Methods for treating atopic dermatitis and related disorders

Abstract

The present invention relates to methods for treating atopic dermatitis in a subject using interleukin-13 (IL-13) binding proteins, such as anti-IL-13 antibodies or IL-13 binding fragments thereof.

Description

[Technical field]

[0001] The present invention relates to methods for treating atopic dermatitis in a subject using interleukin-13 (IL-13) binding proteins, such as anti-IL-13 antibodies or IL-13 binding fragments thereof. [Background technology]

[0002] Atopic dermatitis (AD) is a heterogeneous inflammatory skin disease resulting from genetic and environmental factors that disrupt the skin barrier function and immune response (Leung, DY and Guttman-Yassky, E. Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches. J Allergy Clin Immunol. 2014;134:769-779). Current management generally involves a combination of treatments to suppress inflammation, restore skin barrier function, and prevent superinfection (Wollenberg, A., Oranje, A., Deleuran, M., Simon, D., Szalai, Z., Kunz, B. et al. ETFAD / EADV Eczema task force 2015 position paper on diagnosis and treatment of atopic dermatitis in adult and paediatric patients. J Eur Acad Dermatol Venereol. 2016;30:729-747).

[0003] Topical corticosteroids (TCS) are by far the most frequently prescribed class of medications for AD patients, but long-term application of TCS is not recommended. Topical calcineurin inhibitors (TCIs) are generally effective and safe as short-term treatment. Increased risk of cutaneous malignancies and lymphomas has led regulatory agencies, for example, to mandate warnings regarding the long-term safety of topical tacrolimus and pimecrolimus in prescribing information. First-generation antihistamines are widely prescribed for the acute symptomatic treatment of pruritus (itch), but their efficacy is limited, mainly attributable to their sedative effects. Oral immunosuppressants and glucocorticoids are effective, but can be associated with severe toxicity and side effects, limiting their use to short-term and / or intermittent therapy.

[0004] Cyclosporine A (CSA), a therapy for severe AD in some regions, is an immunosuppressant that affects both humoral and cellular immune responses, which increases susceptibility to infection and reduces cancer immunosurveillance. Other commonly recognized toxicities include hypertension and impaired renal and hepatic function. In addition, CSA may interact with other commonly used drugs, affecting their metabolism and efficacy. Systemic immunosuppressants are usually of limited use in the treatment of moderate to severe AD, as they are associated with adverse events and are not suitable for long-term use (Wollenberg, A., Oranje, A., Deleuran, M., Simon, D., Szalai, Z., Kunz, B. et al. ETFAD / EADV Eczema task force 2015 position paper on diagnosis and treatment of atopic dermatitis in adult and paediatric patients. J Eur Acad Dermatol Venereol. 2016;30:729-747). Therefore, more effective and well-tolerated therapies that target mechanisms of AD pathophysiology rather than simply alleviating symptoms are needed.

[0005] One important feature of AD is the upregulation of IL-13 and interleukin-4 (IL-4) in lesional and non-lesional skin, suggesting that both cytokines may contribute to the pathogenesis of AD (see Nomura, I., Goleva, E., Howell, MD, Hamid, QA, Ong, PY, Hall, CF et al. Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes. J Immunol. 2003;171:3262-3269; Tazawa, T., Sugiura, H., Sugiura, Y., and Uehara, M. Relative importance of IL-4 and IL-13 in lesional skin of atopic dermatitis. Arch Dermatol Res. 2004;295:459-464). Furthermore, AD severity is associated with increased IL-13 and related chemokine mRNA and serum levels, whereas decreased IL-13 concentrations correlate with improved treatment response and clinical outcomes.Treatment with dupilumab, a human mAb that inhibits both IL-4 and IL-13 signaling, has been shown to improve AD symptoms, although the relative contribution of each of these cytokines to AD pathogenesis is unclear.

[0006] In real clinical practice, the prevalence of conjunctivitis in patients receiving dupilumab is estimated to be 26% based on a systematic review of the literature (Halling AS et al. Real-world evidence of dupilumab efficacy and risk of adverse events: A systematic review and meta-analysis. J Am Acad Dermatol 2020) and can persist despite appropriate ophthalmic treatment (Achten R et al. Long-term follow-up and treatment outcomes of conjunctivitis during dupilumab treatment in patients with moderate-to-severe atopic dermatitis. J Allergy Clin Immunol Pract 2020). Furthermore, the incidence of ocular complications from dupilumab, such as conjunctivitis, has been shown to increase with the severity of AD (Simpson EL et al. Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis. N Engl J Med 2017;376:1090-1091, Thyssen JP et al. Incidence, prevalence, and risk of selected ocular disease in adults with atopic dermatitis. J Am Acad Dermatol 2017;77:280-286 e281).Ophthalmological side effects during dupilumab treatment have only been observed in patients with AD, and not in studies of chronic sinusitis with nasal polyps, asthma, or eosinophilic esophagitis (Bachert C et al. Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis: a randomized clinical trial. JAMA 2016;315:469-479, Castro M et al. Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma. N Engl J Med 2018;378:2486-2496, Hirano I et al. Efficacy of dupilumab in a phase 2 randomized trial of adults with active eosinophilic esophagitis. Gastroenterology 2020;158:111-122.e110), suggesting that there is a specific predisposition to AD. Since the introduction of dupilumab as a treatment for AD, conjunctivitis has been identified as an important adverse event, resulting in increased collaboration with ophthalmologists (Agnihotri G et al.A Clinician's Guide to the Recognition and Management of Dupilumab-Associated Conjunctivitis.Drugs in R&D 2019;19:311-318, Wollenberg et al.2018;Wollenberg A et al.Conjunctivitis occurring in atopic dermatitis patients treated with dupilumab-clinical characteristics and treatment.J Allergy Clin Immunol Pract 2018).

[0007] IL-13 is a 114 amino acid cytokine with an unmodified molecular weight of approximately 12 kDa. IL-13 is most closely related to IL-4, sharing 30% sequence homology at the amino acid level. The human IL-13 gene is located on chromosome 5q31 adjacent to the IL-4 gene. Although initially identified as a cytokine from Th2 CD4+ lymphocytes, IL-13 is also produced by Th1 CD4+ T cells, CD8+ T lymphocytes NK cells, and non-T cell populations such as mast cells, basophils, eosinophils, macrophages, monocytes, and airway smooth muscle cells. IL-13 has been associated with multiple diseases, particularly those caused by inflammatory responses. For example, administration of recombinant IL-13 to the airways of naive, unsensitized rodents has been found to induce many aspects of the asthma phenotype, including airway inflammation, mucus production, and airway hyperresponsiveness. A similar phenotype was observed in transgenic mice that overexpressed IL-13 specifically in the lungs, and more chronic exposure to IL-13 also led to fibrosis in this model.

[0008] Several genetic polymorphisms in the IL-13 gene have also been linked to allergic diseases. In particular, a variant of the IL-13 gene in which the arginine residue at amino acid 130 is replaced by glutamine (Q130R) has been linked to bronchial asthma, atopic dermatitis, and elevated serum IgE levels. This particular IL-13 variant is also called the Q110R variant (arginine residue at amino acid 110 is replaced by glutamine) by some groups, who exclude the 20 amino acid signal sequence from its amino acid number.

[0009] Tralokinumab (also known as CAT-354 and BAK502G9) is a fully human therapeutic antibody that binds and neutralizes IL-13, including the Q130R variant. (See Popovic et al. J. Mol. Biol. (2017) 429(2):208-219; May, RD, Monk, PD, Cohen, ES, Manuel, D., Dempsey, F., Davis, NH et al. Preclinical development of CAT-354, an IL-13 neutralizing antibody, for the treatment of severe uncontrolled asthma. Br J Pharmacol. 2012;166:177-193.)

[0010] Tralokinumab was previously tested in a phase 2b study for the treatment of AD in 204 adults. In this study, patients received 45 mg, 150 mg, or 300 mg subcutaneous tralokinumab or placebo every 2 weeks with topical glucocorticoids for 12 weeks and showed improved change from baseline in Eczema Area and Severity Index (EASI) scores, as well as improvements in Scoring of Atopic Dermatitis (SCORAD), Skin Status Questionnaire (DLQI), and Numeric Rating Scale for Pruritus scores compared to placebo (Wollenberg J. Allergy Clin. Immunol. (2019) 143(1):135-141).

[0011] For example, further and improved treatments for AD that address at least some of the problems noted above remain desirable in the art. Summary of the Invention

[0012] The inventors have found that patients whose AD is inadequately controlled by therapeutics that target both IL-13 and IL-4 signaling (e.g., antibodies such as dupilumab) can be effectively treated with an IL-13 binding protein (e.g., an anti-IL13 antibody such as tralokinumab).

[0013] Thus, in one aspect, the invention provides an interleukin-13 (IL-13) binding protein for use in a method of treating atopic dermatitis (AD) in a subject, wherein the AD is inadequately controlled by an agent that inhibits IL-13 and IL-4 signaling, the method comprising administering to the subject the IL-13 binding protein.

[0014] In some embodiments, the methods include selecting a subject whose AD is inadequately controlled by an agent that inhibits IL-13 and IL-4 signaling.

[0015] In another aspect, the invention provides a method of treating atopic dermatitis (AD) in a subject in need thereof, wherein the AD is inadequately controlled by an agent that inhibits IL-13 and IL-4 signaling, the method comprising administering to the subject an IL-13 binding protein.

[0016] In some embodiments, the methods include selecting a subject whose AD is inadequately controlled by an agent that inhibits IL-13 and IL-4 signaling.

[0017] In another aspect, the invention provides the use of an IL-13 binding protein in the manufacture of a medicament for treating AD in a subject, wherein the AD is inadequately controlled by an agent that inhibits IL-13 and IL-4 signaling.

[0018] In any of the aspects or embodiments described herein, the AD can be moderate to severe AD or severe AD.

[0019] In some aspects, the invention provides an IL-13 binding protein for use in a method for treating atopic dermatitis in a subject who experiences conjunctivitis when treated with an agent that inhibits IL-13 and IL-4 signaling, the method comprising administering to the subject the IL-13 binding protein.

[0020] In some aspects, the invention provides methods for treating atopic dermatitis in a subject that experiences conjunctivitis when treated with an agent that inhibits IL-13 and IL-4 signaling, the method comprising administering to the subject an IL-13 binding protein.

[0021] In some aspects, the invention provides use of an IL-13 binding protein in the manufacture of a medicament for treating atopic dermatitis in a subject who experiences conjunctivitis when treated with an agent that inhibits IL-13 and IL-4 signaling, the method comprising administering to the subject the IL-13 binding protein.

[0022] In some embodiments, the methods involve selecting a subject who experienced conjunctivitis when treated with an agent that inhibits IL-13 and IL-4 signaling.

[0023] In any of the aspects or embodiments described herein, the AD may be inadequately controlled by cyclosporine A or the subject may have a contraindication to cyclosporine A.

[0024] In any of the aspects or embodiments described herein, the method may include the steps of (a) administering to the subject a first dose of an IL-13 binding protein; and (b) administering to the subject one or more second dose(s) of the IL-13 binding protein, wherein each second dose is administered to the subject 12 to 35 days after the immediately preceding dose. In preferred embodiments, each second dose is administered to the subject about 12 to 16 days after the immediately preceding dose, or about 25 to 31 days after the immediately preceding dose. In particularly preferred embodiments, each second dose is administered to the subject about 2 weeks after the immediately preceding dose, or about 4 weeks after the immediately preceding dose.

