IL-13 antibody for treating post-inflammatory hyperpigmentation or hypopigmentation of the skin

Abstract

Provided herein are antibodies that bind human IL-13 ("anti-IL-13 antibodies") for use in methods, uses, and pharmaceutical compositions for treating post-inflammatory hyperpigmentation or hypopigmentation of the skin (e.g., post-inflammatory hyperpigmentation or hypopigmentation of the skin associated with atopic dermatitis).

Description

sequence list

[0001] This application is submitted together with a sequence list in ST.26 XML format. The sequence list is provided as a file named "31021_WO_000 Sequence Listing ST26 v2" created on February 26, 2025, and with a size of 20.1 kilobytes. The full text of the ST.26 XML format sequence list information is incorporated herein by reference. Technical Field

[0002] This invention relates to methods, uses, and pharmaceutical compositions for treating post-inflammatory hyperpigmentation or hypopigmentation of the skin (e.g., post-inflammatory hyperpigmentation or hypopigmentation of the skin associated with atopic dermatitis) using antibodies that bind to human IL-13 (“anti-IL-13 antibodies”). Background Technology

[0003] Interleukin (IL)-13 is a key mediator of type 2 T helper cell (Th2) inflammation and is signaled via the heterodimer receptors IL-4Rα / IL-13Rα1. Several pieces of evidence suggest that IL-13 is a key pathogenic component in atopic dermatitis (AD). Increased IL-13 expression has been consistently reported in Alzheimer's disease skin (Hamid Q et al., J Allergy Clin Immunol 98:225-31

[1996] ; Jeong CW et al., Clin Exp Allergy 33:1717-24

[2003] ; Tazawa T et al., Arch Dermatol Res 295:459-64

[2004] ; Neis MM et al., J Allergy Clin Immunol 118:930-7

[2006] ; Suárez-Fariñas M et al., J Allergy Clin Immunol 132:361-70

[2013] ; Choy DF et al., J Allergy Clin Immunol 130:1335-43

[2012] ) and some reports have suggested a relationship between IL-13 expression and disease severity (La Grutta S et al., Allergy 60:391-5

[2005] ). Increased IL-13 in the serum of AD patients has also been reported (Novak N et al., J Invest Dermatol 2002; 119:870-5; WO2016149276), and several studies have reported an increase in T cells expressing IL-13 in the blood of AD patients (Akdis M et al., J Immunol 1997; 159:4611-9; Aleksza M et al., Br J Dermatol 2002;147:1135-41; La Grutta S et al., Allergy 2005; 60:391-5).

[0004] Atopic dermatitis (AD) is a chronic, relapsing, and remission-preserving inflammatory skin disease affecting all age groups. Clinically, AD is characterized by xerosis, erythematous crusting, lichenification, impaired skin barrier, and intense itching (Bieber T., N Engl JMed 2008; 358:1483-94). Data are lacking to guide the diagnosis and treatment of traditionally underrepresented populations in clinical trials, including patients with colored skin (Chen et al., JAMA Dermatol. 2022; 158(3):288-292). Complicating this issue is the complexity of diagnosing moderate to severe AD in this patient population, partly due to historical lack of representation in medical education resources and, in some cases, limited exposure to patients of color in medical training (Ebede et al., J Am Acad Dermatol. 2006; 55(4):687-690; Adelekun et al., J Am Acad Dermatol. 2021; 84(1):194-196; Ibraheim et al., Clin Dermatol. 2021; 25:S0738-081X(21)00257-1; Kurtti et al., 2021, Br J Dermatol. 2002; 147(Supplement 62):25-54). Finally, subtle differences in identifying erythema in patients with colored skin not only affect the accuracy and timeliness of AD diagnosis, but also confuse the use of AD scales commonly used in clinical trials (Zhao et al., Int J Womens Dermatol. 2015; 1(3):150-154).

[0005] There remains an unmet medical need for the treatment of post-inflammatory hyperpigmentation or hypopigmentation of the skin, such as post-inflammatory hyperpigmentation or hypopigmentation of the skin associated with atopic dermatitis, especially for patients with colored skin. Summary of the Invention

[0006] This article provides methods, uses, and pharmaceutical compositions for the treatment of post-inflammatory hyperpigmentation or hypopigmentation of the skin (e.g., post-inflammatory hyperpigmentation or hypopigmentation of the skin associated with atopic dermatitis).

[0007] In one aspect, this article provides a method for treating post-inflammatory hyperpigmentation or hypopigmentation of the skin in patients in need, the method comprising administering a therapeutically effective amount of an anti-IL-13 antibody to the patient. In some embodiments, this article provides a method for treating post-inflammatory hyperpigmentation or hypopigmentation of the skin, the method comprising: selecting a patient suffering from post-inflammatory hyperpigmentation or hypopigmentation of the skin, and administering a therapeutically effective amount of an anti-IL-13 antibody to the patient. In some embodiments, post-inflammatory hyperpigmentation or hypopigmentation of the skin is associated with atopic dermatitis. In some embodiments, the patient's skin hyperpigmentation or hypopigmentation is measured using a Post-inflammatory Hyperpigmentation Scale. In some embodiments, the post-inflammatory hyperpigmentation or hypopigmentation is measured using the Post-inflammatory Hyperpigmentation Scale (PDS) or the Post-inflammatory Hyperpigmentation Clinical Assessment (PDCA-DERM). ™ )Measure whether the patient's skin is hyperpigmented or hypopigmented.

[0008] On the other hand, this document provides an anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody for treating post-inflammatory hyperpigmentation or hypopigmentation of the skin. This document also provides the use of the anti-IL-13 antibody in the manufacture of a pharmaceutical agent for treating post-inflammatory hyperpigmentation or hypopigmentation of the skin. In some embodiments, post-inflammatory hyperpigmentation or hypopigmentation of the skin is associated with atopic dermatitis.

[0009] In some implementations, the patient has had moderate to severe atopic dermatitis (AD) for at least one year at baseline. Moderate to severe AD can be determined using criteria known in the art, such as the American Academy of Dermatology consensus criteria for chronic atopic dermatitis. In some implementations, the patient has an EASI score of 16 or higher, an IGA score of 3 or higher, and AD affects more than 10% of the body surface area (BSA) at baseline. In some implementations, the patient has an inadequate response to topical corticosteroids, topical calcineurin inhibitors, or criborone; or topical corticosteroids, topical calcineurin inhibitors, or criborone are medically undesirable for the patient. In some implementations, the patient is 12 years of age or older.

[0010] In some implementations, the patient has a Fitzpatrick phototype of IV to VI. In some implementations, the patient is not white. In some implementations, the patient is Black or African American, Native American, Alaskan Native, Asian, Native Hawaiian, or Pacific Islander.

[0011] In some embodiments, the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2, and HCDR3 comprising SEQ ID NO: 3, and the VL comprises LCDR1 comprising SEQ ID NO: 4, LCDR2 comprising SEQ ID NO: 5, and LCDR3 comprising SEQ ID NO: 6. In some embodiments, the anti-IL-13 antibody comprises a VH comprising SEQ ID NO: 7 and a VL comprising SEQ ID NO: 8. In some embodiments, the anti-IL-13 antibody comprises a VH comprising SEQ ID NO: 11 and a VL comprising SEQ ID NO: 12. In some embodiments, the anti-IL-13 antibody comprises a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10. In some embodiments, the anti-IL-13 antibody comprises a heavy chain comprising SEQ ID NO: 13 and a light chain comprising SEQ ID NO: 14. In some embodiments, the anti-IL-13 antibody is lerechizumab. In some embodiments, the anti-IL-13 antibody comprises the VH sequence listed in SEQ ID NO: 11, the VL sequence listed in SEQ ID NO: 12, and the human IgG sequence listed in SEQ ID NO: 15. In some embodiments, the anti-IL-13 antibody comprises the VH sequence listed in SEQ ID NO: 11, the VL sequence listed in SEQ ID NO: 12, a human Fc region comprising the human IgG sequence listed in SEQ ID NO: 15, and a constant light chain sequence listed in SEQ ID NO: 16.

