FIELD OF THE INVENTION

The application relates to antibody molecules having specificity for antigenic determinants of both IL-17A and IL-17F, as well as therapeutic uses of the antibody molecules.

BACKGROUND

Interleukin 17 (IL-17), also known as CTLA-8 or IL-17A, is a pro-inflammatory cytokine which stimulates the secretion of a wide range of other cytokines from various non-immune cells. IL-17A is capable of inducing the secretion of IL-6, IL-8, PGE2, MCP-1 and G-CSF by adherent cells like fibroblasts, keratinocytes, epithelial and endothelial cells and is also able to induce ICAM-1 surface expression, proliferation of T cells, and growth and differentiation of CD34+ human progenitors into neutrophils when cocultured in the presence of irradiated fibroblasts (Fossiez et al., 1998, Int. Rev. Immunol. 16, 541-551). IL-17A is predominantly produced 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). It may also act through 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 called ‘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).

A number of homologues of IL-17 have been identified which have both similar and distinct roles in regulating inflammatory responses. For a review of IL-17 cytokine/receptor families 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 as around 55% identical to IL-17A and is thought to share the same receptors 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). While individual signalling molecules of IL-17A are more potent than those of IL-17F, IL-17F has a greater impact in cooperation with other molecules. For example, when IL-17F is added with TNFα to RA synoviocytes, the induction of the potent inflammatory pathway is similar to the response observed with IL-17A and TNFα. (Hot et al., 2011, Ann. Rheumatic Dis., 70, 341-348.)

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

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

Psoriatic arthritis is an inflammatory condition which affects both the joints and the skin. It can lead to significant joint damage and disability over time and can involve both skin and nail abnormalities seen in psoriasis. (Schett et al., 2011, Arthritis Research and Therapy, 13 Suppl. 1: S4.) Psoriatic arthritis may be difficult to distinguish from other forms of arthritis, particularly when skin changes are minimal or absent. Psoriatic arthritis patients often experience a number of other diseases at a higher frequency than the general population including autoimmune conditions such as iritis/uveitis (swelling and irritation of the eye) and inflammatory bowel disease (IBD), as well as cardiovascular disease and osteoporosis.

Psoriatic arthritis can negatively affect many aspects of a patient's life, imposing burdens of pain, physical functioning and fatigue, as well as reductions in psychological, emotional and social well-being 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.) Studies suggest many aspects of health-related quality of life (HRQol) are affected to a similar degree in patients with psoriatic arthritis and rheumatoid arthritis. (Husted et al., 2001, Arthritis Care and Research, 45:151-8). Psoriatic arthritis is associated with a considerable economic burden, both in terms of direct costs (money spent on medication, hospital care, informal care and over-the-counter medication) and indirect costs (those associated with a loss of productivity at work). (Ackermann & Kavanaugh, 2008, Pharmacoeconomics, 26 (2):121-9).

Psoriatic arthritis can develop in individuals with psoriasis, an inflammatory disorder of the skin (Shbeeb et al., 2000, J Rheumatol., 27: 1247-50). Psoriatic arthritis typically develops in patients after the onset of psoriasis. (Gladman et al., 2006, Annuals of the Rheumatic Diseases, 65 (Suppl. III): iii12-iii24). The mean age at which patients with psoriatic arthritis are diagnosed is 41 years, with men often diagnosed at a younger age (20-39 years) than women (40-59 years). (Shbeed et al., 2000, J Rheumatol., 27:1247-50.) Between 3 and 8 people per 100,000 are newly diagnosed with psoriatic arthritis each year. (Gladman et al., 2005, Annuals of the Rheumatic Diseases, 64(Suppl II): ii14-ii17.)

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

However, environmental factors may induce disease onset as well. Risk factors associated with psoriatic arthritis include: psoriasis involving the scalp, intergluteal areas, more than 3 affected sites, nail dystrophy, recent oral ulceration, and trauma leading to medical care. (Ogdie & Gelfand, 2010, Arch. Dermatol. 146 (7):785-8; Pattison et al., 2008, Ann. Rheum. Dis., 67 (5):672-6.)

