CN118103069A

CN118103069A - Method for treating moderate to severe atopic dermatitis

Info

Publication number: CN118103069A
Application number: CN202280065173.4A
Authority: CN
Inventors: A·沃德; F·塞维克巴斯; K·维弗卡
Original assignee: Aslan Pharmaceuticals Pte Ltd
Current assignee: Aslan Pharmaceuticals Pte Ltd
Priority date: 2021-09-27
Filing date: 2022-09-27
Publication date: 2024-05-28

Abstract

The present disclosure relates to the use of an anti-IL-13 ra 1 antibody (such as an ib Sha Jishan antibody) or binding fragment thereof, and pharmaceutical formulations comprising the same, for treating a patient having atopic dermatitis (such as focal atopic dermatitis), e.g., to stimulate disease modification, including a patient population that has received prior treatment with a dutch Li Youshan antibody.

Description

Method for treating moderate to severe atopic dermatitis

The present disclosure relates to the use of an anti-IL-13 ra 1 antibody or binding fragment thereof and pharmaceutical formulations comprising the same for treating patients with atopic dermatitis, such as focal atopic dermatitis, e.g., to stimulate disease modification, including a patient population that has received prior treatment with dupilumab.

Background

One possible way to inhibit IL-13 activity is to interfere with the binding of IL-13 to its receptor IL-13R, for example by using antibodies specific for IL-13R, such as antibodies specific for IL-13Rαl. Potent antibody antagonists of IL-13Rαl may also interfere with IL-13 binding and prevent heterodimerization of IL-4Rαand IL-13Rαl. Such antibodies can inhibit signaling of IL-13 and IL-4 through type II receptors, while retaining signaling of IL-4 through type I receptors. Signaling through the I receptor is critical in the induction phase of the immune response to Th2 cell differentiation. T cells do not express IL-13rαl, so the type II receptor does not play a role in Th2 differentiation. Thus, IL-13Rαl antibodies should not affect the overall Thl/Th2 balance. During established allergic inflammation, signaling through the type II IL-4/IL-13 receptor is critical during the effector a phase of the immune response. Thus, blockade of type II receptors should have a beneficial effect on many symptoms of allergic diseases such as asthma, atopic dermatitis, and other IL-13R mediated disorders, and thus should be a potent disease modifying agent.

Antibodies (monoclonal and polyclonal) to IL-13rαl have been described in the art; see, for example, WO 97/15663, WO 03/80675; WO 03/46009; WO 06/072564; gauchat et al, 1998Eur. J. Immunol.28:4286-4298; gauchat et al 2000Eur.J.Immunol.30:3157-3164; clement et al, 1997cytokine 9 (11): 959 (conference abstract); ogata et al, 1998J.biol. Chem.273:9864-9871; graber et al, 1998Eur. J. Immunol.28:4286-4298; vermot-Desroches et al, 2000Tissue Antigens 5 (journal) 52-53 (conference abstract); poudrier et al 2000Eur.J.Immunol.30:3157-3164; akaiwa et al, 2001Cytokine 13:75-84; cancino-Diaz et al, 2002J.Invest. Dermatol.119:1114-1120; and Krause et al, 2006MoI.Immunol.43:1799-1807.

A particularly promising anti-IL-13R alpha l antibody is described in WO2008/060813 as antibody 10G 5-6. 10G5-6 was designated as Ile Sha Jishan antibody (Eblasakimab) as an IgG4 with a hinge that stabilized serine to proline mutation (S241P Kabat numbering).

The Sha Jishan antibody has been shown to bind human IL-13Rαl with high affinity (e.g., kd may be 500 pM). The anti-IL Sha Jishan has been shown to effectively antagonize IL-13 function by inhibiting IL-13 binding to its receptor IL-13Rαl, and to inhibit IL-13 and IL-4 induced eosinophil chemokine (eotaxin) release in NHDF cells, IL-13 and IL-4 induced STAT6 phosphorylation in NHDF cells, and IL-13 stimulated TARC release in blood or peripheral blood mononuclear cells.

Atopic dermatitis can be a very painful, frustrating and psychological damaging condition. One method of assessing disease is EASI scoring. The scoring range is 0-72.

In some cases, topical medications do not adequately control moderate to severe forms of the disease. In addition, some patients are not likely to take available topical medications. Dupixent (dupilumab) is an antibody inhibitor of interleukin-4 receptor alpha (IL-4 ra) licensed for use in the treatment of atopic dermatitis.

In some cases, patients taking the pralidoxime Li Youshan antibody cease treatment for one or more reasons, such as adverse side effects, inadequate symptom control, and/or dosing problems. This makes it impossible for some patients suffering from moderate to severe local dermatitis to be properly treated.

The scoring range for moderate atopic dermatitis is typically 7.1 to 21.0.

Severe atopic dermatitis ranges from 21.1 or more. Sometimes, severe atopic dermatitis is classified into severe and extremely severe diseases, and the ranges of these groups are 21.1 to 50 and 50.1 to 72.0, respectively.

The inventors have conducted clinical trials and have determined that while a large number of atopic dermatitis patients may benefit from treatment with an antibody or antigen binding fragment thereof, which is an inhibitor of signaling through the receptor by binding to IL-13 ra 1, it appears that patients with a baseline EASI score of at least 16 and/or patients with focal atopic skin may benefit the most from treatment.

The present invention provides a new patient population, for example, patients previously receiving excessive common Li Youshan anti-treatment and/or patients suffering from focal atopic dermatitis.

In some cases, it is useful to combine the baseline EASI score with one or more other markers (such as baseline IgE, TARC, and STAT 6) to define a patient population. Surprisingly, these patients showed the greatest improvement by treatment according to the present disclosure. In some embodiments, the treatment is a disease modification.

Normal levels of TARC in healthy individuals are typically up to 450pg/ml.

Interestingly, the inventors also determined that IL-13 ra-1 was up-regulated in focal atopic dermatitis, so patients with focal atopic dermatitis may benefit especially from anti-IL-13 antibodies such as the Sha Jishan anti-treatment (e.g., as an independent aspect or as an embodiment of moderate/severe atopic dermatitis).

Focal and non-focal atopic dermatitis are distinct subgroups of patients. Non-focal Atopic Dermatitis (AD) has immune abnormalities, including T cell expansion. It has a variable immunophenotype, which depends largely on the extent and severity of the disease. Compared to normal skin, non-focal atopic skin has reduced hydration and impaired lipid synthesis. Abnormal epidermal hyperplasia also exists in non-focal atopic dermatitis, in which the expression of proliferation markers (keratin 16) is increased, which is associated with altered expression of terminally differentiated proteins including papilin (LOR), epigin (IVL) and FLG. Furthermore, increased infiltration of inflammatory T cells in non-focal atopic dermatitis skin has been demonstrated compared to skin from healthy volunteers. In one embodiment, the non-focal atopic dermatitis is characterized by the absence of a focal.

Focal skin from chronic AD patients has a wide variety of changes in the expression of terminally differentiated genes that form the cornified envelope and epidermal differentiation complex, as well as many differences in highly inflammatory genes in focal AD skin. In its simplest form, focal AD is characterized by a lesion.

Disclosure of Invention

1. An antibody or antigen binding fragment thereof that is an inhibitor of signaling through the receptor by binding IL-13 ra 1 for use in the treatment of moderate, severe or very severe atopic dermatitis (particularly poorly controlled moderate to severe atopic dermatitis) by parenteral administration of a treatment cycle comprising a dose in the range of 200mg to 600mg (such as 400 to 600 mg), wherein the disease baseline is characterized by an EASI score of 16 or more (such as ,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).

