JP2024534717A - Methods for the treatment of moderate to severe atopic dermatitis - Google Patents

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, e.g., to stimulate disease modification.
[Selection diagram] None

Description

Application for application of Article 30, Paragraph 2 of the Patent Act 1. https://ir. aslanpharma. com/news-releases/news-release-details/aslan-pharmaceuticals-announcements-positive-data-conclusively (September 27, 2021) 2. https://ir. aslanpharma. com/news-releases/news-release-details/aslan-pharmaceuticals-announces-kol-event-series-discuss-atopic (October 18, 2021) 3. https://ir. aslanpharma. com/news-releases/news-release-details/aslan-pharmaceuticals-announcements-scientific-collaboration-dr-emma (October 22, 2021) 4. https://clinicaltrials. gov/study/NCT05158023 (December 15, 2021) 5. https://ir. aslanpharma. com/news-releases/news-release-details/aslan-pharmaceuticals-present-additional-data-aslan004-proof (January 11, 2020) 6. "Interim analysis results from a proof-of-concept study for ASLAN004 in adult moderate-to-severe atopic dermatitis: a double e-blind, randomized, placebo-controlled study” (2022 Winter Clinical dermatology conference) (January 15, 2020) day)

Application for application of Article 30, Paragraph 2 of the Patent Act 7. https://ir. aslanpharma. com/news-releases/news-release-details/aslan-pharmaceuticals-initiates-phase-2b-study-aslan004 (January 21, 2020) 8. https://ir. aslanpharma. com/news-releases/news-release-details/aslan-pharmaceuticals-announcements-late-breaker-presentation-data (March 28, 2020) 9. “Eblasakimab, a human IL-13Rα1 monoclonal antibody, in adult patients with moderate-to-severe atopic dermatitis: a randomi zed, double-blinded, placebo-controlled, proof of concept study” (2022 American Academy of Dermatology Annual Meeting) (March 28, 2015) 10. https://ir. aslanpharma. com/news-releases/news-release-details/aslan-pharmaceuticals-announcements-acceptance-late-breaking-0 (May 10, 2020) 11. https://ir. aslanpharma. com/news-releases/news-release-details/aslan-pharmaceuticals-initiates-scientific-collaboration (June 7, 2020)

Application for application of Article 30, Paragraph 2 of the Patent Act 12. “New insights into neuronal itch mechanisms by targeting IL-13Rα1 with eblasakimab” (August 1, 2020) 13. https://ir. aslanpharma. com/news-releases/news-release-details/aslan-pharmaceuticals-presents-new-data-eblasakimab-multiple (September 7, 2020) 14. “Eblasakimab, a monoclonal antibody targeting IL-13R alpha-1, reduces serum biomarkers that are associated with atopy and c related with disease severity, in patients with moderate-to-severe atopic dermatitis” (31st European academy of dermatology and venereology (EADV) congress 2022) (September 7, 2020) 15. “Eblasakimab improves itch and sleep loss in adult patients with moderate-to-severe atopic dermatitis in a randomized, “Uble-blinded, placebo-controlled, Phase 1 study” (EADV congress 2022) (September 7, 2020) 16 ．． “Eblaskaimab improves multiple disease measurements in adult patients with moderate-to-severe atopic dermatitis in a randomization ed, double-blinded, placebo-controlled, Phase 1 study” (EADV congress 2022) (September 7, 2020)

Application for application of Article 30, Paragraph 2 of the Patent Act 17. “Eblasakimab, a monoclonal antibody targeting IL-13R alpha-1, reduces serum biomarkers that are associated with atopy and c related with disease severity, in patients with moderate-to-severe atopic dermatitis” (EADV congress 2022) (September 2020) 7th of the month) 18. “Eblasakimab improves itch and sleep loss in adult patients with moderate-to-severe atopic dermatitis in a randomized, “Uble-blinded, placebo-controlled, Phase 1 study” (EADV congress 2022) (September 7, 2020) 19 ．． “Eblaskaimab improves multiple disease measurements in adult patients with moderate-to-severe atopic dermatitis in a randomization ed, double-blinded, placebo-controlled, Phase 1 study” (EADV congress 2022) (September 7, 2020)

Application for application of Article 30, Paragraph 2 of the Patent Act 20. "New insights into neuronal itch mechanisms by targeting IL-13Rα1 with eblasakimab" (Cell Symposia - The Neuro-immune axis c onference 2022) (September 11, 2020) 21. https://ir. aslanpharma. com/news-releases/news-release-details/aslan-pharmaceuticals-announcements-acceptance-two-late-breaking (September 13, 2020) 22. https://ir. aslanpharma. com/news-releases/news-release-details/aslan-pharmaceuticals-commences-clinical-program-study (September 14, 2020) 23. "ASLAN 2022 R&D Day" (September 15, 2020)

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 (e.g., lesional atopic dermatitis), including patient populations that have been previously treated with dupilumab, for example, to stimulate disease modification.