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

Symptoms of psoriatic arthritis include, but are not limited, to: stiffness, pain, tenderness, swelling and throbbing in one or more joints, usually in the hands or feet, but sometimes in the wrists, ankles, knee or lower back; swollen fingers or toes that may result in a “sausage-like” appearance (dactylitis); reduced ability to move; nail changes, such as pitting or separation from the nail bed causing functional impairment, pain and emotional distress; eye redness and pain (uveitis); fatigue and morning stiffness (in affected joints); tenderness, pain and swelling over tendons (enthesitis); psoriatic arthritis may affect a small number of joints (oligoarthritis) or many joints (polyarthritis) and/or spine.

People with psoriatic arthritis symptoms, especially those with psoriasis or a family history of psoriatic arthritis, need to see a specialist (e.g. a rheumatologist), as their joint problems may be similar to those seen in other forms of arthritis (e.g. rheumatoid arthritis, gout and reactive arthritis). (Conaghan & Coates, 2009, The Practioner, 253(1724):15-18.) Diagnosis is based on symptoms, medical history, physical examination, results of blood tests and X rays. (Conaghan & Coates, 2009, The Practioner, 253 (1724); 15-18.)

Mild cases of psoriatic arthritis are usually treated with non-steroidal 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 anti-rheumatic drugs (DMARDs). (Weger, 2010, British Journal of Pharmacology, 160:810-20.) More recently, biological agents including anti-tumour necrosis factor alpha antibodies (TNFα blockers) have become available. (Weger, 2010, British Journal of Pharmacology, 160:810-20.) Clinical evidence has demonstrated that minimal disease activity was achieved in 64% of patients treated with TNF-inhibitors, which means that a considerable portion of patients (36%) did not achieve even this target. (Haddad A et al, Arthritis Care Res. 2015; 67, 842-7).

Some subjects are not responsive to previously known treatments, do not maintain a clinical response (defined as achieving American College of Rheumatology 20% response criteria (“ACR20”), or have contraindications or intolerance to these agents. The availability of effective medicines for psoriatic arthritis that have an alternative mechanism of action will improve the treatment of patients, especially those patients who have not gained benefit from, lost effectiveness to, or could not use TNF-inhibitor medications for safety or tolerability reasons. (Mease P, Curr Opin Rheumatol. 2015, 27: 127-33). Because ACR score is a scale that measures symptoms such as joint effects associated with psoriatic arthritis and rheumatoid arthritis, improvements in ACR score are associated with the treatment of both psoriatic arthritis and rheumatoid arthritis.

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

Drugs that inhibit IL-17 and IL-23 have demonstrated significant benefit in psoriasis and emerging studies are also showing benefit in psoriatic arthritis and ankylosing spondylitis. (Mease P, Curr Opin Rheumatol 2015, 27: 127-33). Biological therapies are being developed which target IL-17A, including the anti-IL-17A antibodies secukinumab and ixekizumab which are currently in Phase III clinical trials for psoriatic arthritis. The results of a Phase II clinical study of secukinumab in psoriatic arthritis are described in Mease et al., 2015, N Engl J Med, 373, 14, 1329-1339 and in ankylosing spondylitis in Baeten et al., N. Engl. J. Med, 2015, 373 (26), 2534-48. The results of a Phase III clinical study of ixekizumab in psoriatic arthritis are described in Mease et al, 2015, ACR Abstract number 977. Brodalumab is an anti IL-17RA monoclonal antibody which, by targeting IL-17RA, blocks IL-17A, IL-17F and IL-17E (IL-25) activity. The results of a Phase II clinical study of brodalumab in psoriatic arthritis are described in Mease et al., 2015, N Engl J Med, 370, 24, 2295-2306. The efficacy of current therapies at week 24 is around 60%, 40% and 20% for ACR20, ACR50 and ACR70 respectively, along with a PASI 75 of around 65% (Table 1 in Sritheran and Ying Leung, Ther. Adv. Musculoskel. Dis., 2015, 7(5), 173-186).