[0025] In some embodiments, the methods described herein are performed for at least 2 weeks, at least 3 weeks, at least 12 weeks, at least 3 months, at least 16 weeks, at least 24 weeks, at least 26 weeks, at least 6 months, at least 32 weeks, at least 36 weeks, at least 1 year, or at least 52 weeks or longer. In a preferred embodiment, the methods are performed for at least 26 weeks.

[0026] In any of the aspects or embodiments described herein, the method may include the steps of: (a) administering to the subject a first dose of about 10 to about 600 mg of an IL13 binding protein; and (b) administering to the subject one or more second dose(s) of about 10 to about 600 mg of an IL13 binding protein, wherein each second dose is administered to the subject 12 to 35 days after the immediately preceding dose.

[0027] In any of the aspects or embodiments described herein, the method may include the steps of: (a) administering to the subject a first dose of about 600 mg of an IL13 binding protein; and (b) administering to the subject one or more second dose(s) of about 300 mg of an IL13 binding protein, wherein each second dose is administered to the subject 12 to 35 days after the immediately preceding dose.

[0028] In a preferred embodiment, each second dose is administered to the subject about 12-16 days after the immediately preceding dose, or about 25-31 days after the immediately preceding dose, In a more preferred embodiment, each second dose is administered to the subject about 2 weeks after the immediately preceding dose, or about 4 weeks after the immediately preceding dose.

[0029] In a preferred embodiment, the IL-13 binding protein is an anti-IL-13 antibody, or an IL-13 binding fragment thereof.

[0030] In some embodiments, the IL-13 binding protein for use according to any of the methods described herein is an anti-IL-13 antibody, or an IL-13 binding fragment thereof, wherein the anti-IL-13 antibody, or an IL-13 binding fragment thereof, is Heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO:1; Heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO:2; Heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO:3; Light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO:4; A light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO:5, and It contains a light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO:6.

[0031] In further embodiments, the anti-IL-13 antibody, or IL-13 binding fragment thereof, comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR): (i) the heavy chain variable region is Heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO:1; A heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO:2, and A heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO:3; (ii) the light chain variable region is Light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO:4; A light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO:5, and It contains a light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO:6.

[0032] In some embodiments, the anti-IL-13 antibody, or IL-13 binding fragment thereof, comprises the heavy chain variable region sequence of SEQ ID NO:8 and the light chain variable region sequence of SEQ ID NO:10.

[0033] In some cases, the anti-IL-13 antibody, or IL-13 binding fragment thereof, comprises the heavy chain sequence of SEQ ID NO:11 and the light chain sequence of SEQ ID NO:12.

[0034] In a preferred embodiment, the anti-IL-13 antibody is tralokinumab.

[0035] The IL-13 binding protein may be administered as a monotherapy or as a combination therapy with a second therapeutic agent. In a preferred embodiment, the IL-13 binding protein is administered in combination with a topical corticosteroid.

[0036] The subject treated with the IL-13 binding protein in the methods described herein has AD, which is inadequately controlled by an agent that inhibits IL-13 and IL-4 signaling. In a preferred embodiment, the agent that inhibits IL-13 and IL-4 signaling may be an antibody or antigen-binding fragment thereof. In a more preferred embodiment, the agent that inhibits IL-13 and IL-4 signaling is an antibody or antigen-binding fragment thereof that binds to IL-4Rα. In an even more preferred embodiment, the agent that inhibits IL-13 and IL-4 signaling is dupilumab.

[0037] It is the goal of the methods described herein to achieve a 50% or greater improvement in Eczema Area Severity Index (EASI-50) compared to baseline. In preferred embodiments, the methods described herein achieve a 75% or greater improvement in Eczema Area Severity Index (EASI-75) compared to baseline. In some embodiments, EASI-50 or EASI-75 is achieved at week 16. In some embodiments, EASI-50 or EASI-75 is achieved at week 26.

[0038] For example, in one embodiment, a method comprises: (a) administering to the subject a first dose of about 600 mg of an IL-13 binding protein; and (b) administering to the subject one or more second dose(s) of about 300 mg of an IL-13 binding protein, each second dose being administered to the subject two weeks after the immediately preceding dose, wherein the IL-13 binding protein is an antibody (e.g., tralokinumab) comprising a heavy chain variable region sequence of SEQ ID NO: 8 and a light chain variable region sequence of SEQ ID NO: 10, and wherein the method is performed for at least 26 weeks, and wherein the method achieves a 75% or greater improvement in Eczema Area Severity Index (EASI-75) compared to baseline at week 26. In some embodiments, (i) the IL-13 binding protein is administered in combination with a topical corticosteroid, and / or (ii) the AD is inadequately controlled by cyclosporine A or the subject has a contraindication to cyclosporine A. [Brief description of the drawings]

[0039] [Figure 1] The study design of the ECZTRA7 study is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0040] The present invention relates to a method for treating atopic dermatitis (AD) in a subject using an interleukin-13 (IL-13) binding protein (e.g., an anti-IL-13 antibody, such as tralokinumab, or an IL-13 binding fragment thereof), where the AD is insufficiently controlled by an agent that inhibits IL-13 and IL-4 signaling (such as dupilumab). Without being bound to any particular theory, the inventors have found that AD can be effectively treated in a subject by administration of an IL-13 binding protein, even when the AD is not sufficiently controlled by an agent that inhibits both IL-13 and IL-4 signaling.

[0041] Atopic dermatitis As used herein, "atopic dermatitis" (AD) means an inflammatory skin disease characterized by intense pruritus (eg, severe itching) and scaly and dry eczematous lesions.

[0042] The term "atopic dermatitis" includes AD caused by or associated with epidermal barrier dysfunction, allergies (e.g., allergies to certain foods, pollen, maids, dust mites, animals, etc.), radiation exposure, and / or asthma. In some embodiments, the present invention relates to moderate to severe or severe AD.

[0043] As used herein, "moderate to severe AD" is characterized by extensive skin lesions with intense pruritus, often complicated by persistent bacterial, viral or fungal infections. Moderate to severe AD also includes chronic AD. Often, chronic lesions include thickened plaques of the skin, lichenification and fibrous papules. Generally, patients with moderate to severe AD also have more than 20% of the body's skin or more than 10% of the skin area affected, in addition to involvement of the eyes, hands and body wrinkles. Moderate to severe AD is also considered to be present in patients who frequently require treatment with topical corticosteroids. In the clinical trials reported herein, subjects with "moderate to severe AD" were those with an IGA score of 3-4.

[0044] As used herein, "severe AD" refers to chronic relapsing AD that is resistant to treatment with medium- and high-potency TCS and / or immunosuppressive therapy. Severe AD is also characterized by chronic, intensely pruritic lesions affecting more than 20% of the body surface area. According to the Eichenfield criteria (Eichenfield et al 2014, J. Am. Acad. Dermatol. 70:338-351), patients with chronic AD may be considered to have severe AD, for which treatment with potent topical corticosteroids (TCS) is indicated, and / or the subject is resistant to treatment with systemic corticosteroids and / or nonsteroidal immunosuppressants. In the clinical trials reported herein, subjects with "severe AD" were those with an IGA score of 4. Thus, in certain embodiments, the method treats severe AD in a subject, and the subject has an IGA score of 4 at baseline. A subject with "severe AD" may have AD affecting at least 10% of their body surface area at screening and baseline, an EASI score of 20 or greater at screening and baseline, and an IGA score of 3 or greater at screening and baseline.

[0045] subject As used herein, the term "subject" includes human and non-human animals, particularly mammals. Typically, the subject is a human, as illustrated in the examples below.

[0046] The subjects treated by the methods of the invention are those with AD (particularly moderate to severe AD or severe AD) who have been previously treated with a therapeutic agent that inhibits both IL-13 and IL-4 signaling, such as an anti-IL4Rα antibody (e.g., dupilumab), but whose AD is inadequately controlled with that agent.

[0047] In some embodiments, "inadequately controlled" by an agent that inhibits IL-13 and IL-4 signaling means that the AD is non-responsive, resistant, or refractory to an agent that inhibits IL-13 and IL-4 signaling, such as an anti-IL4Rα antibody (e.g., dupilumab). In such embodiments, treatment of a subject with AD with an agent that inhibits IL-13 and IL-4 signaling, such as an anti-IL4Rα antibody (e.g., dupilumab), did not have a therapeutic effect. For example, subjects with moderate to severe AD or severe AD (e.g., subjects with chronic relapsing AD) treated with an agent that inhibits IL-13 and IL-4 signaling (e.g., dupilumab) did not show a decrease in one or more AD-related parameter score(s), as described in more detail below. The time for evaluation of the therapeutic effect varies depending on the typical time frame of onset of the action of an agent that inhibits IL-13 and IL-4.

[0048] In some embodiments, the terms "poorly controlled," "non-responsive," "resistant," or "refractory" to an agent that inhibits IL-13 and IL-4 signaling (e.g., dupilumab) refer to a subject having AD who has been treated with an agent that inhibits IL-13 and IL-4 signaling (e.g., dupilumab) where the agent has no therapeutic effect, e.g., a method is described in, e.g., This refers to subjects who did not achieve ≥50% improvement in Eczema Area Severity Index (EASI-50) compared to baseline or did not achieve ≥75% improvement in Eczema Area Severity Index (EASI-75) compared to baseline at weeks 0, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52.

[0049] In some embodiments, the agent that inhibits IL-13 and IL-14 signaling is an antibody. In a preferred embodiment, the agent that inhibits IL-13 and IL-14 signaling is dupilumab.

[0050] In some embodiments, dupilumab treatment is considered medically undesirable for the subject by a physician. Such subjects may be identified by the following criteria: (1) not currently a candidate for dupilumab treatment due to medical contraindication(s), hypersensitivity to dupilumab or excipient(s), use of medications prohibited for concomitant use with dupilumab, (2) previous intolerance, side effects, and / or unacceptable toxicity upon previous exposure to dupilumab, and / or (3) requirement of dupilumab at a dose or for a duration greater than that specified in the prescribing information.

[0051] Common side effects associated with dupilumab include conjunctivitis, eosinophilia, ocular inflammation, ocular pruritus, headache, and oral herpes. In some embodiments, the use of dupilumab has been discontinued in a subject due to adverse side effects, for example, due to conjunctivitis.

[0052] In some aspects, the invention provides an IL-13 binding protein for use in a method of treating atopic dermatitis in a subject who experiences conjunctivitis when treated with an anti-IL4Rα antibody, or an antibody that inhibits IL-4 and IL-13 signaling, e.g., dupilumab, the method comprising administering to the subject the IL-13 binding protein.

[0053] In some aspects, the invention provides an IL-13 binding protein for use in a method of treating atopic dermatitis in a subject, the method comprising the steps of (a) selecting a subject that experiences conjunctivitis when treated with an anti-IL4Rα antibody, or an antibody that inhibits IL-4 and IL-13 signaling, e.g., dupilumab, and (b) administering to the subject an IL-13 binding protein.

[0054] In some aspects, the invention provides a method for treating atopic dermatitis in a subject who experiences conjunctivitis when treated with an anti-IL4Rα antibody, or an antibody that inhibits IL-4 and IL-13 signaling, e.g., dupilumab, comprising administering to the subject an IL-13 binding protein.

[0055] In some aspects, the invention provides methods for treating atopic dermatitis in a subject, the method comprising: (a) selecting a subject that experiences conjunctivitis when treated with an anti-IL4Rα antibody, or an antibody that inhibits IL-4 and IL-13 signaling, e.g., dupilumab; and (b) administering to the subject an IL-13 binding protein.

