Treatment of skin lesions and itching in prurigo nodularis patients

文档序号：260760 发布日期：2021-11-16 浏览：16次中文

阅读说明：本技术 结节性痒疹患者的皮肤病变和瘙痒的治疗 (Treatment of skin lesions and itching in prurigo nodularis patients ) 是由 C·皮凯蒂于 2020-01-28 设计创作，主要内容包括：本文公开了用于选择性地治疗患有慢性痒疹(CP)(包括结节性痒疹(PN))的受试者的瘙痒的方法,用于治疗患有CP或PN的受试者的瘙痒的药物组合物,奈莫利珠单抗或其等同物在制备用于治疗患有CP或PN的受试者的瘙痒的药物中的用途。(Disclosed herein are methods for selectively treating pruritus in a subject with Chronic Prurigo (CP), including Prurigo Nodularis (PN), pharmaceutical compositions for treating pruritus in a subject with CP or PN, use of nemulizumab or an equivalent thereof in the manufacture of a medicament for treating pruritus in a subject with CP or PN.)

1. A method of treating skin lesions and itch in a subject with Chronic Prurigo (CP), the method comprising administering to the subject an effective amount of nemulizumab or an equivalent thereof.

2. The method of claim 1, wherein the subject has Prurigo Nodularis (PN).

3. The method of claim 2, wherein the subject has been diagnosed with PN for at least about 6 months.

4. The method of any one of the preceding claims, wherein the subject has at least about 20 bilaterally distributed nodules on his/her body.

5. The method of any one of the preceding claims, wherein the subject has a prurigo lesion on the upper limb.

6. The method of any preceding claim, wherein the pruritus is assigned a score of at least 4 on the Numerical Rating Scale (NRS).

7. The method of any preceding claim, wherein the pruritus is assigned a score of at least 7 on the Numerical Rating Scale (NRS).

8. The method of any one of the preceding claims, wherein the subject is free of atopic dermatitis.

9. The method of any one of the preceding claims, wherein the effective amount of nemoruzumab, or the equivalent thereof, is about 0.01mg/kg to about 0.1mg/kg, about 0.1mg/kg to about 0.5mg/kg, about 0.5mg/kg to about 1.5mg/kg, about 1.5mg/kg to about 2.5mg/kg, or about 2.5mg/kg to about 10 mg/kg.

10. The method of any one of the preceding claims, wherein the effective amount of nemorubizumab or the equivalent thereof is about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90 mg.

11. The method of any one of the preceding claims, wherein the nemulizumab or the equivalent thereof is administered according to a fixed dosing regimen.

12. The method of any one of the preceding claims, wherein the nemulizumab or the equivalent thereof is administered according to a loading dose regimen.

13. The method of any one of the preceding claims, wherein the nemoruzumab or the equivalent thereof is administered by a topical or parenteral route.

14. The method of any one of the preceding claims, wherein the nemulizumab or the equivalent thereof is administered subcutaneously.

15. The method of any one of the preceding claims, wherein the nemorubizumab or the equivalent thereof is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks.

16. A pharmaceutical composition for treating skin lesions and itch in a subject with Chronic Prurigo (CP), said composition comprising nemoruzumab or an equivalent thereof.

17. The pharmaceutical composition of claim 16, wherein the subject has Prurigo Nodularis (PN).

18. The pharmaceutical composition of claim 17, wherein the subject has been diagnosed with PN for at least about 6 months.

19. The pharmaceutical composition of any one of claims 16-18, wherein the subject has at least about 20 bilaterally distributed nodules on his/her body.

20. The pharmaceutical composition of any one of claims 16-19, wherein the subject has a prurigo lesion on the upper limb.

21. The pharmaceutical composition of any one of claims 16-20, wherein the pruritus is assigned a score of at least 4 on the Numerical Rating Scale (NRS).

22. The pharmaceutical composition of any one of claims 16-21, wherein the pruritus is assigned a score of at least 7 on the Numerical Rating Scale (NRS).

23. The pharmaceutical composition of any one of claims 16-22, wherein the subject is free of atopic dermatitis.

24. The pharmaceutical composition of any one of claims 16-23, further comprising a carrier.

25. The pharmaceutical composition of claim 24, wherein the carrier is a pharmaceutically acceptable carrier.

26. The pharmaceutical composition according to any one of claims 16-25, wherein the nemorubizumab or the equivalent thereof is administered according to a fixed dosing regimen.

27. The pharmaceutical composition of any one of claims 16-25, wherein the nemorubizumab or the equivalent thereof is administered according to a loading dose regimen.

28. The pharmaceutical composition of any one of claims 16-27, wherein the composition comprises about 0.01mg/kg to about 0.1mg/kg, about 0.1mg/kg to about 0.5mg/kg, about 0.5mg/kg to about 1.5mg/kg, about 1.5mg/kg to about 2.5mg/kg, or about 2.5mg/kg to about 10mg/kg nemoruzumab, or the equivalent thereof.

29. The pharmaceutical composition of any one of claims 16-27, wherein the composition comprises about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg of nemorubizumab, or the equivalent thereof.

30. Use of nemoruzumab, or an equivalent thereof, in the manufacture of a medicament for treating skin lesions and pruritus in a subject suffering from Chronic Prurigo (CP).

31. The use of claim 30, wherein the subject has Prurigo Nodularis (PN).

32. The use of claim 31, wherein the subject has been diagnosed with PN for at least about 6 months.

33. The use of any one of claims 30-32, wherein the subject has at least about 20 bilaterally distributed nodules on his/her body.

34. The use of any one of claims 30-33, wherein the subject has a prurigo lesion on an upper limb.

35. The use of any one of claims 30-34, wherein the pruritus is assigned a score of at least 7 on the Numerical Rating Scale (NRS).

36. The use of any one of claims 30-35, wherein the pruritus is assigned a score of at least 7 on the Numerical Rating Scale (NRS).

37. The use of any one of claims 30-36, wherein the subject is free of atopic dermatitis.

38. The use of any one of claims 30-37, wherein the nemorubizumab or the equivalent thereof is administered according to a fixed dosing regimen.

39. The use of any one of claims 30-37, wherein the nemorubizumab or the equivalent thereof is administered according to a loading dose regimen.

40. The use of any one of claims 30-39, wherein the nemoruzumab, or the equivalent thereof, is administered at a dose of about 0.01mg/kg to about 0.1mg/kg, about 0.1mg/kg to about 0.5mg/kg, about 0.5mg/kg to about 1.5mg/kg, about 1.5mg/kg to about 2.5mg/kg, or about 2.5mg/kg to about 10 mg/kg.

41. The use of any one of claims 30-39, wherein the nemorubizumab or the equivalent thereof is administered at a dose of about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90 mg.

Technical Field

Described herein are methods for treating skin lesions and itch in a subject with Chronic Prurigo (CP), including Prurigo Nodularis (PN), pharmaceutical compositions for treating skin lesions and itch in a subject with CP, use of nemulizumab (nemolizumab) or an equivalent thereof in the manufacture of a medicament for treating skin lesions and itch in a subject with CP.

Background

The following discussion is provided to aid the reader in understanding the present disclosure and is not admitted to describe or constitute prior art to the present disclosure.

Chronic Prurigo (CP) is a skin disease caused by the sensitivity of neurons to itching and the development of the itch-scratching cycle. Prurigo Nodularis (PN), a subtype of CP, is a skin disease that causes hard, itchy bumps (nodules) to form on the skin. Itching (pruritus) can be intense, causing people to scratch themselves to a point of bleeding or pain. Scratching can lead to more skin lesions. Pruritus is exacerbated by fever, sweating, or irritation from clothing. In some cases, patients with PN have a history of other diseases, including eczema (atopic dermatitis), diabetes, lymphoma, HIV infection, severe anemia, or renal disease.

The exact reason for CP or PN is not known. Although scratching is known to cause more nodules to appear, it is not clear what causes itch to appear first. The diagnosis of the disease is based on observing signs, such as extreme itching of the skin with nodule formation. In some cases, a skin biopsy is used to confirm the diagnosis. Current treatments may include corticosteroid creams, oral medications, cryotherapy, or photochemotherapy.

There remains a need to develop new therapeutic regimens to treat patients with PN, particularly patients with chronic pruritus.

Disclosure of Invention

Provided herein are methods of treating skin lesions and itch in subjects with Chronic Prurigo (CP), including Prurigo Nodularis (PN), pharmaceutical compositions for treating skin lesions and itch in subjects with CP, including PN, use of nemulizumab or an equivalent thereof in the manufacture of a medicament for treating skin lesions and itch in subjects with CP, including PN.

According to some embodiments, there is provided a method of treating skin lesions and itch in a subject with CP, the method comprising, consisting of, or consisting essentially of administering to the subject an effective amount of nemulizumab or an equivalent thereof.

In some embodiments of the methods, the subject has Prurigo Nodularis (PN). In some embodiments of the method, the subject has been diagnosed with PN for at least about 6 months. In a particular embodiment of the method, the subject has at least about 20 bilaterally distributed nodules on his/her body. In particular embodiments of the method, the subject has a prurigo lesion on the upper limb, and a lesion or no lesion on the torso or lower limb. In particular embodiments of the method, the itch has been assigned a score of at least 4, and in some embodiments, the itch has been assigned a score of at least 7, on a Numerical Rating Scale (NRS). In a particular embodiment of the method, the average of the worst daily intensity of the NRS score is at least 7 on the first 3 days. In other particular embodiments of the method, the average of the worst daily intensity of the NRS score is at least 7 in the previous week.

In some embodiments of the method, the subject does not have atopic dermatitis. In some embodiments of the method, the subject is free of chronic pruritus caused by conditions other than PN, such as scabies, insect bites, chronic lichen simplex, psoriasis, acne, folliculitis, habitual scratching, lymphomatoid papulosis, chronic actinic dermatitis, dermatitis herpetiformis, sporotrichosis, bullous disease. In some embodiments of the method, the subject does not have neuropathic or psychogenic pruritus, such as paresthesia back pain, radial arm pruritus, dilutional parasitic disease (dilutional parasitosis), mimic disease.

In some embodiments of the methods, the effective amount of nemoruzumab, or an equivalent thereof, is in the range of about 0.01mg/kg to about 0.1mg/kg, about 0.1mg/kg to about 0.5mg/kg, about 0.5mg/kg to about 1.5mg/kg, about 1.5mg/kg to about 2.5mg/kg, or about 2.5mg/kg to about 10 mg/kg. In particular embodiments, an effective amount of nemoruzumab, or an equivalent thereof, is about 0.1mg/kg, about 0.5mg/kg, about 1mg/kg, about 1.5mg/kg, about 2mg/kg, or about 2.5 mg/kg. In a particular embodiment, the effective amount of nemorubizumab or equivalent thereof is a 40mg fixed dose (flat dose). In other particular embodiments, the effective amount of nemoruzumab, or an equivalent thereof, is 30mg and the loading dose is 60 mg. In other particular embodiments, the effective amount of nemoruzumab, or an equivalent thereof, is a fixed dose of 660 mg administered once every 4 weeks. In some embodiments of the method, the nemoruzumab, or an equivalent thereof, is administered by a topical or parenteral route. In some embodiments of the method, the nemulizumab or equivalent thereof is administered subcutaneously. In some embodiments, nemoruzumab, or an equivalent thereof, is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks. In certain embodiments, nemulizumab is administered for a period of at least 2 weeks, 3 weeks, 1 month, 1.5 months, 2 months, 3 months, 4 months, 5 months, 6 months, or longer.