SUMMARY OF THE INVENTION

The invention relates to antibody molecules having specificity for antigenic determinants of both IL-17A and IL-17F, therapeutic uses of the antibody molecules in the treatment of dermatological and rheumatological diseases, such as psoriatic arthritis, and methods for producing said antibody molecules. In one example, the antibody of the invention may be used in the treatment of dermatological conditions (such as, but not limited to, psoriasis, atopic dermatitis, discoid lupus erythematosus, alopecia areata, autoimmune urticaria, bullous pemphigoid, dermatitis herpetiformis, hidradenitis suppurativa, linear IgA dermatosis, morphea, pemphigus vulgaris, and pyoderma gangrenosum) and/or rheumatological conditions (such as, but not limited to psoriatic arthritis, axial spondyloarthritis including non-radiographic axial spondyloarthritis and ankylosing spondylitis, systemic lupus erythematosus (SLE), rheumatoid arthritis, vasculitis, Sjogren's syndrome (extraglandular), juvenile idiopathic arthritis, granulomatosis, Behçet's disease (mucocutaneous), antiphospholipid syndrome, giant cell arteritis, scleroderma, polyarteritis nodosa, Behçet's disease (thrombosis), and Takayasu disease). In one example, the antibody of the invention may be used in the treatment of psoriatic arthritis. Neutralising antibodies which bind both IL-17A and IL-17F, such as bimekizumab, may provide a significant improvement over existing psoriatic arthritis therapies, both in the speed and magnitude of clinical effect. For example, they may mediate equivalent or even improved clinical scores by week 8. Suitable clinical scores include American College of Rheumatology (“ACR”) 20/50/70 response for joints and, for skin, the clinical features of psoriasis, Psoriasis Area and Severity Index (“PASI”) 50/75/90 response. For example, these antibodies may increase the number of patients achieving ACR20, ACR50, ACR70 and PASI75 at week 8 or week 12 to greater than 60%, 40%, 20% and 65% respectively (average response rate). They may even have the potential to increase the number of patients achieving ACR20, ACR50, ACR70 and PASI75 at week 8 or week 12 to 60-95%, 40-60%, 20-40% and 80-100% respectively. For example these may be 80%, 60%, 40% and close to 90% or close to 100% respectively. The speed to achieving a beneficial response in subjects administered an antibody as described herein also is remarkable. For example, in various embodiments, the subject achieves ACR20 or ACR50 (or PASI 20 or PASI50) within four weeks (e.g., within three weeks or within two weeks) of a first administration. Additionally, in various embodiments, the beneficial response to the methods described herein may be sustained for a remarkable period of time. For instance, subjects administered three doses of anti-IL-17A/F antibody described herein (e.g., at days 0, 21, and 42) enjoyed near maximal-response to week 20. Thus in various aspects, the methods described herein may achieve a biological response in a subject at week 8 or week 12 that diminishes no more than 10%, no more than 20%, no more than 30%, no more than 40%, or no more than 50% at week 20. In one example, the antibody of the invention may be used in the treatment of any of the symptoms of psoriatic arthritis listed herein below, including but not limited to dactylitis, enthesitis, nail dystrophy, skin manifestations; signs and symptoms of peripheral arthritis; axial disease and structural progression of the disease. In one example, the antibody of the invention may be used to prevent the development of psoriatic arthritis or other conditions in psoriasis patients.

The invention further provides the use of an antibody molecule according to the invention in the manufacture of a medicament for the treatment or prophylaxis of a pathological disorder that is mediated by IL-17A and/or IL-17F or associated with an increased level 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 non-radiographic axial spondyloarthritis.

An antibody molecule of the invention may be utilised in any therapy where it is desired to reduce the effects 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 present in an undesirably high level localised at a particular site in the body, for example a site of inflammation.

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

In one embodiment, the invention also provides an antibody molecule of the invention, in particular a neutralising antibody which binds human IL-17A and human IL-17F, for use in the treatment of human or animal subjects 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 non-radiographic axial spondyloarthritis.

In one embodiment, the invention therefore provides an antibody molecule of the invention, in particular a neutralising antibody which 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-radiographic axial spondyloarthritis.

“Psoriasis” encompasses disorders or skin-related components (i.e., symptoms) of disorders such as, but not limited to, plaque psoriasis, pustular psoriasis, generalised pustular psoriasis, palmo-plantar psoriasis, scalp psoriasis, guttate psoriasis, erythrodermic psoriasis, inversive psoriasis, acrodermatitis continua, SAPHO (Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis) syndrome, hidradenitis suppurativa, and DITRA (deficiency of the IL-36 receptor [IL-36R] antagonist)/DIRA (deficiency of the 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.

An antibody molecule according to the invention may also be used in diagnosis, for example in the in vivo diagnosis and imaging of disease states involving IL-17A and/or IL-17F.