1. Background One possible way to inhibit the activity of IL-13 is to block 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 block the binding of IL-13 and prevent the heterodimerization of IL-4Rα and IL-13Rα1. Such an antibody can block both IL-13 and IL-4 signaling through the type II receptor without utilizing IL-4 signaling through the type I receptor. Signaling through the type I receptor is essential during the induction phase of the immune response, where Th2 cells differentiate. Since T cells do not express IL-13Rα1, the type II receptor plays 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.

Antibodies against IL-13Rα1, both monoclonal and polyclonal, have been described in the art, e.g., WO 97/15663, WO 03/80675; WO 03/46009; WO 06/072564; 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.

One particularly promising anti-IL-13Rα1 antibody is described in WO 2008/060813 as antibody 10G5-6. 10G5-6, as an IgG4 with a hinge stabilizing serine to proline mutation (S241P Kabat numbering), is known as ebrasakimab.

Ebrasakimab has been shown to bind with high affinity to human IL-13Rα1 (e.g., Kd can be 500 pM). Ebrasakimab has been shown to effectively antagonize IL-13 function through inhibition of IL-13 binding to the receptor IL-13Rα1, as well as 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.

Atopic dermatitis can be a very painful, demoralizing, and psychologically damaging disease. One way to assess the disease is the EASI score, which ranges from 0 to 72. In some instances, 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.

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. This leaves some patients with moderate to severe atopic dermatitis without adequate treatment.

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

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.

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.

The present invention provides a new patient population, e.g., patients pretreated with dupilumab and/or patients with lesional 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. Normal levels of TARC in healthy individuals are usually up to 450 pg/ml.

Interestingly, the inventors have also determined that since 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 standalone aspect or as an embodiment for moderate/severe atopic dermatitis).

Lesional and non-lesional atopic dermatitis are distinct subpopulations of patients. Non-lesional AD has immune abnormalities including proliferation of T cells. It has a variable immune phenotype that is determined in large part by the extent and severity of the disease. Decreased hydration and impaired lipid synthesis are found in non-lesional atopic skin compared to normal skin. There is also abnormal epithelial proliferation in non-lesional atopic dermatitis, with increased expression of proliferation markers (keratin 16) 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-lesional atopic dermatitis skin compared to skin of healthy volunteers. In one embodiment, non-lesional atopic dermatitis is characterized by the absence of lesions.

Lesioned skin from patients with chronic AD 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 DISCLOSURE 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, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 11 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.

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, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, etc.) EASI score.

1B. An antibody or antigen-binding fragment thereof that binds to IL-13Rα1 and thereby inhibits signal transduction through said receptor for use in the manufacture of a medicament for the treatment of moderate, severe or very severe atopic dermatitis (particularly difficult-to-control moderate to severe atopic dermatitis) by parenteral administration in a treatment cycle comprising a dose in the range of 200 mg to 600 mg (e.g., 400 to 600 mg), wherein the baseline disease severity is 16 or greater (1 7, 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.) of an antibody or antigen-binding fragment thereof.

1C. An antibody or antigen-binding fragment thereof that binds to IL-13Rα1 and thereby inhibits 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 (e.g., 400 to 600 mg).

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

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

4. Baseline TARC level is 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 0, 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, 27,00 0,28,000,29,000,30,000,31,000,32,000,33,000,34,000,35,000,36,000,37,000,38,000,39,000,40,000,41,000,42,000,43,000,44,000, 45,000, 46,000, 47,000, 48 ,000, 49,000, 50,000, 51,000 or 52,000 pg/ml), in particular at least 1,115 pg/ml, for example within the range of 1,115 pg/ml to 4,300 pg/ml or greater than 4,300 pg/ml.

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

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).

7. Baseline IgE levels (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, at a level such as 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, particularly 10,000 kU/L+/-2,000.

