Methods for the treatment of moderate to severe atopic dermatitis

Abstract

The present disclosure relates to the use of anti-IL-13Rα1 antibodies (such as ebrasakimab) or binding fragments thereof and pharmaceutical formulations comprising same to treat patients with atopic dermatitis (such as lesional atopic dermatitis), including patient populations that have received prior treatment with dupilumab, for example to stimulate disease modification.

Description

[Technical field]

[0001] The present disclosure relates to the use of anti-IL-13Rα1 antibodies or binding fragments thereof, and pharmaceutical formulations comprising same, for treating patients with atopic dermatitis (such as lesional atopic dermatitis), including patient populations that have received prior treatment with dupilumab, e.g., to stimulate disease modification. [Background technology]

[0002] background One possible way to inhibit the activity of IL-13 is to interfere with the binding of IL-13 to the receptor IL-13R, for example by using an antibody specific for IL-13, such as an antibody specific for IL-13Rα1. An effective antibody antagonist to IL-13Rα1 can also interfere with the binding of IL-13 and prevent the heterodimerization of IL-4Rα and IL-13Rα1. Such an antibody can inhibit both IL-13 and IL-4 signaling through type II receptors without utilizing IL-4 signaling through type I receptors. Signaling through type I receptors is essential during the induction phase of the immune response, where Th2 cells differentiate. Since T cells do not express IL-13Rα1, type II receptors play no role in Th2 differentiation. Thus, IL-13Rα1 antibodies should not affect the overall Th1 / Th2 balance. Signaling through the type II IL-4 / IL-13 receptor is crucial in the effector-A-stage of the immune response during the establishment of allergic inflammation. Blockade of the type II receptor should therefore have beneficial effects on many of the symptoms of allergic-type diseases such as asthma, atopic dermatitis and other IL-13R-mediated conditions and should therefore be an effective disease-modifying agent.

[0003] Antibodies against IL-13Rα1, both monoclonal and polyclonal, have been described in the art, e.g., WO97 / 15663, WO03 / 80675; WO03 / 46009; WO06 / 072564; Gauchat et al, 1998 Eur. J. Immunol. 28:4286-4298; Gauchat et al, 2000 Eur. J. Immunol. 30:3157-3164; Clement et al, 1997 Cytokine 9(11):959 (Meeting Abstract); Ogata et al, 1998 J. Biol. Chem. 273:9864-9871; Graber et al, 1998 Eur. J. Immunol. 28:4286-4298;C. Vermot-Desroches et al, 2000 Tissue Antigens 5(Supp.l):52-53(Meeting Abstract);Poudrier et al, 2000 Eur. J. Immunol. 30:3157-3164;Akaiwa et al, 2001 Cytokine 13:75-84; Cancino-Diaz et al, 2002 J. Invest. Dermatol. 119:1114-1120; and Krause et al, 2006 MoI. Immunol. 43:1799-1807.

[0004] One particularly promising anti-IL-13Rα1 antibody is described in WO2008 / 060813 as antibody 10G5-6. 10G5-6, as an IgG4 with a hinge stabilizing serine to proline mutation (S241P Kabat numbering), is known as ebrasakimab.

[0005] Ebrasakimab has been shown to bind to human IL-13Rα1 with high affinity (e.g., Kd can be 500pM). Ebrasakimab has been shown to effectively antagonize IL-13 function through inhibiting IL-13 binding to receptor IL-13Rα1, and inhibit IL-13 and IL-4-induced eotaxin release in NHDF cells, IL-13 and IL-4-induced STAT6 phosphorylation in NHDF cells, and IL-13-stimulated release of TARC in blood or peripheral blood mononuclear cells.

[0006] Atopic dermatitis can be a very painful, depressing, and psychologically damaging disease. One way to evaluate the disease is the EASI score. This score ranges from 0 to 72. In some cases, moderate to severe forms of the disease are not adequately controlled by topical medications. In addition, some patients may not be advised to use available topical medications. Dupixent (dupilumab) is an antibody inhibitor of interleukin-4 receptor alpha (IL-4Rα) approved for the treatment of atopic dermatitis.

[0007] In some instances, patients prescribed dupilumab discontinue treatment for one or more reasons, such as adverse side effects, inadequate control of symptoms, and / or dosing issues, leaving some patients with moderate to severe topic dermatitis without an adequate treatment.

[0008] Moderate atopic dermatitis generally has a score in the range of 7.1 to 21.0.

[0009] Severe atopic dermatitis has a score of 21.1 or higher. Sometimes severe atopic dermatitis is divided into severe and very severe disease, with these groups having ranges of 21.1 to 50 and 50.1 to 72.0, respectively.

[0010] The inventors have conducted clinical trials and determined that the full range of atopic dermatitis patients may benefit from treatment with an antibody or antigen-binding fragment thereof that binds to IL-13Rα1 and thereby inhibits signaling through said receptor, with patients with a baseline EASI score of at least 16 and / or patients with lesional atopic dermis appear to benefit most from the treatment.

[0011] The present invention provides a new patient population, for example, patients who have been pretreated with Dupilumab and / or patients with pathological atopic dermatitis. In some instances, it is useful to combine baseline EASI scores with one or more other markers, such as baseline IgE, TARC and STAT6, to define the patient population. Surprisingly, these patients show the greatest improvement with treatment according to the present disclosure. In some embodiments, the treatment is disease-modifying. The normal level of TARC in healthy individuals is usually up to 450 pg / ml.

[0012] Interestingly, the inventors have also determined that because IL-13Ralpha1 is upregulated in lesional atopic dermatitis, patients with lesional atopic dermatitis may particularly benefit from treatment with an anti-IL-13 antibody such as ebrasakimab (e.g., as a separate embodiment or in moderate / severe atopic dermatitis embodiments).

[0013] Lesionary and non-lesionary atopic dermatitis are distinct subgroups of patients. Non-lesionary AD has immune abnormalities, including T cell proliferation. It has a variable immune phenotype that is largely determined by the extent and severity of the disease. Reduced hydration and impaired lipid synthesis are found in non-lesionary atopic skin compared to normal skin. There is also abnormal epithelial proliferation in non-lesionary atopic dermatitis, and the expression of proliferation markers (keratin 16) is increased, associated with altered expression of terminal differentiation proteins, including loricrin (LOR), involucrin (IVL), and FLG. In addition, increased infiltration of inflammatory T cells has been demonstrated in non-lesionary atopic dermatitis skin compared to skin of healthy volunteers. In one embodiment, non-lesionary atopic dermatitis is characterized by the absence of lesions.

[0014] Lesioned skin of chronic AD patients has many differences in hyperinflammatory genes in lesional AD skin as well as widespread changes in the expression of terminal differentiation genes that form the cornified membrane and epidermal differentiation complex. In its simplest form, lesional AD is characterized by lesions. Summary of the Invention [Problem to be solved by the invention]

[0015] Disclosure Summary 1. An antibody or antigen-binding fragment thereof that binds to IL-13Rα1 and thereby inhibits signaling through said receptor for use in the treatment of moderate, severe or very severe atopic dermatitis (particularly moderate to severe atopic dermatitis that is difficult to control) by parenteral administration with a treatment cycle comprising a dose in the range of 200 mg to 600 mg (such as 400 to 600 mg), wherein the baseline disease severity is 16 or greater (17, 18, 20, 22, 24, 26, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 8, 19, 20, 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, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, etc.

[0016] 1A. A method of treatment for a patient with moderate, severe or very severe atopic dermatitis by parenteral administration of a treatment cycle comprising a dose in the range of 200 mg to 600 mg (e.g., 400 to 600 mg) of an antibody or antigen-binding fragment thereof that binds to IL-13Rα1 and thereby inhibits signal transduction through said receptor, wherein the baseline disease severity is 16 or greater (17, 18, 19, 20, 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, 52, 5 9, 20, 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, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, etc.), as characterized by EASI scores.

[0017] 1B. An antibody or antigen-binding fragment thereof that binds to IL-13Rα1 and thereby inhibits signaling through said receptor, for use in the manufacture of a medicament for the treatment of moderate, severe or very severe atopic dermatitis (particularly moderate to severe atopic dermatitis that is difficult to control) by parenteral administration in a treatment cycle comprising a dose in the range of 200 mg to 600 mg (such as 400 to 600 mg), wherein the baseline disease severity is 16 or greater. (17, 18, 19, 20, 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, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, etc.).