The invention provides a method of treating psoriatic arthritis in a human comprising the step of administering to the human a neutralizing antibody which binds human IL-17A and human IL-17F. In an embodiment, the antibody specifically binds 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 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 on human IL-17A, human IL-17F, or IL-17 A/F heterodimer as a neutralising antibody that has 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 neutralising antibody that has 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 binds 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 variable domain of the light chain 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.

In any of the embodiments of the method of treating psoriatic arthritis in a human comprising the step of administering to the human a neutralizing antibody which 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 of age and/or was diagnosed at least six months prior to administration of the antibody. Also optionally, the human was diagnosed based on the CASPAR criteria. In any of the embodiments described above, the human has active arthritis. This is typically defined as ≥3 tender and ≥3 swollen joints. The patients may have coexistent or concomitant psoriasis and/or a history of psoriasis. For example, the human optionally has active psoriatic lesions or a history of psoriatic lesions.

In any of the embodiments of the method of treating psoriatic arthritis, psoriasis, rheumatoid arthritis or axial spondylitis, including ankylosing spondylitis and non-radiographic spondylitis in a human comprising the step of administering to the human a neutralizing antibody which binds human IL-17A and human IL-17F described herein, the antibody may be administered as a monotherapy.

In any of the embodiments of the method of treating psoriatic arthritis, psoriasis, rheumatoid arthritis or axial spondlyitis, including ankylosing spondylitis and non-radiographic spondylitis in a human comprising the step of administering to the human a neutralizing antibody which binds human IL-17A and human IL-17F described herein, the human optionally is biologic-naïve i.e. has not been previously treated with a biological agent, such as a TNF alpha inhibitor such as an anti-TNF antibody.

In any of the embodiments of the method of treating psoriatic arthritis in a human comprising the step of administering to the human a neutralizing antibody which binds human IL-17A and human IL-17F described herein, the human optionally is an inadequate responder to at least one non-biologic disease-modifying antirheumatic drug (“DMARD”) and/or one or more approved biologic DMARD (e.g., a TNF inhibitor such as an anti-TNF antibody, examples including inflixumab or adalimumab, or a soluble TNF receptor, such as etanercept). Examples of non-biologic DMARDs include sulfsalazine, methotrexate, cyclosporine, hydrozychloroquine, azathioprine and leflunomide. Optionally the human is an inadequate responder to at least one non-steroidal anti-inflammatory drug (NSAID). Examples of suitable NSAIDs include but are not limited to, propionic acid derivative, acetic acid derivative, enolic acid derivatives, fenamic acid derivatives, cox inhibitors, ibuprofen, fenoprofen and aspirin.

The invention also provides a method of treating psoriatic arthritis in a human concurrently treated with methotrexate or other non-biologic DMARD (such as leflunomide) or non-steroidal anti-inflammatory drug (NSAID) and/or steroid comprising the step of administering to the human a neutralizing antibody which binds human IL-17A and human IL-17F. In various embodiments, the antibody specifically binds 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 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 on human IL-17A, human IL-17F, or IL-17 A/F heterodimer as a neutralising antibody that has 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 neutralising antibody that has 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 binds 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, wherein the variable domain of the light chain 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.

The invention includes a method of treating psoriatic arthritis in a human comprising the step of administering to the human a therapeutically effective amount of a neutralizing antibody which binds human IL-17A and human IL-17F. In various aspects, the antibody specifically binds 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 aspects, the antibody specifically binds 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 on human IL-17A, human IL-17F, or IL-17 A/F heterodimer as a neutralising antibody that has 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 neutralising antibody that has 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 binds human IL-17A and human IL-17F. The antibody, in various embodiments, comprises a light chain variable domain and a heavy chain variable domain, wherein the variable domain of the light chain 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 may be administered subcutaneously or intravenously.