8. An 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 prior to initiation of dosing, and in particular wherein patients are identified as a relevant/suitable population prior to treatment.

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 observations and/or EASI scores.

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 in the range of 16 to 21.0.

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.

12. An 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 (e.g., within the range of 130-6,800 IU/L, more particularly 130-479 IU/L).

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.

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 +/- 490 pg/ml.

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 (e.g., within the range of 480-15,100 IU/L).

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 in the range of 50.1 to 72.0.

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

18. An 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% (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.

19. An 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.

20. An 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).

21. An 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 (e.g., day 29) after administration of the first dose.

22. An antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein the reduction in EASI score is present at about 6 weeks (e.g., day 43) after administration of the first dose.

23. An 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.

24. An 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).

25. An antibody or antigen-binding fragment thereof, method, or use according to any preceding paragraph, wherein the reduction in EASI score is present at about 8 weeks (e.g., day 57) after administration of the first dose.

26. An 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.

27. An antibody or binding fragment thereof, method, or use according to any preceding paragraph, wherein 80% of the patient population has an EASI 50 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.

28. An antibody or binding fragment thereof, method, or use according to any preceding paragraph, wherein 90% of the patient population has an EASI 50 score or less at about day 57, particularly where a dosage of at least 550 mg (such as 600 mg) is utilized.

29. An 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.

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, e.g., by about day 15.

31. An 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, e.g., by about day 36.

32. An 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.

33. An 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, e.g., by about day 57.

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

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

36. An 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., a treatment cycle is 4-8 weeks, such as 8 weeks).

37. The antibody or binding fragment thereof, method or use according to paragraph 36, wherein multiple treatment cycles are administered, e.g., 2, 3, 4 or more treatment cycles are administered.

38. 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, etc.). The antibody or binding fragment thereof, method or use according to paragraph 36 or 37.

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

40. The antibody or antigen-binding fragment thereof, method or use according to any one of paragraphs 1, 1A, 1B, 1C to 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).

41. The antibody or antigen-binding fragment thereof, method or use according to any one of paragraphs 1, 1A, 1B, 1C to 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).

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 four weeks (e.g. monthly) (particularly in a single treatment cycle, particularly an eight week cycle).

43. An 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 prior to administration of further doses in a treatment cycle.

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

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

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

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

48. A treatment cycle comprising 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.

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.

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.

51. An 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 first administration on day 1, e.g., maximum disease modification is achieved by about day 57.

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

53. An 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 an amino acid sequence represented by SEQ ID NO:1, a VH CDR2 comprising an amino acid sequence represented by SEQ ID NO:2, and a VH CDR3 comprising an amino acid sequence represented by SEQ ID NO:10.

54. An 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.

55. An 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 an amino acid sequence represented by SEQ ID NO:31, a VL CDR2 comprising an amino acid sequence represented by SEQ ID NO:32, and a VL CDR3 comprising an amino acid sequence represented by SEQ ID NO:45.

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.

57. The antibody is
10-140 mg/ml of antibody or binding fragment;
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);
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%, such as 0.02% w/v, of a non-ionic surfactant;
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.

58. The antibody or antigen-binding fragment thereof, method, or use according to paragraph 57, wherein the osmolality of the formulation is within the range of 350-550 mOsmo/kg, e.g., 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 405-435 mOsmo/kg.

59. The antibody or antigen-binding fragment thereof, method, or use according to paragraph 57 or 58, further comprising 50-200 mM sugar, e.g. 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.

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

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.

62. An 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.

63. Use of an antibody or antigen-binding fragment that 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 ocular treatment.

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

Also provided by the present disclosure is a method 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.

Difficult to control, as used herein, refers to difficulty in control with existing approved drugs, e.g., topical drugs, oral drugs, and/or biologics such as dupilumab (particularly topical drugs or dupilumab).

The results further suggest that ebrasakimab has similar, and in some cases 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.

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., patients who have been previously treated with dupilumab, particularly patients who have failed dupilumab.

In a further aspect, there is provided a 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.

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

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

In one embodiment, the additional agent is for the treatment of atopic dermatitis, e.g., a topical steroid, an oral steroid, and/or an antihistamine. Surprisingly, disease modification following treatment with an anti-IL-13Rα1 antibody or binding fragment thereof according to the present disclosure closely follows the reduction in TARC, and indeed TARC reduction and EASI reduction are closely correlated upon treatment according to the present disclosure.