[0018] 1C. An antibody or antigen-binding fragment thereof that binds to IL-13Rα1 and thereby is an inhibitor of signal transduction through said receptor, for use in the treatment of lesional atopic dermatitis (particularly moderate to severe atopic dermatitis that is difficult to control) by parenteral administration with a treatment cycle comprising a dose in the range of 200 mg to 600 mg (such as 400 to 600 mg).

[0019] 2. The antibody or antigen-binding fragment thereof, method, or use according to paragraph 1, 1A or 1B, wherein the atopic dermatitis is lesional.

[0020] 3. The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein the patient has been previously treated with dupilumab.

[0021] 4. Baseline TARC level of at least 701 pg / ml, e.g., 800-52,000 pg / ml (800, 900, 1,000, 1500, 2,000, 2,500, 3,000, 3,500, 4,000, 4,500, 5,000, 5,500, 6,000, 6,500, 7,000, 7,500, 8,000, 9,000, 10,000, 11,000, 12,000, 13,000, 14,000, 15,000, 16,000, 17,000, 18,000, 19,000, 21,000, 22,000, 23,000, 24,000, 25,000, 26,000, 27,000, 28,000, 29,000, 30,000, 31,000, 32,000, 33,000, 34,000, 35,000, 36,000, 37,000, 38,000, 39,000, 40,000, 41,000, 42,000, 43,000, 44,000, 45,000, 46,000, 47,000, 48,000, 49,000, 50,000, 51,000, 52,000, 53,000, 54,00 00, 8,500, 9,000, 9,500, 10,000, 11,000, 12,000, 13,000, 14,000, 15,000, 16,000, 17,000, 18,000, 19,000, 20,000, 21,000, 22,000, 23,000, 24,000, 25,000, 26,000, 27,0 00, 28,000, 29,000, 30,000, 31,000, 32,000, 33,000, 34,000, 35,000, 36,000, 37,000, 38,000, 39,000, 40,000, 41,000, 42,000, 43,000, 44,000, 45,000, 46,000, 47,000, 4 or 52,000 pg / ml), in particular at least 1,115 pg / ml, for example in the range of 1,115 pg / ml to 4,300 pg / ml or greater than 4,300 pg / ml.

[0022] 5. The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein baseline STAT6 is above normal.

[0023] 6. The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein the patient has a baseline IGA score of 3 or greater, representing moderate to very severe atopic dermatitis, e.g., 3 (moderate atopic dermatitis), 4 (severe atopic dermatitis) or 5 (very severe atopic dermatitis).

[0024] 7. Baseline IgE level (e.g., determined / measured) of at least 130 kU / L, e.g., 150 kU / L, 150-20,000, etc., more specifically, 130, 150, 200, 300, 400, 500, 600, 700, 750, 800, 850, 900, 950, 1000, 1500, 2,000, 2,500, 3,000, 3500, 4,000, 4,500, 5,000, 5,500, 6,000 The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein the antibody or antigen-binding fragment thereof is at a level such as 0, 6,500, 7,000, 7,500, 8,000, 8,500, 9,000, 9,500, 10,000, 11,000, 12,000, 13,000, 14,000, 15,000, 16,000, 17,000, 18,000, 19,000, 20,000 kU / L, in particular 10,000 kU / L+ / -2,000.

[0025] 8. The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein one or more of the parameters (e.g., two or more or all of the parameters) are measured before dosing begins, and in particular the patient is identified as a relevant / suitable population prior to treatment.

[0026] 9. An antibody or antigen-binding fragment, method, or use according to any preceding paragraph, wherein the patient has been identified as having one or more (e.g., all of the parameters) prior to initiating treatment, i.e., the patient has been determined to be in the moderate to severe dermatitis population based on data other than solely clinical observation and / or EASI score.

[0027] 10. The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein the atopic dermatitis is moderate, e.g., having an EASI score within the range of 16 to 21.0.

[0028] 11. The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein the atopic dermatitis is moderate and the TARC score is at least 2,056 + / - 290 pg / ml.

[0029] 12. The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein the atopic dermatitis is moderate and the IgE score is at least 130 IU / L (such as within the range of 130-6,800 IU / L, more particularly 130-479 IU / L).

[0030] 13. The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein the atopic dermatitis is severe, e.g., having an EASI score of 21.1 or greater, e.g., 21.1 to 50.0.

[0031] 14. The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein the atopic dermatitis is severe and the TARC score is at least 4,812+ / -490pg / ml.

[0032] 15. The antibody or antigen-binding fragment thereof, method, or use according to any one of paragraphs 1, 1A, 1B-11, 13 or 14, wherein the atopic dermatitis is severe and the IgE score is at least 480 IU / L (such as within the range of 480 to 15,100 IU / L).

[0033] 16. The antibody or antigen-binding fragment thereof, method, or use according to any one of paragraphs 1, 1A, 1B-11, or 13-15, wherein the atopic dermatitis is very severe, e.g., having a score within the range of 50.1 to 72.0.

[0034] 17. The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein a reduction from baseline in EASI score, such as at least a 15% reduction, is present about 2 weeks (such as day 15) after administration of the first dose.

[0035] 18. The antibody or binding fragment thereof, method, or use according to any preceding paragraph, wherein the reduction from baseline in EASI score is within the range of 15-60% (e.g. at about day 15), such as 25-60% (such as 39-59%, particularly 40-59, more particularly 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58 or 59%), particularly at about day 15.

[0036] 19. The antibody or binding fragment thereof, method, or use according to any preceding paragraph, wherein the reduction from baseline in EASI score is within the range of 50-100% (e.g., 55-97%), particularly at about day 29.

[0037] 20. The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein the reduction in EASI score is within the range of -40 to -85% (e.g. at about day 29).

[0038] 21. The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein the reduction in EASI score is present about 4 weeks (such as day 29) after administration of the first dose.

[0039] 22. The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein the reduction in EASI score is present about 6 weeks (such as day 43) after administration of the first dose.

[0040] 23. The antibody or binding fragment thereof according to any preceding paragraph, wherein the reduction from baseline in EASI score is within the range of 60-100% (e.g., 70-97%), particularly at about day 43.

[0041] 24. The antibody or antigen-binding fragment thereof according to any preceding paragraph, wherein the reduction in EASI score is within the range of -25 to -85% (e.g., at about day 43 or 57).

[0042] 25. The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein the reduction in EASI score is present about 8 weeks (such as day 57) after administration of the first dose.

[0043] 26. The antibody or binding fragment thereof, method, or use according to any preceding paragraph, wherein the reduction from baseline in EASI score is in the range of 65-100% (e.g., 70-100%, such as 90-100%, particularly 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100%), more particularly at about day 57.

[0044] 27. The antibody or binding fragment thereof, method or use according to any preceding paragraph, wherein 80% of the patient population has an EASI50 score or less at about day 29 and / or day 57, particularly where a dosage of at least 350 mg (such as 400 mg) is utilized.

[0045] 28. The antibody or binding fragment thereof, method or use according to any preceding paragraph, wherein 90% of the patient population has an EASI50 score or less at about day 57, particularly where a dosage of at least 550 mg (such as 600 mg) is utilized.

[0046] 29. The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein there is at least a 20% reduction from baseline in IgE by day 57, such as about a 20-60% reduction from baseline.

[0047] 30. An antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein there is at least a 50% reduction from baseline in TARC, for example by about day 15.

[0048] 31. The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein there is at least a 60% reduction from baseline in TARC, for example by about day 36.

[0049] 32. The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein there is at least a 70% reduction from baseline in TARC, e.g., by about day 50.

[0050] 33. The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein there is at least an 80% reduction from baseline in TARC, for example by about day 57.

[0051] 34. The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein treatment is administered intravenously.

[0052] 35. The antibody or antigen-binding fragment thereof, method, or use according to any one of paragraphs 1, 1A, 1B, 1C-33, wherein treatment is administered subcutaneously.

[0053] 36. The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein multiple doses are administered in one treatment cycle (e.g., the treatment cycle is 4 to 8 weeks, such as 8 weeks).

[0054] 37. The antibody or binding fragment thereof, method or use according to paragraph 36, wherein multiple treatment cycles are administered, for example 2, 3, 4 or more treatment cycles are administered.

[0055] 38. The antibody or binding fragment thereof, method or use according to paragraph 36 or 37, wherein following the treatment cycle or cycles and disease modification, a maintenance therapy is administered, e.g. the same dose is administered less frequently (e.g. monthly, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, etc.), or a lower dose (e.g. 200 mg) is administered the same or less frequently (e.g. about every week, every 2 weeks, about every 3 weeks, or about every 4 weeks).