An embodiment of the invention includes a method of treating psoriatic arthritis in a human patient comprising the step of administering to the patient a neutralizing antibody which binds human IL-17A and human IL-17F in an amount that is 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 administered amount is effective to provide an ACR50 response at week 8 or week 12, or an ACR70 response at week 8 or week 12 in the population of patients. In a preferred aspect, the amount is effective to provide an ACR70 response at week 8 or week 12 in the population of patients. Alternatively or in addition, the neutralizing antibody is administered in an amount that is effective to provide a PASI50 response at week 8 or week 12, PASI75 response at week 8 or week 12, or a PASI90 response at week 8 or week 12, such as an amount that is effective to provide a PASI75 response at week 8 or week 12, or a PASI90 response at week 8 or week 12 in the population of patients. In a preferred aspect, the neutralizing antibody is administered in an amount that is effective to provide a PASI90 response or a PASI100 response at week 8 or week 12 in the population of patients. Typically the response is sustained such that ACR50, ACR70 and/or PASI responses may be maintained to week 16, 20, 24 or later. In various aspects, the antibody specifically binds 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 and/or specifically binds 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 on human IL-17A, human IL-17F, or IL-17 A/F heterodimer as a neutralising antibody that has 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 aspects, the antibody cross-blocks a neutralising antibody that has 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 binds human IL-17A and human IL-17F. Optionally, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the variable domain of the light chain comprises the sequence given in SEQ ID NO:10. In a preferred aspect, the antibody is bimekizumab. The antibody is optionally administered as a pharmaceutical composition. The antibody may be administered subcutaneously or intravenously.

The invention further provides a method of reducing psoriasis in a human comprising the step of administering to the human a neutralizing antibody which 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. The reduction of plaque psoriasis is optionally measured by PASI criteria. In various embodiments, the antibody specifically binds 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 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 on human IL-17A, human IL-17F, or IL-17 A/F heterodimer as a neutralising antibody that has 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 neutralising antibody that has 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 binds 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 variable domain of the light chain 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. In one or more embodiments, the psoriasis treated using the method of the present invention may be selected from plaque psoriasis, pustular psoriasis, generalised pustular psoriasis, palmo-plantar psoriasis, nail psoriasis, scalp psoriasis, guttate psoriasis, erythrodermic psoriasis, inversive psoriasis.

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

The invention further provides a method of treating psoriasis in a human patient comprising the step of administering to the patient a neutralizing antibody which binds human IL-17A and human IL-17F in an amount that is effective to provide a PASI75 response at week 8 or week 12, or a PASI90 response at week 8 or week 12. In a preferred aspect, the neutralizing antibody is administered in an amount that is effective to provide a PASI75 response or a PASI90 response at week 8 or week 12 in the population of patients. In various aspects, the antibody specifically binds 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 and/or specifically binds 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 on human IL-17A, human IL-17F, or IL-17 A/F heterodimer as a neutralising antibody that has 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 aspects, the antibody cross-blocks a neutralising antibody that has 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 binds human IL-17A and human IL-17F. Optionally, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the variable domain of the light chain comprises the sequence given in SEQ ID NO:10. In a preferred aspect, the antibody is bimekizumab. The antibody is optionally administered as a pharmaceutical composition. The antibody may be administered subcutaneously or intravenously.

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

In any of the embodiments of the method of treating psoriasis in a human comprising the step of administering to the human a neutralizing antibody which binds human IL-17A and human IL-17F described herein, the human optionally is an inadequate responder to at least one non-biologic disease-modifying antirheumatic drug (“DMARD”) and/or one or more approved biologic DMARD (e.g., a TNF inhibitor such as an anti-TNF antibody, examples including inflixumab or adalimumab, or a soluble TNF receptor, such as etanercept). Examples of non-biologic DMARDs include sulfsalazine, methotrexate, cyclosporine, hydrozychloroquine, azathioprine and leflunomide. Optionally the human is an inadequate responder to at least one non-steroidal anti-inflammatory drug (NSAID). Examples of suitable NSAIDs include but are not limited to, propionic acid derivative, acetic acid derivative, enolic acid derivatives, fenamic acid derivatives, cox inhibitors, ibuprofen, fenoprofen and aspirin.

The invention also provides a method of treating psoriasis in a human concurrently treated with methotrexate or other non-biologic DMARD (such as leflunomide) or non-steroidal anti-inflammatory drug (NSAID) and/or steroid comprising the step of administering to the human a neutralizing antibody which binds human IL-17A and human IL-17F.

The invention also provides a method of reducing joint effects in a human comprising the step of administering to the human a neutralizing antibody which binds human IL-17A and human IL-17F. The reduction of joint effects is optionally measured by ACR criteria. In various aspects, the antibody specifically binds 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 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 on human IL-17A, human IL-17F, or IL-17 A/F heterodimer as a neutralising antibody that has 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 aspects, the antibody cross-blocks a neutralising antibody that has 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 binds human IL-17A and human IL-17F. Optionally, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the variable domain of the light chain 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. Such joint effects may also include peripheral joint involvement, including synovitis, enthesitis and/or dactylitis.