[0012] In some embodiments, the anti-IL-13 antibody is administered subcutaneously to the patient. In some embodiments, the anti-IL-13 antibody is administered at a dose of 250 mg to 500 mg. In some embodiments, the anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 250 mg every two weeks. In some embodiments, the patient is further treated with a 500 mg loading dose of the anti-IL-13 antibody. In some embodiments, the patient is given a loading dose once or twice. In some embodiments, the patient is given a loading dose at week 0 (baseline) and week 2. In some embodiments, the patient is treated with the anti-IL-13 antibody for at least 16 weeks. In some embodiments, the patient is treated with a 500 mg loading dose of the anti-IL-13 antibody at baseline (week 0) and week 2, followed by 250 mg every two weeks for at least 14 weeks.

[0013] In some embodiments, the patient is further treated with a maintenance period of 8 to 36 weeks. In some embodiments, during the maintenance period, the patient is treated with a maintenance dose of 250 mg of anti-IL-13 antibody every two weeks. In some embodiments, during the maintenance period, the patient is treated with a maintenance dose of 250 mg of anti-IL-13 antibody every four weeks. In some embodiments, during the maintenance period, the patient is treated with a maintenance dose of 250 mg of anti-IL-13 antibody every eight weeks.

[0014] In some embodiments, the methods, uses, and pharmaceutical compositions described herein further include administration of one or more topical corticosteroids to a patient. In some embodiments, the anti-IL-13 antibody is used simultaneously, separately, or sequentially in combination with one or more topical corticosteroids. In some embodiments, the topical corticosteroid is triamcinolone acetonide, hydrocortisone, or a combination of triamcinolone acetonide and hydrocortisone. In some embodiments, the topical corticosteroid is administered concurrently with the anti-IL-13 antibody. Attached Figure Description

[0015] Figure 1 This is a schematic diagram of the research design described in Example 1.

[0016] Figure 2 Showing PDCA-DERM ™ Scale.

[0017] Figure 3A The baseline demographics of the enrolled patients are shown. Figure 3B The baseline disease characteristics of the enrolled patients are shown.

[0018] Figure 4 The percentage of patients treated with ridgecizumab achieved IGA (0,1), with ≥2 points of improvement.

[0019] Figure 5 The percentage of patients treated with ridgecizumab achieved EASI-75 is shown.

[0020] Figure 6 The percentage change in mean pruritus NRS relative to baseline is shown.

[0021] Figure 7A The baseline PDCA-DERM is shown. ™ score. Figure 7B This shows the PDCA-DERM for hyperpigmentation lesions from baseline to week 16. ™ Change. Footnote: aFor patients with multiple hypopigmented or hyperpigmented lesions at baseline, only the lesion with the highest severity score was included in the analysis for each lesion type. In the case of a tie, changes relative to baseline that indicate minor improvement or worsening of the condition were included. b Between week 0 and week 16, the number of patients with hyperpigmentation lesions decreased from 27 to 21, which can be attributed to the discontinuation of the study for 3 patients and the missing data for another 3 patients. c Improvement = +3 to +2 / +1 / 0, +2 to +1 / 0, or +1 to 0; d Normal skin tone = +3 / +2 / +1 to 0. e No change / no improvement = +3 to +3 / -1 / -2 / -3, +2 to +3 / +2 / -1 / -2 / -3, +1 to +3 / +2 / +1 / -1 / -2 / -3. Figure 7C This shows the PDCA-DERM for hypopigmentation lesions from baseline to week 16. ™ Change. Footnote: a For patients with multiple hypopigmented or hyperpigmented lesions at baseline, only the lesion with the highest severity score was included in the analysis for each lesion type. In the case of a tie, changes relative to baseline that indicate minor improvement or worsening of the condition were included. b Between baseline and week 0, the number of patients with hypopigmentation lesions decreased from 9 to 5, which can be attributed to the discontinuation of the study for 2 patients and the missing data for another 2 patients. c Improvement = -3 to -2 / -1 / 0, -2 to -1 / 0, or -1 to 0; d Normal skin color = -3 / -2 / -1 to 0. e No change / no improvement = -3 to -3 / +1 / +2 / +3, -2 to -3 / -2 / +1 / +2 / +3, -1 to -3 / -2 / -1 / +1 / +2 / +3. Detailed Implementation

[0022] This article provides methods, uses, and pharmaceutical compositions for the treatment of post-inflammatory hyperpigmentation or hypopigmentation of the skin (e.g., post-inflammatory hyperpigmentation or hypopigmentation of the skin associated with AD).

[0023] In one aspect, this article provides a method for treating post-inflammatory hyperpigmentation or hypopigmentation of the skin in patients in need, the method comprising administering a therapeutically effective amount of an anti-IL-13 antibody to the patient. In some embodiments, this article provides a method for treating post-inflammatory hyperpigmentation or hypopigmentation of the skin, the method comprising: selecting a patient suffering from post-inflammatory hyperpigmentation or hypopigmentation of the skin, and administering a therapeutically effective amount of an anti-IL-13 antibody to the patient. In some embodiments, post-inflammatory hyperpigmentation or hypopigmentation of the skin is associated with AD. In some embodiments, a post-inflammatory hyperpigmentation scale such as the Post-inflammatory Hyperpigmentation Scale (PDS) or the Clinical Assessment of Post-inflammatory Hyperpigmentation (PDCA-DERM) is used. ™ )Measure whether the patient's skin is hyperpigmented or hypopigmented.

[0024] On the other hand, this document provides an anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody for the treatment of post-inflammatory hyperpigmentation or hypopigmentation of the skin. This document also provides the use of the anti-IL-13 antibody in the manufacture of a pharmaceutical agent for the treatment of post-inflammatory hyperpigmentation or hypopigmentation of the skin. In some embodiments, post-inflammatory hyperpigmentation or hypopigmentation of the skin is associated with AD.

[0025] In some implementations, the patient has had moderate to severe AD for at least one year at baseline. In some implementations, the patient has an EASI score of 16 or higher, an IGA score of 3 or higher, and more than 10% of body surface area (BSA) is affected by AD at baseline. In some implementations, the patient has an inadequate response to topical corticosteroids, topical calcineurin inhibitors, or criborone; or topical corticosteroids, topical calcineurin inhibitors, or criborone are medically undesirable for the patient. In some implementations, the patient is 12 years of age or older.

[0026] In some implementations, the patient has a Fitzpatrick phototype of IV to VI. In some implementations, the patient is not white. In some implementations, the patient is Black or African American, Native American, Alaskan Native, Asian, Native Hawaiian, or Pacific Islander.

[0027] In some implementations, the severity of AD can be determined using standards known in the art, such as the Hanifin and Rajka criteria (Acta Derm Venereol (Stockh) 1980; Supplement 92:44-7); the Rajka and Langerand criteria (Rajka G and Langerand T, Acta Derm Venereol (Stockh) 1989; 144 (Supplement):13-4); or the American Academy of Dermatology consensus criteria for chronic atopic dermatitis (Eichenfield LF et al., J Am Acad Dermatol. 2014; 70(2):338-351). In some implementations, the severity of AD is determined using the American Academy of Dermatology consensus criteria for chronic atopic dermatitis. Under this criterion, the basic characteristics of AD include pruritus; eczema (acute, subacute, chronic); typical morphology and age-specific patterns; and a history of chronic or recurrent eczema. Typical morphological and age-specific patterns include involvement of the face, neck, and extensor surfaces in infants and children; current or previous flexor surface lesions in any age group; and absence of involvement of the groin and axillary regions. Other important features that support the diagnosis include early age of onset; atopic dermatitis; personal and / or family history; immunoglobulin E reactivity; and xerosis. Nonspecific associated features that may help suggest a diagnosis of atopic dermatitis but are used in research and epidemiological studies to define or detect AD include: atypical vascular reactions (e.g., facial pallor, white skin scratches, delayed albinism); keratosis pilaris / pityriasis alba / highline palmar lesions / ichthyosis; ocular / periorbital changes; perifollicular exacerbation / lichenification / prurigo lesions. Sometimes, skin biopsy samples or other tests (such as serum immunoglobulin E, potassium hydroxide preparations, patch tests, and / or genetic tests) can help rule out other or associated skin conditions. Exclusionary conditions include scabies; seborrheic dermatitis; contact dermatitis (irritant or allergic); ichthyosis; cutaneous T-cell lymphoma; psoriasis; photosensitive skin diseases; immunodeficiency diseases; and erythroderma of other causes.