[0056] 39. The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein the antibody or binding fragment thereof is administered approximately weekly (particularly in a treatment cycle (such as 1 cycle), especially an 8 week cycle).

[0057] 40. The antibody or antigen-binding fragment thereof, method or use according to any one of paragraphs 1, 1A, 1B, 1C-38, wherein the antibody or antigen-binding fragment thereof is administered approximately once every two weeks (particularly in a treatment cycle (such as one cycle), particularly an 8 week cycle).

[0058] 41. The antibody or antigen-binding fragment thereof, method or use according to any one of paragraphs 1, 1A, 1B, 1C-38, wherein the antibody or antigen-binding fragment thereof is administered approximately once every three weeks (particularly in a treatment cycle (such as one cycle), particularly an 8 week cycle).

[0059] 42. The antibody or antigen-binding fragment thereof, method or use according to any one of paragraphs 1, 1A, 1B, 1C-38, wherein the antibody or antigen-binding fragment thereof is administered approximately once every 4 weeks (e.g. monthly) (particularly in a single treatment cycle, particularly an 8 week cycle).

[0060] 43. The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein a loading dose (e.g., in the range of 400-900 mg, such as 400, 500, 600, 700, 800 or 900 mg) is used before administration of a further dose in a treatment cycle.

[0061] 44. The antibody or antigen-binding fragment thereof, method, or use according to any one of paragraphs 1, 1A, 1B, 1C-42, wherein treatment does not include a loading dose.

[0062] 45. The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein the dosage is 200 mg.

[0063] 46. ​​The antibody or binding fragment thereof, method, or use according to any one of paragraphs 1, 1A, 1B, 1C-44, wherein the dosage is in the range of 350 to 450 mg, such as 400 mg.

[0064] 47. The antibody or binding fragment thereof, method, or use according to any one of paragraphs 1, 1A, 1B, 1C-44, wherein the dosage is 600 mg.

[0065] 48. The treatment cycle comprises an initial dose of 600 mg followed by 400 mg every 3 weeks, for example the treatment cycle is repeated twice, i.e. the two treatment cycles last 8 weeks (with or without a loading dose, i.e. the initial dose is the same as the other doses in the cycle), in particular: The antibody or binding fragment thereof, method, or use according to any preceding paragraph, wherein 600 mg is administered on about day 1, 400 mg on about day 8, 400 mg on about day 15, 400 mg on about day 22, 600 mg on about day 29, 400 mg on about day 36, 400 mg on about day 43, and 400 mg on about day 50.

[0066] 49. The antibody or binding fragment thereof, method, or use according to any preceding paragraph, wherein disease modification occurs by day 4, with day 1 being the first administration of the antibody or binding fragment thereof.

[0067] 50.Disease modifying a. a reduction from baseline in EASI score, e.g., the reduction is a percentage from baseline, e.g., the reduction is in the range of 10-55%; and / or b. A reduction from baseline in TARC, e.g., as described elsewhere herein; and / or c. A reduction from baseline in IgE, e.g., as described elsewhere herein. An antibody or binding fragment thereof, method or use according to any preceding paragraph.

[0068] 51. The antibody or binding fragment thereof according to any preceding paragraph, wherein disease modification within the range of -40 to -100% is achieved by about day 57 after the initial administration on day 1, e.g., maximum disease modification is achieved by about day 57.

[0069] 52. An antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein the antibody or binding fragment binds to epitope FFYQ (e.g., the same epitope as an antibody having a VH as shown in SEQ ID NO:51 and a VL as shown in SEQ ID NO:53).

[0070] 53. The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein the anti-IL-13R antibody comprises a VH CDR1 comprising the amino acid sequence represented by SEQ ID NO:1, a VH CDR2 comprising the amino acid sequence represented by SEQ ID NO:2, and a VH CDR3 comprising the amino acid sequence represented by SEQ ID NO:10.

[0071] 54. The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein the anti-IL-13R antibody comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO:51, or a sequence at least 95% identical thereto.

[0072] 55. The antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein the anti-IL-13R antibody comprises a VL CDR1 comprising the amino acid sequence represented by SEQ ID NO:31, a VL CDR2 comprising the amino acid sequence represented by SEQ ID NO:32, and a VL CDR3 comprising the amino acid sequence represented by SEQ ID NO:45.

[0073] 56. An antibody or antigen-binding fragment thereof, method, or use according to the preceding paragraph, wherein the anti-IL-13R antibody comprises a VL domain comprising the amino acid sequence set forth in SEQ ID NO:53, or a sequence at least 95% identical thereto.

[0074] 57.Antibody, with 10-140 mg / ml of antibody or binding fragment; with 50 mM to 150 mM arginine (e.g., 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145 or 150 mM arginine, such as 100 mM); with 15-25 mM histidine buffer, for example 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25 mM histidine buffer, such as 20 mM; 0.01-0.03% non-ionic surfactant, such as 0.02% w / v; and providing a pharmaceutical formulation comprising: The pH of the formulation is in the range of 5.5 to 7.5, for example 6.2 to 7.2 (such as 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, such as 6.5 to 7.0, especially 6.4 to 6.9), An antibody or antigen-binding fragment thereof, method or use according to any preceding paragraph.

[0075] 58. The antibody or antigen-binding fragment thereof, method, or use according to paragraph 57, wherein the osmolality of the formulation is in the range of 350 to 550 mOsmo / kg, for example 350, 355, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 515, 520, 525, 530, 535, 540, 545, 550, such as 405 to 435 mOsmo / kg.

[0076] 59. The antibody or antigen-binding fragment thereof, method, or use according to paragraph 57 or 58, further comprising 50 to 200 mM sugar, for example 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200 mM sugar, such as 180 mM.

[0077] 60. An antibody or antigen-binding fragment for use according to any one of paragraphs 57 to 59, wherein the pH is 6.5.

[0078] 61. An antibody or antigen-binding fragment thereof for use according to any one of paragraphs 57 to 60, wherein the formulation does not contain NaCl.

[0079] 62. The antibody or antigen-binding fragment thereof for use according to any one of paragraphs 57 to 61, wherein the formulation comprises 50 to 150 mM NaCl, for example 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150 mM NaCl, such as 62.5 or 140 mM.

[0080] 63. Use of an antibody or antigen-binding fragment, which binds to IL-13Rα1 and thereby becomes an inhibitor of signaling through said receptor, according to any one of paragraphs 1 to 58 for the manufacture of a medicament for the treatment of atopic dermatitis, in which the incidence of ocular side effects is reduced compared to treatment with a therapeutic dose of dupilumab for treatment of the eye. [Means for solving the problem]

[0081] In one embodiment, the moderate to severe atopic dermatitis (such as severe AD) is lesional atopic dermatitis.

[0082] Also provided by the present disclosure are methods of treating a patient for atopic dermatitis (e.g., moderate to severe atopic dermatitis, particularly moderate to severe atopic dermatitis that is difficult to control) comprising administering an antibody or antigen-binding fragment thereof, or pharmaceutical formulation disclosed herein.

[0083] As used herein, difficult to control refers to difficult to control with existing approved agents, e.g., topical agents, oral agents, and / or biologics such as dupilumab (particularly topical agents or dupilumab).

[0084] The results further suggest that ebrasakimab has similar, and in some instances greater, efficacy compared to dupilumab, thus demonstrating the potential of ablasakimab as an alternative therapy for the treatment and management of atopic dermatitis, especially in patients who have previously received dupilumab.

[0085] Thus, in one embodiment, treatment is provided for a patient population where the patient has symptoms that are difficult to control and / or has adverse side effects when treated with dupilumab, i.e., the patient population is patients who have been previously treated with dupilumab, particularly patients who have failed dupilumab.

[0086] In a further aspect, there is provided the use of an antibody or antigen-binding fragment, or pharmaceutical formulation disclosed herein for use in the manufacture of a medicament for the treatment of atopic dermatitis according to the present disclosure.

[0087] In one embodiment, a reduction in Investigator Global Assessment (IGA) score of 0, 1 or 2 (no inflammatory signs, almost cleared, and mild disease, respectively) is provided during / after treatment according to the present disclosure. In particular, an IGA score of 0 or 1 is provided.

[0088] In one embodiment, a combination therapy comprising an antibody, antigen-binding fragment thereof, or formulation according to the present disclosure and an additional agent is used.