The invention provides a method of reducing psoriasis and reducing joint effects in a human comprising the step of administering to the human a neutralizing antibody which binds human IL-17A and human IL-17F. In various embodiments, the psoriasis is plaque psoriasis. The reduction of plaque psoriasis is optionally measured by PASI criteria and/or the reduction of joint effects is optionally measured by ACR criteria. Alternatively or in addition, the reduction of joint effects, such as structural progression, may be measured by modified total sharp score (mTSS). Where measured, a reduction in enthesitis or dactylitis may be measured by a reduction in Leeds enthesitis index (LEI) and Leeds dactylitis index (LDI) scores respectively. In various aspects, the antibody specifically binds 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 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 on human IL-17A, human IL-17F, or IL-17 A/F heterodimer as a neutralising antibody that has 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 aspects, the antibody cross-blocks a neutralising antibody that has 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 binds human IL-17A and human IL-17F. Optionally, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the variable domain of the light chain 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.

The invention further provides a method of treating psoriatic arthritis in a human, comprising the step of administering to the human a loading dose of a neutralizing antibody which binds human IL-17A and human IL-17F followed by at least one maintenance dose of the antibody. Optionally, the loading dose is between 80 and 560 mg and the at least one maintenance dose is between 40 and 320 mg. In one aspect of the method, the loading dose is 80 mg and the at least one maintenance dose is 40 mg. In another aspect of the method, the loading dose is 160 mg and the at least one maintenance dose is 80 mg. In a further aspect, the loading dose is 240 mg and the at least one maintenance dose is 160 mg. In a further aspect, the loading dose is 320 mg and the at least one maintenance dose is 160 mg. In another aspect, the loading dose is 560 mg and the at least one maintenance dose is 320 mg. In various embodiments, the loading dose is administered followed by two maintenance doses. Optionally, the loading dose is administered followed by at least one maintenance dose at a three week interval or a four week interval. The antibody, in various embodiments, specifically binds 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 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 on human IL-17A, human IL-17F, or IL-17 A/F heterodimer as a neutralising antibody that has 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 aspects, the antibody cross-blocks a neutralising antibody that has 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 binds human IL-17A and human IL-17F. In various aspects, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the variable domain of the light chain 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.

An embodiment of the invention may include a method of treating psoriatic arthritis in a human, comprising the step of administering to the human at least one dose of a neutralizing antibody which binds human IL-17A and human IL-17F. In various embodiments, at least one dose is between 40 and 640 mg of the antibody. For example, in various aspects, at least one dose is 40 mg of the antibody. In various aspects, at least one dose is 80 mg of the antibody. In various aspects, at least one dose is 160 mg of the antibody. In various aspects, at least one dose is 240 mg of the antibody. In various aspects, at least one dose is 320 mg of the antibody. In various aspects, at least one dose is 480 mg of the antibody. In various aspects, at least one dose is 560 mg of the antibody. In various aspects, at least one dose is 640 mg of the antibody. In any of the aspects, the doses are optionally administered at a three week interval or a four week interval. In any of the aspects, the doses are optionally administered at an eight week interval or a twelve week interval. In any of the aspects, the antibody specifically binds 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 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 on human IL-17A, human IL-17F, or IL-17 A/F heterodimer as a neutralising antibody that has 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 aspects, the antibody cross-blocks a neutralising antibody that has 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 binds human IL-17A and human IL-17F. Optionally, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the variable domain of the light chain 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.

The invention also provides a method of treating rheumatoid arthritis in a human comprising the step of administering to the human a neutralizing antibody which binds human IL-17A and human IL-17F. In various aspects, the antibody specifically binds 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 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 on human IL-17A, human IL-17F, or IL-17 A/F heterodimer as a neutralising antibody that has 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 neutralising antibody that has 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 binds 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 variable domain of the light chain 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.