According to some embodiments, there is provided a pharmaceutical composition for treating skin lesions and itch in a subject with Chronic Prurigo (CP), the composition comprising, consisting of, or consisting essentially of nemulizumab or an equivalent thereof.

In some embodiments of the pharmaceutical composition, the subject has Prurigo Nodularis (PN). In some embodiments of the composition, the subject has been diagnosed with PN for at least about 6 months. In particular embodiments of the composition, the subject has at least about 20 bilaterally distributed nodules on his/her body. In particular embodiments of the composition, the subject has a prurigo lesion on the upper limb, a lesion or no lesion on the torso or lower limb. In particular embodiments of the composition, the itch has been assigned a score of at least 4 on the Numerical Rating Scale (NRS), and in some embodiments, the itch has been assigned a score of at least 7. In particular embodiments of the composition, the average of the worst daily intensity of the NRS score is at least 7 on the first 3 days. In other particular embodiments of the composition, the average of the worst daily intensity of the NRS score is at least 7 in the previous week.

In some embodiments of the pharmaceutical composition, the subject does not have atopic dermatitis. In some embodiments of the composition, the subject is free of chronic pruritus caused by conditions other than PN, such as scabies, insect bites, chronic lichen simplex, psoriasis, acne, folliculitis, habitual scratching, lymphomatoid papulosis, chronic actinic dermatitis, dermatitis herpetiformis, sporotrichosis, bullous disease. In some embodiments of the composition, the subject is free of neuropathic or psychogenic pruritus, such as paresthesia back pain, brachial and radial pruritus, dilutive parasitic disease, mimic disease.

In some embodiments, the pharmaceutical composition further comprises a carrier. In some embodiments, the carrier is a pharmaceutically acceptable carrier.

In some embodiments of the pharmaceutical composition, nemulin or an equivalent thereof is administered according to a fixed dosing regimen, while in some embodiments, nemulin or an equivalent thereof is administered according to a loading dose regimen, wherein the loading dose may be higher than the subsequent series of doses (e.g., a 60mg loading dose followed by a 30mg series dose).

In some embodiments of the pharmaceutical composition, nemoruzumab, or an equivalent thereof, is administered at a dose of about 0.01mg/kg to about 0.1mg/kg, about 0.1mg/kg to about 0.5mg/kg, about 0.5mg/kg to about 1.5mg/kg, about 1.5mg/kg to about 2.5mg/kg, or about 2.5mg/kg to about 10 mg/kg. And in some embodiments, nemulizumab or an equivalent thereof is administered at a dose of about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg of nemulizumab or an equivalent thereof.

According to some embodiments, there is provided a method of treating pruritus in a subject with PN, comprising administering to the subject nemoruzumab or an equivalent thereof.

In some embodiments of the use, the pruritus is moderate to severe. In some embodiments of the use, the subject has been diagnosed with PN for at least 6 months. In a particular embodiment of the use, the subject has at least 20 bilaterally distributed nodules on his/her body. In particular embodiments of the use, the subject has a prurigo lesion on the upper limb, and a lesion or no lesion on the torso or lower limb. In particular embodiments of the use, the itch is assigned a score of at least 4, and in some embodiments, the itch is assigned a score of at least 7, on a Numerical Rating Scale (NRS). In a particular embodiment of the use, the mean value of the worst daily intensity of the NRS score is at least 7 on the first 3 days. In other particular embodiments of the use, the average of the worst daily intensity of the NRS score is at least 7 in the previous week.

In some embodiments of the use, the subject is free of atopic dermatitis. In some embodiments of the use, the subject is free of chronic pruritus caused by conditions other than PN, such as scabies, insect bites, chronic lichen simplex, psoriasis, acne, folliculitis, habitual scratching, lymphomatoid papulosis, chronic actinic dermatitis, dermatitis herpetiformis, sporotrichosis, bullous disease. In some embodiments of the use, the subject is free of neuropathic or psychogenic pruritus, such as paresthesia back pain, brachial and radial pruritus, dilutive parasitic disease, mimic disease.

In some embodiments of the use, nemulizumab or an equivalent thereof is administered according to a fixed dosing regimen, while in some embodiments nemulizumab or an equivalent thereof is administered according to a loading dose regimen, wherein the loading dose can be higher than the subsequent series of doses (e.g., a 60mg loading dose followed by a 30mg series dose).

In some embodiments of the use, nemoruzumab, or an equivalent thereof, is administered at a dose of about 0.01mg/kg to about 0.1mg/kg, about 0.1mg/kg to about 0.5mg/kg, about 0.5mg/kg to about 1.5mg/kg, about 1.5mg/kg to about 2.5mg/kg, or about 2.5mg/kg to about 10 mg/kg. And in some embodiments, nemulizumab or an equivalent thereof is administered at a dose of about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg of nemulizumab or an equivalent thereof.

Drawings

Figure 1 is an overview of a clinical study in which patients with Prurigo Nodularis (PN) were treated with nemulizumab for pruritus. Approximately 70 randomized patients from 2 groups (35 per group) were used to perform a multicenter (20 sites in the european union and united states), randomized, double-blind, placebo-controlled, parallel group study and stratified on an atopic background. Included patients received a dose of 0.5mg/kg nemorubizumab or placebo every 4 weeks from baseline to week 8.

Figure 2 shows the percent change from baseline in the weekly average peak itch value rating scale (NRS) at week 4.

Figure 3 shows the percent change from baseline in the mean peak pruritus NRS weekly over 18 weeks.

Figure 4 shows the absolute change from baseline in the mean peak pruritus NRS weekly over 18 weeks.

Figure 5 shows the absolute change from baseline in the mean weekly peak pruritus NRS over 18 weeks in patients without atopy.

Figure 6 shows the absolute change from baseline in the mean weekly peak pruritus NRS over 18 weeks in patients with atopy.

Figure 7 shows the proportion of subjects who had obtained the global assessment (IGA) success (0/1) of the investigator. The global assessment (IGA) score of the investigator ranged from 0 (clear) to 4 (severe disease) and was expressed as the percentage of patients in the indicated population.

Figure 8 shows the IGA distribution in patients treated over 18 weeks.

Figure 9 shows the percent change in the treated speech rating scale (VRS) over 18 weeks. The speech scoring scale (VRS) is a one-dimensional scale that allows patients to describe their degree of itch by increasing adjectives.

FIG. 10 shows dermatological quality of life index (DLQI) responders (. gtoreq.4) at week 4 and week 12. The dermatological quality of life index (DLQI) score ranges from 0 to 30, with higher scores indicating lower quality of life.

Fig. 11 shows the change from baseline in DLQI at week 4 and week 12.

Figure 12 compares whole body images of patients before nemoruzumab treatment (a and C) and after 16 weeks of treatment (B and D).

Figure 13 compares the whole body images of the patient before nemoruzumab treatment (a and C) and after 16 weeks of treatment (B and D).

Figure 14 compares the whole body images of the patient before nemoruzumab treatment (a and C) and after 16 weeks of treatment (B and D).

Figure 15 shows the percent change in the average pruritus Numerical Rating Scale (NRS) over 18 weeks of treatment.

Figure 16 shows the proportion of subjects cured with a Prurigo Activity Score (PAS) of 75% over 18 weeks of treatment.

Figure 17 shows the proportion of subjects cured with a Prurigo Activity Score (PAS) of 50% over 18 weeks of treatment.

Figure 18 shows the proportion of subjects cured with a Prurigo Activity Score (PAS) of 0-24% over 18 weeks of treatment.

Figure 19 shows the percent change from baseline in NRS for sleep disorders at week 4.

Fig. 20 shows the percentage change of NRS in sleep disorder at week 4.

Detailed Description

Embodiments in accordance with the present disclosure are described more fully below. Aspects of the present disclosure may, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. The terminology used in the description herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of this application and the relevant art and should not be interpreted in an idealized or overly formal sense unless expressly so defined herein. Although not explicitly defined below, such terms should be interpreted according to their usual meaning.

The terminology used in the description herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein can be used in any combination. Furthermore, the present disclosure also contemplates that, in some embodiments, any feature or combination of features set forth herein may be excluded or omitted. For example, if the specification states that a complex comprises components A, B and C, it is specifically intended that any one or combination of A, B or C can be omitted and disclaimed individually or in any combination.

Unless expressly stated otherwise, all specified embodiments, features and terms are intended to include the recited embodiments, features or terms and their biological equivalents.

Definition of

As used herein, the singular forms "a", "an" and "the" refer to the singular and plural referents unless the context clearly dictates otherwise.

It is to be understood that all numerical designations are preceded by the term "about," although this is not always explicitly stated. The term "about" means that the number understood is not limited to the exact number set forth herein, but is intended to refer to a number that substantially surrounds the number without departing from the scope of the invention. As used herein, "about" will be understood by one of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If the use of a term is not clear to one of ordinary skill in the art given the context in which the term is used, then "about" will mean up to plus or minus 15%, 10%, 5%, 1%, or 0.1% of the particular term.

And as used herein, "and/or" refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative ("or").

The terms "administration", "administration" or "administering" as used herein refer to (1) providing, giving, dosing and/or prescribing, such as by or under the direction of a health professional or his or her authorized agent, and (2) taking, taking or using, such as by or by a health professional or subject. Administration shall include, but is not limited to, administration by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection or implant), by inhalation spray nasal, vaginal, rectal, sublingual, urethral (e.g., urethral suppositories), or topical administration routes (e.g., gels, ointments, creams, aerosols, etc.), and may be formulated, alone or together, into suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, excipients, and vehicles appropriate for each route of administration. The present invention is not limited by the route of administration, formulation or dosing regimen.

The terms "treat", "treating" or "treatment" as used herein include slowing, alleviating or ameliorating PN, pruritus or one or more symptoms thereof, whether PN and/or pruritus is considered "cured" or "healed", and whether all symptoms subside. The term also includes reducing or preventing the progression of PN and/or pruritus or one or more symptoms thereof, hindering or preventing the underlying mechanisms of PN and/or pruritus or one or more symptoms thereof, and achieving any therapeutic and/or prophylactic benefit.