[0056] In some aspects, the invention provides use of an IL-13 binding protein in the manufacture of a medicament for treating atopic dermatitis in a subject who experiences conjunctivitis when treated with an anti-IL4Rα antibody, or an antibody that inhibits IL-4 and IL-13 signaling, e.g., dupilumab, the method comprising administering to the subject the IL-13 binding protein.

[0057] In some aspects, the invention provides use of an IL-13 binding protein in the manufacture of a medicament for treating atopic dermatitis in a subject, the method comprising: (a) selecting a subject that experiences conjunctivitis when treated with an anti-IL4Rα antibody, or an antibody that inhibits IL-4 and IL-13 signaling, e.g., dupilumab; and (b) administering to the subject an IL-13 binding protein.

[0058] Also, subjects with AD (especially moderate to severe AD or severe AD) may be resistant, non-responsive or insufficiently responsive to treatment with non-steroidal systemic immunosuppressants. The term "non-steroidal systemic immunosuppressants" includes cyclosporine A (CSA), methotrexate, mycophenolate mofetil, azathioprine, and interferon-gamma. In certain embodiments, the term also includes immunobiological agents, such as tumor necrosis factor alpha (TNFa) inhibitors (e.g., anti-TNFa antibodies such as infliximab), CD11a inhibitors (e.g., anti-CD11a antibodies such as efalizumab), IgE inhibitors (e.g., omalizumab), and CD20 inhibitors (e.g., rituximab). Thus, in some cases, the methods described herein may treat AD in subjects who are resistant, non-responsive (refractory) or insufficiently responsive to treatment with systemic immunosuppressants. The term "resistant, non-responsive or insufficiently responsive to systemic immunosuppressants" refers to a subject with AD who has been treated with a systemic immunosuppressant and for whom the immunosuppressant has not shown a therapeutic effect, e.g., a subject with moderate to severe AD or severe AD (e.g., a subject with chronic relapsing AD) who has been treated with a nonsteroidal systemic immunosuppressant for 1-3 months and has not seen a decrease in one or more AD-related parameter score(s). The time for evaluation of the therapeutic effect varies depending on the typical time frame of the onset of action of the nonsteroidal systemic immunosuppressant. Such time frames are well known. For example, for cyclosporine, the onset of action is usually 2-6 weeks, while for other nonsteroidal systemic immunosuppressants, it is usually about 8-12 weeks.

[0059] In some embodiments, immunosuppressant therapy is considered medically undesirable for the subject by a physician. Such subjects may be identified by the following criteria: (1) currently not a candidate for immunosuppressant therapy due to medical contraindication(s) or hypersensitivity to the immunosuppressant or excipient(s), use of medications prohibited for concomitant use with the immunosuppressant, or increased susceptibility to immunosuppressant-induced kidney damage or increased risk of serious infections, (2) previous intolerance and / or unacceptable toxicity from previous exposure to an immunosuppressant, and / or (3) requirement of immunosuppressant at a dose or duration greater than that specified in the prescribing information.

[0060] In any of the methods described herein for treating atopic dermatitis, e.g., severe atopic dermatitis, the subject may be a subject whose atopic dermatitis is not adequately controlled by cyclosporine A (CSA), e.g., oral cyclosporine A, or the subject may be a subject who has a contraindication to cyclosporine A (CSA), e.g., oral cyclosporine A.

[0061] An inadequate response to CSA is defined as relapse of AD at a high dose (5 mg / kg / day) for up to 6 weeks followed by tapering of CSA to a maintenance dose (2–3 mg / kg / day) or relapse after at least 3 months on the maintenance dose. Relapse is defined as an increase in signs or symptoms leading to an escalation of treatment, which could be an increase in dose, a switch to a higher potency class of TCS, or initiation of another systemic nonsteroidal immunosuppressant.

[0062] Contraindications to CSA include: i. medical contraindications (e.g., uncontrolled hypertension on medication) or hypersensitivity to the active substances or excipients of CSA, ii. Use of prohibited concomitant medications (e.g., statins, digoxin, macrolides, antibiotics, barbiturates, anticonvulsants, nonsteroidal anti-inflammatory drugs, diuretics, angiotensin-converting enzyme inhibitors, Hypericum perforatum); iii. Increased susceptibility to kidney damage (elevated creatinine) and liver damage (elevated function tests) or increased risk of serious infections due to CSA; iv. Intolerance or unacceptable toxicity (e.g., elevated creatinine, elevated liver function tests, uncontrolled hypertension, paresthesia, headache, nausea, hirsutism), or v. Requirement for CSA in a dose greater than 5 mg / kg / day or for a duration greater than that specified in the prescribing information (>1 year).

[0063] IL-13 and IL-4 signaling inhibitors The present invention relates to an IL-13 binding protein for treating AD in a subject, where AD is not adequately controlled by agents that inhibit IL-13 and IL-4 signaling.

[0064] Agents that inhibit IL-13 and IL-4 signaling include, for example, antibodies or antigen-binding fragments thereof, as well as small molecule inhibitors and IL-4 muteins.

[0065] Preferably, in one embodiment, the agent that inhibits IL-4 and IL-13 signaling is an antibody or an antigen-binding fragment thereof, which may be selected from a Fab, a Fab', a F(ab')2, an Fd, an Fv, a single chain Fv (scFv), or a disulfide-linked Fv (sdFv).

[0066] In some embodiments, the agent that inhibits IL-13 and IL-4 signaling is an antibody or antigen-binding fragment thereof that binds to IL-4Rα. An example of an antibody that binds to IL-4Rα is dupilumab. In a preferred embodiment, the antibody that inhibits IL-13 and IL-4 signaling is dupilumab.

[0067] Treatment of AD The methods described herein treat AD. Generally, the terms "treat," "treating," "treatment," and the like refer to temporarily or permanently relieving (alleviating, minimizing, or eliminating) the symptoms or reducing, minimizing, or eliminating the cause of the symptoms.

[0068] AD-related parameters A variety of AD-related parameters are available for measuring the severity of AD and the effect of drugs on AD. These include Investigator Global Assessment (IGA), Eczema Area and Severity Index (EASI), Scoring of Atopic Dermatitis (SCORAD), and / or Numerical Pruritis Scale (NRS). The methods described herein may improve the AD-related parameters of the subject. Alternatively, the methods may maintain the improvement of the AD-related parameters of the subject. The AD-related parameters may be selected from Investigator Global Assessment (IGA), Eczema Area and Severity Index (EASI), Scoring of Atopic Dermatitis (SCORAD), and / or Numerical Pruritis Scale (NRS).

[0069] The IGA is an instrument used to assess the overall severity of AD in subjects in clinical trials and is based on a 5-point scale ranging from 0 (clear) to 4 (severe) based on the disease status at the time of evaluation. [Table 1]

[0070] The EASI is a validated scale used in clinical practice and clinical trials to assess the severity and extent of AD (Hanifin et al. "The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. Experimental dermatology" (2001) 10(1): 11-18). The SCORAD is one of the most commonly used disease severity scores in clinical trials and practice for AD (see "European Task Force on Atopic Dermatitis. Severity scoring of atopic dermatitis: the SCORAD index. Consensus report of the European task force on atopic dermatitis" Dermatology (1993) 186(1): 23-31).

[0071] The Worst Daily Pruritus NRS has been established in accordance with FDA and EMA recommendations (see, e.g., FDA's "The Food and Drug Administration. Guidance for Industry. Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. 2009" and EMA's "Reflection paper on the regulatory guidance for the use of health-related quality of life (HRQoL) measures in the evaluation of medicinal products. EMEA / CHMP / EWP / 139391 / 2004.2005"). For the Pruritus NRS, subjects rate the severity of their worst itch over the past 24 hours using an 11-point NRS ("Worst Daily Pruritus NRS") ranging from 0 (no itch) to 10 (worst itch imaginable).

[0072] For each AD-related parameter, improvement or maintenance of improvement is measured against baseline. The relevant improvement can be a decrease in IGA score, a decrease in EASI score, a decrease in SCORAD score (>50 is severe, 25-50 is moderate, <25 is mild), or a decrease in pruritus NRS score. Each score is compared to the baseline.

[0073] A baseline is an initial measurement of an AD-related parameter or patient-related outcome (or any other parameter) that is taken before the start of administration according to the methods described herein, i.e., a measurement taken before the "baseline dose" (defined elsewhere).

[0074] Investigator Global Assessment 0 or 1 (IGA 0 / 1, inflammatory signs-free or nearly inflammatory signs-free skin) and / or 75% or greater improvement in Eczema Area and Severity Index (EASI-75) are primary efficacy endpoints by regulatory agencies in Phase 3 clinical trials for AD. Thus, the methods described herein may preferably achieve or maintain an Investigator Global Assessment (IGA) score of 0 or 1 and / or 75% or greater improvement in Eczema Area and Severity Index (EASI-75) versus baseline (e.g., as shown in Examples 1 and 2 herein). In some embodiments, the methods may achieve or maintain 50% or greater improvement in Eczema Area and Severity Index (EASI-50) versus baseline.

[0075] Additionally or alternatively, the methods described herein may improve at least one Patient Related Outcome (PRO) selected from the group consisting of: maximum daily Pruritus Numerical Scale (NRS) (see Pruritus NRS above), Eczema-Related Sleep Disturbance, Patient Self Assessment of Eczema (POEM), DermaCognitive Questionnaire (DLQI), Patient Global Impression of Problems (PGI-B), Hospital Anxiety and Depression Questionnaire (HADS), Short Form (36 item) Health Status Questionnaire (SF-36), and Eurocor 5-item Health Survey 5-level (EQ-5D-5L).

[0076] For the Eczema-Related Sleep Disturbance NRS, subjects rate how much their eczema disrupted their sleep the previous night using an 11-point NRS ranging from 0 (no disruption) to 10 (complete disruption). The POEM is a validated questionnaire used to assess disease symptoms in both clinical practice and clinical trials in AD patients (see Charman et al. "The patient-oriented eczema measure: development and initial validation of a new tool for measuring atopic eczema severity from the patients perspective" Arch Dermatol. (2004) 140(12):1513-1519). The DLQI is a validated patient-reported questionnaire with content specific to subjects with skin diseases (see Finlay et al. "Dermatology Life Quality Index (DLQI)-a simple practical measure for routine clinical use" Clin Exp Dermatol. (1994) 19(3):210-216). The Patient Global Impression of Trouble (PGI-B) is designed to capture the subject's perception of how bothered they were by their AD over the past 24 hours at the time of completion. A five-category response scale is used ('not at all', 'slightly', 'somewhat', 'quite a bit', 'very much'). The Hospital Anxiety and Depression Questionnaire (HADS) is a Likert-scaled instrument that is widely used to detect anxiety and depression in the general hospital environment (see Zigmond AS, Snaith RP. "The hospital anxiety and depression scale". Acta Psychiatr Scand. 1983;67(6):361-70). This instrument consists of 14 items assessing the subject's anxiety (7 items) and depression (7 items) over the past week. Each item is scored from 0 to 3, with higher scores indicating more severe anxiety and depression.The Short-Form (36-item) Health Status Survey (SF-36) is a patient-reported survey designed to assess health status by generating scores in eight health domains (physical functioning, role-functioning (physical), bodily pain, general health, vitality, social functioning, daily living functioning (mental), and mental health) and two psychometric summary scores (physical health and mental health) (see Ware JEJ, Sherbourne CD. “The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection.” Med Care. 1992;30(6):473-83). The Eurocol 5-item health survey 5 levels (EQ-5D-5L) is a standardized health status measure developed by the Eurocol group, providing a simple and general health measure for clinical and economic evaluations (see Greiner W et al. “A single European currency for EQ-5D health states. Results from a six-country study” The European journal of health economics: HEPAC: health economics in prevention and care. 2003;4(3):222-31). The EQ-5D-5L is a self-administered questionnaire used to assess health status “today” and is divided into two sections. The first section contains five items (degree of mobility, managing personal care, usual activities, pain / discomfort, and anxiety / depression), each of which is rated by the subject using a five-point scale (‘no problems’, ‘slight problems’, ‘moderate problems’, ‘severe problems’, and ‘extreme problems’). The second section consisted of a vertical visual analogue scale anchored at 0 ('worst imaginable health state') and 100 ('best imaginable health state').