1A method of treatment by parenterally administering to a patient suffering from moderate, severe or very severe atopic dermatitis a treatment cycle comprising a dose ranging from 200mg to 600mg (such as 400mg to 600 mg) of an antibody or antigen binding fragment thereof that is an inhibitor of signaling through the receptor by binding IL-13 ra 1, wherein the disease baseline is characterized by an EASI score of 16 or more (such as ,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).

1B an antibody or antigen binding fragment thereof which is an inhibitor of signaling through the receptor by binding IL-13 ra 1 for use in the manufacture of a medicament for the treatment of moderate, severe or very severe atopic dermatitis, particularly poorly controlled moderate to severe dermatitis, by parenteral administration of a treatment cycle comprising a dose in the range 200mg to 600mg, such as 400 to 600mg, wherein the disease baseline is characterized by an EASI score of 16 or more (such as ,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).

An antibody or antigen binding fragment thereof that is an inhibitor of signaling through the receptor by binding to IL-13 ra 1 for use in the treatment of focal atopic dermatitis (particularly poorly controlled moderate to severe atopic dermatitis) by parenteral administration of a treatment cycle comprising a dose in the range of 200mg to 600mg, such as 400 to 600 mg.

2. The antibody or antigen-binding fragment, method or use of paragraph 1, 1A or 1B, wherein the atopic dermatitis is focal.

3. The antibody, or antigen-binding fragment, method or use thereof, of any of the preceding paragraphs, wherein the patient has been previously treated with a dutch Li Youshan antibody.

4. The antibody, or antigen-binding fragment, method or use thereof, according to any one of the preceding paragraphs, wherein the baseline TARC level is at least 701pg/ml, e.g. in the range 800 to 52,000pg/ml (such as ,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、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、27,000、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 or 52,000 pg/ml), in particular at least 1,115pg/ml, e.g. 1,115pg/ml to 4,300pg/ml or above 4,300pg/ml.

5. The antibody, or antigen-binding fragment, method or use of any of the preceding paragraphs, wherein baseline STAT6 is higher than normal.

6. The antibody or antigen-binding fragment thereof, method or use of any one of the preceding paragraphs, wherein the patient has a baseline IGA score of 3 or higher, which is moderate to extremely severe atopic dermatitis, such as 3 (moderate atopic dermatitis), 4 (severe atopic dermatitis) or 5 (extremely severe atopic dermatitis).

7. An antibody or antigen-binding fragment, method or use thereof according to any one of the preceding paragraphs, wherein the baseline IgE level (e.g. has been determined/measured) is at a level of at least 130kU/L, e.g. 150kU/L, such as 150 to 20,000, more particularly 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、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、20,000kU/L,, particularly 10,000kU/L +/-2,000.

8. An antibody or antigen-binding fragment, method or use thereof according to any one of the preceding paragraphs, wherein one or more of said parameters (e.g. 2 or more or all of said parameters) have been measured prior to the start of administration, in particular, the patient has been identified as a relevant/suitable population prior to treatment.

9. The antibody or antigen-binding fragment, method or use of any of the preceding paragraphs, wherein the patient has been identified as having one or more (e.g. all) of the parameters prior to initiation of treatment, i.e. in particular, the patient has been identified as being in a population of moderate to severe dermatitis based on data other than clinical observations alone and/or EASI scores.

10. The antibody or antigen-binding fragment, method or use of any of the preceding paragraphs, wherein the atopic dermatitis is moderate, e.g. the EASI score ranges from 16 to 21.0.

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

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

13. An antibody or antigen-binding fragment, method or use according to any one of the preceding paragraphs, wherein the atopic dermatitis is severe, e.g. the EASI range is 21.1 or higher, such as 21.1 to 50.0.

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

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

16. The antibody or antigen-binding fragment, method or use of any one of paragraphs 1, 1A, 1B to 11 or 13 to 15, wherein the atopic dermatitis is extremely severe, e.g. scored in the range of 50.1 to 72.0.

17. The antibody, or antigen-binding fragment thereof, method or use of any of the preceding paragraphs, wherein a decrease in EASI score from baseline, e.g. at least 15%, occurs after about two weeks (such as day 15) after administration of the first dose.

18. The antibody, or binding fragment, method or use thereof according to any one of the preceding paragraphs, wherein the EASI score is reduced from baseline by a range of 15% to 60% (e.g. on about day 15), for example 25% to 60% (such as 39% to 59%, in particular 40% to 59%, more particularly 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58% or 59%), especially on about day 15.

19. The antibody, or binding fragment, method or use according to any one of the preceding paragraphs, wherein the decrease in EASI score from baseline ranges from 50% to 100% (e.g. 55% to 97%), particularly on about day 29.

20. The antibody or antigen-binding fragment thereof of any one of the preceding paragraphs, wherein the decrease in EASI score ranges from-40% to-85% (e.g., on about day 29).

21. The antibody, or antigen-binding fragment thereof, method or use of any of the preceding paragraphs, wherein a decrease in EASI score occurs after about four weeks (such as day 29) after administration of the first dose.

22. The antibody, or antigen-binding fragment thereof, method or use of any of the preceding paragraphs, wherein a decrease in EASI score occurs after about six weeks (such as day 43) after administration of the first dose.

23. The antibody or binding fragment thereof according to any one of the preceding paragraphs, wherein the EASI score decreases from baseline by a range of 60% to 100% (e.g., 70% to 97%), particularly on about day 43.

24. The antibody or antigen-binding fragment thereof of any one of the preceding paragraphs, wherein the decrease in EASI score ranges from-25% to-85% (e.g., on about day 43 or 57).

25. The antibody, or antigen-binding fragment thereof, method or use of any of the preceding paragraphs, wherein a decrease in EASI score occurs after about eight weeks (such as day 57) after administration of the first dose.

26. The antibody, or binding fragment, method or use thereof, of any one of the preceding paragraphs, wherein the decrease in EASI score from baseline ranges from 65% to 100% (e.g., 70% to 100%, such as 90% to 100%, particularly 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%), more particularly at about day 57.

27. The antibody, or binding fragment, method or use thereof, according to any one of the preceding paragraphs, wherein 80% of the patient population has an EASI 50 score or less on about day 29 and/or day 57, particularly with a dose of at least 350mg (such as 400 mg).

28. The antibody, or binding fragment, method or use thereof, according to any one of the preceding paragraphs, wherein 90% of the patient population has an EASI 50 score or less on about day 57, particularly when a dose of at least 550mg (such as 600 mg) is employed.

29. The antibody, or antigen-binding fragment thereof, method or use according to any one of the preceding paragraphs, wherein IgE is reduced by at least 20% from baseline, such as about 20% to 60% from baseline, prior to day 57.

30. The antibody, or antigen-binding fragment, method or use according to any one of the preceding paragraphs, wherein TARC is reduced from baseline by at least 50%, for example, about day 15 ago.

31. The antibody, or antigen-binding fragment, method or use according to any one of the preceding paragraphs, wherein TARC is reduced from baseline by at least 60%, e.g., about day 36.

32. The antibody, or antigen-binding fragment, method or use according to any one of the preceding paragraphs, wherein TARC is reduced from baseline by at least 70%, e.g., about day 50.

33. The antibody, or antigen-binding fragment, method or use according to any one of the preceding paragraphs, wherein TARC is reduced from baseline by at least 80%, e.g., about day 57 ago.

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

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

36. The antibody, or antigen-binding fragment thereof, method or use of any of the preceding paragraphs, wherein a plurality of doses are administered in a treatment cycle (e.g., wherein the treatment cycle is 4 to 8 weeks, such as 8 weeks).

37. The antibody or binding fragment, method or use of paragraph 36, wherein a plurality of treatment cycles, e.g., 2, 3, 4 or more treatment cycles, are administered.

