 response at week 8.

21. 21. The method of claim 20, wherein the response provided is an ACR50 response at week 8 or an ACR70 response at week 8 in a population of patients in need of treatment.

22. 21. The method of claim 20, wherein the response provided is an ACR70 response at week 8 in a population of patients in need of treatment.

23. 1. A method of treating psoriatic arthritis in a human comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F in an amount effective to provide a PASI 50 response at week 8, an amount effective to provide a PASI 75 response at week 8, or an amount effective to provide a PASI 90 response at week 8.

24. 24. The method of claim 23, wherein the response provided is a PASI 75 response at week 8 or a PASI 90 response at week 8 in a population of patients in need of treatment.

25. 24. The method of claim 23, wherein the response given is a PASI 90 response at week 8 in a population of patients in need of treatment.

26. A method of reducing psoriasis in a human comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F.

27. 27. The method of claim 26, wherein the psoriasis is plaque psoriasis.

28. 27. The method of claim 26, wherein the reduction in psoriasis vulgaris is measured by PASI criteria.

29. 27. The method of claim 26, comprising administering an amount of the antibody that achieves at least a 75% or 90% change in Lesion Severity Score (LSS) compared to pre-treatment 4, 6, or 8 weeks after administration of the antibody.

30. 27. The method of claim 26, comprising administering an amount of the antibody that achieves at least a 75% or 90% change in Psoriasis Area and Severity Index (PASI) compared to pre-treatment 4, 6, or 8 weeks after administration of the antibody.

31. A method of reducing joint involvement in a human comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F.

32. 32. The method of claim 31, wherein the reduction in joint involvement is measured by the ACR criteria.

33. A method of reducing psoriasis and reducing the involvement of joints in a human comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F.

34. 34. The method of claim 33, wherein the psoriasis is plaque psoriasis.

35. 35. The method of claim 34, wherein the reduction in plaque psoriasis is measured by PASI criteria and the reduction in joint involvement is measured by ACR criteria.

36. A method of treating psoriatic arthritis in a human comprising administering to the human at least one dose of a neutralizing antibody that binds human IL-17A and human IL-17F.

37. A method of treating rheumatoid arthritis in a human comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F.

38. A method of treating rheumatoid arthritis in a human comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F, wherein the human has a diagnosis of adult-onset rheumatoid arthritis.

39. 39. The method of claim 38, wherein the human is at least 18 years of age.

40. 39. The method of claim 38, wherein the human was diagnosed at least 6 months prior to administration of the antibody.

41. 39. The method of claim 38, wherein the human is classified based on the ACR / EULAR 2010 criteria.

42. A method of treating rheumatoid arthritis in a human comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F, wherein the human has active arthritis.

43. A method of treating rheumatoid arthritis in a human, comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F, wherein the human is a poor responder to at least one non-biologic disease-modifying antirheumatic drug ("DMARD") and / or one approved biologic DMARD.

44. A method of treating rheumatoid arthritis in a human currently being treated with methotrexate comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F.

45. A method of treating rheumatoid arthritis in a human comprising administering to the human a therapeutically effective amount of a neutralizing antibody that binds human IL-17A and human IL-17F.

46. 1. A method of treating rheumatoid arthritis in a human patient, comprising administering to the patient, in a population of patients in need of treatment, a neutralizing antibody that binds human IL-17A and human IL-17F in an amount effective to provide an ACR20 response at week 8, an amount effective to provide an ACR50 response at week 8, or an ACR70 response at week 8.

47. 47. The method of claim 46, wherein the response provided is an ACR50 response at week 8 or an ACR70 response at week 8 in a population of patients in need of treatment.

48. 47. The method of claim 46, wherein the response given is an ACR70 response at week 8 in a population of patients in need of treatment.

49. A method of treating rheumatoid arthritis in a human comprising administering to the human at least one dose of a neutralizing antibody that binds human IL-17A and human IL-17F.

50. 50. The method of any one of claims 11-49, wherein the antibody specifically binds to an epitope of human IL-17F, the epitope comprising one or more residues selected from ARG47, ARG73, LEU75 and ILE86 of SEQ ID NO:

27.

51. 51. The method of claim 50, wherein the antibody specifically binds to an epitope of human IL-17A, the epitope comprising one or more residues selected from TYR44, ASN45, ARG46, TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO:

28.

52. 51. The method of claim 50, wherein the antibody binds to the same epitope of human IL-17A, human IL-17F, or human IL-17A / F heterodimer as a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO:11 and a light chain comprising the sequence given in SEQ ID NO:

10.

53. 51. The method of claim 50, wherein the antibody is a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO:11 and a light chain comprising the sequence given in SEQ ID NO:10, and cross-blocks neutralizing antibodies that bind human IL-17A and human IL-17F.