[0077] The method may maintain improvement in at least one patient-related outcome (PRO) selected from the group consisting of daily peak pruritus quantification scale (NRS), eczema-related sleep disturbance, patient self-assessment of eczema (POEM), DLQI, patient global impression of trouble (PGI-B), hospital anxiety and depression questionnaire (HADS), short form (36-item) health status questionnaire (SF-36), and Eurocol 5-item health survey 5 level (EQ-5D-5L). For each PRO, improvement or maintenance of improvement is relative to baseline. The associated improvement may be a decrease in PRO score (e.g., a decrease of 3 or more points) (or, for example, a decrease of 4 or more points for DLQI), the score being compared to baseline.

[0078] In preferred embodiments, the methods described herein may achieve: (a) a 50% or greater improvement in Eczema Area Severity Index (EASI-50), and / or (b) a 75% or greater improvement in Eczema Area Severity Index (EASI-75) (e.g., after 16 weeks or after 26 weeks, as shown in Examples 1 and 2).

[0079] TCS dependency Long-term use of TCS is not recommended due to the risk of skin atrophy, pigmentation disorders, acneiform rashes, and risks associated with systemic absorption (e.g., effects on the hypothalamic-pituitary axis, Cushing's disease, etc.) Repeated application of any topical therapy over long periods or over large surface areas may also lead to poor patient compliance.

[0080] The methods described herein may reduce topical corticosteroid (TCS) dependence in subjects with AD, particularly moderate-to-severe or severe AD.

[0081] The reduction in dependency can be assessed by comparing the cumulative amount (grams) of a formulation containing TCS applied by a subject over a certain time interval (e.g., 16 weeks or 26 weeks) after the initiation of the methods described herein with a subject administered a placebo. For example, a subject may use at least 0.2 g less, at least 0.3 g less, at least 0.4 g less, or at least 0.5 g less of TCS per day compared to a subject administered a placebo. Typically, a subject may use at least 0.5 g less of TCS per day compared to a subject administered a placebo.

[0082] Reduction in dependence may also be assessed by the number of days without TCS use (which may include low-potency TCS and TCI) after initiation of the method, compared to the same measurement taken at baseline.

[0083] TCS can be classified as Class I, II, III and IV topical corticosteroids. According to the World Health Organization Anatomical Therapeutic Chemical Classification, corticosteroids are classified into weak / low (Class I) potency, medium (Class II) and high (Class III) potency and very high (Class IV) potency based on their activity compared to hydrocortisone. Class IV TCS (very high potency) are up to 600 times more potent than hydrocortisone and include clobetasol propionate and halcinonide. Class III TCS (high potency) are 50-100 times more potent than hydrocortisone and include betamethasone valerate, betamethasone dipropionate, diflucortolone valerate, hydrocortisone-17-butyrate, mometasone furoate, and methylprednisolone aceponate. Class II TCS (medium-high potency) are 2-25 times more potent than hydrocortisone and include clobetasone butyrate and triamcinolone acetonide. Class I TCS (low potency) include hydrocortisone.

[0084] The term "TCS-free day" means a day on which the subject does not use Group II, Group III, or Group IV TCS.

[0085] For example, the number of days a subject does not use TCS may be increased by an average of about 0.5 days, about 0.75 days, about 1 day, about 1.5 days, about 2 days, about 3 days, or more per week compared to a subject receiving a placebo. Typically, the number of days a subject does not use TCS may be increased by about 0.5 days compared to a subject receiving a placebo.

[0086] In some embodiments, the IL-13 binding protein can be administered as a monotherapy, e.g., without TCS. In other embodiments, the IL-13 binding protein is administered in combination with a second therapeutic agent selected from the group consisting of TCS, a topical calcineurin inhibitor, an antihistamine, an emollient, or an antibacterial therapeutic agent. In a preferred embodiment, the IL-13 binding protein is administered in combination with TCS.

[0087] The IL-13 binding protein can be combined with TCS to wean the subject off TCS use. Thus, in the methods described herein, a medium-high or high-potency TCS can be administered in parallel with the IL-13 binding protein. Then, after initiation of the method (e.g., over a period of 3-4 months), the amount of TCS can be reduced by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or about 100% compared to the amount of TCS at baseline.

[0088] IL-13 binding protein The IL-13 binding protein is a protein that specifically binds to and neutralizes human IL-13.

[0089] As used herein, the term "specifically binds" means that a protein (e.g., an antibody or antigen-binding fragment thereof) forms a relatively stable complex with an antigen under physiological conditions. Methods for determining whether a protein specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance (e.g., using a BIAcore 200 biosensor (BIAcore AB)), and the like. For example, an IL-13 binding protein (e.g., an anti-IL-13 antibody, or an IL-13 binding fragment thereof) that "specifically binds" to IL-13 has a K D It may bind to IL-13 with less than about 1000 nM, less than about 500 nM, less than about 100 nM, less than about 50 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 1 nM, less than about 0.5 nM, less than about 0.25 nM, less than about 0.1 nM, or less than about 0.05 nM. An exemplary antibody, tralokinumab, has a K as measured by surface plasmon resonance (see WO2005 / 007699 for detailed methods). D 178 pM to human-bound human IL-13. Thus, in a preferred embodiment, the anti-IL-13 antibody has a K D The IL-13 binding protein specifically binds human IL-13, but may have cross-reactivity to other antigens, for example IL-13 from other (non-human) species.

[0090] Methods for measuring neutralizing activity are well known in the art. Neutralizing activity can be measured in an IL-13-dependent TF-1 cell proliferation assay, as described in WO2005 / 007699, in comparison with a control antibody not directed against IL-13. In this assay, inhibition of IL-13-dependent proliferation is determined by measuring the reduction in the incorporation of tritiated thymidine into newly synthesized DNA of dividing cells. Briefly, commercially available TF-1 cells are maintained according to the accompanying protocol. The assay medium comprises RPMI-1640 supplemented with GLUTAMAX I (Invitrogen) containing 5% FBS and 1% sodium pyruvate. Before each assay, TF-1 cells are pelleted by centrifugation at 300xg for 5 minutes, the medium is aspirated, and the cells are resuspended in assay medium. This process is repeated for 10 min. 5 Repeat twice with cells resuspended in assay medium at a final concentration of cells / mL. Dilute antibody test solutions (triplicates) to the desired concentrations in assay medium. An antibody not directed against IL-13 is used as a negative control. Recombinant bacterially derived human or mouse IL-13 was added to a final concentration of 50ng / mL when mixed with the appropriate test antibody in a total volume of 100μL / well in a 96-well assay plate. The concentration of IL-13 used in the assay is selected as the dose at which the final assay concentration gives approximately 80% of the maximum proliferative response. Incubate all samples for 30 minutes at room temperature. Then, add 100μL of resuspended cells to each assay point, bringing the total assay volume to 200μL / well. Incubate the assay plate at 37°C, 5% CO2 for 72 hours. 25μL of tritiated thymidine (10μCi / mL) is then added to each assay point and return the assay plate to the incubator for a further 4 hours. Cells are harvested onto glass fiber filter plates (Perkin Elmer) using a cell harvester. Thymidine incorporation is measured using a Packard TopCount microplate liquid scintillation counter.

[0091] Anti-IL-13 antibodies and their binding to IL-13 Typically, the IL-13 binding protein is an anti-IL-13 antibody or an IL-13 binding fragment thereof.

[0092] As used herein, the term "antibody" includes immunoglobulin molecules comprising four polypeptide chains, i.e., two heavy (H) chains and two light (L) chains, interconnected by disulfide bonds, as well as multimers thereof (e.g., IgM). In a typical antibody, each heavy chain contains a heavy chain variable region (referred to herein as HCVR or V H The heavy chain constant region is made up of three domains: H 1. C H 2 and C H Each light chain comprises a light chain variable region (referred to herein as LCVR or V L The light chain constant region comprises one domain (C L 1) is included. H and V L are further divided into regions of hypervariability called complementarity determining regions (CDRs) interspersed with more conserved regions called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some cases, the FRs of an anti-IL-13 antibody (or an IL-13-binding fragment or derivative thereof) may be identical to human germline sequences or may be naturally or artificially modified.

[0093] The heavy chain constant region of the antibody can be derived from any type of constant region, such as IgG, IgM, IgD, IgA, and IgE. Generally, the antibody is an IgG (e.g., isotype IgG1, IgG2, IgG3, or IgG4). Preferably, the antibody is an IgG4, as exemplified herein.

[0094] The antibody may be a murine, human, primate, humanized or chimeric antibody. The antibody may be polyclonal or monoclonal. For therapeutic applications, monoclonal and human (or humanized) antibodies are preferred. In a particularly preferred embodiment, the antibody is human or humanized and monoclonal.

[0095] The antibody may be a multispecific (e.g., bispecific) antibody. A multispecific antibody or an antigen-binding fragment of an antibody usually comprises at least two different variable domains, each of which can specifically bind to a separate antigen or a different epitope of the same antigen. Any multispecific antibody format can be adapted for use in conjunction with the antibodies or antigen-binding fragments of antibodies described herein using conventional techniques available in the art. For example, a method of using a bispecific antibody, in which one arm of the immunoglobulin is specific for IL-13 and the other arm of the immunoglobulin is specific for a second therapeutic target or is bound to a therapeutic moiety.

[0096] An IL-13-binding fragment of an anti-IL-13 antibody can be any naturally occurring, enzymatically obtained, synthetic, or genetically engineered polypeptide. Such fragments may be obtained from an intact antibody molecule using any suitable standard technique, such as, for example, proteolytic digestion or recombinant genetic engineering techniques, including the manipulation and expression of DNA encoding antibody variable domains and, optionally, constant domains. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, phage antibody libraries), or can be synthesized. The DNA may be sequenced and manipulated chemically or using molecular biology techniques, for example, to place one or more variable and / or constant domains in the appropriate configuration, or to introduce codons, create cysteine ​​residues, modify, add, or delete amino acids, etc.

[0097] Non-limiting examples of IL-13 binding fragments include Fab, Fab', F(ab')2, Fd, Fv, single chain Fv (scFv), disulfide linked Fv, dAb fragments, and other engineered molecules such as domain specific antibodies, single domain antibodies, domain deleted antibodies, chimeric antibodies, CDR grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains.