38. The antibody or binding fragment, method or use of paragraphs 36 or 37, wherein maintenance therapy is administered after one or more cycles of treatment and disease change, e.g., the same dose is administered at a lower frequency (e.g., monthly, such as every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks), or a lower dose (such as 200 mg) is administered at the same frequency or at a lower frequency (such as about weekly, every 2 weeks, about every 3 weeks, or about every 4 weeks).

39. The antibody or antigen-binding fragment, method or use according to any one of the preceding paragraphs, wherein the antibody or binding fragment thereof is administered about weekly (particularly in a treatment cycle (including a single cycle), particularly a cycle of 8 weeks).

40. The antibody or antigen-binding fragment, method or use of any one of paragraphs 1, 1A, 1B, 1C to 38, wherein the antibody or binding fragment thereof is administered about once every two weeks (particularly in a treatment cycle (including a single cycle), particularly a cycle of 8 weeks).

41. The antibody or antigen-binding fragment, method or use of any one of paragraphs 1, 1A, 1B, 1C to 38, wherein the antibody or binding fragment thereof is administered about once every three weeks (particularly in a treatment cycle (including a single cycle), particularly a cycle of 8 weeks).

42. The antibody or antigen-binding fragment, method or use of any one of paragraphs 1, 1A, 1B, 1C to 38, wherein the antibody or binding fragment thereof is administered about once every four weeks (e.g., once a month) (particularly in a single treatment cycle, particularly in a cycle of 8 weeks).

43. An antibody or antigen-binding fragment thereof, method or use according to any one of the preceding paragraphs, wherein a loading dose (e.g. in the range 400 to 900mg, such as 400, 500, 600, 700, 800 or 900 mg) is employed during the treatment cycle, followed by administration of an additional dose.

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

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

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

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

48. The antibody or binding fragment, method or use thereof according to any one of the preceding paragraphs, wherein the treatment cycle comprises a first dose of 600mg followed by a dose of 400mg three times per week, e.g. wherein the treatment cycle is repeated twice, i.e. two treatment cycles last for 8 weeks (with or without loading dose, i.e. wherein the first dose is the same as the other doses in the cycle), in particular:

600mg on day 1, 400mg on about day 8, 400mg on about day 15, 400mg on about day 22, 600mg on about day 29, 400mg on about day 36, 400mg on about day 43, and 400mg on about day 50.

49. The antibody or binding fragment, method or use according to any one of the preceding paragraphs, wherein the disease change occurs before day 4, wherein day 1 is the first administration of the antibody or binding fragment thereof.

50. The antibody, or binding fragment, method or use thereof, of any one of the preceding paragraphs, wherein the disease alteration is a decrease from baseline of:

Easi score, e.g., wherein the decrease is a percentage from baseline, e.g., the decrease ranges from 10% to 55%; and/or

Tarc, e.g., as described elsewhere herein; and/or

Ige, e.g., as described elsewhere herein.

51. An antibody or binding fragment thereof according to any one of the preceding paragraphs, wherein a disease change in the range of-40 to-100% is achieved before about day 57 after the first administration on day 1, e.g. the maximum disease change is achieved before about day 57.

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

53. The antibody, or antigen-binding fragment, method or use of any one of the preceding paragraphs, wherein the anti-IL-13R antibody comprises: a VH CDR1 comprising the amino acid sequence shown in SEQ ID No. 1; a VH CDR2 comprising the amino acid sequence shown in SEQ ID No. 2; and a VH CDR3 comprising the amino acid sequence shown as SEQ ID NO. 10.

54. The antibody or antigen-binding fragment, method or use thereof of any of the preceding paragraphs, wherein the anti-IL-13R antibody comprises a VH domain comprising the amino acid sequence shown in SEQ ID No. 51 or a sequence having at least 95% identity thereto.

55. The antibody, or antigen-binding fragment, method or use of any one of the preceding paragraphs, wherein the anti-IL-13R antibody comprises: VL CDR1 comprising the amino acid sequence shown as SEQ ID NO. 31; VL CDR2 comprising the amino acid sequence shown as SEQ ID NO. 32; and VL CDR3 comprising the amino acid sequence shown as SEQ ID NO. 45.

56. The antibody or antigen-binding fragment, method or use thereof of the preceding paragraph, wherein the anti-IL-13R antibody comprises a VL domain comprising the amino acid sequence shown in SEQ ID No. 53 or a sequence having at least 95% identity thereto.

57. An antibody or antigen-binding fragment, method or use thereof according to any one of the preceding paragraphs, wherein the antibody is provided as a pharmaceutical formulation comprising:

10mg/ml to 140mg/ml of the antibody or binding fragment;

50mM to 150mM arginine (e.g., 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, or 150mM, such as 100mM arginine);

15mM to 25mM histidine buffer, e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25mM, such as 20mM histidine buffer;

from 0.01 to 0.03% of nonionic surfactant, e.g. 0.02% w/v and

Wherein 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, in particular 6.4 to 6.9.

58. An antibody or antigen-binding fragment, method or use according to paragraph 57, wherein the osmolarity of the formulation ranges from 350 to 550mOsmo/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、550mOsmo/kg, such as 405 to 435mOsmo/kg.

59. The antibody or antigen binding fragment, method or use of paragraphs 57 or 58, further comprising 50mM to 200mM 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、200mM, such as 180mM sugar.

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 comprise NaCl.

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 150mM NaCl, e.g., 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, e.g., 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150mM, such as 62.5mM or 140mM NaCl.

63. Use of an antibody or antigen-binding fragment according to any one of paragraphs 1 to 58, which is an inhibitor of signaling through the receptor by binding to IL-13 ra 1, wherein the incidence of ocular side effects is reduced compared to treatment of the same disease with a therapeutic dose of the dopen Li Youshan antibody, for the manufacture of a medicament for the treatment of atopic dermatitis.

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

Also provided is a method of treating atopic dermatitis (e.g., moderate to severe atopic dermatitis, particularly poorly controlled moderate to severe atopic dermatitis) in a patient according to the present disclosure, comprising administering an antibody, or antigen binding fragment thereof, or a pharmaceutical formulation disclosed herein.

Poor control as described herein refers to poor control by currently approved drugs, e.g., topical drugs, oral drugs, and/or biological drugs such as the dopen Li Youshan antibody (particularly topical drugs or the dopen Li Youshan antibody).

The results further demonstrate that the anti-ib Sha Jishan has comparable or in some cases higher efficacy than the anti-dopril Li Youshan, thus demonstrating the potential of the anti-ib Sha Jishan as a replacement therapy for the treatment and management of atopic dermatitis, particularly for patients previously administered the anti-dopril Li Youshan.

Thus, in one embodiment, treatment is provided for a patient population wherein the patient has poorly controlled symptoms and/or adverse side effects when treated with the dopen Li Youshan antibody, i.e., the patient population is a patient population previously receiving excessive dopen Li Youshan antibody treatment, particularly patients who failed treatment with the dopen Li Youshan antibody.

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

In one embodiment, there is provided a reduction in IGA assessed overall by the investigator in/after treatment according to the present disclosure, e.g., as 0,1 or 2 (no signs of inflammation, near clearance, and mild disease, respectively). In particular, an IGA score of 0 or 1 is provided.

In one embodiment, a combination therapy comprising an antibody, antigen-binding fragment or formulation thereof according to the present disclosure and another drug is employed.

In one embodiment, the other drug is used to treat atopic dermatitis, such as a topical steroid, an oral steroid, and/or an antihistamine.

Surprisingly, disease alterations following treatment with anti-IL-13rα1 antibodies or binding fragments thereof according to the present disclosure are closely accompanied by a decrease in TARC, in fact TARC decrease and EASI decrease are closely related to treatment according to the present disclosure.