Interleukin 31 receptor subunit alpha ("IL-31 RA", also known as NR10, glm-r and GPL) is a protein that forms heterodimers with the oncostatin M receptor (OSMR) and acts as an IL-31 receptor. There are a number of known splice variants of human IL-31RA (WO 00/075314): NR10.1 consists of 662 amino acids and contains a transmembrane domain. NR10.2 is a soluble receptor-like protein and consists of 252 amino acids, without a transmembrane domain. Meanwhile, known splice variants of IL-31RA, which are used as transmembrane receptor proteins, include NR10.3 and IL-31RAv 3. Preferred IL-31RA variants include NR10.3 (also known as ILRAv4 (Nature Immunol 5,752-60,2004)) and IL-31RAv 3. NR10.3 (IL31RAv4) consists of 662 amino acids (WO 00/075314; "Natural immunology" 5,752-60,2004) and IL31RAv3 consists of 732 amino acids (GenBank accession No.: NM-139017).

The amino acid sequence of IL31RAv4 is:

MKLSPQPSCVNLGMMWTWALWMLPSLCKFSLAALPAKPENISCVYYYRKNLTCTWSPGKETSYTQYTVKRTYAFGEKHDNCTTNSSTSENRASCSFFLPRITIPDNYTIEVEAENGDGVIKSHMTYWRLENIAKTEPPKIFRVKPVLGIKRMIQIEWIKPELAPVSSDLKYTLRFRTVNSTSWMEVNFAKNRKDKNQTYNLTGLQPFTEYVIALRCAVKESKFWSDWSQEKMGMTEEEAPCGLELWRVLKPAEADGRRPVRLLWKKARGAPVLEKTLGYNIWYYPESNTNLTETMNTTNQQLELHLGGESFWVSMISYNSLGKSPVATLRIPAIQEKSFQCIEVMQACVAEDQLVVKWQSSALDVNTWMIEWFPDVDSEPTTLSWESVSQATNWTIQQDKLKPFWCYNISVYPMLHDKVGEPYSIQAYAKEGVPSEGPETKVENIGVKTVTITWKEIPKSERKGIICNYTIFYQAEGGKGFSKTVNSSILQYGLESLKRKTSYIVQVMASTSAGGTNGTSINFKTLSFSVFEIILITSLIGGGLLILIILTVAYGLKKPNKLTHLCWPTVPNPAESSIATWHGDDFKDKLNLKESDDSVNTEDRILKPCSTPSDKLVIDKLVVNFGNVLQEIFTDEARTGQENNLGGEKNGTRILSSCPTSI(SEQ ID NO:1)

the amino acid sequence of IL31RAv3 is:

MMWTWALWMLPSLCKFSLAALPAKPENISCVYYYRKNLTCTWSPGKETSYTQYTVKRTYAFGEKHDNCTTNSSTSENRASCSFFLPRITIPDNYTIEVEAENGDGVIKSHMTYWRLENIAKTEPPKIFRVKPVLGIKRMIQIEWIKPELAPVSSDLKYTLRFRTVNSTSWMEVNFAKNRKDKNQTYNLTGLQPFTEYVIALRCAVKESKFWSDWSQEKMGMTEEEAPCGLELWRVLKPAEADGRRPVRLLWKKARGAPVLEKTLGYNIWYYPESNTNLTETMNTTNQQLELHLGGESFWVSMISYNSLGKSPVATLRIPAIQEKSFQCIEVMQACVAEDQLVVKWQSSALDVNTWMIEWFPDVDSEPTTLSWESVSQATNWTIQQDKLKPFWCYNISVYPMLHDKVGEPYSIQAYAKEGVPSEGPETKVENIGVKTVTITWKEIPKSERKGIICNYTIFYQAEGGKGFSKTVNSSILQYGLESLKRKTSYIVQVMASTSAGGTNGTSINFKTLSFSVFEIILITSLIGGGLLILIILTVAYGLKKPNKLTHLCWPTVPNPAESSIATWHGDDFKDKLNLKESDDSVNTEDRILKPCSTPSDKLVIDKLVVNFGNVLQEIFTDEARTGQENNLGGEKNGYVTCPFRPDCPLGKSFEELPVSPEIPPRKSQYLRSRMPEGTRPEAKEQLLFSGQSLVPDHLCEEGAPNPYLKNSVTAREFLVSEKLPEHTKGEV(SEQ ID NO:2)

murine IL-31RA includes proteins comprising the amino acid sequence:

MWTLALWAFSFLCKFSLAVLPTKPENISCVFYFDRNLTCTWRPEKETNDTSYIVTLTYSYGKSNYSDNATEASYSFPRSCAMPPDICSVEVQAQNGDGKVKSDITYWHLISIAKTEPPIILSVNPICNRMFQIQWKPREKTRGFPLVCMLRFRTVNSSRWTEVNFENCKQVCNLTGLQAFTEYVLALRFRFNDSRYWSKWSKEETRVTMEEVPHVLDLWRILEPADMNGDRKVRLLWKKARGAPVLEKTFGYHIQYFAENSTNLTEINNITTQQYELLLMSQAHSVSVTSFNSLGKSQEAILRIPDVHEKTFQYIKSMKAYIAEPLLVVNWQSSIPAVDTWIVEWLPEAAMSKFPALSWESVSQVTNWTIEQDKLKPFTCYNISVYPVLGHRVGEPYSIQAYAKEGTPLKGPETRVENIGLRTATITWKEIPKSARNGFINNYTVFYQAEGGKELSKTVNSHALQCDLESLTRRTSYTVWVMASTRAGGTNGVRINFKTLSISVFEIVLLTSLVGGGLLLLSIKTVTFGLRKPNRLTPLCCPDVPNPAESSLATWLGDGFKKSNMKETGNSGDTEDVVLKPCPVPADLIDKLVVNFENFLEVVLTEEAGKGQASILGGEANEYVTSPSRPDGPPGKSFKEPSVLTEVASEDSHSTCSRMADEAYSELARQPSSSCQSPGLSPPREDQAQNPYLKNSVTTREFLVHENIPEHSKGEV(SEQ ID NO:3)

the cynomolgus monkey-derived IL-31RA comprises a protein comprising the amino acid sequence:

MMWTWALWMFPLLCKFGLAALPAKPENISCVYYYRKNLTCTWSPGKETSYTQYTAKRTYAFGKKHDNCTTSSSTSENRASCSFFLPRITIPDNYTIEVEAENGDGVIKSDMTCWRLEDIAKTEPPEIFSVKPVLGIKRMIRIEWIKPELAPVSSDLKYALRFRTVNSTSWMEVNFAKNRKDTNQTYNLMGLQAFTEYVVALRCAVKESKFWSDWSQEKMGMTEEEAPCGLELWRVLKPTEVDGRRPVRLLWKKARGAPVLEKTLGYNIWYFPENNTNLTETVNTTNQQLELHLGGESYWVSMISYNSLGKSPVTTLRIPAIQEKSFRCIEVMQACLAEDQLVVKWQSSALDVNTWMIEWFPDMDSEHPTLSWESVSQATNWTIQQDKLKPFWCYNISVYPMLHDKVGEPYSIQAYAKEGIPSKGPETKVENIGVKTVTITWKEIPKSERKGIICNYTIFYQAEGGKGFSKTVNSSILQYGLESLKRKTSYTVRVMASTSAGGINGTSINFKTLSFSVFEIILITSLIGGGLLILIILTVAYGLKKPNKLTHLCWPSVPNPAESSIATWRGDDFKDKLNLKESDDSVNTEDRILKPCSTPSDKLVIDKSVVNFGNVLQEMFTDEARTGQENNLGGEKNEYVTHPFRADCPLGKSFEELPVSPEIPPRKSQYLRSRMPEGTCLEAEEQLLVSGQSLESLAPDHVREAAAPNPYLKNSVTTREFLVSQKLPEHTKGEV(SEQ ID NO:4)

as used herein, the term "subject" is used interchangeably with "patient" and refers to a mammal, particularly a human, equine, bovine, porcine, feline, canine, murine, rat, or non-human primate. In a preferred embodiment, the subject is a human. In some embodiments, the subject has been diagnosed with PN for at least 6 months. In a particular embodiment, the subject has at least 20 bilaterally distributed nodules on his/her body. In particular embodiments, the subject has a prurigo lesion on the upper limb, and a lesion or no lesion on the torso or lower limb. In particular embodiments, the subject has pruritus that is assigned a score of at least 7 on the Numerical Rating Scale (NRS). In particular embodiments, the average of the worst daily intensity of the NRS score is at least 7 on the first 3 days. In other particular embodiments, the average of the worst daily intensity of the NRS score is at least 7 in the previous week.

In some embodiments, the subject is free of atopic dermatitis. In some embodiments, the subject is free of chronic pruritus caused by conditions other than PN, such as scabies, insect bites, lichen simplex chronicus, psoriasis, acne, folliculitis, habitual scratch, lymphomatoid papulosis, chronic actinic dermatitis, dermatitis herpetiformis, sporotrichosis, bullous disease. In some embodiments, the subject is free of neuropathic or psychogenic pruritus, such as paresthesia back pain, brachial and radial pruritus, dilutive parasitic disease, mimic disease.

The term "chronic prurigo" or ("CP") is used herein as it is in the art, and means a unique disease defined by the presence of chronic prurigo and multiple localized or systemic prurigo lesions. Chronic pruritic conditions are characterized by exfoliative, scaling or crusting plaques and/or papules and/or nodules, often with white or pink centers and hyperpigmented edges and scars. There are four subtypes of chronic pruritus: nodular type (prurigo nodularis or PN), common type (prurigo papulosa), plaque type, and umbilical type (Kyrle type). CP occurs due to the sensitivity of neurons to pruritus and the development of the pruritus-scratching cycle. CP can be dermatological, systemic, neurological, psychiatric/psychosomatic, multifactorial or unexplained. The term CP includes all stages and manifestations of chronic prurigo. The most notable subtype of CP is Prurigo Nodularis (PN). See Pereira et al, Journal of the European Academy of Dermatology and venereal (2018)32: 1059-.

The term "prurigo nodularis" (or "PN") is used herein as it is in the art, and means a skin disease that causes the formation of hard, itchy bumps (nodules) on the skin. Itching (pruritus) can be intense, causing people to scratch themselves to a point of bleeding or pain. Scratching can lead to more skin lesions. Pruritus is exacerbated by fever, sweating, or irritation from clothing. In some cases, patients with PN have a history of other diseases, including eczema (atopic dermatitis), diabetes, lymphoma, HIV infection, severe anemia, or renal disease. The exact cause of PN is not clear. It is believed that nodules are more likely to form when the skin has been scratched or somehow irritated. Thus, the act of a person scratching the skin can result in the formation of nodules. However, the reason why the skin becomes intense itching at first is not clear. Many people with PN have a history of eczema (atopic dermatitis), other skin conditions, or allergies. The main symptom of Prurigo Nodularis (PN) is the formation of hard, very itchy bumps (nodules) on the skin. The nubs may range in size from very small to about one-half inch in diameter. The nodules typically have a rough, dry top, and the number can range from a few to hundreds. Nodules are most often formed on the outer arms, shoulders and legs. Nodules can also form on the neck and torso, and they rarely form on the face and palms. They may be lighter or darker in color than the surrounding skin. Scarring may occur after the nodule begins to heal. Symptoms of PN can begin at any age, but are most commonly found in adults between 20-60 years of age. People with PN may become very concerned about the appearance of nodules, and a strongly itchy skin may interfere with sleep or daily activities. This can lead to stress and depression in people with PN.