[0098] An IL-13 binding fragment of an anti-IL-13 binding antibody typically comprises at least one variable domain. The variable domain may be of any size or amino acid composition and typically comprises at least one CDR, which is adjacent to or in frame with one or more framework sequences. L Domain associated with V H For antigen-binding fragments containing domains, V H Domain and V L The domains may be positioned relative to each other in any suitable configuration. For example, the variable region may be a dimer and the V H -V H , V H -V L or V L -V L Alternatively, the antigen-binding fragment of an antibody may comprise a monomeric V H or V L It may include a domain.

[0099] The anti-IL-13 antibody, or IL-13-binding fragment thereof, may comprise heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO:1, heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO:2, heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO:3, light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO:4, light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO:5, and light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO:6. The anti-IL-13 antibody, or IL-13-binding fragment thereof, comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), in which (i) the heavy chain variable region comprises heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO:1, heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO:2, and heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO:3, and (ii) the light chain variable region comprises light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO:4, light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO:5, and light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO:6. In addition, the anti-IL-13 antibody, or IL-13 binding fragment thereof, may further comprise (i) an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the heavy chain variable region sequence of SEQ ID NO:8, and / or (ii) an amino acid sequence that is 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the light chain variable region sequence of SEQ ID NO:10. The anti-IL-13 antibody, or IL-13 binding fragment thereof, may comprise the heavy chain variable region sequence of SEQ ID NO:8 and the light chain variable region sequence of SEQ ID NO:10.

[0100] An anti-IL-13 antibody, or IL-13 binding fragment thereof, may comprise (i) an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the heavy chain sequence of SEQ ID NO: 11, and / or (ii) an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the light chain sequence of SEQ ID NO: 12. Optionally, an anti-IL-13 antibody, or IL-13 binding fragment or IL-13 binding derivative thereof, comprises a heavy chain of SEQ ID NO: 11 and a light chain sequence of SEQ ID NO:12.

[0101] One such antibody that can be used in the methods described herein is the anti-IL-13 antibody tralokinumab (as listed in "International Nonproprietary Names for Pharmaceutical Substances (INN)" list 102 (WHO Drug Information (2009) 23(4):pp 348)). Tralokinumab is a fully human IgG4-lambda antibody that specifically binds and neutralizes human IL-13. [Table 2-1] [Table 2-2]

[0102] Methods for identifying, isolating and testing (e.g., binding and neutralizing) antibodies and fragments thereof are well known in the art, see WO2005 / 007699, which discloses the identification and characterization of various anti-IL13 antibodies and fragments and provides suitable methods for doing so.

[0103] Dosage and Administration Regimens The present invention provides an interleukin-13 (IL-13) binding protein (e.g., an anti-IL-13 antibody, or an IL-13 binding fragment thereof) as described above for use in any of the methods of treatment described herein, the method comprising the steps of (a) administering to a subject a first dose of the IL-13 binding protein, and (b) administering to the subject one or more second dose(s) of the IL-13 binding protein, wherein each second dose is administered to the subject 12 to 35 days after the immediately preceding dose. Preferably, each second dose is administered to the subject 12 to 16 days after the immediately preceding dose, e.g., 14 days after the immediately preceding dose, or 25 to 31 days after the immediately preceding dose, e.g., about 4 weeks after the immediately preceding dose.

[0104] The term "dose" refers to the amount (mass) of IL-13 binding protein administered to a subject on a particular treatment day. For example, a dose of 300 mg of IL-13 binding protein means that a total of 300 mg of IL-13 binding protein is given to the subject on the treatment day. In some embodiments, the dose is administered in a single administration step (e.g., one injection). However, in some embodiments, one, two, three, four or more administration steps (e.g., one, two, three, four or more injections) may be used to provide the subject with the desired dose.

[0105] The terms "prior dose", "first dose", "second dose", and "third dose" refer to the time sequence of administration of an IL-13 binding protein. The term "first dose" is a single administration of an IL-13 binding protein followed by one or more second dose(s). The first dose may be preceded by one or more prior dose(s) or the "first dose" may be the start of treatment according to the methods described herein (in the latter case, this dose may therefore be referred to as the "baseline dose"). Following the first dose may be one or more second dose(s), which may in turn be followed by one or more third dose(s).

[0106] The term "immediately preceding dose" refers to a dose of an IL-13 binding protein that is administered to a patient in a multiple dose series, without an intervening dose of the IL-13 binding protein prior to administration of the next dose in the series.

[0107] "Dosing frequency" refers to how often a dose of an IL-13 binding protein is administered. Thus, a decrease in dosing frequency means an increase in the time interval between doses. Common terms used in relation to dosing frequency are QW (once a week), Q2W (once every 2 weeks), Q3W (every 3 weeks), or Q4W (every 4 weeks).

[0108] The first dose can be about 10 mg to about 600 mg of IL-13 binding protein, about 50 mg to 500 mg, about 100 mg to about 400 mg, about 250 mg to about 350 mg, or about 280 mg to about 320 mg of IL-13 binding protein. For example, the first dose is about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg. In some cases, the first dose is 600 mg or less, 500 mg or less, 400 mg or less, 300 mg or less, 200 mg or less, or 200 mg or less. In a preferred embodiment, the first dose is about 600 mg of IL-13 binding protein (e.g., as shown in the Examples).

[0109] Each second dose may be administered to the subject 12 to 35 days, 12 to 30 days, 12 to 25 days, 12 to 20 days, 12 to 16 days, 12 to 15 days, 12 to 14 days, 18 to 35 days, 21 to 35 days, 22 to 34 days, 24 to 32 days, 25 to 31 days, 26 to 30 days, or 27 to 29 days after the immediately preceding dose. In certain cases, each second dose may be administered to the subject about 14 days (i.e., 2 weeks) after the immediately preceding dose (as exemplified herein).

[0110] In the methods described herein, the methods can be performed until the improvement of AD-related parameters and / or patient-related outcomes described herein is obtained.In some cases, the methods can provide improvement of AD-related parameters and / or patient-related outcomes for about 2 weeks, about 3 weeks, about 12 weeks, about 3 months, about 16 weeks, about 24 weeks, about 26 weeks, about 6 months, about 32 weeks, about 36 weeks, about 1 year, about 52 weeks, or longer than 52 weeks.In some preferred embodiments, improvement of AD-related parameters and / or patient-related outcomes is provided in about 16 weeks or 26 weeks.

[0111] In some cases, the method can be continued until the subject reaches a low disease state.For example, the subject can reach a low disease state in about 4 weeks, about 8 weeks, about 12 weeks, about 3 months, about 16 weeks, about 24 weeks, about 26 weeks, about 6 months, about 32 weeks, about 36 weeks, about 1 year, about 52 weeks, or more than 52 weeks.In some preferred embodiments, the subject can reach a low disease state in about 16 weeks or 26 weeks.

[0112] In some cases, the method can be carried out for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 3 months, at least 16 weeks, at least 24 weeks, at least 26 weeks, at least 6 months, at least 32 weeks, at least 36 weeks, at least 1 year, or at least 52 weeks or longer. In some cases, the method can be carried out for about 2 weeks, about 3 weeks, about 12 weeks, about 3 months, about 16 weeks, about 24 weeks, about 6 months, about 32 weeks, about 36 weeks, about 1 year, about 52 weeks. In a preferred embodiment, the method is carried out for at least 26 weeks.

[0113] As used herein, the term "low disease status" refers to an Investigator Global Assessment (IGA) score of 0 or 1 and / or a 75% or greater improvement in Eczema Area and Severity Index (EASI-75) versus baseline.

[0114] Step (b) of the method (i.e., administering to the subject one or more second dose(s) of the IL-13 binding protein) may be continued for 8 weeks to 52 weeks, 12 to 40 weeks, or 16 to 36 weeks (i.e., by administering multiple second doses). The one or more second dose(s) may be administered for at least 8 weeks, at least 12 weeks, at least 3 months, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 6 months, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 1 year, at least 52 weeks, or longer. Step (b) of the method may be continued for about 8 weeks, about 12 weeks, about 3 months, about 16 weeks, about 20 weeks, about 24 weeks, about 6 months, about 28 weeks, about 32 weeks, about 36 weeks, about 1 year, about 52 weeks, or longer (i.e., by administering multiple second doses). In some embodiments, the one or more second dose(s) are administered for at least 16 weeks, at least 24 weeks, or at least 26 weeks. Additionally or alternatively, step (b) may be continued until the method results in an improvement in the AD-related parameters and / or patient-related outcomes described herein. Step (b) may be continued to maintain the improvement in the AD-related parameters and / or patient-related outcomes described herein. In certain cases, step (b) may be continued until the subject reaches a low disease state.

[0115] Each second dose may be about 10 mg to about 600 mg of IL-13 binding protein, about 50 mg to 500 mg, about 100 mg to about 400 mg, about 250 mg to about 350 mg, or about 280 mg to about 320 mg of IL-13 binding protein. For example, each second dose is about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg. In some cases, each second dose is 600 mg or less, 500 mg or less, 400 mg or less, 300 mg or less, 200 mg or less, or 200 mg or less. In a preferred embodiment, each second dose is about 300 mg of IL-13 binding protein (e.g., in the case of the Examples, etc.). In some embodiments, the first dose and the one or more second dose(s) are the same amount (i.e., milligrams) of IL-13 binding protein. In other embodiments, the first dose is greater than the one or more second doses. For example, in some embodiments, the first dose is 600 mg and the one or more second doses is 300 mg.

[0116] In a preferred embodiment, the method includes the steps of (a) administering to the subject a first dose of about 600 mg of an IL-13 binding protein (e.g., tralokinumab), and (b) administering to the subject one or more second dose(s) of about 300 mg of an IL-13 binding protein (e.g., tralokinumab), each second dose being administered to the subject about 2 weeks after the immediately preceding dose, optionally for about 26 weeks. Preferably, each administration is by subcutaneous injection.

[0117] In some embodiments, the first dose is a bolus dose, which is twice the amount of the dose following the bolus dose. In some embodiments, the first dose is a 600mg dose, and the dose(s) following the 600mg dose are 300mg dose(s). The bolus dose is usually twice the amount of the dose administered in the next administration. For example, when the next dose administered is 300mg, the 600mg dose is used as the bolus dose.

[0118] Administration In the methods described herein, the IL-13 binding protein (e.g., an anti-IL-13 antibody or IL-13 binding fragment thereof) may be administered by any suitable method. Typically, administration is parenteral, such as intradermal, intramuscular, intravenous, and subcutaneous. Subcutaneous administration is particularly preferred (e.g., as shown in the Examples). Thus, each dose of the IL-13 binding protein may be administered subcutaneously.

[0119] Administration is preferably in a "therapeutically effective amount", which is sufficient to show improvement or sustained improvement in one or more AD-related parameters or patient-related outcomes described herein, or to achieve a reduced disease state.

[0120] Administration may be by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous layers (eg, oral, rectal and intestinal mucosa, etc.).

[0121] Subcutaneous or intravenous delivery may be by standard needle and syringe (including, for example, pre-filled syringe). It is envisioned that the methods described herein are not limited to use in clinics. Therefore, subcutaneous injection using needleless devices is also desirable. Such delivery devices may be reusable or disposable. Many reusable pen and auto-injector delivery devices are known in the art and may find use in the present invention. Examples include AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25™ pen, HUMALOG™ pen, HUMALIN 70 / 30™ pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN™ 1, 11 and 111 (Nova Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Nova Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™, and OPTICLIK™ (Sanofi-Aventis, Frankfurt, Germany). Exemplary disposable pen delivery devices for subcutaneous delivery that may be used in the present application include the SOLOSTAR™ pen (Sanofi-Aventis), FLEXPEN™ (Nova Nordisk), and KWIKPEN™ (Eli Lilly), SURECLICK™ Autoinjector (Amgen, Thousand Oaks, CA), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA™ pen (Abbott Labs, Abbott Park IL).