[0028] Anti-IL-13 antibodies suitable for the methods and uses provided herein have been previously described, for example, WO2005062967. In some embodiments, the anti-IL-13 antibody binds to IL-13 with high affinity and blocks signaling via the active IL-4Rα / IL-13Rα1 heterodimer. In some embodiments, the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2, and HCDR3 comprising SEQ ID NO: 3, and the VL comprises LCDR1 comprising SEQ ID NO: 4, LCDR2 comprising SEQ ID NO: 5, and LCDR3 comprising SEQ ID NO: 6. In some embodiments, the anti-IL-13 antibody comprises VH comprising SEQ ID NO: 7 and VL comprising SEQ ID NO: 8. In some embodiments, the anti-IL-13 antibody comprises a VH sequence comprising SEQ ID NO: 11 and a VL sequence comprising SEQ ID NO: 12. In some embodiments, the anti-IL-13 antibody comprises a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10. In some embodiments, the anti-IL-13 antibody comprises a heavy chain comprising SEQ ID NO: 13 and a light chain comprising SEQ ID NO: 14. In some embodiments, the anti-IL-13 antibody comprises the VH sequence listed in SEQ ID NO: 11, the VL sequence listed in SEQ ID NO: 12, and the human IgG sequence listed in SEQ ID NO: 15. In some embodiments, the anti-IL-13 antibody comprises the VH sequence listed in SEQ ID NO: 11, the VL sequence listed in SEQ ID NO: 12, a human Fc region comprising the human IgG sequence listed in SEQ ID NO: 15, and a constant light chain sequence listed in SEQ ID NO: 16. In some implementations, the anti-IL-13 antibody is lerechizumab (CAS No. 953400-68-5). Lerechizumab is a humanized monoclonal IgG4 antibody that binds specifically to IL-13 with high affinity and blocks signaling through the active IL-4Rα / IL-13Rα1 heterodimer. The amino acid sequence of lerechizumab is provided in Table 1. C-terminal cleavage of the IgG antibody may occur when one or two C-terminal amino acids are removed from the heavy chain. For example, if a C-terminal lysine (K) is present, it can be truncated or cleaved from the heavy chain. The penultimate glycine (G) can also be truncated or cleaved from the heavy chain. Modification of the N-terminal amino acids of IgG may also occur. For example, N-terminal glutamine (Q) or glutamate (E) can spontaneously cyclize to pyroglutamic acid (pE).SEQ ID NO: 9 reflects these potential modifications to the heavy chain of lerechizumab. Similarly, SEQ ID NO: 11, 13 and 15 reflect these potential modifications to the lerechizumab variant VH, lerechizumab variant HC and the human IgG1 Fc region, respectively.

[0029] Table 1. Sequence of Levitracizumab

[0030]

[0031] In some embodiments, the anti-IL-13 antibody is a lerechizumab variant containing the same HCDR and LCDR sequences as lerechizumab. In some embodiments, the anti-IL-13 antibody is a lerechizumab variant described in WO2023245187, such as constructs 133, 134, 136, and 141. In some embodiments, the anti-human IL-13 antibody is APG777. The amino acid sequences of the lerechizumab variants are also provided in Table 1.

[0032] Other exemplary anti-IL-13 antibodies include, but are not limited to, IMA-026, IMA-638 (also known as tranexamic acid, QAX-576, CAS No. 910649-32-0), tranexamic acid (also known as CAT-354, CAS No. 1044515-88-9), tranexamic acid (also known as CC-93538, RPC4046, ABT-308, CAS No. 2151032-62-9), AER-001, and ABT-308 (also known as humanized 13C5.5 antibody). Examples of such anti-IL-13 antibodies and other inhibitors of IL-13 are disclosed, for example, in WO2008 / 086395, WO2006 / 085938, US 7,615,213, US 7,501,121, US 7,935,343, US 7,829,090, US7,947,273, WO2007 / 036745, WO2010 / 073119, WO2007 / 045477, and WO 2014 / 165771. In some embodiments, the anti-human IL-13 antibody is trorocalumab. In some embodiments, the anti-human IL-13 antibody is sendazumab.

[0033] Anti-IL-13 antibodies (e.g., lerechizumab) can be formulated with a suitable carrier or excipient into a pharmaceutical composition suitable for administration to a patient. For example, anti-IL-13 antibodies (e.g., lerechizumab) can be formulated in a pharmaceutical composition as described in WO 2013 / 066866. The pharmaceutical composition may contain 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg of anti-IL-13 antibody. In some embodiments, the pharmaceutical composition contains 250 mg or 500 mg of anti-IL-13 antibody. In some embodiments, the concentration of anti-IL-13 antibody in the pharmaceutical composition is between 100 mg / mL and 150 mg / mL, for example, 125 mg / mL. The pharmaceutical composition may also contain 5 mM-40 mM histidine acetate buffer, pH 5.4 to 6.0. In some embodiments, the pharmaceutical composition further comprises a polyol (e.g., a sugar) at a concentration between 100 mM and 200 mM and / or a surfactant (e.g., polysorbate 20) at a concentration of 0.01%-0.1%. In one embodiment, the pharmaceutical composition comprises 125 mg / mL of an anti-IL-13 antibody (e.g., lerechizumab), 20 mM histidine acetate buffer (pH 5.7), 175 mM sucrose, and 0.03% polysorbate 20. In some embodiments, this document provides pharmaceutical compositions comprising means for inhibiting IL-13 and pharmaceutically acceptable carriers or excipients.

[0034] In some embodiments, an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient. In some embodiments, the anti-IL-13 antibody is administered at a dose of 250 mg to 500 mg. In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered to the patient every two weeks, every four weeks, or every eight weeks. In some embodiments, the anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 250 mg every two weeks. In some embodiments, the patient is further treated with a 500 mg loading dose of the anti-IL-13 antibody. In some embodiments, the loading dose is administered to the patient once or twice. In some embodiments, the loading dose is administered to the patient at week 0 (baseline) and week 2. In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered to the patient every eight weeks, every twelve weeks, every twenty-four weeks, every 36 weeks, or every 52 weeks. In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered to the patient about every eight weeks, about every twelve weeks, about every twenty-four weeks, about every 36 weeks, or about every 52 weeks. In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg every eight weeks. In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg every twelve weeks. In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg every twenty-four weeks. In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg every thirty-six weeks. In some embodiments, an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg every 52 weeks. In some embodiments, an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg approximately every 8 weeks. In some embodiments, an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg approximately every 12 weeks. In some embodiments, an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg approximately every 24 weeks. In some embodiments, an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg approximately every 36 weeks. In some embodiments, an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg approximately every 52 weeks.In some embodiments, the patient is further treated with a loading dose of 720 mg of anti-IL-13 antibody. In some embodiments, the loading dose is administered to the patient once or twice. In some embodiments, the loading dose is administered to the patient at week 0 (baseline) and week 2.

[0035] In some embodiments, a subcutaneous administration device is used to administer an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody to a patient. The subcutaneous administration device may be selected from pre-filled syringes, disposable pen-type injection devices, microneedle devices, microinfusion devices, needle-free injection devices, or auto-injector devices. Various subcutaneous administration devices, including auto-injector devices, are known in the art and are commercially available. Exemplary devices include, but are not limited to, pre-filled syringes (such as the BD HYPAK SCF from Becton Dickinson). ® READYFILL ™ and STERIFILL SCF ™ ;Clearshot from Baxter ™ Copolymer prefilled syringes; and Daikyo Seiko CRYSTAL ZENITH available from West Pharmaceutical Services. ® Prefilled syringes); disposable pen-type injection devices, such as the BD pen from Becton Dickinson; ultra-sharp and microneedle devices (such as the INJECT-EASE from Becton Dickinson). ™ And micro-infusion set; and H-PATCH available from Valeritas. ™ ) and needle-free injection devices (such as the BIOJECTOR available from Bioject) ® and IJECT ® ; and SOF-SERTER available from Medtronic ® (and patch device). In some embodiments, the subcutaneous application device is an autoinjector device described in WO 2008 / 112472, WO 2011 / 109205, WO 2014 / 062488 and / or WO 2016 / 089864.

[0036] In some implementations, patients may be treated with anti-IL-13 antibodies or pharmaceutical compositions containing anti-IL-13 antibodies for cycles of 16 to 52 weeks, such as 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks, 34 weeks, 36 weeks, 38 weeks, 40 weeks, 42 weeks, 44 weeks, 46 weeks, 48 ​​weeks, 50 weeks, and 52 weeks.