Disease alterations as described herein relate to improvements in disease states, in particular to a decrease in EASI score. In one embodiment, this decrease is maintained for at least a period of time even after the treatment is stopped.

Baseline as described herein refers to the level prior to the initiation of treatment according to the present disclosure. Typically, a baseline is measured and/or recorded.

Loading dose as described herein refers to a dose that is higher than the "normal dose" in the treatment cycle. Loading doses are typically employed to load the patient's system with medication such that when a subsequent dose is administered, the level in the necessary tissue is maintained at or above a minimum predetermined level.

By "about day" as described herein is meant about that day of administration, e.g., +/-1, 2, 3, 4,5, 6, or 7 days. The early dose of the treatment cycle may need to be administered near the indicated date, e.g., +/-1 day. The later dose may allow for a greater degree of freedom, i.e., +/-up to 7 days.

Atopic dermatitis as described herein refers to skin inflammation and includes: dry/itchy skin and rash.

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

Severe atopic dermatitis includes extremely severe atopic dermatitis. Extremely severe atopic dermatitis is a subset of atopic dermatitis.

As used herein, the researcher overall assessment (IGA) refers to a tool to assess atopic dermatitis. Depending on the severity of the patient's symptoms, a 0-5 split is used:

Interleukin-13 receptor (IL-13R), as used herein, is a type I cytokine receptor that binds interleukin-13. It consists of two subunits, encoded by IL13R alpha 1 and IL4R, respectively. These two genes encode the proteins IL-13Rα1 and IL-4Rα. They bind IL-13Rα1 chain as IL-13 to form dimers, and IL-4Rα stabilizes this interaction. IL13R may also trigger IL-4 signaling due to the presence of the IL4R subunit. In both cases, this occurs via activation of the Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway, resulting in phosphorylation of STAT 6. Uniprot number of human IL-13 ra1 is P3597.

IL-13Rα2, previously referred to as IL-13R and IL-13Rα, is another receptor capable of binding IL-13. However, in contrast to IL-13R alpha 1, this protein binds IL-13 with high affinity, but does not bind IL-4. Uniprot number of human IL-13 ra 2 is Q14627.

In one embodiment, CDRH1 comprises amino acid sequence GYSFTSYWIG (SEQ ID NO: 1).

In one embodiment, CDRH2 comprises amino acid sequence VIYPGDSYTR (SEQ ID NO: 2).

In one embodiment, CDRH3 comprises the formula:

SEQ ID NO:3X₁ Pro Asn Trp Gly X₆ X₇ Asp X₉

X ₁ represents Phe, met, gln, leu or Val

X ₆ represents Ser or Ala

X ₇ represents Phe, leu, ala or Met

X ₉ represents Tyr, gln, lys, arg, trp, his, ala, thr, ser,

Asn or Gly

In one embodiment, the IL13-r1α1 antibody or binding fragment used in the formulations of the present disclosure comprises a CDRH3 independently selected from the group consisting of sequences comprising SEQ ID NOs 4 to 30:

In one embodiment, an anti-IL 13R antibody or binding fragment employed in the present disclosure comprises: a VH CDR1 comprising the amino acid sequence shown in SEQ ID No. 1; a VH CDR2 comprising the amino acid sequence shown in SEQ ID No. 2; and VH CDR3 comprising the amino acid sequence shown as SEQ ID NO. 3.

In one embodiment, an anti-IL 13R antibody or binding fragment used in the present disclosure comprises: CDRH1 comprising an amino acid sequence as set forth in SEQ ID NO. 1; CDRH2 comprising an amino acid sequence as shown in SEQ ID NO. 2; and CDRH3 comprising an amino acid sequence as set forth in 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, an anti-IL 13R antibody or binding fragment used in the present disclosure comprises: CDRH1 comprising an amino acid sequence as set forth in SEQ ID NO. 1; CDRH2 comprising an amino acid sequence as shown in SEQ ID NO. 2; and CDRH3 comprising the amino acid sequence shown in 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 comprises the formula:

SEQ ID NO:33Gln X₂X₃X₄X₅

X ₂ represents Gln, arg, met, ser, thr or Val.

X ₃ represents Tyr or Val.

X ₄ represents Glu, ala, gly or Ser.

X ₅ represents Thr, ala or Ser.

In one embodiment, the IL-13Rα1 antibody used in the formulations of the present disclosure comprises a CDRL3 independently selected from the group consisting of sequences comprising SEQ ID NOs 34 to 47:

SEQ ID NO:	CDR L3 sequences
		34	QRYAT
35	QRYST
		36	QMYST
37	QQVGT
		38	QQVST
39	QQYST
		40	QSYST
41	QQYAT
		42	QQYSS
43	QTYST
		44	QQYGS
45	QQYAS
		46	QQYEA
47	QQYET

In one embodiment, the anti-IL-13 Rα antibodies or binding fragments used in the present disclosure comprise: CDRL1 comprising the amino acid sequence SEQ ID NO. 31; CDRL2 comprising the amino acid sequence SEQ ID NO. 32; and CDRL3 comprising the amino acid sequence set forth in SEQ ID NO. 33.

In one embodiment, the anti-IL-13 Rα antibodies of the disclosure comprise: VL CDR1 comprising the amino acid sequence SEQ ID NO 84; VL CDR2 comprising the amino acid sequence SEQ ID NO 85; and VL CDR3 comprising an amino acid sequence as set forth in SEQ ID NO 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 or 47.

In one embodiment, the anti-IL-13 Rα antibodies of the disclosure comprise: CDRL1 comprising the amino acid sequence SEQ ID NO. 31; CDRL2 comprising the amino acid sequence SEQ ID NO. 32; and CDRL3 comprising the amino acid sequence set forth in SEQ ID NO. 45.

In one embodiment, an anti-IL 13R antibody of the disclosure comprises: CDRH1 comprising an amino acid sequence as set forth in SEQ ID NO. 1; CDRH2 comprising an amino acid sequence as shown in SEQ ID NO. 2; and CDRH3 comprising the amino acid sequence shown in SEQ ID NO. 3; CDRL1 comprising the amino acid sequence SEQ ID NO. 31; CDRL2 comprising the amino acid sequence SEQ ID NO. 32; and CDRL3 comprising the amino acid sequence set forth in SEQ ID NO. 33.

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

In one embodiment, an anti-IL 13R antibody of the disclosure comprises: CDRH1 comprising an amino acid sequence as set forth in SEQ ID NO. 1; CDRH2 comprising an amino acid sequence as shown in SEQ ID NO. 2; and CDRH3 comprising an amino acid sequence as set forth in SEQ ID NO. 3 or 10; CDRL1 comprising the amino acid sequence SEQ ID NO. 31; CDRL2 comprising the amino acid sequence SEQ ID NO. 32; and CDRL3 comprising the amino acid sequence set forth in SEQ ID NO. 45.

In one embodiment, an anti-IL 13R antibody of the disclosure comprises: CDRH1 comprising an amino acid sequence as set forth in SEQ ID NO. 1; CDRH2 comprising an amino acid sequence as shown in SEQ ID NO. 2; and CDRH3 comprising the amino acid sequence shown in SEQ ID NO. 10; CDRL1 comprising the amino acid sequence SEQ ID NO. 31; CDRL2 comprising the amino acid sequence SEQ ID NO. 32; and CDRL3 comprising the amino acid sequence set forth in SEQ ID NO. 45.