The term "itch" is used herein as it is in the art, and refers to skin itch and/or a sense of itch. Pruritus may be caused by PN or other diseases or conditions, such as dry skin. In some cases, the itch relates to systemic itch of the skin throughout the body. In some cases, the itch is localized to a particular area of the body, such as on the arms or legs. Pruritus may be chronic or acute. Symptoms of itch include, but are not limited to, excoriation, redness, bumps, blotchiness, blisters, dry skin, chapped skin, and a leather-like or scaly texture of the skin. In some cases, itching does not result in a detectable change in the skin. Behavioral responses to itch include, but are not limited to, skin scratching and/or skin massaging. In some cases, skin scratching can result in exfoliation ranging from mild to severe. In some cases, patients with itching avoid scratching and/or massaging the skin. Traditional treatments for itch include, but are not limited to, skin moisturizers, topical emollients, antihistamines (such as diphenhydramine), corticosteroids (such as hydrocortisone topical creams), counter-irritants (such as peppermint, menthol or camphor), clomiphene (an antipruritic commonly used to treat scabies), topical anesthetics (such as benzocaine topical creams), and phototherapy. A common type of light used for phototherapy is UVB.

As used herein, the term "antibody" is collectively referred to as an immunoglobulin or immunoglobulin-like molecule, including, for example, but not limited to, IgA, IgD, IgE, IgG, and IgM, combinations thereof, or fragments thereof. Fragments of antibodies include, for example, but are not limited to, Fab fragments and single chain variable fragments (scFv), and similar molecules produced during the immune response of any vertebrate, for example, similar molecules produced in mammals such as humans, goats, rabbits and mice, and non-mammalian species such as shark immunoglobulins.

In terms of antibody structure, immunoglobulins typically have a heavy (H) chain and a light (L) chain interconnected by disulfide bonds. There are two types of light chains, λ (λ) and κ (κ). There are five main heavy chain classes (or isotypes) that determine the functional activity of an antibody molecule: IgM, IgD, IgG, IgA, and IgE. Each heavy and light chain comprises a constant region and a variable region (these regions are also referred to as "domains"). In combination, the heavy and light chain variable regions (also referred to as "Fab regions") specifically bind to an antigen. The light and heavy chain variable regions comprise "framework" regions, also referred to as "complementarity determining regions" or "CDRs," interrupted by three hypervariable regions. The framework regions and the extent of the CDRs have been defined (see Kabat et al, Sequences of Proteins of Immunological Interest, the U.S. department of Health and Human Services, 1991, which is hereby incorporated by reference). The Kabat database is now maintained online. The sequences of the framework regions of different light or heavy chains are relatively conserved across species. The framework regions of the antibody (i.e., the combined framework regions that make up the light and heavy chains) adopt predominantly a β -sheet conformation, and the CDRs form loops that connect, and in some cases form part of, the β -sheet structure. Thus, the framework regions act to form a scaffold that positions the CDRs in the correct orientation by non-covalent interactions between the chains.

The CDRs are primarily responsible for binding to epitopes of the antigen. The CDRs of each chain are commonly referred to as CDR1, CDR2, and CDR3, numbered sequentially from the N-terminus, and are also commonly identified by the chain in which the particular CDR is located. Thus, V_HCDR3 is located in the variable domain of the heavy chain of the antibody in which it is found, and V_LCDR1 is the CDR1 from the variable domain of the light chain of the antibody in which it is found. Antibodies that bind IL-31RA will have a particular V_HRegion and V_LA region sequence, and fromBut rather have specific CDR sequences. Antibodies with different specificities (i.e., different binding sites for different antigens) have different CDRs. Although CDRs vary from antibody to antibody, only a limited number of amino acid positions in a CDR are directly involved in antigen binding. These positions in the CDRs are called Specificity Determining Residues (SDRs). The bases of antibodies play a role in modulating immune cell activity. This region is called the Fc fragment region (Fc) and consists of two heavy chains that contribute two or three constant domains depending on the class of antibody. The Fc region ensures that each antibody generates the appropriate immune response to a given antigen by binding to a specific class of proteins known as "Fc receptors" found on certain cells (such as B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, etc.). Since the constant domains of the heavy chains constitute the Fc region of an antibody, the class of heavy chains in an antibody determines their class effect. Heavy chains in antibodies include α, γ, δ, ε, and μ, and are associated with the antibody isotypes IgA, IgG, IgD, IgE, and IgM, respectively. This infers that antibodies of different isotypes have different class effects due to their different Fc regions binding and activating different types of receptors.

There are 4 subclasses of IgG (which is the most abundant antibody isotype found in human serum). Four highly conserved subclasses IgG1, IgG2, IgG3 and IgG 4. See generally, the world Wide Web, ncbi, nlm, nih, gov/PMC/articles/PMC 4202688/. The Amino acid sequences of the constant regions of these peptides are known in the art, see, for example, Rutishauser, U.S. et al, (1968) "Amino acid sequence of the Fc region of human gamma G-immunoglobulin (Amino acid sequence of the Fc region of human gamma G-immunoglobulin)" PNAS61(4): 1414-1421; shinoda et al, (1981) "Complete amino acid sequence of Fc region of human delta chain (Complete amino acid sequence of the Fc region of a human delta chain)" PNAS 78(2): 785-; and Robinson et al (1980) "Complete amino acid sequence of mouse immunoglobulin alpha chain (MOPC 511) (Complete amino acid sequence of a mouse immunoglobulin alpha chain (MOPC 511))" PNAS 77(8): 4909-4913.

Therapeutic antibodies

"Nemolizumab" is a humanized monoclonal antibody that binds to IL-31 RA. Nemulizumab is annotated as follows: immunoglobulin G2- κ, anti- [ homo sapiens IL31RA (interleukin 31 receptor subunit α) ], humanized monoclonal antibody; γ 2 heavy chain (1-445) [ humanized VH (homo IGHV1-2 x 02 (83.70%) - (IGHD) -IGHJ5 x 01) [8.8.14] (1-121) -homo sapiens IGHG2 x 01(CH 1C 10> S (135), R12> K (137), E16> G (141), S17> G (142) (122-; dimer (227: "230-. Nemolizumab has a disulfide bond at the following positions, Intra-H (C23-C104) 22-96148-204261-321367-42522 "-96" 148 "-204" 261 "-321" 367 "-425"; Intra-L (C23-C104)23'-88'134'-194'23 '-88' -134 '-194'; Inter-H-L (H5-CL 126)224-214'224 "-214'"; Inter-H-H (H8, H11) 227-. Nemulizumab has N-glycosylation sites at the following positions: h CH 2N 84.4:297,297'. Nemoruzumab lacks H chain C-terminal glycine and lysine (CHS G1> del, K2> del).

Nemulizumab heavy chain amino acid sequence:

QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYIMNWVRQAPGQGLEWMGLINPYNGGTDYNPQFQDRVTITADKSTSTAYMELSSLRSEDTAVYYCARDGYDDGPYTLETWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSP(SEQ ID NO:5)

nemoruzumab light chain amino acid sequence:

DIQMTQSPSSLSASVGDRVTITCQASEDIYSFVAWYQQKPGKAPKLLIYNAQTEAQGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHHYDSPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:6)

the variable domains of the heavy and light chain sequences are shown in bold above, and the CDR sequences are underlined/italicized.

Equivalent antibodies to nemulizumab include, but are not limited to: (i) an antibody having a heavy chain comprising at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99% or 100% amino acid sequence identity to the heavy chain sequence of nemulin, (ii) an antibody having a light chain comprising at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99% or 100% amino acid sequence identity to the light chain sequence of nemulin, (iii) an antibody having a variable region comprising at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or the variable region sequence of nemulin, At least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity, (iv) an antibody having a CDR comprising at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the CDR sequence of nemulin, (v) an antibody that binds to the same isoform of IL-31RA as nemulin (e.g., IL31-RAv3), optionally, the same epitope of IL-31RA, (vi) an antibody that blocks or neutralizes IL-31RA, (vii) an antibody that binds to the tumor suppressor M receptor (OSMR), and (viii) combinations thereof. For example, suitable equivalents include immunoglobulins or immunoglobulin-like molecules having the same or substantially similar heavy and light chain amino acid sequences as nemoruzumab. Additional exemplary nemulizumab equivalents are described, for example, in WO 2010/064697.

The equivalent of nemoruzumab may be a monoclonal antibody or a polyclonal antibody. Such monoclonal antibodies with IL31-RA binding and/or neutralizing activity can be obtained, for example, by the following procedure: an anti-IL 31-RA monoclonal antibody is prepared by using IL31-RA or a fragment thereof derived from a mammal such as a human or a mouse by a known method as an antigen, and then an antibody having IL31-RA binding and/or neutralizing activity is selected from the thus obtained anti-IL 31-RA monoclonal antibodies. Specifically, according to a conventional immunization method, a desired antigen or a cell expressing the desired antigen is used as a sensitizing antigen for immunization. The anti-IL 31-RA monoclonal antibody can be prepared by fusing the obtained immune cells with known parent cells using a conventional cell fusion method and screening it for monoclonal antibody-producing cells (hybridomas) by a conventional screening method. The animal to be immunized includes, for example, mammals such as mice, rats, rabbits, sheep, monkeys, goats, donkeys, cows, horses, and pigs. The antigen can be prepared according to known methods using known IL31-RA gene sequences, for example by methods using baculovirus (e.g., WO 98/46777).

Hybridomas can be prepared, for example, according to the method of Milstein et al (Kohler, G.and Milstein, C., (Methods Enzymol.) (1981)73: 3-46). When the immunogenicity of the antigen is low, immunization may be performed after linking the antigen to a macromolecule having immunogenicity such as albumin. The antigens used for the preparation of monoclonal antibodies having binding and/or neutralizing activity against human IL31-RA are not particularly limited as long as they are capable of preparing antibodies having binding and/or neutralizing activity against human IL31-RA. For example, it is known that there are variants of human IL31-RA, and any variant can be used as an immunogen, as long as it is capable of producing antibodies with binding and/or neutralizing activity against human IL31-RA. Alternatively, under the same conditions, peptide fragments of IL31-RA or proteins into which artificial mutations have been introduced in the native IL31-RA sequence may be used as immunogens. In the present disclosure, human IL31-RA.3 is one of the preferred immunogens in the preparation of antibodies with binding and/or neutralizing IL31-RA activity.