[0037] In some embodiments, patients are treated with an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody for a treatment period of at least 16 weeks (e.g., induction phase or phase I). In such embodiments, the anti-IL-13 antibody is administered at baseline (week 0) and week 2 as a loading dose of 500 mg, followed by subsequent doses of 250 mg every two weeks for at least 14 weeks. In some embodiments, patients are treated with an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody for a treatment period of 16 weeks (e.g., induction phase or phase I). In such embodiments, the anti-IL-13 antibody is administered at baseline (week 0) and week 2 as a loading dose of 500 mg, followed by subsequent doses of 250 mg every two weeks for 14 weeks.

[0038] Before, during, and after anti-IL-13 antibody treatment, one or more characteristics of a patient can be assessed to identify certain signs, symptoms, features, or parameters associated with Alzheimer's disease (AD) that can be assessed quantitatively or qualitatively. Exemplary characteristics include, but are not limited to, the Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), Body Surface Area (BSA), Face Investigator Global Assessment (F-IGA), Post-inflammatory Hyperpigmentation Scale (PDS), or Clinical Assessment of Post-inflammatory Hyperpigmentation (PDCA-DERM). ™ The following metrics can be used: Patient-Directed Atopic Dermatitis Rating Scale (PO-SCORAD), Numerical Rating Scale for Pruritus (NRS), NRS Scale for Skin Pain, Sleep Deprivation Scale, Patient-Directed Eczema Measurement (POEM), Dermatology Quality of Life Index (DLQI) or Childhood Dermatology Quality of Life Index (cDLQI), Atopic Dermatitis Control Tool (ADCT), Work Productivity and Activity Impairment Questionnaire-Atopic Dermatitis (WPAI-AD), Participant-Reported Satisfaction Questionnaire, Fitzpatrick Skin Photomorphology Assessment, or Fitzpatrick Scale. Characteristics can be measured at baseline and at one or more time points following administration of an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody. The difference between the characteristic value at a specific time point after the start of treatment and the characteristic value at baseline is used to determine whether there is an improvement (e.g., a reduction) in the characteristic.

[0039] In some embodiments, the methods and therapeutic uses described herein further include determining one or more of the following characteristics of the patient at baseline and during and after the induction (or phase I) period: EASI score; IGA score; F-IGA score; percentage of BSA affected by AD; PDS or PDCA-DERM. ™; PO-SCORAD; NRS score for pruritus; sleep deficit score; NRS score for skin pain; POEM; DLQI or cDLQI score; ADCT; WPAI-AD; Fitzpatrick score.

[0040] In some implementations, the patient's EASI score is determined after the treatment period (e.g., induction phase or phase I). In some implementations, a 50% or greater reduction in the patient's EASI score compared to baseline after the treatment period (e.g., induction phase or phase I) signifies that the patient has achieved "EASI-50". In some implementations, a 75% or greater reduction in the patient's EASI score compared to baseline after the treatment period (e.g., induction phase or phase I) signifies that the patient has achieved "EASI-75". In some implementations, a 90% or greater reduction in the patient's EASI score compared to baseline after the treatment period (e.g., induction phase or phase I) signifies that the patient has achieved "EASI-90". When a patient achieves EASI-75 after the induction phase (or phase I), the patient is considered a responder to the anti-IL13 antibody.

[0041] In some implementations, the patient's IGA score is determined after the treatment period (e.g., induction period or phase I). A patient is considered a responder to the anti-IL13 antibody when their IGA score is 0 or 1 after the treatment period (e.g., induction period or phase I). In some implementations, a patient is considered a responder to the anti-IL13 antibody when their IGA score is 0 or 1 after the treatment period (e.g., induction period or phase I) and their IGA score decreases by 2 or more points compared to their baseline IGA score after the treatment period (e.g., induction period or phase I).

[0042] After the induction phase (or Phase I) is completed, the patient can proceed to the maintenance phase (or Phase II). During the maintenance phase (or Phase II), the patient is further treated with anti-IL-13 antibodies or pharmaceutical compositions containing anti-IL-13 antibodies. The dosing regimen for the maintenance phase (or Phase II) can be selected based on the patient's assessment and response to the IL-13 antibody after the induction phase (or Phase I), such as the patient's IGA or EASI score after the induction phase (or Phase I), and / or the patient's own characteristics, such as weight, age, and ethnicity.

[0043] The maintenance period (or second phase) can be 8 to 36 weeks (e.g., 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks). In some embodiments, the maintenance period (or second phase) is 8 weeks. In some embodiments, the maintenance period (or second phase) is 36 weeks.

[0044] In some embodiments, the methods and therapeutic uses described herein also include determining one or more of the following characteristics of a patient during and after the maintenance (or second) phase: EASI score; IGA score; F-IGA score; percentage of BSA affected by AD; PDS or PDCA-DERM. ™ ; PO-SCORAD; NRS score for pruritus; sleep deficit score; NRS score for skin pain; POEM; DLQI or cDLQI score; ADCT; WPAI-AD; Fitzpatrick score.

[0045] The Investigator Overall Assessment (IGA) is an investigator-reported single-item scale that assesses the severity of Alzheimer's disease (AD) in participants (Simpson E et al., J Am Acad Dermatol. 2020; 83(3):839-846). The IGA consists of a 5-point scale ranging from 0 (smooth) to 4 (severe), and scores are selected using descriptors that best describe the overall appearance of the lesions at a given time point (see Table 2).

[0046] Table 2. Investigator Overall Assessment (IGA)

[0047]

[0048] The Eczema Area and Severity Index (EASI) is a measure used in clinical settings to assess the severity and extent of Alzheimer's disease (AD) (Hanifin et al., Exp Dermatol. 2001; 10:11-18). The EASI is an investigator-reported 20-item scale that assesses AD on two dimensions: disease severity in four body regions (head or neck, trunk, upper extremities, and lower extremities) and four clinical signs (erythema, induration or papules, epidermal exfoliation, and lichenification). The severity of clinical signs is assessed on a scale of 0 (absent) to 3 (severe). Scores for each of the four body regions are summed. The specified percentages of the BSA for each body part are 10% for the head or neck, 20% for the upper extremities, 30% for the trunk, and 40% for the lower extremities. Each subtotal score is multiplied by the BSA represented by that region. Furthermore, based on the percentage of skin affected by AD within that area, each body region was assigned an area score from 0 to 6: 0 (none), 1 (1% to 9%), 2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), or 6 (90% to 100%). Each body area score was multiplied by the affected area. The resulting EASI score ranged from 0 to 72, with the highest score indicating a more severe degree of AD (Hanifin et al., 2001). The review period for this scale is the current time.

[0049] Body surface area (BSA) is an investigator-reported assessment that estimates the extent of disease or skin involvement in a participant with Alzheimer's disease (AD). BSA is expressed as a percentage of total body surface area and is reported by body location. The review period for this assessment is the current time.

[0050] The Face Investigator Overall Assessment (F-IGA) is an investigator-managed single-item scale that assesses the severity of AD in participants' faces. The F-IGA consists of a 5-point scale ranging from 0 (smooth) to 4 (severe), and scores are selected using descriptors that best describe the overall appearance of facial lesions at a given time point.

[0051] Post-inflammatory pigmentary dysphoria scale (PDS) or post-inflammatory pigmentary dysphoria clinical assessment (PDCA-DERM) ™ The Post-inflammatory Diabetic Angiopigmentation (PIA) scale is an investigator's assessment of post-inflammatory hyperpigmentation and / or hypopigmentation. This is a measure of post-inflammatory skin changes; therefore, this scale should not be used to assess active inflammatory AD lesions with hyperpigmentation. Areas of normal pigmentation without post-inflammatory hyperpigmentation or hypopigmentation will be scored 0. Areas of post-inflammatory hyperpigmentation compared to adjacent normal skin (0) should be scored 1 (mild / virtually imperceptible hyperpigmentation), 2 (moderate / obvious hyperpigmentation), or 3 (severe / significant hyperpigmentation). Areas of post-inflammatory hypopigmentation compared to adjacent normal skin (0) should be scored -1 (mild / virtually imperceptible hypopigmentation), -2 (moderate / obvious hypopigmentation), or -3 (severe / significant hypopigmentation). See also Figure 2 .