54. 51. The method of claim 50, wherein the antibody comprises a light chain variable domain and a heavy chain variable domain, and the light chain variable domain comprises the sequence given in SEQ ID NO:

10.

55. The method of any one of claims 11 to 54, wherein the antibody is bimekizumab.

56. The method of any one of claims 11 to 55, wherein the antibody is administered as a pharmaceutical composition.

57. The method of any one of claims 11 to 56, wherein the antibody is administered subcutaneously.

58. The method of any one of claims 11 to 56, wherein the antibody is administered intravenously.

59. 59. The method of any one of claims 1-58, wherein the method comprises administering a dose comprising between 40 and 640 mg of antibody.

60. 60. The method of claim 59, wherein the dose is 40 mg of antibody.

61. 60. The method of claim 59, wherein the dose is 80 mg of antibody.

62. 60. The method of claim 59, wherein the dose is 160 mg of antibody.

63. 60. The method of claim 59, wherein the dose is 240 mg of antibody.

64. 60. The method of claim 59, wherein the dose is 320 mg of antibody.

65. 60. The method of claim 59, wherein the dose is 480 mg of antibody.

66. 60. The method of claim 59, wherein the dose is 560 mg of antibody.

67. 60. The method of claim 59, wherein the dose is 640 mg of antibody.

68. 59. The method of any one of claims 1 to 58, comprising administering between 80 and 720 mg of the antibody.

69. 69. The method of claim 68, comprising administering between 160 and 640 mg of the antibody.

70. 70. The method of any one of claims 59 to 69, wherein the method comprises administering multiple doses, the doses being administered at intervals of three weeks.

71. 70. The method of any one of claims 59 to 69, wherein the method comprises administering multiple doses, the doses being administered at intervals of four weeks.

72. 60. The method of any one of claims 1 to 59, comprising administering to a human a loading dose of a neutralizing antibody followed by at least one maintenance dose of the antibody.

73. 73. The method of claim 72, wherein the loading dose is from 80 to 560 mg and at least one maintenance dose is from 40 to 320 mg.

74. 73. The method of claim 72, wherein the loading dose is 80 mg and at least one maintenance dose is 40 mg.

75. 73. The method of claim 72, wherein the loading dose is 160 mg and at least one maintenance dose is 80 mg.

76. 73. The method of claim 72, wherein the loading dose is 240 mg and at least one maintenance dose is 160 mg.

77. 73. The method of claim 72, wherein the loading dose is 320 mg and at least one maintenance dose is 160 mg.

78. 73. The method of claim 72, wherein the loading dose is 560 mg and at least one maintenance dose is 320 mg.

79. 73. The method of claim 72, wherein the loading dose is 480 mg of antibody.

80. 80. The method of any one of claims 72 to 79, wherein a loading dose is administered followed by two maintenance doses.

81. 81. The method of any one of claims 72-80, wherein a loading dose is administered followed by at least one maintenance dose at three week intervals.

82. 81. The method of any one of claims 72-80, wherein a loading dose is administered followed by at least one maintenance dose at four week intervals.

83. 59. The method of treating psoriatic arthritis of any one of claims 1-25, 36, or 50-58, wherein the method comprises administering (a) 16 mg of antibody every 4 weeks, (b) 160 mg of antibody every 4 weeks, (c) a loading dose of 320 mg of antibody followed by a maintenance dose of 160 mg of antibody every 4 weeks, or (d) 320 mg of antibody every 4 weeks.

84. 36. The method of treating psoriasis according to any one of claims 26-30 and 33-35, wherein the method comprises administering: (a) 64 mg of antibody every 4 weeks; (b) 160 mg of antibody every 4 weeks or every 8 weeks; (c) 320 mg of antibody every 4 weeks or every 8 weeks; (d) a loading dose of 320 mg of antibody followed by a maintenance dose of 160 mg of antibody every 4 weeks; or (e) 480 mg of antibody every 4 weeks.

85. 85. The method of any one of claims 59-84, wherein the method comprises administering multiple doses over a treatment period of at least 12 weeks.

86. 86. The method of claim 85, wherein the method comprises administering multiple doses over a treatment period of at least 24 weeks.

87. 86. The method of claim 85, wherein the method comprises administering multiple doses over a treatment period of at least 48 weeks.

88. 86. The method of claim 85, wherein the method comprises administering multiple doses over a treatment period of at least 52 weeks.

89. A method of treating psoriatic arthritis, psoriasis, rheumatoid arthritis or ankylosing spondylitis in a human comprising administering to the human a loading dose of a neutralizing antibody that binds human IL-17A and human IL-17F, followed by at least one maintenance dose of the antibody.

90. 90. The method of claim 89, wherein the antibody specifically binds to an epitope of human IL-17F, the epitope comprising one or more residues selected from ARG47, ARG73, LEU75 and ILE86 of SEQ ID NO:

27.