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

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

As used herein, a loading dose 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, levels in required tissues are maintained at or above a minimum predetermined level.

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.

As used herein, atopic dermatitis refers to inflammation of the skin and includes dry/itchy skin and a red rash.

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

Severe atopic dermatitis encompasses very severe atopic dermatitis. Very severe atopic dermatitis is a subset of atopic dermatitis.

Investigator Global Assessment (IGA) as used herein refers to a tool for the assessment of atopic dermatitis. It uses a 0-5 point scale depending on the severity of the patient's symptoms.

As used herein, the interleukin-13 receptor (IL-13R) is a type I cytokine receptor that binds 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.

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

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).

In one embodiment, CDRH3 has the formula:
SEQ ID NO: 3 X ₁ ProAsnTrpGlyX ₆ X ₇ AspX ₉
( _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.

In one embodiment, the IL13-R1α1 antibodies or binding fragments used in the formulations of the present disclosure comprise a CDRH3 independently selected from a sequence comprising SEQ ID NOs: 4-30.

In one embodiment, the 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.

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

In one embodiment, the 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.

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

In one embodiment, CDRL2 is an amino acid sequence comprising GASSRAT SEQ ID NO: 32. In one embodiment, CDL3 is a sequence of the formula:
SEQ ID NO:33 GlnX ₂ X ₃ X ₄ X ₅
( _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).

In one embodiment, the IL-13Rα1 antibodies used in the formulations of the present disclosure comprise a CDRL3 independently selected from the sequences comprising SEQ ID NOs: 34-47.

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

In one embodiment, the anti-IL-13Rα antibody of the present 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.

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

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

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

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

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

In one embodiment, the VH region is
SEQ ID NO:48
EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARFPNWGSFDYWGQGTLVTVSS,
SEQ ID NO:49
EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARMPNWGSFDYWGQGTLVTVSS,
SEQ ID NO:50
EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCVRMPNWGSLDHWGQGTLVTVSS,
SEQ ID NO:51
EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARMPNWGSLDHWGQGTLVTVSS,
or a sequence that is at least 95% identical to any one of them.

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 that is at least 95% identical to any one of them ( ^* K deleted in post-translational modification).

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 thereto).

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 thereto).

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 thereto).

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 thereto).

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).

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 thereto).

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 thereto).

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).

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).

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

In one embodiment, the heavy chain comprises:
SEQ ID NO:56
EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARMPNWGSFDYWGQGTLVTVSSAST KGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGP PCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE ^＊ 、
SEQ ID NO:57
EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCVRMPNWGSLDHWGQGTLVTVSSAST KGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGP PCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE ^＊ 、
SEQ ID NO:58
EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCVRMPNWGSLDHWGQGTLVTVSSASI KGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGP PCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE ^＊ 、
SEQ ID NO:59
EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARMPNWGSLDHWGQGTLVTVSSAST KGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGP PCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE ^＊ 、
SEQ ID NO:60
EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARMPNWGSLDHWGQGTLVTVSSASI KGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGP PCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE ^＊ 、
SEQ ID NO:61
EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARMPNWGSLDHWGQGTLVTVSSAST KGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVTSSNFGTQTYTCNVDHKPSNTKVDKTVERKCC ^{VECPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPRE} PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
or a sequence independently selected from a sequence at least 95% identical to any one of them ( ^* K deleted in post-translational modification).

In one embodiment, the light chain comprises:
SEQ ID NO:62
EIVLTQSPGTLSLSPGERATLSCRASQSISSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYASFGQGTKVEIKRTVAAPSVFIFPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC,
SEQ ID NO:63
EIVLTQSPGTLSLSPGERATLSCRASQSISSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYEAFGQGTKVEIKRTVAAPSVFIFPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC,
SEQ ID NO:64
EIVLTQSPGTLSLSPGERATLSCRASQSISSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYETFGQGTKVEIKRTVAAPSVFIFPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC,
or a sequence at least 95% identical to any one of them.

In one embodiment, the heavy chains are 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 chains are independently selected from SEQ ID NOs: 62, 63 and 64 (or a sequence at least 95% identical to any one of them).

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 thereto).

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 thereto).

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 thereto).

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 thereto).

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 thereto).

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 thereto).

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).

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

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

As used herein, "derived from" 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.

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.