In one embodiment, the VH region is independently selected from the sequence comprising:

SEQ ID NO:48

EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARFPNWGSFDYWGQGTLVTVSS

SEQ ID NO:49

EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARMPNWGSFDYWGQGTLVTVSS

SEQ ID NO:50

EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCVRMPNWGSLDHWGQGTLVTVSS

SEQ ID NO:51

EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWM GVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARMPN WGSLDHWGQGTLVTVSS,

or a sequence having at least 95% identity thereto.

In one embodiment, VL is independently selected from a sequence comprising:

SEQ ID NO:52

EIVLTQSPGTLSLSPGERATLSCRASQSISSSYLAWYQQKPGQAPRLLIYG ASSRATGIP

DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYETFGQGTKVEI*

SEQ ID NO:53

EIVLTQSPGTLSLSPGERATLSCRASQSISSSYLAWYQQKPGQAPRLLIYG ASSRATGIP

DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYASFGQGTKVEI*

SEQ ID NO:54

EIVLTQSPGTLSLSPGERATLSCRASQSISSSYLAWYQQKPGQAPRLLIYG ASSRATGIP

DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYEAFGQGTKVEI*

SEQ ID NO. 55 (empty sequence)

Or a sequence having at least 95% identity thereto (K is deleted in a post-translational modification).

In one embodiment, the VH sequence is SEQ ID NO. 48 (or a sequence having at least 95% identity 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 having at least 95% identity thereto).

In one embodiment, the VH sequence is SEQ ID NO. 49 (or a sequence having at least 95% identity 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 having at least 95% identity thereto).

In one embodiment, the VH sequence is SEQ ID NO. 50 (or a sequence having at least 95% identity 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 having at least 95% identity thereto).

In one embodiment, the VH sequence is SEQ ID NO. 51 (or a sequence having at least 95% identity 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 having at least 95% identity thereto).

In one embodiment, the VL sequence is SEQ ID NO. 52 (or a sequence having at least 95% identity 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 having at least 95% identity thereto)

In one embodiment, the VL sequence is SEQ ID NO. 53 (or a sequence having at least 95% identity 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 having at least 95% identity thereto).

In one embodiment, the VL sequence is SEQ ID NO. 54 (or a sequence having at least 95% identity 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 having at least 95% identity thereto).

In one embodiment, the VL sequence is SEQ ID NO. 55 (or a sequence having at least 95% identity 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 having at least 95% identity thereto).

In one embodiment, the VH sequence is SEQ ID NO. 51 (or a sequence having at least 95% identity thereto) and the VL sequence is SEQ ID NO. 53 (or a sequence having at least 95% identity thereto).

Variable region as used herein refers to a region in an antibody chain that comprises CDRs and a suitable framework.

In one embodiment, the heavy chain comprises a sequence independently selected from the group consisting of:

SEQ ID NO:56

EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARMPNWGSFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG*

SEQ ID NO:57

EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCVRMPNWGSLDHWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG*

SEQ ID NO:58

EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCVRMPNWGSLDHWGQGTLVTVSSASIKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG*

SEQ ID NO:59

EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARMPNWGSLDHWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG*

SEQ ID NO:60

EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARMPNWGSLDHWGQGTLVTVSSASIKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG*

SEQ ID NO:61

EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARMPNWGSLDHWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVTSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG*,

Or a sequence having at least 95% identity thereto (K deleted in a post-translational modification) in one embodiment, the light chain is independently selected from:

SEQ ID NO:62

EIVLTQSPGTLSLSPGERATLSCRASQSISSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYASFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO:63

EIVLTQSPGTLSLSPGERATLSCRASQSISSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYEAFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO:64

EIVLTQSPGTLSLSPGERATLSCRASQSISSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYETFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

or a sequence having at least 95% identity thereto.

In one embodiment, the heavy chains are independently selected from SEQ ID NOS: 56, 57, 58, 59, 60 and 61 (or sequences having at least 95% identity thereto) and the light chains are independently selected from SEQ ID NOS: 62, 63 and 64 (or sequences having at least 95% identity thereto).

In one embodiment, the heavy chain is SEQ ID NO. 56 (or a sequence having at least 95% identity thereto), and the light chain is independently selected from SEQ ID NO. 62, 63 and 64 (or a sequence having at least 95% identity thereto).

In one embodiment, the heavy chain is SEQ ID NO. 57 (or a sequence having at least 95% identity thereto), and the light chain is independently selected from SEQ ID NO. 62, 63 and 64 (or a sequence having at least 95% identity thereto).

In one embodiment, the heavy chain is SEQ ID NO. 58 (or a sequence having at least 95% identity thereto), and the light chain is independently selected from SEQ ID NO. 62, 63 and 64 (or a sequence having at least 95% identity thereto).

In one embodiment, the heavy chain is SEQ ID NO 59 (or a sequence having at least 95% identity thereto), and the light chain is independently selected from SEQ ID NO 62, 63 and 64 (or a sequence having at least 95% identity thereto).

In one embodiment, the heavy chain is SEQ ID NO. 60 (or a sequence having at least 95% identity thereto), and the light chain is independently selected from SEQ ID NO. 62, 63 and 64 (or a sequence having at least 95% identity thereto).

In one embodiment, the heavy chain is SEQ ID NO. 61 (or a sequence having at least 95% identity thereto), and the light chain is independently selected from SEQ ID NO. 62, 63 and 64 (or a sequence having at least 95% identity thereto).

In one embodiment, the heavy chain is SEQ ID NO 59 or 61 (or a sequence having at least 95% identity thereto) and the light chain has the sequence shown in SEQ ID NO 62 (or a sequence having at least 95% identity thereto).

In one embodiment, the heavy chain is SEQ ID NO. 59 (or a sequence having at least 95% identity thereto) and the light chain has the sequence shown in SEQ ID NO. 62 (or a sequence having at least 95% identity thereto).

In one embodiment, the heavy chain is SEQ ID NO. 61 (or a sequence having at least 95% identity thereto) and the light chain has the sequence shown in SEQ ID NO. 62 (or a sequence having at least 95% identity thereto).

Derived as used herein means that the sequence used or a sequence highly similar to the sequence used is obtained from the original genetic material, such as the light chain or heavy chain of an antibody.

"At least 95% identical" as used herein is intended to mean an amino acid sequence that has 95% identity or greater, such as 96%, 97%, 98% or 99% identity, over its entire length to a reference sequence. A software program may be employed to calculate percent identity.

Any discussion herein of a protein, antibody, or amino acid sequence will be understood to include any variant of a protein, antibody, or amino acid sequence that is produced during manufacture and/or storage. For example, during manufacture or storage, the antibody may be deamidated (e.g., at asparagine or glutamine residues), and/or its glycosylation altered, and/or its glutamine residues converted to pyroglutamic acid, and/or its N-terminal or C-terminal residues removed or "sheared off" (the C-terminal lysine residues of the encoded antibody are typically removed during the manufacturing process), and/or part or all of the signal sequence is not fully processed, and thus remains at the end of the antibody. It will be appreciated that an antibody comprising a particular amino acid sequence or binding fragment thereof may be a heterogeneous mixture of variants of the or encoding sequence and/or the or encoding sequence or binding fragment thereof.

In one embodiment, the disclosure extends to the sequences explicitly disclosed herein, wherein the C-terminal lysine has been cleaved.

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

Humanization, which includes CDR-grafted antibodies, as used herein refers to molecules 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., US 5,585,089; wo 91/09967). It should be appreciated that it may only be necessary to transfer specific determining residues of the CDR, not the entire CDR (see, e.g., kashmiri et al 2005, methods,36, 25-34). The humanized antibody may also optionally comprise one or more framework residues derived from the non-human species from which the CDRs are derived. For reviews see Vaughan et al Nature Biotechnology,16,535-539,1998.