[0089] In one embodiment, the additional agent is for treating atopic dermatitis, for example topical steroids, oral steroids, and / or antihistamines.Surprisingly, the disease modification after treatment with anti-IL-13Rα1 antibody or its binding fragment according to the present disclosure closely follows the reduction of TARC, and in fact, the reduction of TARC and the reduction of EASI are closely correlated in the treatment according to the present disclosure.

[0090] As used herein, disease modification refers to an improvement in the disease state, in particular a reduction in the EASI score, which in one embodiment is maintained for at least a period of time after treatment has ceased.

[0091] As used herein, baseline refers to the level before treatment according to the present disclosure begins. Typically, the baseline is measured and / or recorded.

[0092] A loading dose, as used herein, refers to a dose that is higher than the "normal dose" in a treatment cycle. A loading dose is typically used to load a patient's body with drug so that when the next dose is administered, the levels of the required tissues are maintained at or above a minimum predetermined level.

[0093] As used herein, "about days" means administration on approximately days, e.g., + / - 1, 2, 3, 4, 5, 6, or 7 days. Early doses in a treatment cycle may need to be administered closer to the specified day, e.g., + / - 1 day. Late doses may be allowed a more liberal range, i.e., up to + / - 7 days.

[0094] Atopic dermatitis, as used herein, refers to inflammation of the skin and includes dry / itchy skin and red rash.

[0095] Moderate to severe atopic dermatitis is defined by one or more, such as all, of the parameters defined herein.

[0096] Severe atopic dermatitis includes very severe atopic dermatitis, which is a subset of atopic dermatitis.

[0097] As used herein, Investigator Global Assessment (IGA) refers to a tool for the assessment of atopic dermatitis. It uses a 0 to 5 point scale depending on the severity of the patient's symptoms. [Table 1]

[0098] Interleukin-13 receptor (IL-13R) as used herein is a type I cytokine receptor that binds to interleukin-13. It consists of two subunits, encoded by IL13Rα1 and IL4R, respectively. These two genes code for the proteins IL-13Rα1 and IL-4Rα, which form dimers with IL-13 binding to the IL-13Rα1 chain, and IL-4Rα stabilizes these interactions. Due to the presence of the IL-4R subunit, IL-13R can also initiate IL-4 signaling. In both instances, this occurs via activation of the Janus kinase (JAK) / signal transducer and activator of transcription (STAT) pathway, leading to phosphorylation of STAT6. Human IL-13Rα1 has the Uniprot number P3597.

[0099] IL-13Rα2, previously referred to as IL-13R and IL-13Rα, is another receptor capable of binding IL-13. However, in contrast to IL-13Rα1, this protein binds IL-13 with high affinity, whereas it does not bind IL-4. Human IL-13Rα2 has the Uniprot number Q14627.

[0100] In one embodiment, CDRH1 comprises the amino acid sequence GYSFTSYWIG (SEQ ID NO: 1). In one embodiment, CDRH2 comprises the amino acid sequence VIYPGDSYTR (SEQ ID NO: 2).

[0101] In one embodiment, CDRH3 has the formula: SEQ ID NO:3 X1ProAsnTrpGlyX6X7AspX9 (X1 represents Phe, Met, Gln, Leu or Val, X6 represents Ser or Ala; X7 represents Phe, Leu, Ala or Met; X9 represents Tyr, Gln, Lys, Arg, Trp, His, Ala, Thr, Ser, Asn or Gly).

[0102] In one embodiment, the IL13-R1α1 antibody or binding fragment used in the formulation of the present disclosure comprises a CDRH3 independently selected from a sequence comprising SEQ ID NOs: 4-30. [Table 2]

[0103] In one embodiment, an anti-IL-13R antibody or binding fragment used in the present disclosure comprises a VH CRD1 comprising the amino acid sequence represented by SEQ ID NO:1, a VH CRD2 comprising the amino acid sequence represented by SEQ ID NO:2, and a VH CRD3 comprising the amino acid sequence represented by SEQ ID NO:3.

[0104] In one embodiment, an anti-IL-13R antibody or binding fragment used in the present disclosure comprises a CRDH1 comprising the amino acid sequence represented by SEQ ID NO:1, a CRHD2 comprising the amino acid sequence represented by SEQ ID NO:2, and a CDRH3 comprising the amino acid sequence represented by SEQ ID NO:4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.

[0105] In one embodiment, an anti-IL-13R antibody or binding fragment used in the present disclosure comprises a CRDH1 comprising the amino acid sequence represented by SEQ ID NO:1, a CRHD2 comprising the amino acid sequence represented by SEQ ID NO:2, and a CDRH3 comprising the amino acid sequence represented by SEQ ID NO:10.

[0106] In one embodiment, CDRL1 is an amino acid sequence comprising RASQSISSSYLA SEQ ID NO:31.

[0107] In one embodiment, CDRL2 is an amino acid sequence comprising GASSRAT SEQ ID NO:32. SEQ ID NO:33 GlnX2X3X4X5 (X2 represents Gln, Arg, Met, Ser, Thr or Val; X3 represents Tyr or Val; X4 represents Glu, Ala, Gly or Ser; X5 represents Thr, Ala or Ser).

[0108] In one embodiment, the IL-13Rα1 antibody used in the formulation of the present disclosure comprises a CDRL3 independently selected from a sequence including SEQ ID NOs:34-47. [Table 3]

[0109] In one embodiment, an anti-IL-13Rα antibody or binding fragment used in the present disclosure comprises a CDRL1 comprising the amino acid sequence of SEQ ID NO:31, a CDRL2 comprising the amino acid sequence of SEQ ID NO:32, and a CDRL3 comprising the amino acid sequence represented by SEQ ID NO:33.

[0110] In one embodiment, an anti-IL-13Rα antibody of the disclosure comprises a VL CDR1 comprising the amino acid sequence SEQ ID NO:84, a VL CDR2 comprising the amino acid sequence SEQ ID NO:85, and a VL CDR3 comprising the amino acid sequence represented by SEQ ID NO:34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, or 47.

[0111] In one embodiment, an anti-IL-13Rα antibody of the disclosure comprises a CDRL1 comprising the amino acid sequence of SEQ ID NO:31, a CDRL2 comprising the amino acid sequence of SEQ ID NO:32, and a CDRL3 comprising the amino acid sequence represented by SEQ ID NO:45.

[0112] In one embodiment, an anti-IL-13R antibody of the disclosure comprises a CDRH1 comprising the amino acid sequence represented by SEQ ID NO:1, a CDRH2 comprising the amino acid sequence represented by SEQ ID NO:2, a CDRH3 comprising the amino acid sequence represented by SEQ ID NO:3, a CDRL1 comprising the amino acid sequence represented by SEQ ID NO:31, a CDRL2 comprising the amino acid sequence represented by SEQ ID NO:32, and a CDRL3 comprising the amino acid sequence represented by SEQ ID NO:33.

[0113] In one embodiment, an anti-IL-13R antibody of the disclosure comprises a CDRH1 comprising the amino acid sequence represented by SEQ ID NO:1, a CDRH2 comprising the amino acid sequence represented by SEQ ID NO:2, a CDRH3 comprising the amino acid sequence represented by SEQ ID NO:3 or 10, a CDRL1 comprising the amino acid sequence of SEQ ID NO:31, a CDRL2 comprising the amino acid sequence of SEQ ID NO:32, and a CDRL3 comprising the amino acid sequence represented by SEQ ID NO:34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, or 47.

[0114] In one embodiment, an anti-IL-13R antibody of the disclosure comprises a CDRH1 comprising the amino acid sequence represented by SEQ ID NO:1, a CDRH2 comprising the amino acid sequence represented by SEQ ID NO:2, a CDRH3 comprising the amino acid sequence represented by SEQ ID NO:3 or 10, a CDRL1 comprising the amino acid sequence of SEQ ID NO:31, a CDRL2 comprising the amino acid sequence of SEQ ID NO:32, and a CDRL3 comprising the amino acid sequence represented by SEQ ID NO:45.

[0115] In one embodiment, an anti-IL-13R antibody of the disclosure comprises a CDRH1 comprising the amino acid sequence represented by SEQ ID NO:1, a CDRH2 comprising the amino acid sequence represented by SEQ ID NO:2, a CDRH3 comprising the amino acid sequence represented by SEQ ID NO:10, a CDRL1 comprising the amino acid sequence represented by SEQ ID NO:31, a CDRL2 comprising the amino acid sequence represented by SEQ ID NO:32, and a CDRL3 comprising the amino acid sequence represented by SEQ ID NO:45.