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 manufacture and/or storage. For example, during manufacture or storage, an antibody may be deaminated (e.g., at an asparagine or glutamine residue) 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 manufacturing process) and/or have some or all of a signal sequence incompletely processed, resulting in retention of the antibody termini. 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.

In one embodiment, the disclosure extends to sequences expressly disclosed herein in which the C-terminal lysine is truncated.

In one embodiment, the antibody or binding fragment thereof used in the formulation of the present disclosure is humanized.

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 framework regions from a human immunoglobulin molecule (see, e.g., U.S. Pat. No. 5,585,089; WO 91/09967). 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.

When CDRs or specificity determining residues are grafted, any suitable acceptor variable region framework sequence may be used that has relevance to the class/type of the donor antibody from which the CDRs were derived, 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/.

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.

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 acceptor framework regions that may need to be changed are presented in WO 91/09967.

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

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 substantially identical to sequences of human origin, not necessarily sequences from the same antibody. Examples of fully human antibodies include antibodies generated, for example, by phage display methods described above, and antibodies generated in mice in which murine immunoglobulin variable region genes, and optionally constant region genes, have been replaced with human equivalents, generally as described in EP 0546073, U.S. Pat. No. 5,545,806, U.S. Pat. No. 5,569,825, U.S. Pat. No. 5,625,126, U.S. Pat. No. 5,633,425, U.S. Pat. No. 5,661,016, U.S. Pat. No. 5,770,429, EP 0438474, and EP 0463151.

A constant region, as used herein, is intended to refer to the portion of the constant region located between two variable domains, e.g., non-cognate variable domains, in a heavy chain. Thus, the anti-IL13R antibodies disclosed herein may include 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 in which one, two, three, four or five amino acids in the naturally occurring sequence have been 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.

If desired, antibodies for use in the present invention may be conjugated to one or more effector molecule(s). 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 an antibody of the present invention. Where 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. 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). Particular chemical procedures include, for example, those described in WO 93/06231, WO 92/22583, WO 89/00195, WO 89/01476 and WO 03031581. Alternatively, when the effector molecule is a protein or polypeptide, the linkage may be achieved using recombinant DNA procedures, for example as described in WO 86/01533 and EP 0 392 745.

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

Other effector molecules may include detectable substances 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. Pat. 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.

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 an epithelial barrier to the immune system. Examples of suitable effector molecules of this type include polymers, albumin, albumin-binding proteins, or albumin-binding compounds, such as those described in WO 05/117984. When the effector molecule is a polymer, it may 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.

Specific optional substituents that may be present on the above-mentioned synthetic polymers include one or more hydroxy, methyl or methoxy groups.

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.

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

As used herein, "derivative" is 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 recognized 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.

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

In one example, an 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 techniques (see, e.g., U.S. Pat. No. 5,219,996; U.S. Pat. No. 5,667,425; WO 98/25971, WO 2008/038024). In one example, the antibody molecule of the present invention is a modified Fab fragment, the modification being the addition of one or more amino acids to the C-terminus of the heavy chain to allow for the attachment of an effector molecule. Suitably, the added amino acids form a modified hinge region containing one or more cysteine residues to which an effector molecule may be attached. Multiple sites can be used to attach two or more PEG molecules.

In one embodiment, the formulations herein are administered in combination with another treatment.

As used herein, "in combination" is intended to include instances in which an anti-IL13R antibody is administered prior to or simultaneously with another treatment.

As used herein, treatment refers to the improvement of a disease's symptoms or condition, including stabilizing the disease and/or moving the disease into remission, reducing the likelihood of relapse or similar, particularly without inducing dose-limiting side effects. For example, an appropriate therapeutic dose is generally a balance between therapeutic efficacy and tolerable toxicity, provided that benefit is realized from the treatment, and where side effects and toxicity are tolerable.

In a separate aspect, there is provided 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 atopic dermatitis (moderate, severe or very severe atopic dermatitis, particularly difficult to control moderate to severe atopic dermatitis), by parenteral administration with a treatment cycle comprising a dose in the range of 200 mg to 600 mg (e.g., 400 to 600 mg), in which the incidence of conjunctivitis is minimized, e.g., as detailed herein.

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.

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

In the context of this specification, "comprising" should be interpreted as "including". An embodiment of the invention comprising a particular feature/element is also intended to cover alternative embodiments "consisting of" or "consisting essentially of" the relevant element/feature. Where technically appropriate, embodiments of the invention may be combined.