[0052] The Patient-Directed Atopic Dermatitis Rating Scale (PO-SCORAD) is a patient-reported scale used to assess the condition of patients with eczema in adult and adolescent participants over the past 3 days. Questions covered the spread of eczema across the body surface, the severity of dry skin beyond the eczema-affected area, the intensity of symptoms across the eczema-affected area (including skin redness / darkening, swelling, oozing / scabbing, scratching, and thickening), the intensity of eczema-related itching, and sleep disturbances. There were 9 items, and response options varied for each item. For questions regarding symptom intensity, the accompanying user guide showed visual and descriptive anchors for each response option. The total PO-SCORAD score ranged from 0 to 104, with higher scores indicating more severe AD (Stalder et al., Allergy. 2011; 66(8):1114-21; Faye et al., J Eur Acad Dermatol Venereol. 2020; 34(4):795-799). The review period for this scale was the last 3 days.

[0053] The Numerical Rating Scale for Pruritus (NRS) was a participant-reported, single-item, 11-point daily scale. Participants used the Pruritus NRS to rate the severity of their most severe pruritus over the past 24 hours, with 0 representing “no pruritus” and 10 representing “the most severe pruritus imaginable.” Assessments were recorded daily by participants. The minimum clinically significant change was 3 points. (Yosipovitch et al., J Dermatol. 2019; 181(4):761-769; Yosipovitch et al., Revolutionizing Atopic Dermatitis – December 2021).

[0054] The Sleep Deprivation Scale is a participant-reported, single-item, daily scale that measures the degree of sleep deprivation caused by disturbance from itching the previous night. The Sleep Deprivation Scale is assessed based on a 5-point Likert scale (0 [absolutely no sleep] to 4 [absolutely unable to sleep]). Assessments are recorded daily by participants. The minimum clinically significant variation is 3 points. (Yosipovitch et al., 2021).

[0055] The skin pain NRS is an 11-point participant-reported scale anchored on a scale of 0 to 10, where 0 represents “no pain” and 10 represents “the most severe pain imaginable.” The overall severity of a participant’s skin pain was indicated by selecting the number that best described the most severe level of skin pain over the past 24 hours. Assessments were recorded daily by the participants (Newton L et al., J Patient Rep Outcomes. July 16, 2019; 3:42; Silverberg et al., 2021).

[0056] The Patient-Directed Eczema Measurement (POEM) is a simple, participant-reported seven-item scale that assesses disease severity in children and adults. Participants respond to questions about the frequency of seven symptoms (itching, sleep disturbance, bleeding, oozing / exudation, cracking, peeling, and dryness / roughness) over the past week. Response categories include “day 0,” “day 1–2,” “day 3–4,” “day 5–6,” and “daily,” with corresponding scores of 0, 1, 2, 3, and 4, respectively. Scores range from 0 to 28, with higher total scores indicating greater disease severity (Charman et al., Arch Dermatol. 2004; 140(12):1513–1519).

[0057] The Dermatology Quality of Life Index (DLQI) is a simple, participant-reported 10-item adult QoL questionnaire covering six domains (symptoms and feelings, daily activities, leisure, work and school, interpersonal relationships, and treatment). The review period for this scale is within the last week. Response categories include “nothing at all,” “very little,” “a lot,” and “very much,” with corresponding scores of 0, 1, 2, and 3, respectively. Unanswered (or “irrelevant”) responses are scored as 0. Scores range from 0 to 30, with higher scores indicating greater QoL impairment. The total DLQI score of 0 to 1 was considered to have no effect on participants’ health-related QoL (Hongbo et al., J Invest Dermatol. 2005; 125(4):659-664), and a change of 4 points from baseline was considered to be the threshold for the smallest clinically important difference (Khilji et al., Br J Dermatol. 2002; 147(Supplement 62):25-54; Basra et al., Dermatology. 2015; 230(1):27-33).

[0058] Participants under 16 years of age at baseline will complete the pediatric DLQI (cDLQI) and should continue to complete the cDLQI for the duration of the study (Lewis-Jones MS, Finlay AY. British Journal of Dermatology, 1995;132:942-949).

[0059] The Atopic Dermatitis Control Tool (ADCT) is a simple, short, patient-reported tool for adults and adolescents that assesses six symptoms and their impact on AD over the past week: overall severity of symptoms, number of days with severe episodes of itching, intensity of disturbance, sleep problems, impact on daily activities, and impact on mood or affect. Each of the six ADCT items has a rating range from 0 (no problem) to 4 (worst) to assess the severity of each concept; the total score ranges from 0 to 24, which is the sum of responses to all items. A score ≥7 was derived as the threshold for identifying a patient as “uncontrolled.” The threshold for meaningful intra-individual variation was estimated to be 5 (Simpson et al., BMC Dermatol. 2019;19(1):15; Pariser et al., Curr Med Res Opin. 2020; 36(3):367-376).

[0060] The Work Productivity and Activity Impairment Questionnaire-Atopic Dermatitis (WPAI-AD) is a participant-reported six-item questionnaire that records impairments caused by AD in adolescents and adults over the past seven days. WPAI-AD consists of six items grouped into four domains: absence (missed work hours), working while ill (work impairment / reduced work productivity), loss of work productivity (overall work impairment / absence plus working while ill), and activity impairment. Absence, working while ill, and work productivity are reported only by currently employed (paid) individuals at the time of questionnaire completion. The review period for the questionnaire is the past seven days. Scores are calculated as a percentage of impairment (Reilly et al., Pharmacoeconomics. 1993; 4(5): 353-365), with higher scores indicating greater impairment and lower productivity.

[0061] Regarding the satisfaction questions reported by participants, the question asked, "How satisfied are you with this treatment for your skin condition?" The response options ranged from 1 (dissatisfied) to 5 (completely satisfied).

[0062] The Fitzpatrick skin light pattern assessment uses the Fitzpatrick scale, a clinician-assessed scale based on participants' skin responses to sun exposure and baseline skin pigmentation. The Fitzpatrick skin light pattern ranges from I to VI, with I indicating "always sunburnt, never tans, fair skin" and VI indicating "never sunburnt, very easily tanned, dark skin" (High et al., Dermatology (3rd edition). China: Elsevier; 2012:8). When recording the Fitzpatrick skin light pattern, researchers will follow the descriptive terminology included in the protocol. Sun sensitivity measurements will be expressed as each participant's Fitzpatrick scale score. The review period for this scale is the current time.

[0063] In some embodiments, the methods and uses described herein also include administering one or more topical corticosteroids to a patient. In some embodiments, an anti-IL-13 antibody is used simultaneously, separately, or sequentially in combination with one or more topical corticosteroids. Exemplary topical corticosteroids include, but are not limited to, triamcinolone acetonide, hydrocortisone, and combinations of triamcinolone acetonide and hydrocortisone. Triamcinolone acetonide is typically formulated in creams at a concentration of 0.1%, and hydrocortisone is typically formulated in creams at a concentration of 1% or 2.5%. Some topical corticosteroids are considered highly potent, such as, for example, betamethasone dipropionate, clobetasol propionate, diflubenzuron diacetate, fluocinolone acetonide, and halobetasol propionate. Some topical corticosteroids are considered highly potent, such as, for example, amcinonide, desoxymethasone, halcinonide, and triamcinolone acetonide. Some topical corticosteroids are considered to be of moderate potency, such as betamethasone valerate, clotropone neopentate, fluocinolone acetate, fludrosol, fluocinolone acetate, fluticasone propionate, hydrocortisone butyrate, hydrocortisone valerate, mometasone furoate, and prednisolone. Some topical corticosteroids are considered to be of low potency, such as aclomethasone dipropionate, desonide, and hydrocortisone. TCS can be administered once daily, twice daily, three times daily, or as needed to the affected area. In some implementations, the patient's condition is not adequately controlled with topical corticosteroids. In some implementations, the topical corticosteroid is triamcinolone, hydrocortisone, or a combination of triamcinolone and hydrocortisone. In some implementations, the topical corticosteroid is administered concomitantly or sequentially with an anti-IL-13 antibody. In some implementations, the topical corticosteroid is administered concomitantly with an anti-IL-13 antibody.

[0064] As used herein, unless otherwise stated herein or clearly contradicted by the context, the terms “a,” “an,” “the,” and similar terms used in the context of this disclosure (especially in the context of the claims) shall be construed as covering both the singular and the plural.