In various embodiments of the method of treating rheumatoid arthritis in a human, the human has a diagnosis of adult-onset rheumatoid arthritis; optionally, the human is at least 18 years of age. Also optionally, the human was diagnosed at least six months prior to administration of the antibody. In various embodiments, the human was classified based on 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 is an inadequate responder to at least one non-biologic disease-modifying antirheumatic drug (“DMARD”) and/or at least one approved biologic DMARD. Alternatively, or in addition, the human may be an inadequate responder to at least one non-steroidal anti-inflammatory drug (NSAID).

The invention provides a method of treating rheumatoid arthritis in a human concurrently treated with methotrexate or other non-biologic DMARD (such as leflunomide) or non-steroidal anti-inflammatory drug (NSAID) and/or steroid comprising the step of administering to the human a neutralizing antibody which binds human IL-17A and human IL-17F. In various aspects, the antibody specifically binds 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 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 on human IL-17A, human IL-17F, or IL-17 A/F heterodimer as a neutralising antibody that has 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 aspects, the antibody cross-blocks a neutralising antibody that has 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 binds human IL-17A and human IL-17F. In various aspects, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the variable domain of the light chain 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.

The invention includes a method of treating rheumatoid arthritis in a human comprising the step of administering to the human a therapeutically effective amount of a neutralizing antibody which binds human IL-17A and human IL-17F. In various aspects, the antibody specifically binds 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 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 on human IL-17A, human IL-17F, or IL-17 A/F heterodimer as a neutralising antibody that has 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 aspects, the antibody cross-blocks a neutralising antibody that has 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 binds human IL-17A and human IL-17F. Optionally, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the variable domain of the light chain 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.

The invention further includes a method of treating rheumatoid arthritis in a human patient comprising the step of administering to the patient a neutralizing antibody which binds human IL-17A and human IL-17F in an amount that is 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 aspects, the amount administered is effective to provide an ACR50 response at week 8 or week 12, or an ACR70 response at week 8 or week 12 in the population of patients. In a preferred aspect, the amount is 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 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 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 on human IL-17A, human IL-17F, or IL-17 A/F heterodimer as a neutralising antibody that has 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 neutralising antibody that has 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 binds human IL-17A and human IL-17F. Optionally, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the variable domain of the light chain 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.

The invention also provides a method of treating rheumatoid arthritis in a human, comprising the step of administering to the human a loading dose of a neutralizing antibody which 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 between 80 and 560 mg and the at least one maintenance dose is between 40 and 320 mg. For example, in various embodiments, the loading dose is 80 mg and the at least one maintenance dose is 40 mg, the loading dose is 160 mg and the at least one maintenance dose is 80 mg, the loading dose is 240 mg and the at least one maintenance dose is 160 mg, the loading dose is 320 mg and the at least one maintenance dose is 160 mg, or the loading dose is 560 mg and the at least one maintenance dose is 320 mg. Optionally, the loading dose is administered followed by two maintenance doses. Also optionally, the loading dose is administered followed by at least one maintenance dose at a three week interval or a four week interval. In various embodiments, the antibody specifically binds 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 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 on human IL-17A, human IL-17F, or IL-17 A/F heterodimer as a neutralising antibody that has 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 aspects, the antibody cross-blocks a neutralising antibody that has 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 binds human IL-17A and human IL-17F. Optionally, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the variable domain of the light chain 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.

The invention further provides a method of treating rheumatoid arthritis in a human, comprising the step of administering to the human at least one dose of a neutralizing antibody which binds human IL-17A and human IL-17F. Optionally, the at least one dose is between 40 and 640 mg of the antibody. For example, at least one dose is 40 mg of the antibody or 80 mg of the antibody or 160 mg of the antibody or 240 mg of the antibody or 320 mg of the antibody or 480 mg of the antibody or 560 mg of the antibody or 640 mg of the antibody. Also optionally, the doses are administered at a three week interval or a four week interval. In various aspects, the antibody specifically binds 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 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 on human IL-17A, human IL-17F, or IL-17 A/F heterodimer as a neutralising antibody that has 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 aspects, the antibody cross-blocks a neutralising antibody that has 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 binds human IL-17A and human IL-17F. Optionally, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the variable domain of the light chain 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.