[0116] In one embodiment, the VH region comprises: SEQ ID NO:48 EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARFPNWGSFDYWGQGTLVTVSS, SEQ ID NO:49 EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARMPNWGSFDYWGQGTLVTVSS, SEQ ID NO:50 EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCVRMPNWGSLDHWGQGTLVTVSS, SEQ ID NO:51 EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARMPNWGSLDHWGQGTLVTVSS, or a sequence at least 95% identical to any one of them The sequences are independently selected from sequences comprising:

[0117] In one embodiment, the V is SEQ ID NO:52 EIVLTQSPGTLSLSPGERATLSCRASQSISSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYETFGQGTKVEI * , SEQ ID NO:53 EIVLTQSPGTLSLSPGERATLSCRASQSISSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYASFGQGTKVEI * , SEQ ID NO:54 EIVLTQSPGTLSLSPGERATLSCRASQSISSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYEAFGQGTKVEI * , SEQ ID NO:55 (null sequence) or a sequence at least 95% identical to any one of them are independently selected from sequences containing * K) deleted by post-translational modification.

[0118] In one embodiment, the VH sequence is SEQ ID NO:48 (or a sequence at least 95% identical thereto) and the VL sequence is SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54 or SEQ ID NO:55 (or a sequence at least 95% identical to any one of them).

[0119] In one embodiment, the VH sequence is SEQ ID NO:49 (or a sequence at least 95% identical thereto) and the VL sequence is SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54 or SEQ ID NO:55 (or a sequence at least 95% identical to any one of them).

[0120] In one embodiment, the VH sequence is SEQ ID NO:50 (or a sequence at least 95% identical thereto) and the VL sequence is SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54 or SEQ ID NO:55 (or a sequence at least 95% identical to any one of them).

[0121] In one embodiment, the VH sequence is SEQ ID NO:51 (or a sequence at least 95% identical thereto) and the VL sequence is SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54 or SEQ ID NO:55 (or a sequence at least 95% identical to any one of them).

[0122] In one embodiment, the VL sequence is SEQ ID NO:52 (or a sequence at least 95% identical thereto) and the VH sequence is SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50 or SEQ ID NO:51 (or a sequence at least 95% identical thereto).

[0123] In one embodiment, the VL sequence is SEQ ID NO:53 (or a sequence at least 95% identical thereto) and the VH sequence is SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50 or SEQ ID NO:51 (or a sequence at least 95% identical to any one of them).

[0124] In one embodiment, the VL sequence is SEQ ID NO:54 (or a sequence at least 95% identical thereto) and the VH sequence is SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50 or SEQ ID NO:51 (or a sequence at least 95% identical to any one of them).

[0125] In one embodiment, the VL sequence is SEQ ID NO:55 (or a sequence at least 95% identical thereto) and the VH sequence is SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50 or SEQ ID NO:51 (or a sequence at least 95% identical thereto).

[0126] In one embodiment, the VH sequence is SEQ ID NO:51 (or a sequence at least 95% identical thereto) and the VL sequence is SEQ ID NO:53 (or a sequence at least 95% identical thereto).

[0127] As used herein, a variable region refers to the region in an antibody chain that contains the CDRs and an appropriate framework.

[0128] In one embodiment, the heavy chain comprises: SEQ ID NO:56 EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARMPNWGSFDYWGQG TLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGP PCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKT ISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG * , SEQ ID NO:57 EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCVRMPNWGSLDHWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG * 、 SEQ ID NO:58 EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCVRMPNWGSLDHWGQGTLVTVSSASIKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG * 、 SEQ ID NO:59 EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYCARMPNWGSLDHWGQGTLVTSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPAPEFLGPSVFLFPPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG * 、 SEQ ID NO:60 EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYCARMPNWGSLDHWGQGTLVTVSSAIKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCAPEFLGPSVFLFPPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG * 、 SEQ ID NO:61 EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARMPNWGSLDHWGQ GTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVTSSNFGTQTYTCNVDHKPSNTKVDKTVERKCC VECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKT ISKTKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG * , or a sequence at least 95% identical to any one of them (including sequences independently selected from * K) deleted by post-translational modification.

[0129] In one embodiment, the light chain comprises: SEQ ID NO:62 EIVLTQSPGTLSLSPGERATLSCRASQSISSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYASFGQGTKVEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC, SEQ ID NO:63 EIVLTQSPGTLSLSPGERATLSCRASQSISSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYEAFGQGTKVEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC, SEQ ID NO:64 EIVLTQSPGTLSLSPGERATLSCRASQSISSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYETFGQGTKVEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC, or a sequence at least 95% identical to any one of them are independently selected from

[0130] In one embodiment, the heavy chain is independently selected from SEQ ID NOs:56, 57, 58, 59, 60 and 61 (or a sequence at least 95% identical to any one of them), and the light chain is independently selected from SEQ ID NOs:62, 63 and 64 (or a sequence at least 95% identical to any one of them).

[0131] In one embodiment, the heavy chain is SEQ ID NO:56 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NO:62, 63 and 64 (or a sequence at least 95% identical to any one of them).

[0132] In one embodiment, the heavy chain is SEQ ID NO:57 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NO:62, 63 and 64 (or a sequence at least 95% identical to any one of them).

[0133] In one embodiment, the heavy chain is SEQ ID NO:58 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NO:62, 63 and 64 (or a sequence at least 95% identical to any one of them).

[0134] In one embodiment, the heavy chain is SEQ ID NO:59 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NO:62, 63 and 64 (or a sequence at least 95% identical to any one of them).

[0135] In one embodiment, the heavy chain is SEQ ID NO:60 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NO:62, 63 and 64 (or a sequence at least 95% identical to any one of them).

[0136] In one embodiment, the heavy chain is SEQ ID NO:61 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NO:62, 63 and 64 (or a sequence at least 95% identical to any one of them).

[0137] In one embodiment, the heavy chain has a sequence as set forth in SEQ ID NO:59 or 61 (or a sequence at least 95% identical to any one of them) and the light chain has a sequence as set forth in SEQ ID NO:62 (or a sequence at least 95% identical thereto).

[0138] In one embodiment, the heavy chain has a sequence as shown in SEQ ID NO:59 (or a sequence at least 95% identical thereto) and the light chain has a sequence as shown in SEQ ID NO:62 (or a sequence at least 95% identical thereto).

[0139] In one embodiment, the heavy chain has a sequence as shown in SEQ ID NO:61 (or a sequence at least 95% identical to any one of them) and the light chain has a sequence as shown in SEQ ID NO:62 (or a sequence at least 95% identical to it).

[0140] "Derived from" as used herein refers to the fact that the sequence used or a sequence very similar to the sequence used is obtained from original genetic material such as the light or heavy chain of an antibody.

[0141] As used herein, "at least 95% identical" refers to an amino acid sequence that is 95% or more identical to a reference sequence, such as 96, 97, 98 or 99% identical over its entire length. Software programs can be used to calculate the percentage of identity.

[0142] It will be understood that any discussion of a protein, antibody or amino acid sequence herein includes any variant of the protein, antibody or amino acid sequence produced during production and / or storage. For example, during production or storage, an antibody may be deaminated (e.g., at asparagine or glutamine residues) and / or have altered glycosylation, and / or have glutamine residues converted to pyroglutamate, and / or have N- or C-terminal residues removed or "clipped" (the C-terminal lysine residue of an encoded antibody is often removed during the production process), and / or have some or all of an incompletely processed signal sequence, resulting in retention of the antibody terminus. It will be understood that an antibody comprising a particular amino acid sequence or binding fragment thereof may be a heterogeneous mixture of the referenced or encoded sequence and / or a variant of the referenced or encoded sequence, or a binding fragment thereof.

[0143] In one embodiment, the present disclosure extends to sequences explicitly disclosed herein where the C-terminal lysine has been truncated.

[0144] In one embodiment, the antibodies or binding fragments thereof used in the formulations of the present disclosure are humanized.

[0145] As used herein, humanized (including CDR-grafted antibodies) refers to a molecule having one or more complementarity determining regions (CDRs) from a non-human species and a framework region from a human immunoglobulin molecule (see, e.g., U.S. Pat. No. 5,585,089; WO91 / 09967). It will be recognized that it may only be necessary to transfer the specificity determining residues of the CDRs rather than the entire CDR (see, e.g., Kashmiri et al., 2005, Methods, 36, 25-34). A humanized antibody may optionally further comprise one or more framework residues from the non-human species from which the CDRs were derived. For a review, see Vaughan et al, Nature Biotechnology, 16, 535-539, 1998.