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

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.

The background section of this specification contains relevant technical information and may be used as a basis for amendments.

The headings in the subject index of this specification are used to separate the document into paragraphs and are not to be used to interpret the meaning of the disclosure provided herein.

The invention is further described, by way of example only, in the following examples.

Patient demographics for the full analysis set are shown. Baseline disease characteristics of the full analysis population are shown. Baseline characteristics of efficacy evaluable data are presented. % change from baseline in EASI scores at day 57 is shown. % change from baseline in EASI scores at day 57 is shown. % change from baseline in EASI scores at day 57 is shown. The percent change from baseline in EASI scores at day 29 is shown. The percent change from baseline in EASI scores at day 29 is shown. The percent change from baseline in EASI scores over time is shown. The percent change from baseline in EASI scores over time is shown. 4 shows the percent change from baseline in EASI scores over time for individual patients. The percent change from baseline in EASI scores over time for individual patients is shown. The percent change from baseline in EASI scores over time for individual patients is shown. The percent change from baseline in EASI scores over time for individual patients is shown. 57-day sensitivity analysis in mITT is shown. Sensitivity analysis in mITT is shown (200, 400 and 600 mg). Analysis in mITT is shown (low and high dose). EASI50, EASI75 and EASI90 on day 57 are shown. EASI50 on day 57 is shown (200, 400 and 600 mg). EASI50 on day 57 is shown (low and high doses). EASI 75 on day 57 is shown (200, 400 and 600 mg). EASI75 on day 57 is shown (low and high doses). EASI90 on day 57 is shown (200, 400 and 600 mg). EASI90 on day 57 is shown (low and high doses). The percent reduction in EASI50 over time is shown. The percent reduction in EASI 75 over time is shown. The percent reduction in EASI90 over time is shown. Sensitivity analysis on Mitt is shown. The percentage of patients with an IGA score of 0 or 1 at day 57 in a summary table is shown. The percentage of patients with an IGA score of 0 or 1 at day 57 is shown. The percentage of patients with an IGA score of 0 or 1 is shown. Patient baseline TARC and IgE are shown. Mean % change from baseline TARC is shown (200 mg and 400 mg). Mean % change from baseline TARC is shown (400 mg and placebo). The percent change from baseline TARC for individual patients is shown. The % IgE change from baseline is shown (200 mg and 400 mg). Mean IgE % change from baseline is shown (200 mg and 400 mg). Percent IgE change from baseline for three individual patients is shown. Percent IgE change from baseline for 4 individual patients for 200 mg is shown. Percent IgE change from baseline for 6 individual patients for 400 mg is shown. Ebrasakimab exposure, mean EASI score, mean TARC level and mean IgE level are shown. Showing ebrasakimab efficacy vs dupilumab efficacy. 1 shows the median percent change from baseline in IgE dupilumab. % change from baseline for dupilumab 300 mg administered weekly is shown. Shown is the staining intensity of IL-13Rα1 expression in healthy skin, non-lesional atopic dermatitis and lesional atopic dermatitis. Shown is staining of IL-13Rα1 expression in mast cells and eosinophils for healthy skin, non-lesional atopic dermatitis and lesional atopic dermatitis. Gene expression for type I and type II IL-13 receptors is shown.

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.

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.

Results Table 1 shows the percent change from baseline in EASI scores at Day 57 (8 weeks).

Table 2 shows the percent change from baseline in EASI scores at Day 29 (4 weeks).

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

Table 4 provides an overview of the proportion of patients who achieved EASI 50, EASI 75 and EASI 90 at 57 days.

Results show that ebrasakimab provides 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 EASI-50, 89% achieved versus 40% with placebo;
o EASI-75, 67% achieved versus 0% with placebo;
o EASI-90, 56% achieved versus 0% with placebo.

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.

Example 2
Among the 32 patients who completed at least 29 days of dosing at all protocol-defined sites as the 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 were no incidences of conjunctivitis in the expansion cohort.

Ebrasakimab achieved 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).

Following a meeting with the Data Monitoring Committee prior to unblinding, a revised ITT population (RITT, n=29) 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 (p<0.025) in the % change from baseline in EASI, demonstrating greater improvement versus placebo in key efficacy endpoints versus the ITT population.

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 may present to the clinic with "symptoms," such as itchy skin, but the underlying cause 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.