The invention also provides a method of treating axial spondyloarthritis (e.g., ankylosing spondylosis) comprising the step of administering to the human a neutralizing antibody which binds human IL-17A and human IL-17F. Axial spondyloarthritis refers to a group of inflammatory arthritis diseases which primarily affects the spine and other joints, causing inflammation and chronic pain in the spine and sacroliliac joints which may eventually result in syndemophyte formation and which includes both ankylosing spondylitis and nonradiographic spondylitis. Thus, the invention provides a method for treating (e.g., ameliorating the symptoms of, reducing the progression of) ankylosing spondylosis and/or nonradiographic axial spondyloarthritis (nr-axSpA). In various aspects, the antibody specifically binds 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 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 on human IL-17A, human IL-17F, or IL-17 A/F heterodimer as a neutralising antibody that has 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 aspects, the antibody cross-blocks a neutralising antibody that has 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 binds human IL-17A and human IL-17F. Optionally, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the variable domain of the light chain 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. Preferably the antibody is administered in a therapeutically effective amount. Any of the dosing regimens described herein are suitable for use in the context of this method. For example, in various embodiments, the method comprises administering to a subject a 16 mg, 64 mg, 160 mg, or 320 mg of antibody every four weeks, optionally for a treatment period of 12 weeks, 36 weeks, 48 weeks, or 52 weeks. The amount and timing of administration is preferably sufficient to achieve at least an ASAS20 response (e.g., ASAS40,) at week 2, week 4, week 8, or week 12 of treatment. ASAS scoring and methods of evaluating 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 provide at least 30% or at least 40% or at least 45% or at least 50% of subjects achieving an ASAS40 response at week 12 of treatment. In various embodiments, the invention provides a method of inhibiting (e.g., slowing the progression of) periosteal bone formation in a human, such as a human suffering from spondyloarthritis (e.g., ankylosing spondylosis), by administering a neutralizing antibody which binds human IL-17A and human IL-17F as described herein. Periosteal bone formation is evaluated via, e.g., radiography

In any of the embodiments of the method of treating axial spondyloarthitis including ankylosing spondylitis and nr-axSpA in a human comprising the step of administering to the human a neutralizing antibody which 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 of age and/or was diagnosed at least six months prior to administration of the antibody. Also optionally, the human has been classified based on the modified New York or ASAS criteria. In any of the embodiments described above, the human has active axial arthritis.

In any of the embodiments of the method of treating axial spondyloarthritis including ankylosing spondylitis and/or nr-axSpA in a human comprising the step of administering to the human a neutralizing antibody which binds human IL-17A and human IL-17F described herein, the human optionally is an inadequate responder to at least one nonsteroidal anti-inflammatory drug (“NSAID”) and/or one or more approved biologic DMARD (e.g., a TNF inhibitor such as an anti-TNF antibody, examples including inflixumab or adalimumab, or a soluble TNF receptor, such as etanercept).

The invention also provides a method of treating axial spondyloarthritis including ankylosing spondylitis and/or nr-axSpA in a human concurrently treated with a non-steroidal anti-inflammatory drug (NSAID) comprising the step of administering to the human a neutralizing antibody which binds human IL-17A and human IL-17F.

Also included in the invention is a method of treating psoriatic arthritis comprising the step of administering a neutralizing antibody which binds human IL-17A and human IL-17F in an amount that is effective to provide at least 50% of subjects achieving an ACR20 response at week 8 or week 12. For example, the amount is effective to provide at least 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64 or 65% of subjects achieving an ACR20 response at week 8 or week 12. In one example, the amount is effective to provide at least 50-90% or 60-90% or 63-91% of subjects achieving an ACR20 response at week 8 or week 12. In one example, the amount is effective to provide at least 40%, at least 45%, at least 50% or at least 55% of subjects achieving an ACR50 response at week 8 or week 12 or week 20. Alternatively or in addition, the amount of neutralizing antibody is effective to provide at least 80% of subjects achieving a PASI75 response at week 8 or week 12. For example, the amount is effective to provide 80-100% of subjects achieving a PASI75 response at week 8 or week 12, such as an amount effective to provide at least 80, 85, 90, 95 or 99% of subjects achieving a PASI75 response at week 8 or week 12. In various embodiments, the amount of neutralizing antibody is effective to provide at least 60% of subjects achieving a PASI90 response or a PASI100 response at week 8 or week 12, e.g., an amount effective to provide 60-100% or 62-96% of subjects achieving a PASI90 response at week 8 or week 12 (such as an amount effective to provide at least 60, 65, 70, 75, 80, 85, 90, 95 or 96% of subjects achieving a PASI90 response at week 8 or week 12).