When grafting CDRs or specificity determining residues, any suitable acceptor variable region framework sequences can be used, including mouse, primate, and human framework regions, considering the class/type of donor antibody from which the CDRs are derived. Examples of human frameworks that can be used in the present invention are KOL, NEWM, REI, EU, TUR, TEI, LAY and POM (Kabat et al). For example, the heavy chain may use KOL and nemm, the light chain may use REI, and the heavy and light chains may use EU, LAY, and POM. Alternatively, human germline sequences may be used; these can be obtained as follows: http:// vbase. Mrc-cpe. Cam. Ac. Uk +.

In the humanized antibody used in the present invention, the heavy and light chains of the receptor do not necessarily need to be derived from the same antibody, and may, if desired, comprise a composite chain having framework regions derived from different chains.

The framework regions need not have exactly the same sequence as the sequence of the recipient antibody. For example, for the class or type of receptor chain, unusual residues may be changed to more frequently occurring residues. Alternatively, selected residues in the acceptor framework regions may be altered so that they correspond to residues present at the same position in the donor antibody (see Reichmann et al, 1998, nature,332, 323-324). Such changes should be kept to a minimum required to restore the affinity of the donor antibody. A scheme for selecting residues in the acceptor framework region that may need to be altered is described in WO 91/09967.

In one embodiment, the anti-IL 13R antibodies of the present disclosure are fully human, in particular, one or more variable domains are fully human.

Fully human molecules are those in which the variable and constant regions of the heavy and light chains, if present, are all of human origin, or are substantially identical to sequences of human origin, not necessarily from the same antibody. Examples of fully human antibodies may include antibodies produced, for example, by phage display methods described above and antibodies produced by mice in which the murine immunoglobulin variable and optionally constant region genes have been replaced by their human counterparts, such as those generally described in EP0546073 B1、US 5,545,806、US 5,569,825、US 5,625,126、US 5,633,425、US 5,661,016、US5,770,429、EP 0438474 and EP 0463151.

A constant region as described herein means that portion of the constant region that is located between two variable domains (e.g., non-homologous variable domains) in a heavy chain. Thus, the anti-IL 13R antibodies disclosed herein may comprise one or more constant regions, such as naturally occurring constant domains or derivatives of naturally occurring domains.

Derivatives of naturally occurring domains as used herein are intended to refer to substitutions or deletions of one, two, three, four or five amino acids in a naturally occurring sequence, such as by eliminating unwanted properties, for example, to optimize the properties of the domain, but wherein the characteristics of the domain are preserved.

Antibodies for use in the invention may be conjugated to one or more effector molecules, if desired. It will be appreciated that an effector molecule may comprise a single effector molecule or two or more such molecules that are so linked to form a single moiety that may be attached to an antibody of the invention. When it is desired to obtain an antibody fragment linked to an effector molecule, it can be prepared by standard chemical or recombinant DNA procedures, wherein the antibody fragment is linked to the effector molecule 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, 2 nd edition, robinson et al, 1987, pages 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 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 0392745.

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 radioiodides; a radioisotope; chelating a metal; a nanoparticle; and reporter groups such as fluorescent compounds or compounds that can be detected by NMR or ESR spectroscopy.

Other effector molecules may include detectable substances that may be used, for example, in diagnostics. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, radionuclides, positron emitting metals (for 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 isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; suitable luminescent materials include luminol; suitable bioluminescent materials include luciferase, luciferin and aequorin; and suitable radionuclides include 125I, 131I, 111In, and 99Tc.

In another example, effector molecules may increase the in vivo half-life of an antibody, and/or reduce the immunogenicity of an antibody and/or enhance delivery of an antibody across an epithelial barrier to the immune system. Examples of suitable effector molecules of this type include polymers, 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 occurring polymer, such as an optionally substituted linear or branched polyalkylene, polyalkylene or polyoxyalkylene polymer or a branched or unbranched polysaccharide, such as a homopolysaccharide or heteropolysaccharide.

Specific optional substituents that may be present on the synthetic polymers mentioned above 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, especially optionally substituted poly (ethylene glycol), such as methoxy poly (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 attached to the polymer directly or through a linker segment. It will be appreciated that residues of such groups will in some cases form part of the product as linking groups between the antibody fragment and the polymer.

Suitable polymers include polyalkylene polymers such as poly (ethylene glycol) or especially methoxy poly (ethylene glycol) or derivatives thereof, and especially molecular weights in the range of about 15000Da to about 40000 Da.

In one example, the antibodies used in the present invention are attached to a poly (ethylene glycol) (PEG) moiety. In a specific 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 (e.g., any free amino, imino, thiol, hydroxyl, or carboxyl group) located in the antibody fragment. Such amino acids may naturally occur in antibody fragments, or may be engineered into fragments using recombinant DNA methods (see, e.g., US 5,219,996;US 5,667,425;WO98/25971; wo 2008/038024). In one example, the antibody molecule of the invention is a modified Fab fragment, wherein the modification is the addition of one or more amino acids at the C-terminus of its heavy chain to effect attachment of an effector molecule. Suitably, the further amino acid forms a modified hinge region containing one or more cysteine residues to which effector molecules may be attached. Multiple sites may be used to attach two or more PEG molecules.

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

A "combination" as described herein is intended to encompass the case where an anti-IL 13R antibody is administered prior to, concurrent with, another therapy.

Therapy as described herein refers to ameliorating symptoms or conditions of a disease, including stabilizing the disease and/or alleviating the disease, making onset unlikely, etc., particularly without causing dose limiting side effects. Suitable therapeutic doses are typically a balance between therapeutic effects and tolerable toxicity, e.g., where side effects and toxicity are tolerable in view of the benefits achieved by therapy.

In a separate aspect, an antibody or antigen binding fragment thereof is provided that is an inhibitor of signaling through the receptor by binding IL-13 ra 1 for use in treating atopic dermatitis (moderate, severe or extremely severe atopic dermatitis, particularly poorly controlled moderate to severe atopic dermatitis) by parenteral administration of a treatment cycle comprising a dose in the range of 200mg to 600mg (such as 400mg to 600 mg), wherein the occurrence of conjunctivitis is minimized, e.g., as detailed herein.

Conjunctivitis can be a side effect of biotherapy for atopic dermatitis. Advantageously, such side effects are minimized in therapies according to the present disclosure, particularly where such side effects are not observed with the Sha Jishan anti-treatment.

In one embodiment, a formulation according to the present disclosure (including formulations comprising the same) is administered monthly, for example, during a treatment cycle or as maintenance therapy.

In the context of this specification, "comprising" should be interpreted as "including". Embodiments of the invention that include certain features/elements are also intended to extend to alternative embodiments that "consist of" or "consist essentially of the relevant elements/features. Embodiments of the invention may be combined where technically appropriate.

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

Any of the embodiments specifically and explicitly recited herein may form the basis of disclaimers, alone or in combination with one or more additional embodiments.

The background section of the present specification contains relevant technical information and may be used as a basis for modification.

The subject matter headings herein are used to divide a document into sections and are not intended to interpret the meaning of the disclosure provided herein.

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

Drawings

FIG. 1A shows patient demographics for a complete analysis set

FIG. 1B shows baseline disease characteristics of a complete analysis set

FIG. 1C shows baseline characteristics of data for evaluable efficacy

FIG. 2A shows the percent change from baseline in EASI score on day 57

Fig. 2B shows the percent change from baseline in EASI scores on day 57.