[0146] When CDRs or specificity determining residues are grafted, any suitable acceptor variable region framework sequence that has a relationship to the class / type of the donor antibody from which the CDRs are derived may be used, including mouse, primate and human framework regions. Examples of human frameworks that may be used in the present invention are KOL, NEWM, REI, EU, TUR, TEI, LAY and POM (Kabat et al.,). For example, KOL and NEWM may be used for the heavy chain, REI may be used for the light chain, and EU, LAY and POM may be used for both the heavy and light chains. Alternatively, human germline sequences may be used, which are available at http: / / vbase.mrc-cpe.cam.ac.uk / .

[0147] In the humanized antibodies used in the present invention, the acceptor heavy and light chains do not necessarily have to be derived from the same antibody and may, if desired, include composite chains having framework regions derived from different chains.

[0148] The framework regions need not have exactly the same sequence as that of the acceptor antibody. For example, unusual residues may be changed to residues that occur more frequently in the acceptor chain class or type. Alternatively, selected residues in the acceptor framework regions may be changed so that they correspond to residues found at the same positions in the donor antibody (see Reichmann et al., 1998, Nature, 332, 323-324). Such changes should be kept to the minimum necessary to restore the affinity of the donor antibody. Protocols for selecting residues in the acceptor framework regions that may need to be changed are presented in WO91 / 09967.

[0149] In one embodiment, the anti-IL13R antibodies of the disclosure are fully human, in particular one or more of the variable domains are fully human.

[0150] A fully human molecule is one in which the variable and constant regions (if present) of both the heavy and light chains are all of human origin or are substantially identical to sequences of human origin, not necessarily sequences from the same antibody. Examples of fully human antibodies include antibodies produced, for example, by the phage display methods described above, and mice in which the murine immunoglobulin variable region genes, and optionally the constant region genes, have been replaced with human equivalents, generally as described in EP 0546073, U.S. Patent No. 5,545,806, U.S. Patent No. 5,569,825, U.S. Patent No. 5,625,126, U.S. Patent No. 5,633,425, U.S. Patent No. 5,661,016, U.S. Patent No. 5,770,429, EP 0438474, and EP 0463151.

[0151] A constant region, as used herein, is intended to refer to the constant region portion located between two variable domains, e.g., non-cognate variable domains, in a heavy chain. Thus, an anti-IL13R antibody disclosed herein may comprise one or more constant regions, such as a naturally occurring constant domain or a derivative of a naturally occurring domain. A derivative of a naturally occurring domain, as used herein, is intended to refer to one, two, three, four or five amino acids in the naturally occurring sequence being substituted or deleted to optimize the properties of the domain, e.g., by retaining the characteristic shape(s) of the domain while eliminating undesirable properties.

[0152] If desired, the antibody for use in the present invention may be conjugated to one or more effector molecules (multiple). It will be understood that the effector molecule may comprise a single effector molecule, or two or more such molecules linked to form a single molecule that can be attached to the antibody of the present invention. If it is desired to obtain an antibody fragment linked to an effector molecule, this may be prepared by standard chemical or recombinant DNA procedures in which the antibody fragment is linked to the effector molecule either directly or via a coupling agent. The techniques for conjugating such effector molecules to antibodies are well known in the art (see Hellstrom et al., Controlled Drug Delivery, 2nd Ed., Robinson et al., eds., 1987, pp. 623-53; Thorpe et al., 1982, Immunol. Rev., 62:119-58, and Dubowchik et al., 1999, Pharmacology and Therapeutics, 83, 67-123).Specific chemical procedures include, for example, those described in WO93 / 06231, WO92 / 22583, WO89 / 00195, WO89 / 01476 and WO03031581. Alternatively, where the effector molecule is a protein or polypeptide, linkage may be achieved using recombinant DNA procedures, for example as described in WO 86 / 01533 and EP 0 392 745.

[0153] The term effector molecule as used herein includes, for example, biologically active proteins, e.g. enzymes, other antibodies or antibody fragments, synthetic or naturally occurring polymers, nucleic acids and fragments thereof, e.g. DNA, RNA and fragments thereof, radionuclides, in particular radioactive iodine, radioisotopes, chelated metals, nanoparticles, and reporter groups such as fluorescent compounds or compounds that can be detected by NMR or ESR spectroscopy.

[0154] Other effector molecules may include detectable substances that are useful, for example, in diagnosis. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, radionuclides, positron-emitting metals (for use in positron emission tomography), and non-radioactive paramagnetic metal ions. See generally U.S. Patent No. 4,741,900 for metal ions that can be conjugated to antibodies for use as diagnostic agents. Suitable enzymes include horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase; suitable prosthetic groups include streptavidin, avidin, and biotin; suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride, and phycoerythrin; suitable luminescent materials include luminol; suitable bioluminescent materials include luciferase, luciferin, and aequorin; suitable radionuclides include 125I, 131I, 111In, and 99Tc.

[0155] In another example, the effector molecule may increase the half-life of the antibody in vivo, and / or reduce the immunogenicity of the antibody, and / or increase the delivery of the antibody through epithelial barriers to the immune system.Examples of suitable effector molecules of this type include polymers, albumin, albumin-binding proteins, or albumin-binding compounds, such as those described in WO05 / 117984.When the effector molecule is a polymer, it can generally be a synthetic or naturally derived polymer, such as an optionally substituted linear or branched polyalkylene, polyalkenylene, or polyoxyalkylene polymer, or a branched or unbranched polysaccharide, such as a homo- or heteropolysaccharide.

[0156] Particular optional substituents which may be present on the above-mentioned synthetic polymers include one or more hydroxy, methyl or methoxy groups.

[0157] Specific examples of synthetic polymers include optionally substituted linear or branched poly(ethylene glycol), poly(propylene glycol) poly(vinyl alcohol), or derivatives thereof, particularly optionally substituted poly(ethylene glycol), such as methoxypoly(ethylene glycol), or derivatives thereof.

[0158] Exemplary naturally occurring polymers include lactose, amylose, dextran, glycogen, or derivatives thereof.

[0159] As used herein, "derivatives" are intended to include reactive derivatives, e.g., thiol-selective reactive groups such as maleimides and the like. The reactive groups may be linked to the polymer directly or through a linker segment. It will be appreciated that the residue of such a group will in some instances form part of the product as the linking group between the antibody fragment and the polymer.

[0160] Suitable polymers include polyalkylene polymers such as poly(ethylene glycol) or especially methoxypoly(ethylene glycol) or derivatives thereof, especially having a molecular weight within the range of about 15,000 Da to about 40,000 Da.

[0161] In one example, the antibody for use in the present invention is attached to a poly(ethylene glycol) (PEG) moiety. In one particular example, the antibody is an antibody fragment, and the PEG molecule may be attached through any available amino acid side chain or terminal amino acid functional group located within the antibody fragment, such as any free amino, imino, thiol, hydroxyl, or carboxyl group. Such amino acids may be naturally occurring in the antibody fragment, or may be engineered into the fragment using recombinant DNA methods (see, for example, U.S. Pat. No. 5,219,996; U.S. Pat. No. 5,667,425; WO98 / 25971, WO2008 / 038024). In one example, the antibody molecule of the present invention is a modified Fab fragment, and the modification is the addition of one or more amino acids to the C-terminus of the heavy chain to allow the attachment of an effector molecule. Suitably, the added amino acids form a modified hinge region containing one or more cysteine ​​residues to which the effector molecule can be attached. Multiple sites may be used to attach two or more PEG molecules.

[0162] In one embodiment, the combinations herein are administered in combination with another treatment.

[0163] As used herein, "in combination" is intended to include instances where an anti-IL13R antibody is administered prior to, or concurrently with, another treatment.

[0164] As used herein, treatment refers to the improvement of disease symptoms or conditions, including stabilizing disease and / or moving disease into remission, and reducing the likelihood of recurrence or similar, particularly without inducing dose-limiting side effects.For example, when side effects and toxicity are tolerated, provided that treatment achieves benefit, appropriate therapeutic dose is generally a balance between therapeutic effect and tolerable toxicity.

[0165] In a separate aspect, there is provided an antibody or antigen-binding fragment thereof that binds to IL-13Rα1 and thereby is an inhibitor of signaling through said receptor, for use in the treatment of atopic dermatitis (moderate, severe or very severe atopic dermatitis, particularly moderate to severe atopic dermatitis that is difficult to control), by parenteral administration with a treatment cycle comprising a dose in the range of 200 mg to 600 mg (such as 400 to 600 mg), in which the incidence of conjunctivitis is minimized, e.g., as detailed herein.