The IL31-RA binding activity of an equivalent antibody can be determined by methods known to those skilled in the art. Methods for determining the antigen-binding activity of an antibody include, for example, ELISA (enzyme linked immunosorbent assay), EIA (enzyme immunoassay), RIA (radioimmunoassay), and fluorescent antibody methods. For example, when using an enzyme immunoassay, a sample containing an antibody (such as purified antibody and a culture supernatant of antibody-producing cells) is added to an antigen-coated plate. A secondary antibody labeled with an enzyme, such as alkaline phosphatase, is added and the plate is incubated. After washing, an enzyme substrate such as p-nitrophenyl phosphate is added and absorbance is measured to evaluate antigen binding activity. The binding and/or neutralizing activity of an equivalent antibody against IL31-RA can be measured, for example, by observing the effect of inhibiting the growth of an IL-31-dependent cell line. For example, purified mouse IL-31 antibody activity can be determined by assessing IL-31 dependent growth of Ba/F3 cells transfected with mouse IL-31 receptor alpha and mouse OSMR genes.

The inventors have hypothesized that anti-pruritus agents may have a greater effect on PN in patients with moderate to severe pruritus.

In some embodiments, the pruritus is scored as none, mild, moderate, or severe. "none," "light," "moderate," and "heavy" are terms that describe the presence, extent, and/or intensity of scratches. The skilled person will know the boundaries of these terms.

In some embodiments, the pruritus is characterized according to one or more of the following methods known to those skilled in the art. For example, intensity can be measured rapidly with a single dimensional scale conventionally used in clinical care. See Pereira et al, International allergy (allergy International) 2017, 66:3-78, incorporated herein by reference. For example, patients may be asked to rate their intensity of itch from 0 ("no itch") 10 ("imaginable most severe itch") using a Numeric Rating Scale (NRS). Another single dimensional scale, the Visual Analog Scale (VAS), provides the patient with an opportunity to indicate the intensity of his itch by marking on a ruler-like scale 10cm long. Both endpoints are labeled with numbers corresponding to intensity, where 0 indicates "no itch" and 10 indicates "the most severe itch imaginable". A score of VAS/NRS below 3.0 points is generally associated with mild itching, while a score above 6.9 indicates severe itching. Scores above 9.0 represent very severe itching. The speech scoring scale (VRS) is an additional single dimensional scale that allows patients to describe their intensity of itch by increasing adjectives (0-no itch, 4-imaginable most severe itch). NRS, VAS and VRS have been validated in large-scale studies consisting of chronic pruritic patients with pruritic dermatoses or pruritus of various origins. These instruments have high reproducibility and there is a high correlation between scales 6, 7, 8. Chronic pruritus can greatly reduce the quality of life of a patient. Therefore, the dermatological quality of life index (DLQI) is widely used and has been validated. DLQI scores range from 0 to 30, with higher scores indicating lower quality of life. The global assessment (IGA) score of the investigators ranged from 0 (clear) to 5 (very severe disease) and was expressed as the percentage of patients in the indicated population. In this study, the IGA score ranged from 0 to 4.

Pharmaceutical composition

Provided herein are pharmaceutical compositions for treating skin lesions and itch in a subject with Chronic Prurigo (CP), the compositions comprising, consisting of, or consisting essentially of nemulizumab or an equivalent thereof. In addition, the present disclosure provides a therapeutic agent for CP comprising nemoruzumab or an equivalent thereof as an active ingredient.

In some embodiments, the subject has Prurigo Nodularis (PN). In some embodiments, the subject has been diagnosed with PN for at least about 6 months. In particular embodiments, the subject has at least about 20 bilaterally distributed nodules on his/her body. In particular embodiments, the subject has a prurigo lesion on the upper limb, and a lesion or no lesion on the torso or lower limb. In particular embodiments, the itch is assigned a score of at least 7 on the Numeric Rating Scale (NRS). In particular embodiments, the average of the worst daily intensity of the NRS score is at least 7 on the first 3 days. In other particular embodiments, the average of the worst daily intensity of the NRS score is at least 7 over the previous week.

The phrase "comprising nemulizumab or its equivalent as an active ingredient" means that nemulizumab or its equivalent is contained as at least one of the active ingredients, and the ratio of the antibodies is not limited. In addition, the therapeutic agents for PN in the present disclosure may also include other ingredients that enhance the treatment of PN in combination with nemulizumab or its equivalent. For example, the composition may include one or more of a topical corticosteroid cream or injection, an ointment containing menthol or phenol to cool and relieve itching of the skin, a capsaicin cream, an oral corticosteroid, a selective 5-hydroxytryptamine reuptake inhibitor (SSRI), and an oral antihistamine.

Pharmaceutical compositions of nemulizumab or an equivalent thereof of the present disclosure can be prepared as formulations according to standard methods (see, e.g., Remington's Pharmaceutical Science, Mark Publishing Company, easton, usa). In some embodiments, the pharmaceutical composition comprises a carrier and/or an additive. In some embodiments, the carrier is a pharmaceutically acceptable carrier. For example, in some embodiments, the pharmaceutical composition comprises one or more surfactants (e.g., PEG and tween), excipients, antioxidants (e.g., ascorbic acid), colorants, flavors, preservatives, stabilizers, buffers (e.g., phosphoric acid, citric acid, and other organic acids), chelating agents (e.g., EDTA), suspending agents, isotonic agents, binders, disintegrants, lubricants, flowability enhancers, flavoring agents, light anhydrous silicic acid, lactose, crystalline cellulose, mannitol, starch, carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylacetate, polyvinylpyrrolidone, gelatin, medium chain fatty acid triglycerides, polyoxyethylene hydrogenated castor oil 60, sucrose, carboxymethylcellulose, corn starch, and inorganic salts. In some embodiments, the pharmaceutical composition comprises one or more other low molecular weight polypeptides, proteins such as serum albumin, gelatin, and immunoglobulins, and amino acids such as glycine, glutamine, asparagine, arginine, and lysine.

When nemulizumab or an equivalent thereof is prepared as an aqueous injection solution, nemulizumab or an equivalent thereof can be dissolved in an isotonic solution containing, for example, physiological saline, glucose, or other adjuvants. Adjuvants may include, for example, D-sorbitol, D-mannose, D-mannitol, and sodium chloride. In addition, suitable solubilizing agents, such as alcohols (e.g., ethanol), polyols (e.g., propylene glycol and PEG), and nonionic detergents (polysorbate 80 and HCO-50) may be used together.

If necessary, nemorubizumab or its equivalent can be encapsulated in microcapsules (microcapsules made of hydroxymethylcellulose, gelatin, polymethylmethacrylate, etc.) and made as a component of a colloidal drug delivery system (liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) (see, for example, "&, Oslo Ed. (1980) in Remington pharmaceutical sciences, 16 th edition). In addition, methods for the preparation of sustained release drugs are known and these methods can be applied to nemorubizumab or its equivalent (Langer et al, J.biomed.Mater.Res.) (1981)15,167-277; Langer, chemical technology (chem.Tech.) (1982)12, 98-105; U.S. Pat. No. 3,773,919; European patent application (EP) No. 58,481; Sidman et al, biopolymer (Biopolymers) (1983)22,547-56; EP 133,988).

The pharmaceutical compositions of the present disclosure may be administered orally or parenterally, but preferably parenterally. In particular, the pharmaceutical composition is administered to a patient by injection or transdermal administration. Injections include, for example, intravenous, intramuscular, and subcutaneous injections, for systemic or local administration. The pharmaceutical composition may be administered to the site or area surrounding the site where inflammation is to be inhibited by local infusion or intramuscular injection. In some embodiments, the pharmaceutical composition is administered at or near one or more sites of exfoliation.

The administration method may be appropriately selected according to the age and condition of the patient. The single administration dose may be selected, for example, from the range of 0.0001mg to 100mg of active ingredient per kg body weight. Alternatively, for example, when the medicament is administered to a human patient, the dose of the active ingredient may be selected from the range of 0.001mg/kg to 1,000mg/kg body weight. In some embodiments, the composition is formulated to administer a composition containing, for example, about 0.01mg/kg to 50mg/kg, about 0.01mg/kg to about 0.1mg/kg, about 0.05mg/kg to 0.15mg/kg, about 0.1mg/kg to about 0.6mg/kg, about 0.1mg/kg to about 1mg/kg, about 0.25mg/kg to about 0.75mg/kg, about 0.4mg/kg to about 0.8mg/kg, about 0.4mg/kg to about 1.8mg/kg, about 0.5 to about 2.5mg/kg, about 0.8mg/kg to about 2.2mg/kg, about 1mg/kg to about 2.5mg/kg, about 1mg/kg to about 3.5mg/kg, about 1mg/kg to about 5mg/kg, about 2mg/kg to about 4mg/kg, about 2.5mg/kg to about 10mg/kg, about 10mg/kg, A dose of nemorubizumab or equivalent thereof at about 10mg/kg to about 20mg/kg, about 10mg/kg to about 40mg/kg, about 20mg/kg to about 50mg/kg, about 25mg/kg to about 75mg/kg, about 50mg/kg to about 100mg/kg or about 100mg/kg to about 500mg/kg or about 100mg/kg to about 1000mg/kg body weight. In preferred embodiments, the dosage range is from about 0.01mg/kg to about 0.1mg/kg, from about 0.1mg/kg to about 0.5mg/kg, from about 0.5mg/kg to about 1.5mg/kg, from about 1.5mg/kg to about 2.5mg/kg, or from about 2.5mg/kg to about 10 mg/kg. In some embodiments, the dose is about 0.01mg/kg, about 0.02mg/kg, about 0.03mg/kg, about 0.04mg/kg, about 0.05mg/kg, about 0.06mg/kg, about 0.07mg/kg, about 0.08mg/kg, about 0.09mg/kg, about 0.1mg/kg, about 0.2mg/kg, about 0.3mg/kg, about 0.4mg/kg, about 0.5mg/kg, about 0.6mg/kg, about 0.7mg/kg, about 0.8mg/kg, about 0.9mg/kg, about 1mg/kg, about 1.1mg/kg, about 1.2mg/kg, about 1.3mg/kg, about 1.4mg/kg, about 1.5mg/kg, about 1.6mg/kg, about 1.7mg/kg, about 1.8mg/kg, about 1.9mg/kg, about 2mg/kg, about 0.7mg/kg, about 2mg/kg, about 0.8mg/kg, about 2mg/kg, about 0.7mg/kg, about 0.9mg/kg, about 2mg/kg, about 0.7mg/kg, about 0.8mg/kg, about 0.2mg/kg, about 0.1.1.6 mg/kg, about 0.8mg/kg, about 0.7mg/kg, about 2mg/kg, about 0.2mg/kg, about 0.1.6 mg/kg, about 0.1.1.2 mg/kg, about 0mg/kg, about 0.8mg/kg, about 0mg/kg, about 0.6mg/kg, about 0.1.1.2 mg/kg, about 0.1.1.1.1.1 mg/kg, about 0mg/kg, about 0.1.1.1.1 mg/kg, about 0mg/kg, about 2mg/kg, about 0mg/kg, about 0.1.1.1 mg/kg, about 0mg/kg, about 0.1.1.1.1.1.1.1.1.1 mg/kg, about 0mg/kg, about 0.1.1 mg/kg, about 0mg/kg, about 0.1.1.1.1 mg/kg, about 0mg/kg, about 0.1.2 mg/kg, about 0mg/, About 2.3mg/kg, about 2.4mg/kg, about 2.5mg/kg, about 2.6mg/kg, about 2.7mg/kg, about 2.8mg/kg, about 2.9mg/kg, about 3mg/kg, about 3.5mg/kg, about 4mg/kg, about 4.5mg/kg, about 5mg/kg, about 6mg/kg, about 7mg/kg, about 8mg/kg, about 9mg/kg, about 10mg/kg, about 15mg/kg, about 25mg/kg, about 50mg/kg, about 75mg/kg, about 100mg/kg, about 500mg/kg, or about 1,000 mg/kg. In particular embodiments, an effective amount of nemoruzumab, or an equivalent thereof, is about 0.1mg/kg, about 0.5mg/kg, about 1mg/kg, about 1.5mg/kg, about 2mg/kg, or about 2.5 mg/kg. In a preferred embodiment, the dose is about 0.5 mg/kg.