FIG. 2C shows the percent change from baseline in EASI score on day 57

FIG. 3A shows the percent change from baseline in EASI score on day 29

FIG. 3B shows the percent change from baseline in EASI score on day 29

FIG. 4A shows the percent change in EASI score from baseline over time

FIG. 4B shows the percent change in EASI score from baseline over time

Figure 5A shows the percent change in EASI score from baseline over time for individual patients

FIG. 5B shows the percent change from baseline in EASI score over time for 200mg of individual patients

FIG. 5C shows the percent change from baseline in EASI score over time for 400mg of individual patients

FIG. 5D shows the percent change from baseline in EASI score over time for 600mg of individual patients

FIG. 6A shows a day 57 sensitivity assay in mITT

FIG. 6B shows sensitivity analysis in mITT (200, 400 and 600 mg)

FIG. 6C shows analysis in mITT (low and high dose)

FIG. 7A shows EASI 50, EASI 75 and EASI 90 on day 57

FIG. 7B shows EASI 50 (200, 400 and 600 mg) on day 57

FIG. 7C shows EASI 50 (low and high dose) on day 57

FIG. 7D shows EASI 75 (200, 400 and 600 mg) on day 57

FIG. 7E shows EASI 75 (low and high dose) on day 57

FIG. 7F shows EASI 90 (200, 400 and 600 mg) on day 57

FIG. 7G shows EASI 90 (low and high dose) on day 57

FIG. 8A shows the percent decrease in EASI 50 over time

FIG. 8B shows the percent decrease in EASI 75 over time

FIG. 8C shows the percent decrease in EASI 90 over time

FIG. 9 shows sensitivity analysis in Mitt

FIG. 10A shows in summary form the proportion of patients with IGA score of 0 or 1 on day 57

FIG. 10B shows the proportion of patients with IGA score of 0 or 1 on day 57

FIG. 10C shows the proportion of patients with IGA score of 0 or 1

FIG. 11 shows baseline TARC and IgE for patients

FIG. 12A shows the average percent change from baseline TARC (200 mg and 400 mg)

FIG. 12B shows the mean percent change from baseline TARC (400 mg and placebo)

FIG. 12C shows the percent change in TARC from baseline for individual patients

FIG. 13A shows percentage IgE change from baseline (200 mg and 400 mg)

FIG. 13B shows the average percentage change in IgE from baseline (200 mg and 400 mg)

Figure 13C shows the percentage IgE change from baseline for 3 individual patients

FIG. 13D shows percentage IgE change from baseline for 4 individual patients receiving 200mg

FIG. 13E shows percentage IgE change from baseline for 6 individual patients receiving 400mg

Figure 14 shows the anti-exposure of Sha Jishan, average EASI score, average TARC level and average Ige level.

FIG. 15 shows a comparison of the anti-efficacy of Sha Jishan versus the anti-efficacy of Dupu Li Youshan

FIG. 16 shows the median percent change from baseline for IgE-degree-common Li Youshan antibodies

FIG. 17 shows the percent change from baseline for 300mg of Li Youshan antibody administered weekly

FIG. 18 shows the intensity of staining for IL-13Rα1 expression in healthy skin, non-focal atopic dermatitis and focal atopic dermatitis

FIG. 19 shows stained IL-13Rα1 expression on mast cells and eosinophils for healthy skin, non-focal atopic dermatitis and focal atopic dermatitis

FIG. 20 shows gene expression of type I and type II IL-13 receptors

Detailed Description

Example 1

Study protocol (initial MAD increment)

Patients entered the incremental dose cohort for group ib Sha Jishan antibodies (SEQ ID NOs: 51, 53, and 59 herein): 200mg, 400mg, 600mg. ASLAN low dose = i Sha Jishan anti-200 mg, aslan high dose = i Sha Jishan anti-400 mg + i Sha Jishan anti-600 mg.

The details of the patient are shown in figure 1. Initially, doses (QW) were administered weekly. In each cohort, patients were randomized at a 3:1 ratio of Sha Jishan anti-placebo

Results

Table 1 shows the percentage change in baseline of EASI scores on day 57 (week 8).

Table 1-percent change in baseline of EASI scores on day 57 (8 weeks)

Table 2 shows the percentage change in baseline of EASI scores on day 29 (week 4).

Table 2-percent change in baseline of EASI scores on day 29 (4 weeks)

Table 3 shows sensitivity analysis of the 57 day mITT (modified intent-to-treat) group

TABLE 3 sensitivity analysis of mITT at 57 th day

Table 4 shows a summary of patient proportions that achieved EASI 50, EASI 75 and EASI 90 on day 57.

Table 4-day 57 EASI 50, EASI 75 and EASI 90

The results indicated that the Sha Jishan antibody significantly improved EASI scores compared to placebo. In particular, at week 8, the mean decrease in EASI from baseline at therapeutic doses (400 mg and 600mg cohorts) was 74% (n=9) compared to 42% (n=5) for placebo patients.

O 89% achieved EASI-50, 40% relative to placebo;

o 67% achieved EASI-75, 0% relative to placebo;

o 56% realizes EASI-90, 0% relative to placebo

The results further demonstrate that the anti-i Sha Jishan has comparable or in some cases higher efficacy compared to the anti-duprin Li Youshan, thus demonstrating the potential of the anti-i Sha Jishan as a replacement therapy for the treatment and management of atopic dermatitis.

Example 2

Of the 32 patients (defined in the protocol as an evaluable efficacy set) who completed the indicated 29-day dosing on all sites, the mean decrease from baseline for EASI at 8 weeks was 73% (n=19), compared to 44% (n=13) for 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. In the expansion queue, conjunctivitis did not occur.

TABLE 5

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¹ Single-sided p-value

The Sha Jishan antibody achieved statistically significant improvement over placebo at the primary efficacy endpoint of the percent change from baseline in Eczema Area Severity Index (EASI) (p < 0.025), and also showed significant improvement at other key efficacy endpoints (p < 0.05): EASI-50, EASI-75, peak itching and Patient derived evaluation of eczema (Patent-Oriented Eczema Measure, POEM).

After the pre-blinding discussion with the data review board (Data Monitoring Committee), a revised intent-to-treat group (RITT, n=29) was defined to exclude a study site where all patients participating in the study were shown to be atypical 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 of moderate to severe AD), the i Sha Jishan antibody also achieved statistically significant improvement over placebo in terms of percent change from baseline for EASI (p < 0.025) and showed greater improvement over placebo in terms of key efficacy endpoints compared to ITT population.

Example 3

Patients with atopic dermatitis were enrolled in multicentric, randomized, double blind, placebo-controlled, multiple ascending doses of studies on safety, tolerability and pharmacokinetics of subcutaneous delivery of the Sha Jishan antibody. While a patient may clinically develop "symptoms" such as itch of skin, the root cause may be a variety of pathological changes. The TARC levels exhibited in clinical trials for patients with moderate to severe atopic dermatitis range from 214pg/ml to about 22,600pg/ml. The baseline IgE levels for patients identified as having relevant criteria for moderate to severe atopic dermatitis ranged from 434pg/ml to 19,175pg/ml.

Example 4

IHC was performed on focal (L) and non-focal (NL) skin from 14 AD patients and 10 matched controls (HC). Skin samples were stained for IL-13 ra 1, tryptase and major basic proteins to determine the distribution of IL-13 ra 1 in AD and its relationship to mast cells and eosinophils.

U937 cells are a monocyte cell line used to evaluate the function of type I and type II receptors because these cells express both receptors. Cells were incubated with Sha Jishan anti-IL-13 ra 1 to block type II receptors, with anti-common gamma chains to block type I receptors, and with anti-IL 4 ra to block type I and type II receptors. After 24 hours of incubation, the cells were stimulated with vehicle or a mixture of IL-4+IL-13 and RNA sequencing was performed. IHC data were quantified using ImageJ. RNA sequencing data were subjected to differential expression analysis using DESeq2 package for R.