[0166] Conjunctivitis can be a side effect of biological treatments for atopic dermatitis. Advantageously, such side effects are minimized with treatment according to the present disclosure, and in particular, such side effects were not observed with ebrasakimab treatment.

[0167] In one embodiment, a formulation according to the disclosure (such as a formulation including ebrasakimab) is administered monthly, for example in a treatment cycle or as a maintenance therapy.

[0168] In the context of this specification, "comprising" should be interpreted as "including". Embodiments of the invention comprising specific features / elements are also intended to extend to alternative embodiments "consisting of" or "consisting essentially of" the relevant element / feature. Where technically appropriate, embodiments of the invention may be combined.

[0169] Technical references, such as patents and patent applications, are incorporated herein by reference.

[0170] Any embodiment specifically and expressly recited herein may form the basis of a disclaimer either alone or in combination with one or more additional embodiments.

[0171] The background portion of this specification contains relevant technical information and may be used as a reference for revision.

[0172] The headings of the subject index herein are used to divide the document into sections and are not intended to be used to interpret the meaning of the disclosure provided herein.

[0173] The invention is further described, by way of example only, in the following examples. [Brief description of the drawings]

[0174] [Figure 1A] Patient demographics for the full analysis set are shown. [Figure 1B] Baseline disease characteristics of the full analysis population are shown. [Figure 1C] Baseline characteristics of efficacy evaluable data are presented. [Figure 2A] The % change from baseline in EASI score at day 57 is shown. [Figure 2B] The % change from baseline in EASI score at day 57 is shown. [Figure 2C] The % change from baseline in EASI score at day 57 is shown. [Figure 3A] The % change from baseline in EASI score at day 29 is shown. [Figure 3B] The % change from baseline in EASI score at day 29 is shown. [Figure 4A] The % change from baseline in EASI scores over time is shown. [Figure 4B] The % change from baseline in EASI scores over time is shown. [Figure 5A] The % change from baseline in EASI scores over time for individual patients is shown. [Figure 5B] The percentage change from baseline in EASI scores over time for individual patients is shown. [Figure 5C] The percentage change from baseline in EASI scores over time for individual patients is shown. [Figure 5D]The percentage change from baseline in EASI scores over time for individual patients is shown. [Figure 6A] Sensitivity analysis at day 57 in mITT is shown. [Figure 6B] Sensitivity analyses in mITT are shown (200, 400 and 600 mg). [Figure 6C] Analysis in mITT is shown (low and high dose). [Figure 7A] EASI50, EASI75 and EASI90 on day 57 are shown. [Figure 7B] EASI50 on day 57 is shown (200, 400 and 600 mg). [Figure 7C] EASI50 on day 57 is shown (low and high dose). [Figure 7D] EASI75 on day 57 is shown (200, 400 and 600 mg). [Figure 7E] EASI75 on day 57 is shown (low and high dose). [Figure 7F] EASI90 on day 57 is shown (200, 400 and 600 mg). [Figure 7G] EASI90 at day 57 is shown (low and high dose). [Figure 8A] The percentage reduction in EASI50 over time is shown. [Figure 8B] The percentage reduction in EASI75 over time is shown. [Figure 8C] The percentage reduction in EASI90 over time is shown. [Figure 9] Sensitivity analysis for Mitt is shown. [Figure 10A] The percentage of patients with an IGA score of 0 or 1 at day 57 in the summary table is shown. [Figure 10B] The percentage of patients with an IGA score of 0 or 1 at day 57 is shown. [Figure 10C] The percentage of patients with an IGA score of 0 or 1 is shown. [Figure 11] Patient baseline TARC and IgE are shown. [Figure 12A]Mean % change from baseline TARC is shown (200 mg and 400 mg). [Figure 12B] Mean % change from baseline TARC is shown (400 mg and placebo). [Figure 12C] The % change from baseline TARC for individual patients is shown. [Figure 13A] Percentage change in IgE from baseline is shown (200mg and 400mg). [Figure 13B] Mean IgE % change from baseline is shown (200mg and 400mg). [Figure 13C] The % IgE change from baseline for three individual patients is shown. [Figure 13D] The % IgE change from baseline for 200 mg for 4 individual patients is shown. [Figure 13E] The % IgE change from baseline for 6 individual patients for 400 mg is shown. [Figure 14] Ebrasakimab exposure, mean EASI score, mean TARC level and mean IgE level are shown. [Figure 15] Shows efficacy of ebrasakimab vs dupilumab. [Figure 16] Median percent change from baseline in IgE dupilumab is shown. [Figure 17] The percent change from baseline for dupilumab 300 mg administered weekly is shown. [Figure 18] Shown is the staining intensity of IL-13Rα1 expression in healthy skin, non-lesional atopic dermatitis and lesional atopic dermatitis. [Figure 19] Shown is staining for IL-13Rα1 expression in mast cells and eosinophils for ealthy skin, non-lesional atopic dermatitis and lesional atopic dermatitis. [Figure 20] Gene expression for type I and type II IL-13 receptors is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0175] Working Example Example 1 Testing Protocol (Initial MAD Escalation) Patients enrolled in dose escalation cohorts of ebrasakimab (SEQ ID NOs: 51, 53, and 59 herein): 200 mg, 400 mg, 600 mg. ASLAN low dose = ebrasakimab 200 mg, ASLAN high dose = ebrasakimab 400 mg + ebrasakimab 600 mg.

[0176] Patient details are shown in Figure 1. Initial doses were given once weekly (QW). Within each cohort, patients were randomized to ebrasakimab:placebo in a 3:1 ratio.

[0177] result Table 1 shows the % change from baseline in EASI scores at day 57 (8 weeks). [Table 4]

[0178] Table 2 shows the % change from baseline in EASI scores at day 29 (4 weeks). [Table 5]

[0179] Table 3 shows the sensitivity analysis in the mITT (modified intention to treat) population at day 57. [Table 6]

[0180] Table 4 provides an overview of the proportion of patients achieving EASI50, EASI75 and EASI90 at day 57. [Table 7]

[0181] Results show that ebrasakimab produced significant improvements in EASI scores compared to placebo, particularly at week 8, with a mean reduction in EASI from baseline at therapeutic doses (400 mg and 600 mg cohorts) of 74% (n=9) compared to 42% (n=5) in placebo patients. o 89% achieved EASI-50 versus 40% with placebo; o 67% achieved EASI-75 versus 0% with placebo; o 56% achieved EASI-90 vs. 0% on placebo

[0182] The results further suggest that ebrasakimab has similar, and in some cases greater, efficacy compared to dupilumab, thus demonstrating the potential of ebrasakimab as an alternative therapy for the treatment and management of atopic dermatitis.

[0183] Example 2 Among the 32 patients who completed at least 29 days of treatment at all sites defined by the protocol as an efficacy-evaluable dataset, the mean reduction from baseline in EASI at week 8 was 73% (n=19) compared with 44% (n=13) of placebo patients (p=0.007 1 The proportion of patients with adverse events and treatment-related adverse events was similar in the treatment and placebo groups. There was no incidence of conjunctivitis in the expansion cohort. [Table 8]

[0184] Ebrasakimab delivered a statistically significant improvement (p<0.025) versus placebo in the primary efficacy endpoint of percent change from baseline in Eczema Area and Severity Index (EASI), as well as significant improvements (p<0.05) in other key efficacy endpoints: EASI-50, EASI-75, Peak Purity and Patient-Oriented Eczema Assessment Score (POEM).

[0185] Following a meeting with the Data Monitoring Committee prior to unblinding, a revised intention-to-treat (RITT, n=29) population was defined to exclude one study site where all patients enrolled in the study were deemed atypical for moderate-to-severe AD patients based on biomarkers such as TARC and patient medical history. In the RITT population, which is more comparable to other published studies in moderate-to-severe AD, ebrasakimab also achieved a statistically significant improvement versus placebo in % change from baseline in EASI (p<0.025) and demonstrated greater improvement versus placebo in key efficacy endpoints versus the ITT population.