Methods of treatment

According to some embodiments, there is provided a method of treating pruritus in a subject with Prurigo Nodularis (PN), the method comprising, consisting of, or consisting essentially of administering to the subject an effective amount of nemulizumab or an equivalent thereof.

In some embodiments, the pruritus is moderate to severe. In some embodiments of the method, the subject has been diagnosed with PN for at least 6 months. In a particular embodiment of the method, the subject has at least 20 bilaterally distributed nodules on his/her body. In particular embodiments of the method, the subject has a prurigo lesion on the upper limb, and a lesion or no lesion on the torso or lower limb. In a particular embodiment of the method, the pruritus is assigned a score of at least 7 on the Numerical Rating Scale (NRS). In a particular embodiment of the method, the average of the worst daily intensity of the NRS score is at least 7 on the first 3 days. In other particular embodiments of the method, the average of the worst daily intensity of the NRS score is at least 7 in the previous week.

In some embodiments of the method, the subject does not have atopic dermatitis. In some embodiments of the method, the subject is free of chronic pruritus caused by conditions other than PN, such as scabies, insect bites, chronic lichen simplex, psoriasis, acne, folliculitis, habitual scratching, lymphomatoid papulosis, chronic actinic dermatitis, dermatitis herpetiformis, sporotrichosis, bullous disease. In some embodiments of the method, the subject is free of neuropathic or psychogenic pruritus, such as paresthesia back pain, brachial and radial pruritus, dilutive parasitic disease, mimic disease.

An "effective amount" is an amount sufficient to achieve a beneficial or desired result, such as alleviation of at least one or more symptoms of PN and/or itch. An effective amount as used herein will also include an amount sufficient to delay the development of AD and/or itch, alter the course of PN and/or itch symptoms (e.g., sleep efficiency), or reverse the symptoms of PN and/or itch. Therefore, the exact "effective amount" cannot be specified. However, for any given situation, an appropriate "effective amount" may be determined by one of ordinary skill in the art using only routine experimentation.

An effective amount may be administered in one or more administrations, applications or doses. Such delivery depends on a number of variables, including the time period over which the individual dosage units are used, the bioavailability of the therapeutic agent, the route of administration, and the like. It will be understood, however, that the specific dose level of a therapeutic agent of the present disclosure for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex and diet of the subject, the time of administration, the rate of excretion, drug combination and the severity and form of the particular disorder being treated. Therapeutic doses can generally be titrated to optimize safety and efficacy. The dosage can be determined by a physician and adjusted as necessary to accommodate the observed therapeutic effect. In general, dose-effect relationships from in vitro and/or in vivo tests may initially provide useful guidance for the correct dose to be administered to a patient. In general, it is desirable to administer an amount of a compound effective to achieve serum levels commensurate with concentrations found to be effective in vitro. The determination of these parameters is well within the skill of the art. These considerations, as well as effective formulations and administration procedures, are well known in the art and are described in standard texts.

Dosage regimens for treating CP and PN can include fixed dosing (i.e., repeated administration of the same dose at predetermined intervals) or include a loading dose (i.e., administration of an initial dose that is higher or different than the subsequent series of doses). For either type of dosing regimen, the effective dose may be administered topically, parenterally, subcutaneously, intradermally, or intramuscularly.

In some embodiments, the loading dose and the subsequent series of doses can be administered by the same route (e.g., subcutaneously), while in some embodiments, the loading dose and the subsequent series of doses can be administered by different routes (e.g., parenterally and subcutaneously, respectively). In some embodiments, the loading dose may be about 5mg, about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, or higher. In some embodiments, the loading dose can be 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, or higher. In some embodiments, the loading dose may be about 0.01mg/kg, about 0.02mg/kg, about 0.03mg/kg, about 0.04mg/kg, about 0.05mg/kg, about 0.06mg/kg, about 0.07mg/kg, about 0.08mg/kg, about 0.09mg/kg, about 0.1mg/kg, about 0.2mg/kg, about 0.3mg/kg, about 0.4mg/kg, about 0.5mg/kg, about 0.6mg/kg, about 0.7mg/kg, about 0.8mg/kg, about 0.9mg/kg, about 1mg/kg, about 1.1mg/kg, about 1.2mg/kg, about 1.3mg/kg, about 1.4mg/kg, about 1.5mg/kg, about 1.6mg/kg, about 1.7mg/kg, about 1.8mg/kg, about 1.9mg/kg, about 2mg/kg, about 0.7mg/kg, about 2mg/kg, about 0.8mg/kg, about 2mg/kg, about 0.7mg/kg, about 0.1.9 mg/kg, about 2mg/kg, about 0.7mg/kg, about 2mg/kg, about 0.9mg/kg, about 2mg/kg, about 0.1.9 mg/kg, about 0.7mg/kg, about 0.8mg/kg, about 2mg/kg, about 0.1.1.1.8 mg/kg, about 0.8mg/kg, about 2mg/kg, about 0.6mg/kg, about 0.9mg/kg, about 2mg/kg, about 0.1.1.1.1.1.1.1.1.1.1.1.8 mg/kg, about 2mg/kg, about 0mg/kg, about 2mg/kg, about 0.1.1.1 mg/kg, about 2mg/kg, about 0mg/kg, about 0.1.1 mg/kg, about 0mg/kg, about 0.1.1.1.1 mg/kg, about 0mg/kg, about 0.1.1.1.1.1.1.1 mg/kg, about 0mg/kg, about 0.1.1.1 mg/kg, about 0mg/kg, about 0.1.1.1.1 mg/kg, about 0mg/kg, about 0.1.1.1.1.1.1.1.1 mg/kg, about 0mg/kg, about 2.3mg/kg, about 2.4mg/kg, about 2.5mg/kg, about 2.6mg/kg, about 2.7mg/kg, about 2.8mg/kg, about 2.9mg/kg, about 3mg/kg, about 3.5mg/kg, about 4mg/kg, about 4.5mg/kg, about 5mg/kg, about 6mg/kg, about 7mg/kg, about 8mg/kg, about 9mg/kg, about 10mg/kg, about 15mg/kg, about 25mg/kg, about 50mg/kg, about 75mg/kg, about 100mg/kg, about 500mg/kg, or about 1,000 mg/kg. In some embodiments, the loading dose may be 0.01mg/kg, 0.02mg/kg, 0.03mg/kg, 0.04mg/kg, 0.05mg/kg, 0.06mg/kg, 0.07mg/kg, 0.08mg/kg, 0.09mg/kg, 0.1mg/kg, 0.2mg/kg, 0.3mg/kg, 0.4mg/kg, 0.5mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1mg/kg, 1.1mg/kg, 1.2mg/kg, 1.3mg/kg, 1.4mg/kg, 1.5mg/kg, 1.6mg/kg, 1.7mg/kg, 1.8mg/kg, 1.9mg/kg, 2mg/kg, 2.1mg/kg, 2.2.2 mg/kg, 2.5mg/kg, 2.6mg/kg, 2mg/kg, 2.7mg/kg, 2.8mg/kg, 2mg/kg, 2.6mg/kg, 2mg/kg, 2.6mg/kg, 2 mg/2.6 mg/kg, 2mg/kg, 2.6mg/kg, 2.1 mg/2.6 mg/kg, 2mg/kg, 2.6mg/kg, 2mg/kg, 2 mg/2.1 mg/kg, 2mg/kg, 2.1.1 mg/kg, 2mg/kg, 2.6mg/kg, 2.1.1 mg/kg, 2mg/kg, 2.1.1.6 mg/kg, 2 mg/0.1.1.1.1.1.1.1.1 mg/kg, 2mg/kg, 2.1.1 mg/kg, 2.6mg/kg, 2.1mg/kg, 2 mg/0.1.1 mg/kg, 2.1mg/kg, 2mg/kg, 2.1mg, 2.7mg/kg, 2.8mg/kg, 2.9mg/kg, 3mg/kg, 3.5mg/kg, 4mg/kg, 4.5mg/kg, 5mg/kg, 6mg/kg, 7mg/kg, 8mg/kg, 9mg/kg, 10mg/kg, 15mg/kg, 25mg/kg, 50mg/kg, 75mg/kg, 100mg/kg, 500mg/kg or 1,000mg/kg, and in some embodiments, the loading dose is administered as a single injection. In some embodiments, the loading dose is administered in multiple injections, which may be administered simultaneously or separately at defined intervals.