91. 90. The method of claim 89, wherein the antibody specifically binds to an epitope of human IL-17A, the epitope comprising one or more residues selected from TYR44, ASN45, ARG46, TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO:

28.

92. 90. The method of claim 89, wherein the antibody binds to the same epitope of human IL-17A, human IL-17F, or human IL-17A / F heterodimer as a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO:11 and a light chain comprising the sequence given in SEQ ID NO:

10.

93. 90. The method of claim 89, wherein the antibody is a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO:11 and a light chain comprising the sequence given in SEQ ID NO:10, and cross-blocks neutralizing antibodies that bind human IL-17A and human IL-17F.

94. 90. The method of claim 89, wherein the antibody comprises a light chain variable domain and a heavy chain variable domain, and the light chain variable domain comprises the sequence given in SEQ ID NO:

10.

95. The method of any one of claims 89 to 94, wherein the antibody is bimekizumab.

96. The method of any one of claims 89 to 95, wherein the antibody is administered as a pharmaceutical composition.

97. The method of any one of claims 89 to 96, wherein the antibody is administered subcutaneously.

98. The method of any one of claims 89 to 96, wherein the antibody is administered intravenously.

99. 99. The method of any one of claims 89-98, wherein the loading dose is from 80 to 560 mg and at least one maintenance dose is from 40 to 320 mg.

100. 100. The method of claim 99, wherein the loading dose is 80 mg and at least one maintenance dose is 40 mg.

101. 100. The method of claim 99, wherein the loading dose is 160 mg and at least one maintenance dose is 80 mg.

102. 100. The method of claim 99, wherein the loading dose is 240 mg and at least one maintenance dose is 160 mg.

103. 100. The method of claim 99, wherein the loading dose is 320 mg and at least one maintenance dose is 160 mg.

104. 100. The method of claim 99, wherein the loading dose is 560 mg and at least one maintenance dose is 320 mg.

105. 100. The method of claim 99, wherein the loading dose is 480 mg of antibody.

106. 106. The method of any one of claims 99 to 105, wherein a loading dose is administered followed by two maintenance doses.

107. 106. The method of any one of claims 99 to 105, wherein a loading dose is administered followed by at least one maintenance dose at three week intervals.

108. 106. The method of any one of claims 99 to 105, wherein a loading dose is administered followed by at least one maintenance dose at four week intervals.

109. 106. The method of any one of claims 99-105, wherein the method comprises administering doses over a treatment period of at least 12 weeks.

110. 110. The method of claim 109, wherein the method comprises administering doses over a treatment period of at least 24 weeks.

111. 110. The method of claim 109, wherein the method comprises administering doses over a treatment period of at least 48 weeks.

112. 110. The method of claim 109, wherein the method comprises administering doses over a treatment period of at least 52 weeks.

113. A method of treating ankylosing spondylitis in a human comprising administering to the human a neutralizing antibody that binds human IL-17A and human IL-17F.

114. The method of claim 113, wherein the antibody specifically binds to an epitope of human IL-17F, the epitope comprising one or more residues selected from ARG47, ARG73, LEU75 and ILE86 of SEQ ID NO:

27.

115. 114. The method of claim 113, wherein the antibody specifically binds to an epitope of human IL-17A, the epitope comprising one or more residues selected from TYR44, ASN45, ARG46, TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO:

28.

116. The method of claim 113, wherein the antibody binds to the same epitope of human IL-17A, human IL-17F, or human IL-17A / F heterodimer as a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO:11 and a light chain comprising the sequence given in SEQ ID NO:

10.

117. The method of claim 113, wherein the antibody is a neutralizing antibody having a heavy chain comprising the sequence given in SEQ ID NO:11 and a light chain comprising the sequence given in SEQ ID NO:10, and cross-blocks neutralizing antibodies that bind human IL-17A and human IL-17F.

118. The method of claim 113, wherein the antibody comprises a light chain variable domain and a heavy chain variable domain, and the light chain variable domain comprises the sequence given in SEQ ID NO:

10.

119. The method of claim 113, wherein the antibody is bimekizumab.

120. The method of any one of claims 113 to 119, wherein the antibody is administered as a pharmaceutical composition.

121. The method of any one of claims 113 to 120, wherein the antibody is administered subcutaneously.

122. The method of any one of claims 113 to 120, wherein the antibody is administered intravenously.

123. 123. The method of treating ankylosing spondylitis according to any one of claims 113-122, wherein the method comprises administering (a) 16 mg of antibody every 4 weeks, (b) 160 mg of antibody every 4 weeks, (c) a loading dose of 320 mg of antibody followed by a maintenance dose of 160 mg of antibody every 4 weeks, or (d) 320 mg of antibody every 4 weeks.

124. The method of any one of claims 1 to 123, wherein the antibody has an affinity for IL-17A of 100 pM or less and for IL-17F of 100 pM or less as determined by surface plasmon resonance.

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