[0186] Example 3 Patients with atopic dermatitis were enrolled in a multicenter, randomized, double-blind, placebo-controlled, multiple-ascending dose study of the safety, tolerability, and pharmacokinetics of subcutaneously delivered ebrasakimab. Patients with "symptoms" such as itchy skin may present in the clinic, but the underlying cause of this may be a multitude of pathologies. The range of TARC levels presented in clinical trials for patients with moderate to severe atopic dermatitis was 214 pg / ml to approximately 22,600 pg / ml. Baseline IgE levels in patients determined to have relevant criteria for moderate to severe atopic dermatitis ranged from 434 pg / ml to 19,175 pg / ml.

[0187] Example 4 IHC was performed on lesional (L) and non-lesional (NL) skin of 14 AD patients and 10 matched controls (HC). To determine the distribution of IL-13Rα1 in AD and its association with mast cells and eosinophils, skin samples were stained for IL-13Rα1, tryptase, and major basic protein. U937 cells, a monocytic cell line, express both type I and type II receptors and were therefore used to assess the function of both receptors. Cells were incubated with ebrasakimab (anti-IL-13R?1) to block type II, with anti-common gamma chain to block type I, and with anti-IL4R? to block both type I and type II receptors. After 24 h incubation, cells were stimulated with vehicle or a mixture of IL-4 + IL-13 and subjected to RNA sequencing. IHC data were quantified using ImageJ. Differential expression analysis was performed on the RNA sequencing data using the DESeq2 package for R. IHC showed increased IL-13Rα1 staining in L (P<0.001) and NL (P=0.045) AD skin compared to HC. The mean IL-13Rα1 staining intensity of mast cells was increased in L (P=0.034) and NL (P=0.031) AD samples compared to HC. The mean IL-13Rα1 staining intensity of eosinophils was also increased in L (P=0.024) and NL (P=0.046) AD skin compared to HC. Type I receptor blockade with anti-common gamma chain antibody resulted in upregulation of genes such as MMP9 (P<0.001). Type II receptor blockade with ebrasakimab resulted in suppression of genes such as XBP1 (P<0.001) and CXCL8 (P=0.046). Figure 20 shows differentially expressed genes upon type I receptor blockade with anti-chain antibody. B) Differentially expressed genes upon type II receptor blockade with ebrasakimab.

[0188] overview IL-13Rα1 expression is increased in both L and NL AD skin compared to HC. Mast cell IL-13Rα1 expression is increased in L and NL AD skin compared to HC. Eosinophil IL-13Rα1 expression is increased in L and NL AD skin compared to HC. Signaling differences exist between type I and type II receptors.

Claims

1. An antibody or antigen-binding fragment thereof that binds to IL-13Rα1 and thereby acts as an inhibitor of signal transduction through said receptor, for use in the treatment of moderate to severe atopic dermatitis that is difficult to control with existing approved drugs, including topical medications, oral medications, and / or biological agents (particularly topical medications or dupilumab), by parenteral administration in a treatment cycle comprising a dose in the range of 200 mg to 600 mg (such as 400 to 600 mg), wherein the antibody or antigen-binding fragment thereof inhibits signal transduction through said receptor, and the antibody or antigen-binding fragment thereof is characterized by an EASI score of 16 or greater (17, 18, 19, 20, 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, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, etc.); An antibody or antigen-binding fragment thereof, comprising a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 51 or a sequence at least 95% identical thereto, and a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 53 or a sequence at least 95% identical thereto.

2. The antibody or antigen-binding fragment thereof for use according to claim 1, wherein the atopic dermatitis is lesional.

3. 2. The antibody or antigen-binding fragment thereof for use according to claim 1, wherein the antibody or fragment is administered to a patient who has previously received dupilumab, e.g., a patient who had an adverse reaction to dupilumab.

4. The antibody or antigen-binding fragment thereof for use according to claim 1, wherein the IL-13Rα1 has reduced side effects and / or improved efficacy compared to dupilumab.

5. The antibody or antigen-binding fragment thereof for use according to claim 1, wherein the baseline TARC level is at least 1,115 pg / ml, for example, in the range of 1,115 pg / ml to 4,300 pg / ml or greater than 4,300 pg / ml.

6. The antibody or antigen-binding fragment thereof for use according to claim 1, wherein the baseline STAT6 is above normal.

7. 2. The antibody or antigen-binding fragment thereof for use according to claim 1, wherein the patient has a baseline IGA score of 3 or higher, representing moderate to very severe atopic dermatitis, such as 3 (moderate atopic dermatitis), 4 (severe atopic dermatitis) or 5 (very severe atopic dermatitis).

8. 2. The antibody or antigen-binding fragment thereof for use according to claim 1, wherein the baseline IgE level is at least 150 KU / L, for example at a level of 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 950 KU / L, such as 10,000 kU / L + / - 2,000.

9. The antibody or antigen-binding fragment thereof for use according to claim 1, wherein the one or more parameters (e.g., two or more or all of the parameters) are measured prior to administration.

10. The antibody or antigen-binding fragment for use according to claim 1, wherein the patient has been identified as having one or more (e.g., all) of the parameters prior to initiating treatment (e.g., as identified in the desired patient population).

11. The antibody or antigen-binding fragment thereof for use according to claim 1, wherein the atopic dermatitis is moderate, for example with a score within the range of 16 to 21.

0.

12. 2. The antibody or antigen-binding fragment thereof for use according to claim 1, wherein the atopic dermatitis is severe, e.g., with an EASI score of 21.1 or greater, e.g., within the range of 21.1 to 50.0, or very severe, e.g., with a score within the range of 50.1 to 72.

0.

13. 2. The antibody or antigen-binding fragment thereof for use according to claim 1, wherein the reduction in EASI score is present about 2 weeks (such as on day 15) after administration of the first dose.

14. 2. The antibody or antigen-binding fragment thereof for use according to claim 1, wherein the reduction in EASI score is present at about 4 weeks (such as day 29) after administration of the first dose.

15. 2. The antibody or antigen-binding fragment thereof for use according to claim 1, wherein the reduction in EASI score is present at about 6 weeks (such as day 43) after administration of the first dose.

16. 2. The antibody or antigen-binding fragment thereof for use according to claim 1, wherein the reduction in EASI score is present at about 8 weeks (such as day 57) after administration of the first dose.

17. The antibody or antigen-binding fragment thereof for use according to claim 1 , wherein the treatment is administered subcutaneously.

18. The antibody or antigen-binding fragment thereof for use according to claim 1, wherein the dose is 200 mg.

19. 2. The antibody or antigen-binding fragment thereof for use according to claim 1, wherein the dose is in the range of 350-450 mg, e.g., 400 mg, and 80% of the patient population has an EASI50 at about day 29 and / or day 57.

20. The antibody or binding fragment thereof of claim 1, wherein the dose is 600 mg.

21. 2. The antibody or antigen-binding fragment thereof for use according to claim 1, wherein the reduction in EASI score is within the range of -25 to -60% (e.g., -39 to -59%, such as -40 to -59%, particularly -47, -48, -49, -50, -51, -52, -53, -54, -55, -56, -57, -58 or -59%), for example at about day 15.

22. said reduction in EASI score being a. 50 to -100% (e.g., -55 to -97%), particularly at about day 29, and / or b. -60 to -100% (e.g., -70 to -97%), particularly at about day 43, and / or c. −65 to −100% (e.g., −70 to −100%, such as −90 to −100%, especially 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100%), especially at about day 57 22. The antibody or antigen-binding fragment thereof for use according to any one of claims 13 to 16 and 21, wherein the antibody or antigen-binding fragment thereof is within the range of:

23. The antibody or antigen-binding fragment thereof for use according to claim 1, wherein 90% of the patient population has an EASI50 at about day 57.

24. 2. The antibody or antigen-binding fragment thereof for use according to claim 1, wherein the treatment cycle comprises an initial dose of 600 mg, followed by 400 mg every three weeks, e.g., the treatment cycle is repeated twice, i.e., two treatment cycles lasting 8 weeks, in particular, on day 1: 600 mg, on approximately day 8: 400 mg, on approximately day 15: 400 mg, on approximately day 22: 400 mg, on approximately day 29: 600 mg, on approximately day 36: 400 mg, on approximately day 43: 400 mg, and on approximately day 50: 400 mg.

25. The antibody or antigen-binding fragment thereof for use according to claim 1, wherein disease modification occurs by day 4, where day 1 is the first administration of the antibody or antigen-binding fragment thereof, e.g., the disease modification is a reduction in EASI score, the reduction being a percentage from baseline in the range of -10 to 55% (particularly, the disease modification in the range of -40 to -100% is achieved by about day 57 after the first administration on day 1, e.g., maximum disease modification is achieved by about day 57), etc.

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