Subsequent series of doses of the loading dose regimen are typically lower than the loading dose. For example, in some embodiments, a dosing regimen may include a loading dose of 60mg and a series of doses of 30mg, which may be administered at defined intervals, e.g., every 4 weeks. In some embodiments, the series of doses of the dosing regimen may be about 5mg, about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, or higher. In some embodiments, the series of doses can be 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, or more. In some embodiments, the series of doses may be about 0.01mg/kg, about 0.02mg/kg, about 0.03mg/kg, about 0.04mg/kg, about 0.05mg/kg, about 0.06mg/kg, about 0.07mg/kg, about 0.08mg/kg, about 0.09mg/kg, about 0.1mg/kg, about 0.2mg/kg, about 0.3mg/kg, about 0.4mg/kg, about 0.5mg/kg, about 0.6mg/kg, about 0.7mg/kg, about 0.8mg/kg, about 0.9mg/kg, about 1mg/kg, about 1.1mg/kg, about 1.2mg/kg, about 1.3mg/kg, about 1.4mg/kg, about 1.5mg/kg, about 1.6mg/kg, about 1.7mg/kg, about 1.8mg/kg, about 1.9mg/kg, about 2mg/kg, about 0.7mg/kg, about 2mg/kg, about 0.8mg/kg, about 2mg/kg, about 0.7mg/kg, about 2mg/kg, about 0.1.9 mg/kg, about 2mg/kg, about 0.7mg/kg, about 0.1.7 mg/kg, about 2mg/kg, about 0.1.8 mg/kg, about 0.1.1.7 mg/kg, about 2mg/kg, about 0.1.9 mg/kg, about 2mg/kg, about 0.1.1.7 mg/kg, about 2mg/kg, about 0.8mg/kg, about 0.9mg/kg, about 0.1.1.1.1.6 mg/kg, about 2mg/kg, about 0.1.1.1.1 mg/kg, about 0.1mg/kg, about 0.1.1.1 mg/kg, about 2mg/kg, about 0.1.1 mg/kg, about 0mg/kg, about 2mg/kg, about 0mg/kg, about 0.1mg/kg, about 0mg/kg, about 0.1.1.1.1.1 mg/kg, about 0mg/kg, about 0.1.1.1.1.1.1.1 mg/kg, about 0mg/kg, about 0.1.1 mg/kg, about 0mg/kg, about 0.1.1.1 mg/kg, about 0mg/kg, about 0.1.1 mg/kg, about 0mg/kg, about 0.1.1.1.1.1 mg/kg, about 0mg/kg, About 2.3mg/kg, about 2.4mg/kg, about 2.5mg/kg, about 2.6mg/kg, about 2.7mg/kg, about 2.8mg/kg, about 2.9mg/kg, about 3mg/kg, about 3.5mg/kg, about 4mg/kg, about 4.5mg/kg, about 5mg/kg, about 6mg/kg, about 7mg/kg, about 8mg/kg, about 9mg/kg, about 10mg/kg, about 15mg/kg, about 25mg/kg, about 50mg/kg, about 75mg/kg, about 100mg/kg, about 500mg/kg, or about 1,000 mg/kg. In some embodiments, the series of doses may be 0.01mg/kg, 0.02mg/kg, 0.03mg/kg, 0.04mg/kg, 0.05mg/kg, 0.06mg/kg, 0.07mg/kg, 0.08mg/kg, 0.09mg/kg, 0.1mg/kg, 0.2mg/kg, 0.3mg/kg, 0.4mg/kg, 0.5mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1mg/kg, 1.1mg/kg, 1.2mg/kg, 1.3mg/kg, 1.4mg/kg, 1.5mg/kg, 1.6mg/kg, 1.7mg/kg, 1.8mg/kg, 1.9mg/kg, 2mg/kg, 2.1mg/kg, 2.2.2 mg/kg, 2.5mg/kg, 2.6mg/kg, 2mg/kg, 2.6mg/kg, 2mg/kg, 2.6mg/kg, 2mg/kg, 2.6mg/kg, 2.1.6 mg/kg, 2mg/kg, 2.1 mg/2.6 mg/kg, 2mg/kg, 2.6mg/kg, 2.1.6 mg/kg, 2 mg/0.1 mg/kg, 2 mg/0 mg/kg, 2mg/kg, 2.1.1 mg/kg, 2 mg/0.1 mg/kg, 2mg/kg, 2.1.1 mg/kg, 2 mg/0.1 mg/0.1.1.1 mg/0 mg/0.1.1.1.1.1 mg/0.1.1 mg/0.1 mg/kg, 2.1mg/kg, 2.1.1 mg/0.1.1 mg/0.1 mg/kg, 2.1 mg/0.1 mg/kg, 2.1mg/kg, 2mg/kg, 2.1mg/, 2.7mg/kg, 2.8mg/kg, 2.9mg/kg, 3mg/kg, 3.5mg/kg, 4mg/kg, 4.5mg/kg, 5mg/kg, 6mg/kg, 7mg/kg, 8mg/kg, 9mg/kg, 10mg/kg, 15mg/kg, 25mg/kg, 50mg/kg, 75mg/kg, 100mg/kg, 500mg/kg or 1,000 mg/kg.

For the loading dose regimen, the first series of doses can be administered 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks after the initial loading dose. In some embodiments, the first series of doses is administered 4 weeks after the initial loading dose. In some embodiments, subsequent series of doses are administered once every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks. In some embodiments, the series of doses are 4 weeks apart (i.e., nemulizumab or its equivalent is administered once every 4 weeks).

In some embodiments, the dose of nemulizumab or equivalent thereof administered to the subject is in the range of 0.001 to 1,000mg/kg body weight of the subject. In some embodiments, the dose range of nemoruzumab, or an equivalent thereof, is about 0.01 to 50mg/kg, about 0.01mg/kg to about 0.1mg/kg, about 0.05mg/kg to 0.15mg/kg, about 0.1mg/kg to about 0.6mg/kg, about 0.1mg/kg to about 1mg/kg, about 0.25mg/kg to about 0.75mg/kg, about 0.4mg/kg to about 0.8mg/kg, about 0.4mg/kg to about 1.8mg/kg, about 0.5 to about 2.5mg/kg, about 0.8mg/kg to about 2.2mg/kg, about 1mg/kg to about 2.5mg/kg, about 1mg/kg to about 3.5mg/kg, about 1mg/kg to about 5mg/kg, about 2mg/kg to about 4mg/kg, about 2.5mg/kg to about 10mg/kg, about 10mg/kg, From about 10mg/kg to about 20mg/kg, from about 10mg/kg to about 40mg/kg, from about 20mg/kg to about 50mg/kg, from about 25mg/kg to about 75mg/kg, from about 50mg/kg to about 100mg/kg or from about 100mg/kg to about 500mg/kg or from about 100mg/kg to about 1000mg/kg of body weight. In preferred embodiments, the dosage range is from about 0.01mg/kg to about 0.1mg/kg, from about 0.1mg/kg to about 0.5mg/kg, from about 0.5mg/kg to about 1.5mg/kg, from about 1.5mg/kg to about 2.5mg/kg, or from about 2.5mg/kg to about 10 mg/kg. In some embodiments, the dose is about 0.01mg/kg, about 0.02mg/kg, about 0.03mg/kg, about 0.04mg/kg, about 0.05mg/kg, about 0.06mg/kg, about 0.07mg/kg, about 0.08mg/kg, about 0.09mg/kg, about 0.1mg/kg, about 0.2mg/kg, about 0.3mg/kg, about 0.4mg/kg, about 0.5mg/kg, about 0.6mg/kg, about 0.7mg/kg, about 0.8mg/kg, about 0.9mg/kg, about 1mg/kg, about 1.1mg/kg, about 1.2mg/kg, about 1.3mg/kg, about 1.4mg/kg, about 1.5mg/kg, about 1.6mg/kg, about 1.7mg/kg, about 1.8mg/kg, about 1.9mg/kg, about 2mg/kg, about 0.7mg/kg, about 2mg/kg, about 0.8mg/kg, about 2mg/kg, about 0.7mg/kg, about 0.9mg/kg, about 2mg/kg, about 0.7mg/kg, about 0.8mg/kg, about 0.2mg/kg, about 0.1.1.6 mg/kg, about 0.8mg/kg, about 0.7mg/kg, about 2mg/kg, about 0.2mg/kg, about 0.1.6 mg/kg, about 0.1.1.2 mg/kg, about 0mg/kg, about 0.8mg/kg, about 0mg/kg, about 0.6mg/kg, about 0.1.1.2 mg/kg, about 0.1.1.1.1.1 mg/kg, about 0mg/kg, about 0.1.1.1.1 mg/kg, about 0mg/kg, about 2mg/kg, about 0mg/kg, about 0.1.1.1 mg/kg, about 0mg/kg, about 0.1.1.1.1.1.1.1.1.1 mg/kg, about 0mg/kg, about 0.1.1 mg/kg, about 0mg/kg, about 0.1.1.1.1 mg/kg, about 0mg/kg, about 0.1.2 mg/kg, about 0mg/, About 2.3mg/kg, about 2.4mg/kg, about 2.5mg/kg, about 2.6mg/kg, about 2.7mg/kg, about 2.8mg/kg, about 2.9mg/kg, about 3mg/kg, about 3.5mg/kg, about 4mg/kg, about 4.5mg/kg, about 5mg/kg, about 6mg/kg, about 7mg/kg, about 8mg/kg, about 9mg/kg, about 10mg/kg, about 15mg/kg, about 25mg/kg, about 50mg/kg, about 75mg/kg, about 100mg/kg, about 500mg/kg, or about 1,000 mg/kg. In particular embodiments, an effective amount of nemoruzumab, or an equivalent thereof, is about 0.1mg/kg, about 0.5mg/kg, about 1mg/kg, about 1.5mg/kg, about 2mg/kg, or about 2.5 mg/kg. In a preferred embodiment, the dose is about 0.5 mg/kg.

In some embodiments, the dose of nemoruzumab, or an equivalent thereof, administered to a subject is in the range of 1 to 100mg, 25 to 75mg, 30 to 60mg, 40 to 80mg, 20 to 80mg, 1 to 25mg, 1 to 50mg, 10 to 90mg, 15 to 85mg, or a range therebetween. In some embodiments, the dose may be about 5mg, about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, or higher. In some embodiments, the dose may be 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, or higher.

In particular embodiments, a loading dose of about 60mg of nemulin, or an equivalent thereof, may be administered to a subject in need thereof, followed by a subsequent series of doses of about 30mg of nemulin, or an equivalent thereof, once every 4 weeks.

In some embodiments of the method, the nemoruzumab, or an equivalent thereof, is administered by a topical or parenteral route. In some embodiments of the method, the nemulizumab or equivalent thereof is administered subcutaneously. In some embodiments, the dose is administered subcutaneously at or near the site of one or more nodules.

In some embodiments, nemorubizumab or its equivalent is administered daily, every other day, twice weekly, three times weekly, four times weekly, five times weekly, six times weekly, once biweekly, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, once every twelve weeks, twice annually, once annually, and/or as needed for the appearance of symptoms of atopic dermatitis or pruritus (e.g., CP or PN). In a preferred embodiment, nemulizumab or an equivalent thereof is administered once every four weeks or every eight weeks.

In some embodiments, the duration of treatment is about 1 day, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 24 weeks, about 30 weeks, about 36 weeks, about 40 weeks, about 48 weeks, about 50 weeks, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or as needed based on the appearance of symptoms of atopic dermatitis or pruritus (e.g., CP or PN). In preferred embodiments, the duration of treatment is from about 12 weeks to about 24 weeks, from about 12 weeks to about 36 weeks, from about 12 weeks to about 48 weeks, or from about 24 weeks to about 36 weeks.

According to some embodiments, there is provided a use of nemulizumab or an equivalent thereof in the manufacture of a medicament for treating pruritus in a subject with Prurigo Nodularis (PN).

In some embodiments of the use, the pruritus is moderate to severe. In some embodiments of the use, the subject has been diagnosed with PN for at least 6 months. In a particular embodiment of the use, the subject has at least 20 bilaterally distributed nodules on his/her body. In particular embodiments of the use, the subject has a prurigo lesion on the upper limb, and a lesion or no lesion on the torso or lower limb. In a particular embodiment of the method, the pruritus is assigned a score of at least 7 on the Numerical Rating Scale (NRS). In a particular embodiment of the use, the mean value of the worst daily intensity of the NRS score is at least 7 on the first 3 days. In other particular embodiments of the use, the average of the worst daily intensity of the NRS score is at least 7 in the previous week.