[0122] Each dose of IL-13 binding protein is not necessarily administered in one administration step (e.g., one injection or one tablet, etc.). Indeed, depending on the concentration of IL-13 binding protein (e.g., in a pharmaceutical composition), one, two, three, four or more administration steps (e.g., one, two, three, four or more injections) may be required to provide the required amount of IL-13 binding protein (e.g., a 300 mg dose) to the subject. Thus, in some embodiments, each dose of IL-13 binding protein is administered in two or four (e.g., subcutaneous) injections. In some embodiments, each injection provides 150 mg of IL-13 binding protein, with two injections required for a 300 mg dose and four injections required for a 600 mg dose. Typically, a subcutaneous injection has a volume of about 1.5 mL or less, e.g., a volume of 0.2 to 1.5 mL, e.g., about 1 mL.

[0123] Monotherapy and Combination Therapy The method described herein may be monotherapy.As used herein, the term "monotherapy" refers to a therapy that uses a single drug to treat a disease or condition.Thus, the subject treated with monotherapy is administered only a single drug to treat related disorder, i.e., AD.For example, anti-IL-13 antibody monotherapy refers to the monotherapy that comprises administering anti-IL-13 antibody to a subject as the only drug for treating AD.

[0124] The method described herein can be combination therapy.As used herein, the term "combination therapy" refers to the therapy that uses two or more drugs to treat disease or condition.For example, the subject that is treated with combination therapy is administered two or more (for example, two, three or more) drugs to treat AD.

[0125] In some embodiments, the IL-13 binding protein is administered in combination with a local therapy (e.g., a topical corticosteroid or a topical calcineurin inhibitor). Optionally, an additional treatment (e.g., a TCS or TCI) is administered as needed by the subject.

[0126] In some cases, the IL-13 binding protein is administered in combination with a second therapeutic agent selected from the group consisting of a topical corticosteroid, a topical calcineurin inhibitor, an antihistamine, an emollient, or an antibacterial therapeutic agent. In some cases, the IL-13 binding protein is administered in combination with a Class I, Class II, Class III, or Class IV corticosteroid. Preferably, the IL-13 binding protein may be administered in combination with mometasone furoate (e.g., 0.1% cream).

[0127] Pharmaceutical Compositions and Formulations The present invention contemplates methods in which each dose of an IL-13 binding protein (eg, an anti-IL-13 antibody or IL-13 binding fragment thereof) is administered as a pharmaceutical composition.

[0128] Pharmaceutical compositions may be formulated using suitable carriers, excipients, and other agents that provide for proper migration, delivery, tolerance, etc. Numerous formulations can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, a formulary known to all pharmacists.

[0129] The dose administered to a patient according to the methods described herein may vary depending on the age and size of the patient, symptoms, condition, route of administration, etc. The dose may be calculated according to body weight or surface area.

[0130] Thus, a pharmaceutical composition may contain, in addition to the active ingredient (i.e., IL-13 binding protein), pharma- ceutically acceptable excipients, carriers, buffers, stabilizers, or other materials known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other materials will depend on the route of administration, which may be oral or by injection, e.g., intravenous or subcutaneous. Pharmaceutical compositions for oral administration may be in tablet, capsule, powder, or liquid form. Tablets may contain a solid carrier, e.g., gelatin, or an adjuvant. Liquid pharmaceutical compositions generally contain a liquid carrier, e.g., water, petroleum, animal or vegetable oil, mineral oil, or synthetic oil. Saline, dextrose or other sugar solution, or glycols, e.g., ethylene glycol, propylene glycol, or polyethylene glycol, may also be included.

[0131] For intravenous or subcutaneous injection, the pharmaceutical composition may be a parenterally acceptable aqueous solution that is pyrogen-free and has appropriate pH, isotonicity and stability.Those skilled in the art can easily prepare appropriate solutions using, for example, isotonic vehicles such as sodium chloride injection, Ringer's solution, lactated Ringer's solution.Preservatives, stabilizers, buffers, antioxidants and / or other additives may be included as necessary.

[0132] The pharmaceutical composition may be a liquid formulation or a lyophilized formulation that is reconstituted before use.For example, sugar alcohol or sugars (e.g., mannitol or glucose) may be used as excipients for lyophilized formulations.For liquid formulations, the pharmaceutical composition is usually provided in the form of a container with a specified volume, including sealed and sterilized plastic or glass vials, ampoules and syringes, and in the form of a large-capacity container such as bottles.Preferably, in the method described herein, the pharmaceutical composition is a liquid formulation.

[0133] Exemplary pharmaceutical compositions that may be used in accordance with the present invention are disclosed, for example, in WO2007 / 036745 and WO2018 / 158332.

[0134] Preferably, the IL-13 binding protein may be contained in the pharmaceutical composition at a concentration of 1 mg / mL to 200 mg / mL, more preferably 150 mg / mL.

[0135] Preferably, the pharmaceutical composition may be buffered to a pH of 5.2 to 5.7, most preferably 5.5 (e.g., ±0.1). Such a pH selection provides greater stability to the pharmaceutical composition. Examples of alternative buffers that control the pH in this range include succinic acid, gluconic acid, histidine, citric acid, phosphoric acid, glutaric acid, cacodylic acid, sodium hydrogen maleate, tris(hydroxymethyl)aminomethane (Tris), 2-(N-morpholino)ethanesulfonic acid (MES), and imidazole. Preferably, the buffer is an acetate buffer, more preferably a sodium acetate buffer.

[0136] Preferably, the acetate buffer is contained in the pharmaceutical composition in an amount of 1 mM to 100 mM, more preferably 30 mM to 70 mM, and particularly 50 mM.

[0137] Reference to a "pharmaceutical acceptable excipient" should be understood to include reference to any excipient conventionally used in pharmaceutical compositions. Such excipients may typically include one or more surfactants, inorganic or organic salts, stabilizers, diluents, solubilizing agents, reducing agents, antioxidants, chelating agents, preservatives, and the like.

[0138] Representative examples of surfactants include nonionic surfactants (HLB 6 to 18), such as sorbitan fatty acid esters (e.g., sorbitan monocaprylate, sorbitan monolaurate, sorbitan monopalmitate), glycerin fatty acid esters (e.g., glycerin monocaprylate, glycerin monomyristate, glycerin monostearate), polyglycerin fatty acid esters (e.g., decaglyceryl monostearate, decaglyceryl distearate, decaglyceryl monolinoleate), and polyoxyethylene sorbitan fatty acid esters. (e.g., polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan trioleate, polyoxyethylene sorbitan tristearate), polyoxyethylene sorbitol fatty acid esters (e.g., polyoxyethylene sorbitol tetrastearate, polyoxyethylene sorbitol tetraoleate), polyoxyethylene glycerin fatty acid esters (e.g., polyoxyethylene sorbitol tetraoleate), polyoxyethylene sorbitol glycerin fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan trioleate), polyoxyethylene sorbitol fatty acid esters (e.g., polyoxyethylene sorbitol tetrastearate, polyoxyethylene sorbitol tetraoleate), polyoxyethylene sorbitol fatty acid esters (e.g., polyoxyethylene sorbitol glycerin fatty acid esters), diethylene glyceryl monostearate), polyethylene glycol fatty acid esters (e.g., polyethylene glycol distearate), polyoxyethylene alkyl ethers (e.g., polyoxyethylene lauryl ether), polyoxyethylene polyoxypropylene alkyl ethers (e.g., polyoxyethylene polyoxypropylene glycol ether, polyoxyethylene polyoxypropylene propyl ether, polyoxyethylene polyoxypropylene cetyl ether), polyoxyethylene alkyl phenyl ethers (e.g., polyoxyethylene nonyl phenyl ether), polyoxyethylene hydrogenated castor oil (e.g., polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil), polyoxyethylene beeswax derivatives (e.g., polyoxyethylene sorbitol beeswax), polyoxyethylene lanolin derivatives (e.g., polyoxyethylene lanolin), and polyoxyethylene fatty acid amides (e.g., polyoxyethylene stearyl amide), anionic surfactants, for example, C10-C18 alkyl sulfates (e.g., sodium cetyl sulfate, sodium lauryl sulfate,Examples of surfactants include polyoxyethylene C10-C18 alkyl ether sulfates containing an average of 2 to 4 moles of ethylene oxide (e.g., sodium polyoxyethylene lauryl sulfate), and C8-C18 alkyl sulfosuccinate salts (e.g., sodium lauryl sulfosuccinate), as well as natural surfactants such as lecithin, glycerophospholipids, sphingophospholipids (e.g., sphingomyelin), and sucrose C12-C18 fatty acid esters. The surfactant may be selected from polyoxyethylene sorbitan fatty acid esters. Preferred surfactants are polysorbates 20, 21, 40, 60, 65, 80, 81 and 85, and most preferably polysorbates 20 and 80, especially polysorbate 80.

[0139] Preferably, the surfactant is included in the pharmaceutical composition in an amount of 0.001% to 0.1% (w / w), more preferably 0.005% and 0.05% (w / w), especially 0.01% (w / w).

[0140] Representative examples of inorganic salts include sodium chloride, potassium chloride, calcium chloride, sodium phosphate, sodium sulfate, ammonium sulfate, potassium phosphate and sodium bicarbonate or any other sodium, potassium or calcium salt. Preferably, the inorganic salt is sodium chloride.

[0141] Preferably, the inorganic salt is contained in the pharmaceutical composition in an amount of 10 mM to 200 mM, more preferably 60 mM to 130 mM, particularly 85 mM.

[0142] Examples of reducing agents include N-acetylcysteine, N-acetylhomocysteine, thioctic acid, thiodiglycol, thioethanolamine, thioglycerol, thiosorbitol, thioglycolic acid and its salts, sodium thiosulfate, glutathione, and C1-C7 thioalkanoic acids.

[0143] Examples of antioxidants include erythorbic acid, dibutylhydroxytoluene, butylhydroxyanisole, alpha-tocopherol, tocopherol acetate, L-ascorbic acid and its salts, L-ascorbic acid palmitate, L-ascorbic acid stearate, sodium bisulfite, sodium sulfite, triamyl gallate, and propyl gallate.

[0144] Examples of chelating agents include disodium ethylenediaminetetraacetic acid (EDTA), sodium pyrophosphate, and sodium metaphosphate.

[0145] Examples of stabilizers include amino acids selected from creatinine, histidine, alanine, glutamic acid, glycine, leucine, phenylalanine, methionine, isoleucine, proline, aspartic acid, arginine, lysine and threonine, carbohydrates selected from sucrose, trehalose, sorbitol, xylitol and mannose, surfactants selected from polyethylene glycols (PEG, e.g., PEG3350 or PEG4000) or polyoxyethylene sorbitan fatty acid esters (e.g., polysorbate 20 or polysorbate 80), or any combination thereof.

[0146] In one preferred embodiment, the stabilizer comprises a simple carbohydrate (eg, trehalose).

[0147] In an alternative preferred embodiment, the stabilizer comprises an amino acid in combination with a carbohydrate (eg, trehalose and alanine, or trehalose, alanine and glycine).