[0065] As used herein, the term “about” means within a reasonable range of the value, such as 10% of the value plus or minus the value.

[0066] As used herein, the term "antibody" refers to an immunoglobulin molecule that binds to an antigen. Antibody implementations include monoclonal antibodies, polyclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, or conjugated antibodies. These antibodies can belong to any class (e.g., IgG, IgE, IgM, IgD, IgA) and any subclass (e.g., IgG1, IgG2, IgG3, IgG4).

[0067] An exemplary antibody is an immunoglobulin G (IgG) antibody, which consists of four polypeptide chains: two heavy chains (HC) and two light chains (LC) cross-linked by interchain disulfide bonds. The amino-terminal portion of each of the four polypeptide chains contains a variable region of approximately 100 to 125 or more amino acids primarily responsible for antigen recognition. The carboxyl-terminal portion of each of the four polypeptide chains contains a constant region primarily responsible for effector function. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region. Each light chain consists of a light chain variable region (VL) and a light chain constant region. IgG isotypes can be further subdivided into subclasses (e.g., IgG1, IgG2, IgG3, and IgG4).

[0068] The VH and VL regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs), which are interspersed with more conserved regions called framework regions (FRs). CDRs are exposed on the protein surface and are important regions for antigen-binding specificity of antibodies. Each VH and VL consists of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In this paper, the three CDRs of the heavy chain are referred to as "HCDR1, HCDR2, and HCDR3," and the three CDRs of the light chain are referred to as "LCDR1, LCDR2, and LCDR3." These CDRs contain most of the residues that specifically interact with the antigen. The allocation of amino acid residues to the CDR can be performed according to well-known schemes, including those described in the following literature: Kabat (Kabat et al., “Sequences of Proteins of Immunological Interest,” National Institutes of Health, Bethesda, Md. (1991)), Chothia (Chothia et al., “Canonical structures for the hypervariable regions of immunoglobulins”, Journal of Molecular Biology, 196, 901-917 (1987); Al-Lazikani et al., “Standard conformations for the canonical structures of immunoglobulins”, Journal of Molecular Biology, 273, 927-948 (1997)), and North (North et al., “A New Clustering of Antibody CDR Loop Conformations”, Journal of Molecular Biology, 406, 228-256). (2011) or IMGT (International Immunogenetics Database available at www.imgt.org; see Lefranc et al., Nucleic Acids Res. 1999; 27:209-212).

[0069] Exemplary embodiments of the antibodies disclosed herein also include antibody fragments or antigen-binding fragments comprising at least a portion of an antibody that retains the ability to specifically interact with an antigen, such as Fab, Fab', F(ab')2, Fv fragments, scFv, scFab, disulfide-linked Fv (sdFv), Fd fragments, and linear antibodies.

[0070] As used herein, the term “baseline” means before or at the time of administration of the first dose (week 0) of the anti-IL-13 antibody or a pharmaceutical composition containing the anti-IL-13 antibody.

[0071] Unless otherwise stated, the term “binding” as used herein refers to the ability of a protein or molecule to form a chemical bond or attractive interaction with another protein or molecule, which results in the two proteins or molecules coming into close proximity, as determined by commonly used methods known in the art.

[0072] As used in this article, the term "high affinity" refers to the strength of the binding between the antibody and human IL-13, and its equilibrium dissociation constant (K0). D Less than approximately 10 -8 M, for example, 10 -15 M to 10 -8 M, or 10 -12 M to 10 -9 M.

[0073] The term "human IL-13" refers to human interleukin-13 (also known as P600), an immunomodulatory cytokine primarily produced by activated Th2 cells. Two known human IL-13 isotypes exist: isotype a and isotype b. As used herein, the term "human IL-13" refers to all human IL-13 isotypes. The amino acid sequence of human IL-13 isotype a is available at NCBI accession number NP_002179.2. The amino acid sequence of human IL-13 isotype b is available at NCBI accession number NP_001341922.1.

[0074] As used herein, the term “inadequate response” means that, after treatment for the duration recommended in the product prescribing information, good disease control is not achieved (e.g., IGA ≤ 2 or EASI 75 for AD is not achieved), or an AD seizure occurs during treatment.

[0075] As used herein, the terms “intolerance” or “intolerant” refer to unacceptable toxicity (e.g., elevated creatinine, elevated liver function tests, uncontrolled hypertension, loss of sensation in the lower body, headache, nausea, hirsutism), or a requirement for a dose or duration of medication exceeding the dose or duration specified in the prescribing information.

[0076] As used in this article, the term "patient" refers to a person who is a patient.

[0077] As used herein, the term "topical corticosteroid" or "TCS" includes Group I, Group II, Group III, and Group IV topical corticosteroids. According to the World Health Organization's Anatomical Therapeutic Chemistry (ATC) classification system, corticosteroids are classified as weak (Group I), moderately effective (Group II), effective (Group III), and very effective (Group IV) based on their activity compared to hydrocortisone. Group IV TCSs (very effective) are up to 600 times more potent than hydrocortisone and include clobetasol and halcinonide. Group III TCSs (effective) are 50 to 100 times more potent than hydrocortisone and include, but are not limited to, betamethasone valerate, betamethasone dipropionate, diflucolone valerate, hydrocortisone 17-butyrate, mometasone furoate, and methylprednisolone acetate. Group II TCSs (moderately effective) are 2 to 25 times more potent than hydrocortisone and include, but are not limited to, clobetasol and triamcinolone. Group I TCSs (weak or mild) include hydrocortisone, prednisolone, and methylprednisolone.

[0078] As used herein, the term “topical calcineurin inhibitor” or “TCI” includes pimecrolimus, tacrolimus, and other inhibitors that inhibit calcineurin activity and can be applied topically to a patient’s skin.

[0079] As used herein, “treat,” “treatment,” or “treating” means any process that may slow, control, delay, or stop the progression of the disorder or disease disclosed herein, or improve the symptoms of the disorder or disease, but does not necessarily indicate the complete elimination of all symptoms of the disorder or disease. Treatment includes the administration of proteins or nucleic acids or carriers or compositions to treat a patient’s (especially a human) disease or condition.

[0080] Example

[0081] Example 1. Evaluation of the efficacy of lejuzumab in patients with moderate to severe atopic dermatitis and pigmented skin. Safety and efficacy studies in human and adolescent participants .

[0082] patient group

[0083] Inclusion criteria: Participants are eligible for inclusion in the study only if all of the following criteria apply:

[0084] 1. Participants must be 12 years of age or older when signing informed consent or consent forms.

[0085] 2. Participant in Fitzpatrick phototype IV-VI.

[0086] 3. Self-reported participants of races other than white, including but not limited to those who identify themselves as Black or African American, Native American or Alaskan Native, Asian, Native Hawaiian or other Pacific Islander.

[0087] 4. Having chronic atopic dermatitis (AD) for ≥1 year prior to the screening visit (according to the American Academy of Dermatology consensus criteria for chronic atopic dermatitis).

[0088] 5. At the baseline visit, the Eczema Area and Severity Index (EASI) score is ≥16.

[0089] 6. At the baseline visit, the Investigator’s Overall Assessment (IGA) score is ≥3 (on a scale of 0 to 4).

[0090] 7. At baseline visit, the patient has ≥10% of the body surface area affected by AD (BSA).

[0091] 8. A history of inadequate response to topical drug treatment; or it has been determined that topical treatment in other ways is medically inadvisable.

[0092] 9. For adolescent participants, baseline weight ≥40kg.

[0093] 10. Male and / or female

[0094] a. Except in cases that meet specific local government research requirements, male contraception is not necessary.

[0095] b. Female participants of childbearing potential must agree to abstain from sexual intercourse (avoiding heterosexual intercourse) or use highly effective contraception during the treatment period and for at least 18 weeks after the last dose of study drug. Women of childbearing potential (WNOCBP) may participate without any contraceptive requirements.

[0096] 11. Informed Consent / Consent Form

[0097] a. For adult participants: Able to provide signed informed consent.

[0098] b. For adolescent participants: Parents or legal guardians must be able to read, understand, and provide written informed consent for the child's participation in the study.

[0099] 12. Willing and able to comply with all clinical visit and research-related questionnaire procedures.