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-13Rα1) to block type II, with anti-common gamma chain to block type I, and with anti-IL4Rα 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 with type I receptor blockade using anti-chain antibodies. B) Differentially expressed genes with type II receptor blockade using ebrasakimab.

Summary 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 (25)

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 , 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.
(Claim 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 signaling 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, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 109, 109, 109, 110, 111, , 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 for use or method according to any preceding claim, wherein the atopic dermatitis is pathological. An antibody or antigen-binding fragment thereof for use or method according to any preceding claim, 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. An antibody or antigen-binding fragment thereof for use or method according to any preceding claim, wherein the IL-13Rα1 has reduced side effects and/or improved efficacy compared to dupilumab. The antibody or antigen-binding fragment thereof, or method according to any preceding claim, wherein the baseline TARC level is at least 1,115 pg/ml, e.g., in the range of 1,115 pg/ml to 4,300 pg/ml or greater than 4,300 pg/ml. The antibody or antigen-binding fragment thereof, or method according to any preceding claim, wherein the baseline STAT6 is above normal. The antibody or antigen-binding fragment thereof, or method according to any one of claims 1 to 4, wherein the patient has a baseline IGA score of 3 or higher, which indicates moderate to very severe atopic dermatitis, e.g., 3 (moderate atopic dermatitis), 4 (severe atopic dermatitis), or 5 (very severe atopic dermatitis). The antibody or antigen-binding fragment thereof, or method according to any one of claims 1 to 5, wherein the baseline IgE level is at least 150 KU/L, e.g., a level of 1000, 1500, 2,000, 2,500, 3,000, 3500, 4,000, 4,500, 5,000, 5,500, 6,000, 6,500, 7,000, 7,500, 8,000, 8,500, 9,000, 9.50 KU/L, such as 10,000 kU/L +/- 2,000. The antibody or antigen-binding fragment thereof according to any preceding claim, wherein the one or more parameters (e.g., two or more or all of the parameters) are measured prior to administration. The antibody or antigen-binding fragment of any preceding claim, wherein the patient is identified (e.g., identified as being similar to the desired patient population) as having one or more (e.g., all) of the parameters prior to initiating treatment. The antibody or antigen-binding fragment thereof according to any one of the preceding claims, wherein the atopic dermatitis is moderate, for example having a score within the range of 16 to 21.0. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 10, wherein the atopic dermatitis is severe, e.g., with an EASI score of 21.1 or more, 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. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 12, wherein the reduction in EASI score is present about 2 weeks (e.g., on the 15th day) after administration of the first dose. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 13, wherein the reduction in EASI score is present about 4 weeks (e.g., day 29) after administration of the first dose. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 14, wherein the reduction in EASI score is present about 6 weeks (e.g., day 43) after administration of the first dose. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 15, wherein the reduction in EASI score is present about 8 weeks (e.g., day 57) after administration of the first dose. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 16, wherein the treatment is administered subcutaneously. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 17, wherein the dose is 200 mg. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 17, 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. The antibody or binding fragment thereof according to any one of claims 1 to 17, wherein the dose is 600 mg. An antibody or antigen-binding fragment thereof according to any preceding claim, in which the reduction in EASI score is within the range of -25 to -60% (e.g., -39 to -59%, such as -40 to -59%, in particular -47, -48, -49, -50, -51, -52, -53, -54, -55, -56, -57, -58 or -59%), for example at about day 15. said reduction in EASI score being
a. 50 to -100% (e.g. -55 to -97%), especially at about day 29, and/or b. -60 to -100% (e.g. -70 to -97%), especially 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.
The antibody or antigen-binding fragment thereof according to any one of claims 32 to 35, wherein the antibody or antigen-binding fragment thereof is within the range of The antibody or antigen-binding fragment thereof according to any one of claims 32 to 37, wherein 90% of the patient population has an EASI50 at about day 57. The antibody or antigen-binding fragment of any one of claims 1 to 38, wherein the treatment cycle comprises an initial dose of 600 mg followed by 3-weekly doses of 400 mg, e.g., the treatment cycle is repeated twice, i.e., two treatment cycles lasting 8 weeks, in particular, 600 mg on 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 are administered. The antibody or antigen-binding fragment of any one of claims 1 to 39, wherein disease modification occurs by day 4, where day 1 is the first administration of the antibody or 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.