[0148] In further alternative preferred embodiments, the stabilizer comprises an amino acid in combination with a carbohydrate and a surfactant (e.g., trehalose, alanine and PEG3350, trehalose, proline and PEG3350, trehalose, alanine and polysorbate 80, trehalose, proline and polysorbate 80, trehalose, alanine, glycine and PEG3350, trehalose, alanine, glycine and polysorbate 80).

[0149] In yet a further alternative preferred embodiment, the stabilizer comprises an amino acid in combination with a surfactant (eg, alanine and PEG3350 or alanine, glycine and PEG3350).

[0150] In yet a further alternative preferred embodiment, the stabilizer comprises a carbohydrate in combination with a surfactant (eg, trehalose and PEG3350 or trehalose and polysorbate 80).

[0151] Examples of preservatives include octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride (a mixture of alkylbenzyldimethylammonium chlorides in which the alkyl groups are long-chain compounds), benzethonium chloride, aromatic alcohols such as phenol, butyl alcohol and benzyl alcohol, alkylparabens such as methylparaben or propylparaben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol. In a preferred embodiment, a pharmaceutical composition comprises an IL-13 binding protein as described herein, a surfactant, and an inorganic salt, and is buffered to a pH of 5.5±0.1 with an acetate buffer.

[0152] In a further preferred embodiment, a pharmaceutical composition comprises an IL-13 binding protein as described herein, sodium chloride and polysorbate 80, buffered to a pH of 5.5±0.1 with sodium acetate buffer.

[0153] In an even more preferred embodiment, a pharmaceutical composition comprises an IL-13 binding protein described herein (e.g., tralokinumab), 50 mM sodium acetate buffer, 85 mM sodium chloride, 0.01% (w / v) polysorbate 80, wherein the pharmaceutical composition has a pH of 5.5.

[0154] In an even more preferred embodiment, the pharmaceutical composition comprises 150 mg / mL of an IL-13 antibody (e.g., tralokinumab), 50 mM sodium acetate buffer, 85 mM sodium chloride, 0.01% (w / v) polysorbate 80, and the pharmaceutical composition has a pH of 5.5.

[0155] Other definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0156] The articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0157] The terms "comprise" and "comprising" are used in their inclusive and open sense, meaning that additional elements may be included.

[0158] In general, a method "comprising" several steps does not require that the steps be performed in a particular order. If a method includes several sequentially numbered or alphabetically ordered steps (e.g., (1), (2), (3), (i), (ii), (iii), or (a), (b), (c), etc.), this means that the steps must be performed in the given order, unless otherwise specified.

[0159] The term "including" is used herein to mean "including, but not limited to."

[0160] The term "about" in relation to a numerical value x is arbitrary and means, for example, x±10%.

[0161] Generally, the terms "treat," "treating," "treatment," and the like refer to temporarily or permanently relieving (alleviating, minimizing, or eliminating) symptoms or alleviating, minimizing, or eliminating the cause of symptoms. All publications mentioned herein are incorporated by reference in their entirety. EXAMPLES

[0162] The present invention will be further described by the following examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the invention described above. Modifications of details can be made without departing from the gist of the present invention.

[0163] Example 1: Efficacy and safety of tralokinumab plus topical corticosteroids in patients with severe atopic dermatitis and prior dupilumab treatment: A post-hoc subgroup analysis from the ECZTRA7 trial method ECZTRA7 was a randomized, double-blind, multicenter, placebo-controlled Phase 3 study.

[0164] Key selection criteria for ECZTRA7: Adult patients with AD who have had an inadequate response to topical or documented systemic medications within the past year. Patients with disease not adequately controlled with oral cyclosporine A or with contraindications to the use of oral cyclosporine A. - AD lesions in ≥10% of body surface area (BSA); ●And EASI ≥20 and IGA ≥3 at screening and baseline, - Mean daily peak pruritus quantification scale (NRS) score of 4 or greater in the week prior to baseline.

[0165] Eligible patients were randomized 1:1 to TCS (as needed) plus 300 mg subcutaneous tralokinumab every 2 weeks or TCS (as needed) plus placebo for a 26-week treatment period, followed by a 600-mg loading dose on day 0.

[0166] For this analysis, past history of dupilumab treatment was confirmed and further details were collected via queries prior to unblinding of the study. Dupilumab-experienced patients were defined as those with confirmed history of dupilumab use prior to the study, and dupilumab-refractory patients were defined as those who discontinued dupilumab due to lack of efficacy or adverse events per queries prior to unblinding. For analysis, Cochran-Mantel-Haenszel with treatment as the only stratum was used.

[0167] result The dupilumab-experienced (n=14) and dupilumab-naive (n=263) cohorts had comparable baseline characteristics, except for the median (IQR) age, which was 51.5 (43.0, 57.0) years for dupilumab-experienced patients and 33.0 (25.0, 45.0) years for dupilumab-naive patients. The median (interquartile range, IQR) EASI and percent of patients with an IGA of 4 were 35.5 (24.8, 39.6) and 57.1% for dupilumab-experienced patients and 28.7 (22.4, 39.5) and 49.0% for dupilumab-naive patients, respectively. Among dupilumab-experienced patients, baseline and clinical characteristics were similar between tralokinumab + TCS (as needed) (n=6) and placebo + TCS (as needed) (n=8). Fifty percent of patients in each of these two groups discontinued dupilumab due to either lack of efficacy or safety concerns. Thus, of the six patients treated with dupilumab and randomized to receive tralokinumab, two patients discontinued dupilumab treatment due to conjunctivitis, and one patient had failure of dupilumab treatment due to lack of efficacy. [Table 3]

[0168] Among dupilumab-experienced patients at week 16, 100% (n / N, 6 / 6) of patients receiving tralokinumab plus TCS achieved EASI-75 without the use of salvage therapy compared with 50% (4 / 8) of patients receiving placebo plus TCS (difference [95% CI]: 50.0 [15.4, 84.6]). Thus, patients who did not respond to dupilumab responded to tralokinumab. A numerically higher proportion of dupilumab-experienced patients receiving tralokinumab + TCS achieved an IGA of 0 / 1 at week 16 (4 / 6, 66.7%; placebo + TCS: 3 / 8, 37.5%; difference: 29.2 [-21.3, 79.6]) and a ≥ 4-point improvement in daily peak Pruritus NRS (weekly mean) (3 / 6, 50%; placebo + TCS: 3 / 8, 37.5%; difference: 12.5 [-39.7, 64.7]). Similarly, at week 26, a numerically higher proportion of dupilumab-experienced patients receiving tralokinumab + TCS compared with placebo + TCS achieved EASI-75 (6 / 6, 100%; placebo + TCS: 3 / 8, 37.5%; difference: 62.5 [29.0, 96.0]), IGA0 / 1 (4 / 6, 66.7%; placebo + TCS: 2 / 8, 25%; difference: 41.7 [-6.5, 89.9]), and ≥ 4-point improvement in daily peak Pruritus NRS (weekly average) (3 / 6, 50%; placebo + TCS: 3 / 8, 37.5%; difference: 12.5 [-39.7, 64.7]). [Table 4]

[0169] Through 26 weeks, 66.7% (4 / 6) of dupilumab-experienced patients receiving tralokinumab plus TCS reported adverse events compared with 87.5% (7 / 8) of patients receiving placebo plus TCS. One placebo patient reported two conjunctivitis events (one mild and one moderate). One tralokinumab patient reported one mild conjunctivitis event. No serious adverse events occurred in either treatment group.

[0170] From a safety perspective, two patients had previously discontinued dupilumab due to conjunctivitis. No adverse events of conjunctivitis were reported for any patient during the 26 weeks of tralokinumab + TCS treatment. [Table 5]

[0171] conclusion This post-hoc subgroup analysis indicates that dupilumab-experienced patients may benefit from tralokinumab + TCS (as needed). The overall frequency of adverse events in dupilumab-experienced patients treated with tralokinumab + TCS (as needed) was consistent with the pooled analysis of tralokinumab phase 2 and 3 trials. List of abbreviations AD, atopic dermatitis AE, adverse event AESI, particularly important adverse events BSA, body surface lesions CI, confidence interval DLQI, skin condition questionnaire EASI, Eczema Area Severity Index At least a 50% reduction in EASI-50, Eczema Area and Severity Index score At least a 75% reduction in EASI-75, Eczema Area and Severity Index score EQ-5D-5L, Eurocor 5-item health survey 5 level HADS, Hospital Anxiety and Depression Questionnaire HRQoL, health-related quality of life IGA, investigator global assessment IGA-0 / 1, Investigator Global Assessment score of 0 (clear) or 1 (almost clear) IMP, investigational drug IQR, interquartile range NRS, Numeric Rating Scale PT, basic word PYE, patient year Q2W, every other week, i.e. every two weeks Q4W, every 4 weeks R, rate (number of AEs divided by PYEs multiplied by 100); SAE, serious adverse event SCORAD, Scoring for Atopic Dermatitis SE, standard error SF-36, Short Form (36-item) Health Status Questionnaire TCS, topical corticosteroids.

[0172] The following numbered clauses, which describe aspects of the present invention, are part of this specification. 1. An interleukin-13 (IL-13) binding protein for use in a method of treating atopic dermatitis (AD) in a subject, said AD being inadequately controlled by an agent that inhibits IL-13 and IL-4 signaling, e.g., an anti-IL4Rα antibody (e.g., dupilumab), said method comprising administering to said subject said IL-13 binding protein.

[0173] 2. A method for treating atopic dermatitis (AD) in a subject in need thereof, wherein the AD is inadequately controlled by an agent that inhibits IL-13 and IL-4 signaling, e.g., an anti-IL4Rα antibody (e.g., dupilumab), the method comprising administering to the subject the IL-13 binding protein.

[0174] 3. The IL-13 binding protein for use according to clause 1 or the method according to clause 2, wherein said method comprises the step of selecting a subject in whom AD is insufficiently controlled by an agent that inhibits IL-13 and IL-4 signaling, e.g., an anti-IL4Rα antibody (e.g., dupilumab).

[0175] 4. An IL-13 binding protein for use in a method for treating atopic dermatitis in a subject who experiences conjunctivitis when treated with an antibody that inhibits IL-4 and IL-13 signaling, such as an anti-IL4Rα antibody (e.g. dupilumab), said method comprising administering said IL-13 binding protein to said subject.

[0176] 5. A method for treating atopic dermatitis in a subject who experiences conjunctivitis when treated with an antibody that inhibits IL-4 and IL-13 signaling, e.g., an anti-IL4Rα antibody (e.g., dupilumab), the method comprising administering to the subject the IL-13 binding protein.

[0177] 6. The IL-13 binding protein for use according to clause 4 or the method according to clause 5, wherein the method comprises the step of selecting a subject who experienced conjunctivitis when treated with an antibody that inhibits IL-4 and IL-13 signaling, e.g., an anti-IL4Rα antibody (e.g., dupilumab).

[0178] 7. The IL-13 binding protein for use or method of any one of the preceding clauses, wherein the agent that inhibits IL-13 and IL-14 signaling (e.g., dupilumab) does not result in a 75% or greater improvement in Eczema Area Severity Index (EASI-75) compared to baseline.

[0179] 8. The IL-13 binding protein for use or method according to any one of the preceding clauses, wherein said AD is also inadequately controlled by cyclosporine A.

[0180] 9. The IL-13 binding protein for use or method of any one of the preceding clauses, wherein the method comprises the steps of: (a) administering to the subject a first dose of the IL-13 binding protein; and (b) administering to the subject one or more second dose(s) of the IL-13 binding protein, wherein each second dose is administered to the subject 12 to 35 days after administration of the immediately preceding dose.