[0100] Exclusion criteria: Participants will be excluded from the study if any of the following criteria apply:

[0101] 1. History of human immunodeficiency virus (HIV) infection or positive HIV serological history at the time of screening.

[0102] 2. Having a current or chronic infection with hepatitis B virus (HBV) at the time of screening, i.e., being positive for hepatitis B surface antigen (HBsAg) and / or HBV DNA polymerase chain reaction.

[0103] 3. Having a current infection with hepatitis C virus (HCV) at the time of screening, i.e., HCV RNA positive.

[0104] 4. Those with uncontrolled chronic diseases may require multiple intermittent use of oral corticosteroids during screening.

[0105] 5. Suffering from uncontrolled asthma,

[0106] a. May require an oral or systemic corticosteroid flare-up, or

[0107] b. Due to ≥1 worsening within the 12 months prior to baseline, the following is required:

[0108] i. Systemic (oral and / or parenteral) corticosteroid therapy, or

[0109] ii. Hospitalization > 24 hours.

[0110] 6. Having a known history of cirrhosis and / or chronic hepatitis of any cause.

[0111] 7. History of malignant tumors within 5 years prior to screening, including mycosis fungoides or cutaneous T-cell lymphoma, except for completely treated cervical carcinoma in situ, or completely treated and regressed non-metastatic squamous cell carcinoma or basal cell carcinoma of the skin, with no signs of recurrence in the past 12 weeks.

[0112] 8. Be diagnosed with an infection of live internal parasites or be at high risk of such infections.

[0113] 9. Despite the resolution of infection, there is a known or suspected history of immunosuppression, including a history of invasive opportunistic infections (e.g., tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystis infection, and aspergillosis); or, in the investigator's judgment, unusually frequent, recurrent, or persistent infections.

[0114] 10. The presence of comorbid skin conditions that may interfere with the study evaluation.

[0115] 11. Having a serious comorbidity will adversely affect a patient's participation in the study in the researcher's judgment.

[0116] 12. Having any other medical or psychological condition that the researchers believe may indicate a new and / or poorly understood disease, may pose an unreasonable risk to the study participant by participating in the clinical trial, may make the patient's participation unreliable, or may interfere with the study evaluation.

[0117] 13. Have had any of the following types of infection within 3 months of screening, or develop any of these infections during the screening period:

[0118] a. Severe (requiring hospitalization and / or intravenous or equivalent oral antibiotic treatment)

[0119] b. Opportunity

[0120] c. Chronic (symptoms, signs, and / or treatment duration of 6 weeks or longer)

[0121] d. Relapse (including but not limited to recurrent cellulitis and chronic osteomyelitis).

[0122] 14. Having an active or acute infection within 2 weeks prior to the baseline visit that requires treatment with systemic antibiotics, antiviral agents, antiparasitic agents, antiprotozoal agents, or antifungal agents (baseline; visit 2), or having a superficial skin infection within 1 week prior to the baseline visit.

[0123] 15. Previously treated with trolurumab.

[0124] 16. Previously treated with dupilumab.

[0125] 17. Treat with topical medications within 2 weeks prior to the baseline visit: corticosteroids, calcineurin inhibitors, JAK inhibitors, or phosphodiesterase-4 inhibitors (such as criborone).

[0126] 18. Treat with any of the following medications within 4 weeks prior to the baseline visit:

[0127] a. Systemic immunosuppressive or immunomodulatory drugs (e.g., systemic corticosteroids, cyclosporine, mycophenolate mofetil, IFN-γ, azathioprine, methotrexate, and other immunosuppressants); small molecules (JAK inhibitors).

[0128] b. Small molecules (e.g., JAK inhibitors)

[0129] c. Phototherapy and photochemotherapy for AD.

[0130] 19. During the 4 weeks of the screening visit, frequently use (more than 2 visits per week) the tanning room or beauty salon.

[0131] 20. Currently receiving cumulative doses of allergen immunotherapy (allergy injection).

[0132] 21. Treat with B-cell depletion biologics (including rituximab) within 6 months prior to baseline visit.

[0133] 22. Use a prescription moisturizer for 7 days after the baseline visit.

[0134] 23. Receive any live attenuated vaccine within 4 weeks of the baseline visit, or intend to receive a live attenuated vaccine during the study or within 4 weeks of receiving the last study intervention dose.

[0135] 24. Received BCG vaccination or treatment within 4 weeks prior to the baseline visit, or intend to receive BCG vaccination or treatment during the study period.

[0136] 25. Using cannabis or cannabinoids to treat itching, pain, and / or AD.

[0137] 26. Any clinically significant laboratory results from chemical or hematological examinations obtained at the screening visit (first visit), as noted by the investigator.

[0138] 27. Currently involved in any other clinical or medical research involving the investigational product that has been determined to be scientifically or medically incompatible with this study.

[0139] 28. Treatment with the study drug for 8 weeks or 5 half-lives (if known), whichever is longer before the baseline visit.

[0140] 29. A dose of lerizhizumab has been administered in any prior clinical study of lerizhizumab.

[0141] 30. Is a Lilly employee, or an employee of any third party involved in the research, which requests the exclusion of its employees.

[0142] 31. Researchers directly affiliated with this study and / or their immediate family members. Immediate family members are defined as spouses, parents, children, or siblings, whether biological or legally adopted.

[0143] 32. Becoming pregnant or breastfeeding during the study period or planning to become pregnant or breastfeeding.

[0144] 33. Any component of lericizumab has known hypersensitivity.

[0145] 34. Participants or caregivers who are unwilling to receive SC injections of the investigational drug.

[0146] Research drugs :

[0147] The pharmaceutical composition containing 125 mg / mL lerechizumab or placebo is provided as a sterile pre-filled syringe with a pre-assembled needle safety device (PFS-NSD) for subcutaneous administration to patients. The lerechizumab sequence is provided in Table 1. The placebo solution is identical in appearance and volume to the active solution, except that it does not contain lerechizumab.

[0148] Research Design :

[0149] The research design is shown in Figure 1 middle.

[0150] The experiment has three study periods:

[0151] • Screening (≤30 days prior to baseline);

[0152] • Treatment (24 weeks);

[0153] • Safety follow-up (around week 34 or approximately 12 weeks after the last treatment).

[0154] During the 24-week treatment period, approximately 95 participants will receive treatment:

[0155] • At baseline and week 2, administer a loading dose of 500 mg subcutaneously (SC) every 2 weeks (Q2W), followed by 250 mg SC Q2W until week 16.

[0156] • Respondents, defined as those who achieve IGA(0,1) or EASI-75 at week 16, will receive 250 mg SC every 4 weeks (Q4W).

[0157] • Inadequate responders at week 16 will continue to receive 250 mg SC Q2W.

[0158] Goals and End Points

[0159] The goals and endpoints of this study are shown in Table 3.

[0160] Table 3. Goals and Endpoints

[0161]

[0162] Statistical analysis was performed on primary, secondary, and exploratory endpoints.

[0163] result

[0164] The results are shown in Figures 3 to 4. Figure 6 middle. Figure 3A The baseline demographics of the enrolled patients are shown. Figure 3B The baseline disease characteristics of the enrolled patients are shown. Figure 4 The study showed that 39% of patients treated with ridgecizumab achieved IGA (0,1) at week 16, with ≥2 points of improvement. Figure 5 The study showed that 68% of patients treated with ridgecizumab achieved EASI-75 at week 16. Figure 6The mean percentage change in pruritus NRS relative to baseline was -54% at week 16.

[0165] Figure 7A Baseline PDCA-DERM is shown ™ Scoring. For patients with multiple hypopigmented or hyperpigmented lesions at baseline, only the lesion with the highest severity score was included in the analysis for each lesion type. In the case of a tie, changes relative to baseline that indicate minor improvement or worsening of the condition were included. Figure 7B This shows the PDCA-DERM for hyperpigmentation lesions from baseline to week 16. ™ Changes. 12 of the 21 patients (57.1%) showed improvement in hyperpigmentation, and 6 of the 21 patients (28.6%) improved to normal skin color. Figure 7C This shows the PDCA-DERM from baseline to week 16 for hypopigmentation lesions. ™ Changes. One in five patients (20%) showed improvement in hypopigmentation.