IHC showed increased IL-13 ra 1 staining in L (P < 0.001) and NL (p=0.045) AD skin compared to HC. Compared to HC, the average IL-13 ra 1 staining intensity of mast cells in L (p=0.034) and NL (p=0.031) AD samples was increased. The average IL-13 ra 1 staining intensity of eosinophils in L (p=0.024) and NL (p=0.046) AD skin was also increased compared to HC. Blocking type I receptors with anti-common gamma chain antibodies results in up-regulation of genes such as MMP9 (P < 0.001). The use of the Sha Jishan anti-blocking type II receptor results in inhibition of genes such as XBP1 (P < 0.001) and CXCL8 (p=0.046). FIG. 20 shows the use of anti-chain antibodies to block differentially expressed genes of type I receptors. B) The use of ib Sha Jishan anti-blocking genes for differential expression of type II receptors.

Summary

Increased IL-13Rα1 expression in L and NL AD skin compared to HC

Increased mast cell IL-13Rα1 expression in L and NL AD skin compared to HC

Increased eosinophil IL-13Rα1 expression in L and NL AD skin as compared to HC

There is a signaling difference between type I and type II receptors.

Claims

1. An antibody or antigen binding fragment thereof that is an inhibitor of signaling through the IL-13 ra 1 receptor by binding to IL-13 ra 1 for use in the treatment of moderate, severe or extremely severe atopic dermatitis (particularly poorly controlled moderate to severe atopic dermatitis) by parenteral administration of a treatment cycle comprising a dose in the range of 200mg to 600mg (such as 400mg to 600 mg), characterized by an EASI score of 16 or more (such as ,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).

1A, a method of treatment by parenterally administering to a patient suffering from moderate, severe or very severe atopic dermatitis a treatment cycle comprising a dose ranging from 200mg to 600mg (such as 400mg to 600 mg) of an antibody or antigen binding fragment thereof which is an inhibitor of signaling through the IL-13 ra 1 receptor by binding to IL-13 ra 1, characterized by an EASI score of 16 or more (such as ,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).

2. The antibody or antigen-binding fragment thereof for use or the method of any one of the preceding claims, wherein the atopic dermatitis is focal.

3. The antibody or antigen-binding fragment thereof or method for use of any one of the preceding claims, wherein the antibody or fragment is administered to a patient previously receiving excessive use Li Youshan of antibodies, e.g., a patient having side effects using dutch Li Youshan of antibodies.

4. The antibody or antigen binding fragment thereof or method for use of any one of the preceding claims, wherein the IL-13 ra 1 has reduced side effects and/or improved efficacy compared to the degree pro Li Youshan antibody.

5. The antibody or antigen-binding fragment thereof or method of any one of the preceding claims, wherein baseline TARC level is at least 1,115pg/mL, e.g., in the range of 1,115pg/mL to 4,300pg/mL or above 4,300pg/mL

6. The antibody or antigen binding fragment thereof or method of any one of the preceding claims, wherein baseline STAT6 is higher than normal.

7. The antibody or antigen-binding fragment thereof or method of any one of claims 1 to 4, wherein the patient has a baseline IGA score of 3 or higher, which is moderate to severe atopic dermatitis, such as 3 (moderate atopic dermatitis), 4 (severe atopic dermatitis), or 5 (severe atopic dermatitis).

8. The antibody or antigen-binding fragment thereof or method of any one of claims 1 to 5, wherein baseline IgE levels are at a level of at least 150KU/L, e.g., 1000KU/L、1500KU/L、2,000KU/L、2,500KU/L、3,000KU/L、3500KU/L、4,000KU/L、4,500KU/L、5,000KU/L、5,500KU/L、6,000KU/L、6,500KU/L、7,000KU/L、7,500KU/L、8,000KU/L、8,500KU/L、9,000KU/L、9,50KU/L, such as 10,000KU/L +/-2,000.

9. The antibody or antigen binding fragment thereof of any one of the preceding claims, wherein the one or more of the parameters (e.g., 2 or more or all of the parameters) have been measured prior to administration.

10. The antibody or antigen binding fragment of any one of the preceding claims, wherein the patient has been identified as having one or more (e.g., all) parameters (e.g., has been identified as being in a desired patient population) prior to initiation of treatment.

11. The antibody or antigen binding fragment thereof of any one of the preceding claims, wherein the atopic dermatitis is moderate, e.g. scored in the range of 16 to 21.0.

12. The antibody or antigen-binding fragment thereof of any one of claims 1 to 10, wherein the atopic dermatitis is severe, e.g., EASI score of 21.1 or higher, such as in the range of 21.1 to 50.0, or extremely severe, e.g., in the range of 50.1 to 72.0.

13. The antibody or antigen-binding fragment thereof of any one of claims 1 to 12, wherein a decrease in EASI score occurs after about two weeks (such as day 15) after administration of the first dose.

14. The antibody or antigen-binding fragment thereof of any one of claims 1 to 13, wherein a decrease in EASI score occurs after about four weeks (such as day 29) after administration of the first dose.

15. The antibody or antigen-binding fragment thereof of any one of claims 1 to 14, wherein a decrease in EASI score occurs after about six weeks (such as day 43) after administration of the first dose.

16. The antibody or antigen-binding fragment thereof of any one of claims 1 to 15, wherein a decrease in EASI score occurs after about eight weeks (such as day 57) after administration of the first dose.

17. The antibody or antigen-binding fragment thereof of any one of claims 1 to 16, wherein the treatment is administered subcutaneously.

18. The antibody or antigen-binding fragment thereof of any one of claims 1 to 17, wherein the dose is 200mg.

19. The antibody or antigen binding fragment thereof of any one of claims 1 to 17, wherein the dose ranges from 350 to 450mg, such as 400mg, e.g., wherein 80% of patient populations have EASI 50 at about day 29 and/or 57.

20. The antibody or binding fragment thereof of any one of claims 1 to 17, wherein the dose is 600mg.

21. The antibody or antigen binding fragment thereof of any one of the preceding claims, wherein the decrease in EASI score ranges from-25% to-60% (e.g. from-39% to-59%, such as from-40% to-59%, in particular from-47%, -48%, -49%, -50%, -51%, -52%, -53%, -54%, -55%, -56%, -57%, -58% or-59%), e.g. on about 15 days.

22. The antibody or antigen-binding fragment thereof of any one of claims 32 to 35, wherein the range of decrease in EASI score is:

from 50% to-100% (e.g., from-55% to-97%), particularly on 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. from-70% to-100, such as from-90% to-100%, in particular 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%), in particular on about day 57.

23. The antibody or antigen-binding fragment thereof of any one of claims 32 to 37, wherein 90% of patient populations have EASI 50 at about day 57.

24. The antibody or antigen binding fragment thereof of any one of claims 1 to 38, wherein the treatment cycle comprises a first dose of 600mg followed by a dose of 400mg three times per week, e.g. wherein the treatment cycle is repeated twice a week, i.e. two treatment cycles last for 8 weeks, in particular administered as follows: day 1: 600mg, about day 8: 400mg, about day 15: 400mg, about day 22: 400mg, about day 29: 600mg, about day 36: 400mg, about day 43: 400mg, about day 50: 400mg.

25. The antibody or antigen binding fragment of any one of claims 1 to 39, wherein a disease change occurs prior to day 4, wherein day 1 is the first administration of the antibody or binding fragment thereof, e.g., wherein the disease change is a decrease in EASI score, such as wherein the decrease is a percentage from baseline ranging from-10% to 55% (particularly wherein a disease change ranging from-40% to-100% is achieved prior to about day 57 after the first administration on day 1, e.g., the maximum disease change is achieved prior to about day 57).