[0181] 10. The IL-13 binding protein for use or method according to clause 9, wherein each second dose is administered to the subject about 2 weeks or about 4 weeks after the immediately preceding dose.

[0182] 11. The IL-13 binding protein for use or method according to any one of the preceding clauses, wherein the method is carried out for at least 2 weeks, at least 3 weeks, at least 12 weeks, at least 3 months, at least 16 weeks, at least 24 weeks, at least 26 weeks, at least 6 months, at least 32 weeks, at least 36 weeks, at least 1 year, or at least 52 weeks or more.

[0183] 12. The IL-13 binding protein for use or method according to clause 11, wherein said method is carried out for at least 26 weeks.

[0184] 13. The IL-13 binding protein for use or method of any one of the preceding clauses, wherein the method comprises the steps of: (a) administering to the subject a first dose of the IL-13 binding protein of from about 10 to about 600 mg; and (b) administering to the subject one or more second dose(s) of the IL-13 binding protein of from about 10 to about 600 mg, wherein each second dose is administered to the subject 12 to 35 days after the immediately preceding dose.

[0185] 14. The IL-13 binding protein for use or method according to clause 13, wherein the method comprises the steps of: (a) administering to the subject a first dose of about 600 mg of the IL-13 binding protein; and (b) administering to the subject one or more second dose(s) of about 300 mg of the IL-13 binding protein, wherein each second dose is administered to the subject 12 to 35 days after the immediately preceding dose.

[0186] 15. The IL-13 binding protein for use or method according to clause 14, wherein said method comprises administering to said subject each second dose about 2 weeks or about 4 weeks after the immediately preceding dose.

[0187] 16. The IL-13 binding protein for use or method according to any one of the preceding clauses, wherein said AD is moderate to severe or severe AD.

[0188] 17. The IL-13 binding protein for use or method according to any one of the preceding clauses, wherein said IL-13 binding protein is administered subcutaneously.

[0189] 18. The IL-13 binding protein for use or method according to any one of the preceding clauses, wherein said IL-13 binding protein is administered as a pharmaceutical composition comprising 50 mM sodium acetate buffer, 85 mM sodium chloride, 0.01% (w / v) polysorbate 80, said pharmaceutical composition having a pH of 5.5.

[0190] 19. The IL-13 binding protein for use or method according to any one of the preceding clauses, wherein said IL-13 binding protein is an anti-IL-13 antibody, or an IL-13-binding fragment thereof.

[0191] 20. The IL-13 binding protein for use or method according to any one of the preceding clauses, wherein said IL-13 binding protein is a monoclonal anti-IL-13 antibody, or an IL-13 binding fragment thereof.

[0192] 21. The IL-13 binding protein for use or method according to any one of the preceding clauses, wherein said IL-13 binding protein is a human anti-IL-13 antibody, or an IL-13-binding fragment thereof.

[0193] 22. The IL-13 binding protein for use or method according to any one of clauses 19 to 21, wherein said IL-13 antibody is an IgG4 antibody.

[0194] 23. The IL-13 binding protein or method for use according to any one of clauses 19 to 22, wherein said IL-13 binding fragment is selected from a Fab, Fab', F(ab')2, Fd, Fv, single-chain Fv (scFv), or disulfide-linked Fv (sdFv).

[0195] 24. The anti-IL-13 antibody, or the IL-13-binding fragment thereof, Heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO:1; Heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO:2; Heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO:3; Light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO:4; A light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO:5, and 24. The IL-13 binding protein for use or method according to any one of clauses 19 to 23, comprising a light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO:6.

[0196] 25. The anti-IL-13 antibody, or the IL-13-binding fragment thereof, comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR); (i) the heavy chain variable region is Heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO:1; A heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO:2, and A heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO:3; (ii) the light chain variable region is Light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO:4; A light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO:5, and 25. The IL-13 binding protein for use or method according to any one of clauses 19 to 24, comprising a light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO:6.

[0197] 26. The anti-IL-13 antibody, or the IL13-binding fragment thereof, further comprising: (i) an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the heavy chain variable region sequence of SEQ ID NO:8, and / or (ii) an IL-13 binding protein for use or method according to any one of clauses 19 to 25, comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the light chain variable region sequence of SEQ ID NO: 10.

[0198] 27. The IL-13 binding protein or method for use according to any one of clauses 19 to 26, wherein said anti-IL-13 antibody, or said IL-13 binding fragment thereof, comprises a heavy chain variable region sequence of SEQ ID NO:8 and a light chain variable region sequence of SEQ ID NO:10.

[0199] 28. An IL-13 binding protein or method for use according to any one of clauses 19 to 27, wherein said anti-IL-13 antibody, or said IL-13-binding fragment thereof, comprises (i) an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the heavy chain sequence of SEQ ID NO:11, and / or (ii) an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the light chain sequence of SEQ ID NO:12.

[0200] 29. The IL-13 binding protein or method for use according to any one of clauses 19 to 28, wherein said anti-IL-13 antibody, or said IL-13 binding fragment thereof, comprises a heavy chain of SEQ ID NO:11 and a light chain of SEQ ID NO:12.

[0201] 30. The IL-13 binding protein for use or method according to clause 29, wherein said anti-IL-13 antibody is tralokinumab.

[0202] 31. The IL-13 binding protein for use or method according to any one of the preceding clauses, wherein said IL-13 binding protein is administered as monotherapy.

[0203] 32. The IL-13 binding protein for use or method of any one of the preceding clauses, wherein said IL-13 binding protein is administered in combination with a second therapeutic agent selected from the group consisting of a topical corticosteroid, a topical calcineurin inhibitor, an antihistamine, an emollient, or an antibacterial therapeutic agent.

[0204] 33. The IL-13 binding protein for use or method according to clause 32, wherein said IL-13 binding protein is administered in combination with a topical corticosteroid.

[0205] 34. An IL-13 binding protein for use or a method according to any one of the preceding clauses, wherein said agent that inhibits IL-13 and IL-4 signalling is an antibody or an antigen-binding fragment thereof.

[0206] 35. The IL-13 binding protein or method for use according to clause 34, wherein the agent that inhibits IL-13 and IL-4 signaling is an antigen-binding fragment, and the antigen-binding fragment is selected from a Fab, a Fab', a F(ab')2, an Fd, an Fv, a single-chain Fv (scFv), or a disulfide-linked Fv (sdFv).

[0207] 36. An IL-13 binding protein for use or a method according to clause 34 or 35, wherein said agent that inhibits IL-13 and IL-4 signalling is an antibody or antigen-binding fragment thereof that binds to IL-4Rα.

[0208] 37. The IL-13 binding protein for use or method according to any one of clauses 34 to 36, wherein said agent that inhibits IL-13 and IL-4 signalling is dupilumab.

[0209] 38. The IL-13 binding protein for use or method according to any one of the preceding clauses, wherein said method achieves a 50% or greater improvement in Eczema Area Severity Index (EASI-50) compared to baseline.

[0210] 39. The IL-13 binding protein for use or method according to any one of the preceding clauses, wherein said method achieves a 75% or greater improvement in Eczema Area Severity Index (EASI-75) compared to baseline.

[0211] 40. The IL-13 binding protein for use or method according to clause 39, wherein said method achieves a 75% or greater improvement in Eczema Area Severity Index (EASI-75) at week 16 compared to baseline.

[0212] 41. The IL-13 binding protein for use or method according to clause 39, wherein said method achieves a 75% or greater improvement in Eczema Area Severity Index (EASI-75) at week 26 compared to baseline.

[0213] 42. The IL-13 binding protein for use or method according to any one of the preceding clauses, wherein the method comprises: (a) administering to the subject a first dose of about 600 mg of the IL-13 binding protein; and (b) administering to the subject one or more second dose(s) of about 300 mg of the IL-13 binding protein, wherein each second dose is administered to the subject 2 weeks or 4 weeks after the immediately preceding dose, wherein the IL-13 binding protein is an antibody comprising a heavy chain variable region sequence set forth in SEQ ID NO:8 and a light chain variable region sequence set forth in SEQ ID NO:10, and wherein the method is performed for at least 26 weeks, and wherein the method achieves a 75% or greater improvement in Eczema Area Severity Index (EASI-75) compared to baseline at week 26.

Claims

1. A medicament for use in a method of treating atopic dermatitis (AD) in a subject, wherein the medicament comprises tralokinumab, and the subject is (i) experiencing conjunctivitis when treated with dupilumab, and / or (ii) treatment with dupilumab does not result in an improvement of 75% or more in the Eczema Area and Severity Index (EASI-75) compared to baseline, and the method comprises subcutaneously administering tralokinumab to the subject, and the method comprises (a) administering a first dose of about 600 mg of tralokinumab to the subject; and (b) administering one or more second doses of about 300 mg of tralokinumab to the subject, each second dose being administered to the subject about 2 weeks or about 4 weeks after the immediately preceding dose, and the treatment is carried out for at least 2 weeks.

2. The medicament for use according to claim 1, wherein the method comprises selecting a subject in whom AD is inadequately controlled by dupilumab such that treatment with dupilumab does not result in an improvement of 75% or more in the Eczema Area and Severity Index (EASI-75) compared to baseline.

3. The medicament for use according to claim 1, wherein the method comprises selecting a subject who experienced conjunctivitis when treated with dupilumab.

4. The medicament for use according to claim 1, wherein the AD is inadequately controlled by cyclosporine A such that treatment with cyclosporine A does not result in an improvement of 75% or more in the Eczema Area and Severity Index (EASI-75) compared to baseline.

5. The medicament for use according to claim 1, wherein the method is carried out for at least 2 weeks, at least 3 weeks, at least 12 weeks, at least 3 months, at least 16 weeks, at least 24 weeks, at least 26 weeks, at least 6 months, at least 32 weeks, at least 36 weeks, at least 1 year, or at least 52 weeks or longer. **Claim 6**: The tralokinumab is administered as a pharmaceutical composition comprising 50 mM sodium acetate buffer, 85 mM sodium chloride, and 0.01% (w / v) polysorbate 80, and the pharmaceutical composition has a pH of 5.5, a pharmaceutical for use according to claim 1. **Claim 7** The pharmaceutical for use according to claim 1, wherein the tralokinumab is administered as a monotherapy. **Claim 8** The pharmaceutical for use according to claim 1, wherein the tralokinumab is administered in combination with a second therapeutic agent selected from the group consisting of a topical corticosteroid, a topical calcineurin inhibitor, an antihistamine, an emollient, or an antibacterial therapeutic agent. **Claim 9** The pharmaceutical for use according to claim 8, wherein the tralokinumab is administered in combination with a topical corticosteroid. **Claim 10** The pharmaceutical for use according to claim 1, wherein the method achieves an improvement of 50% or more in the Eczema Area and Severity Index (EASI-50) compared to baseline. **Claim 11** The pharmaceutical for use according to claim 1, wherein the method achieves an improvement of 75% or more in the Eczema Area and Severity Index (EASI-75) compared to baseline. **Claim 12** The pharmaceutical for use according to claim 11, wherein the method achieves an improvement of 75% or more in the Eczema Area and Severity Index (EASI-75) compared to baseline at week 16. **Claim 13** The pharmaceutical for use according to claim 11, wherein the method achieves an improvement of 75% or more in the Eczema Area and Severity Index (EASI-75) compared to baseline at week 26.

Images