[0166] These data show that ridgecizumab treatment improved AD symptoms in patients with pigmented skin after 16 weeks of treatment. No serious adverse events occurred. PDCA-DERM ™ The scale showed that lejuzumab treatment led to improvement in hyperpigmentation or hypopigmentation of the skin in some patients.

Claims

1. A method for treating post-inflammatory hyperpigmentation or hypopigmentation of the skin in a patient in need, the method comprising administering to the patient a therapeutically effective amount of an anti-IL-13 antibody, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2, and HCDR3 comprising SEQ ID NO: 3, and the VL comprises LCDR1 comprising SEQ ID NO: 4, LCDR2 comprising SEQ ID NO: 5, and LCDR3 comprising SEQ ID NO:

6.

2. A method for treating post-inflammatory hyperpigmentation or hypopigmentation of the skin, the method comprising: Select patients with post-inflammatory hyperpigmentation or hypopigmentation of the skin, and The patient is given a therapeutically effective amount of an anti-IL-13 antibody, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2, and HCDR3 comprising SEQ ID NO: 3, and the VL comprises LCDR1 comprising SEQ ID NO: 4, LCDR2 comprising SEQ ID NO: 5, and LCDR3 comprising SEQ ID NO:

6.

3. The method of claim 1 or 2, wherein the post-inflammatory hyperpigmentation or hypopigmentation of the skin is associated with atopic dermatitis (AD).

4. The method according to any one of claims 1 to 3, wherein the anti-IL-13 antibody comprises VH comprising SEQ ID NO: 7 and VL comprising SEQ ID NO:

8.

5. The method according to any one of claims 1 to 4, wherein the anti-IL-13 antibody comprises a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO:

10.

6. The method according to any one of claims 1 to 5, wherein the anti-IL-13 antibody is lerechizumab.

7. The method according to any one of claims 1 to 6, wherein the anti-IL-13 antibody is administered subcutaneously to the patient.

8. The method according to any one of claims 1 to 7, wherein the anti-IL-13 antibody is administered at a dose of 250 mg to 500 mg.

9. The method according to any one of claims 1 to 8, wherein the anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 250 mg every two weeks.

10. The method of claim 9, wherein the patient is further treated with a loading dose of the anti-IL-13 antibody of 500 mg.

11. The method of claim 10, wherein the loading dose is administered to the patient during week 0 and week 2.

12. The method according to any one of claims 1 to 11, wherein the patient is treated with the anti-IL-13 antibody for at least a period of 16 weeks.

13. The method according to any one of claims 1 to 12, wherein the anti-IL-13 antibody is administered at baseline (week 0) and week 2 at 500 mg, followed by 250 mg every two weeks for at least 14 weeks.

14. The method according to any one of claims 1 to 13, the method further comprising determining whether the patient is a responder to the anti-IL-13 antibody after the treatment.

15. The method of claim 14, wherein the patient is a responder when the patient's EASI score determined after the treatment is 75% or more lower than the patient's EASI score at baseline.

16. The method of claim 14, wherein the patient is a responder when the patient's IGA score is 0 or 1 after the treatment and the patient's IGA score after the treatment is 2 points or more lower than the patient's IGA score at baseline.

17. The method according to any one of claims 1 to 16, wherein the patient is further treated for a maintenance period of 8 to 36 weeks.

18. The method according to any one of claims 1 to 16, wherein the patient is further treated for a maintenance period of 8 weeks.

19. The method of claim 17 or 18, wherein during the maintenance period, the patient is treated with a maintenance dose of 250 mg of anti-IL-13 antibody every two weeks.

20. The method of claim 17 or 18, wherein during the maintenance period, the patient is treated with a maintenance dose of the anti-IL-13 antibody of 250 mg every four weeks.

21. The method according to claim 17 or 18, wherein during the maintenance period, the patient is treated with a maintenance dose of the anti-IL-13 antibody of 250 mg every eight weeks.

22. The method according to any one of claims 1 to 21, wherein the anti-IL-13 antibody is administered to the patient using a subcutaneous administration device.

23. The method of claim 22, wherein the subcutaneous application device is selected from a pre-filled syringe, a disposable pen-type injection device, a microneedle device, a microinfusion device, a needle-free injection device, or an auto-injector device.

24. The method of any one of claims 1 to 23, wherein the patient had moderate to severe AD for at least one year at the baseline.

25. The method of claim 24, wherein the moderate to severe AD is determined by the American Academy of Dermatology consensus criteria for chronic atopic dermatitis.

26. The method according to any one of claims 1 to 25, wherein, At baseline, the patient had an EASI score of 16 or higher, an IGA score of 3 or higher, and more than 10% of their body surface area (BSA) was affected by atopic dermatitis.

27. The method according to any one of claims 1 to 26, wherein the patient has an inadequate response to topical corticosteroids, topical calcineurin inhibitors, or criborone; or the topical corticosteroids, topical calcineurin inhibitors, or criborone are medically undesirable for the patient.

28. The method according to any one of claims 1 to 27, wherein the patient is 12 years of age or older.

29. The method according to any one of claims 1 to 28, wherein the patient is a Fitzpatrick phototype IV to VI.

30. The method according to any one of claims 1 to 29, wherein the patient is not white.

31. The method according to any one of claims 1 to 30, wherein the patient is a Black or African American, Native American or Alaskan Native, Asian, Native Hawaiian or Pacific Islander.

32. The method according to any one of claims 1 to 31, wherein the patient's skin hyperpigmentation or hypopigmentation is measured by a post-inflammatory pigmentation disorder scale.

33. The method according to any one of claims 1 to 32, wherein the method further comprises administering one or more topical corticosteroids to the patient.

34. The method of claim 33, wherein the one or more topical corticosteroids are triamcinolone, hydrocortisone, or a combination of triamcinolone and hydrocortisone.

35. An anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody for treating post-inflammatory hyperpigmentation or hypopigmentation of the skin, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2, and HCDR3 comprising SEQ ID NO: 3, and the VL comprises LCDR1 comprising SEQ ID NO: 4, LCDR2 comprising SEQ ID NO: 5, and LCDR3 comprising SEQ ID NO:

6.

36. Use of an anti-IL-13 antibody in the manufacture of a pharmaceutical agent for treating post-inflammatory hyperpigmentation or hypopigmentation of the skin, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2, and HCDR3 comprising SEQ ID NO: 3, and the VL comprises LCDR1 comprising SEQ ID NO: 4, LCDR2 comprising SEQ ID NO: 5, and LCDR3 comprising SEQ ID NO:

6.

37. The anti-IL-13 antibody for use according to claim 35 or the use according to claim 36, wherein the post-inflammatory hyperpigmentation or hypopigmentation of the skin is associated with AD.

38. The anti-IL-13 antibody for use according to claim 35 or 37, or the use according to claim 36 or 37, wherein the patient had moderate to severe AD for at least one year at the baseline.

39. The anti-IL-13 antibody for use according to any one of claims 35, 37 to 38, or the use according to any one of claims 36 to 38, wherein, At baseline, the patient had an EASI score of 16 or higher, an IGA score of 3 or higher, and more than 10% of body surface area (BSA) affected by AD.

40. The anti-IL-13 antibody for use according to any one of claims 35, 37 to 39, or the use according to any one of claims 36 to 40, wherein the patient has an inadequate response to topical corticosteroids, topical calcineurin inhibitors, or criborone; or wherein topical corticosteroids, topical calcineurin inhibitors, or criborone are medically undesirable for the patient.

41. The anti-IL-13 antibody for use according to any one of claims 35, 37 to 40, or the use according to any one of claims 36 to 40, wherein the patient is 12 years of age or older.

42. The anti-IL-13 antibody for use according to any one of claims 35, 37 to 41, or the use according to any one of claims 36 to 41, wherein the patient is a Fitzpatrick phototype IV to VI.

43. The anti-IL-13 antibody for use according to any one of claims 35, 37 to 42, or the use according to any one of claims 36 to 42, wherein the patient is not white.

44. The anti-IL-13 antibody for use according to any one of claims 35, 37 to 43, or the use according to any one of claims 36 to 43, wherein the patient is Black or African American, Native American or Alaskan Native, Asian, Native Hawaiian or Pacific Islander.

45. The anti-IL-13 antibody for use according to any one of claims 35, 37 to 44, or the use according to any one of claims 36 to 44, wherein the anti-IL-13 antibody is used simultaneously, separately, or sequentially in combination with one or more topical corticosteroids.

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