Examples of the invention

Example 1 determination of the efficacy of nemoruzumab in the treatment of pruritus in PN patients

A multicenter (20 sites in the european union and united states), randomized, double-blind, placebo-controlled, parallel group study was performed, including 2 groups (35 per group) of approximately 70 randomized patients stratified on an atopic background. Patients in the cohort received subcutaneous nemoruzumab or placebo at a dose of 0.5mg/kg every 4 weeks. Patients were selected according to the following criteria.

Inclusion criteria were:

1. male or female at least 18 years of age at screening.

Clinical diagnosis of PN for at least 6 months with: (a) prurigo of the upper extremities with or without lesions of the trunk or lower extremities; (b) at least 20 nodules distributed bilaterally

3. Severe itching based on the Numerical Rating Scale (NRS). NRS was determined by screening follow-up and baseline follow-up. Screening and follow-up: the mean of the worst daily intensity of NRS scores for the first 3 days was 7 or more. Baseline follow-up: the mean of the worst intensity per day for the NRS scores of the previous week was > 7.

4. Female subjects must meet one of the following criteria: (a) female subjects with no fertility (postmenopausal, i.e. no menstrual bleeding 1 year before screening, no other medical cause, hysterectomy or bilateral ovariectomy); (b) female subjects with fertility potential who agree to real abstinence (when complying with the preferred and usual lifestyle of the subject) or use an effective contraceptive method throughout the clinical trial and within 120 days after the last study drug administration.

Patients with the following conditions were excluded.

Exclusion criteria:

1. chronic pruritus caused by other conditions than PN, such as scabies, insect bites, lichen simplex chronicus, psoriasis, acne, folliculitis, habitual scratching, lymphomatoid papulosis, chronic actinic dermatitis, dermatitis herpetiformis, sporotrichosis, bullous diseases.

2. Unilateral prurigo lesions (e.g., only one arm is affected).

3. Bacterial or viral infection of the skin within 1 week prior to baseline follow-up.

4. Infections requiring treatment with oral or parenteral antibiotics, antivirals, antiparasitics or antifungals within 1 week prior to the screening visit or during the screening period unless they completely subside at the screening/baseline visit, respectively.

5. Any uncontrolled or severe disease that may interfere with interpretation of the clinical trial results and/or place the subject at significant risk, or any medical or surgical condition (e.g., solid cancer, AIDS, severe or uncontrolled heart disease), as judged by the investigator at screening or baseline.

6. Any active skin disorder that would require immediate treatment.

7. Active atopic dermatitis or recurrent attacks known to be accompanied by atopic dermatitis

8. Neuropathic and psychogenic pruritus (paresthesia back pain, itching of the radial arm, dilutive parasitic diseases, mimic diseases).

9. Positive serological results were hepatitis b surface antigen (HBsAg) or hepatitis b core antibody (hbcabs), hepatitis c antibody or Human Immunodeficiency Virus (HIV) antibody at screening visit.

10. The following exceptional laboratory criteria were listed at screening visit: increased ALT/AST is more than or equal to 3ULN, increased CPK>1.5ULN, neutrophil count<1.5x 10³Mu.l, creatinine clearance<60ml/min/1.73m²；

11. A history of asthma that satisfies one or more of (i) exacerbations of asthma that require hospitalization within the last 12 months prior to the screening visit; (ii) asthma was not well controlled during the last 3 months prior to the screening visit (i.e. symptoms > 2 days per week, nocturnal arousals > 1-3 times per week, or some interference with normal activity); PEF < 80% of predicted values at screening visit or baseline visit.

12. Latent or active TB as determined by Quantiferon-based TB test results positive at screening visit.

13. Any treatment was withheld for a specified time frame prior to baseline follow-up:

table 1: forbidden therapy

If the investigator deems medically necessary, from day 29 onwards, rescue treatment for pruritus may be associated with the investigational drug. All efficacy and safety assessments should be completed before beginning rescue treatment.

TABLE 2 rescue therapy

End point:

the primary endpoint of this study was the percentage reduction in NRS itch from Baseline (BL) at week 4.

The secondary endpoint of this study was a decline in each follow-up visit up to 18 weeks, characterized by NRS, VRS or DPS. The safety assessment was also performed at the secondary endpoint. Prurigo relief is characterized by a Prurigo Activity Score (PAS) and an IGA.

Pharmacokinetic (PK) profiles of PN patients were measured. Pharmacodynamic (PD) profiles of PN patients were measured in blood, biopsy and D-scale samples of patients. The quality of life of PN patients was measured by DLQI. Sleep improvement and scratching (via Actiwatch) were evaluated using a actigraph. A picture of the PN patient is taken by the FotoFinder at the selected center.

The results of the clinical study are presented in the table below.

TABLE 3 demographic and baseline characteristics

Note that: the percentages are based on the number of subjects with non-missing values in the respective treatment groups.

As shown in table 3, the placebo and nemoruzumab treated groups in the study presented comparable compositions in terms of gender, race, age and body weight.

TABLE 4 Baseline clinical disease characteristics

As shown in table 4, the placebo and nemoruzumab treated groups in the study exhibited comparable baseline levels of itch, as measured by the number of systemic nodules, the weekly peak itch rating scale (NRS) score, the weekly average itch NRS score, and the Investigator's Global Assessment (IGA) score.

TABLE 5 incidence of rescue medication

As shown in table 5, the placebo group had a higher incidence of local rescue medication and systemic rescue medication.

Efficacy results are shown in figures 2-15. In particular, at the primary endpoint, nemulizumab treatment significantly reduced pruritus at week 4 as shown by the percentage change from baseline in the mean peak pruritus NRS per week (fig. 2). Thus, at week 4, nemoruzumab at a dose of 0.5mg/kg was superior to placebo (-38%, 95% CI [ -51%, -25% ]) and was statistically significant (p < 0.001).

At the secondary endpoint, nemorlizumab treated groups consistently showed more reduction in pruritus throughout the 18 week study as evidenced by the percent change (fig. 3) and absolute change (fig. 4) in peak pruritus NRS, and the results were statistically significant (p < 0.001). The same results were also observed in patients without or with atopic dermatitis (fig. 5 and 6).

The global assessment (IGA) score of the investigators ranged from 0 (clear) to 4 (severe disease) and was expressed as the percentage of patients in the indicated population. The percentage of IGA success obtained for patients treated with nemoruzumab was much higher compared to the placebo group (IGA 0/1) (fig. 7). Furthermore, the IGA profile showed that the percentage of patients with decreased IGA in the nemoruzumab treated group was consistently higher compared to the placebo group (fig. 8). The results at week 12 and 18 were statistically significant (p < 0.05).

The speech rating scale (VRS) is a single dimensional scale that allows patients to describe their intensity of itch by increasing adjectives (1 ═ no itch, and 4 ═ very severe itch). In other words, the nemoruzumab treated group consistently showed higher percent change in negative values compared to the placebo group, which translates to less reduction in itch throughout the 18 week study period (fig. 9). The results were statistically significant (p < 0.001).

The dermatological quality of life index (DLQI) score ranges from 0 to 30, with higher scores indicating lower quality of life. As shown in fig. 10, the percentage of responders with DLQI scores ≧ 4 in nemulizumab-treated group at weeks 4 and 12 was higher compared to placebo group. As shown in fig. 11, the change in DLQI from baseline at week 4 was statistically significant (p <0.01), favoring nemulizumab, but not statistically significant at week 12.

A representative patient was imaged whole body. As shown in fig. 12-14, nemulizumab treatment significantly reduced the number of nodules on the patient's body after 16 weeks.

Preliminary safety results

As shown in tables 6 and 7, nemulizumab treated and placebo groups showed comparable numbers of adverse events (TEAEs) occurring during treatment of all causes, as well as comparable incidence of TEAEs of Systemic Organ Class (SOC) of all causes. Overall, nemulizumab is well tolerated.

TABLE 6 safety-general summary of adverse events (TEAE) occurring during treatment for all causes

TABLE 7 incidence of TEAE per Systemic Organ Class (SOC) (> 5%) for all causes

SEQUENCE LISTING

<110> Gao De Mei Consortium Ltd

Chugai Pharmaceutical Co.,Ltd.

<120> treatment of skin lesions and itching in prurigo nodularis patients

<130> P21116392WP

<150> US 62/797,803

<151> 2019-01-28

<150> US 62/809,404

<151> 2019-02-22

<160> 6

<170> PatentIn version 3.5

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Gln Asn Pro Tyr Leu Lys Asn Ser Val Thr Thr Arg Glu Phe Leu Val

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His Glu Asn Ile Pro Glu His Ser Lys Gly Glu Val

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Ala Phe Thr Glu Tyr Val Val Ala Leu Arg Cys Ala Val Lys Glu Ser

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Lys Phe Trp Ser Asp Trp Ser Gln Glu Lys Met Gly Met Thr Glu Glu

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Val Asp Gly Arg Arg Pro Val Arg Leu Leu Trp Lys Lys Ala Arg Gly

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Glu Asn Asn Thr Asn Leu Thr Glu Thr Val Asn Thr Thr Asn Gln Gln

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Leu Glu Leu His Leu Gly Gly Glu Ser Tyr Trp Val Ser Met Ile Ser

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Tyr Asn Ser Leu Gly Lys Ser Pro Val Thr Thr Leu Arg Ile Pro Ala

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Ile Gln Glu Lys Ser Phe Arg Cys Ile Glu Val Met Gln Ala Cys Leu

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Ala Glu Asp Gln Leu Val Val Lys Trp Gln Ser Ser Ala Leu Asp Val

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Asn Thr Trp Met Ile Glu Trp Phe Pro Asp Met Asp Ser Glu His Pro

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Thr Leu Ser Trp Glu Ser Val Ser Gln Ala Thr Asn Trp Thr Ile Gln

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Gln Asp Lys Leu Lys Pro Phe Trp Cys Tyr Asn Ile Ser Val Tyr Pro

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Met Leu His Asp Lys Val Gly Glu Pro Tyr Ser Ile Gln Ala Tyr Ala

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Lys Glu Gly Ile Pro Ser Lys Gly Pro Glu Thr Lys Val Glu Asn Ile

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Gly Val Lys Thr Val Thr Ile Thr Trp Lys Glu Ile Pro Lys Ser Glu

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Arg Lys Gly Ile Ile Cys Asn Tyr Thr Ile Phe Tyr Gln Ala Glu Gly

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Gly Lys Gly Phe Ser Lys Thr Val Asn Ser Ser Ile Leu Gln Tyr Gly

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Leu Glu Ser Leu Lys Arg Lys Thr Ser Tyr Thr Val Arg Val Met Ala

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Ser Thr Ser Ala Gly Gly Ile Asn Gly Thr Ser Ile Asn Phe Lys Thr

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Leu Ser Phe Ser Val Phe Glu Ile Ile Leu Ile Thr Ser Leu Ile Gly

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Gly Gly Leu Leu Ile Leu Ile Ile Leu Thr Val Ala Tyr Gly Leu Lys

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Lys Pro Asn Lys Leu Thr His Leu Cys Trp Pro Ser Val Pro Asn Pro

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Ala Glu Ser Ser Ile Ala Thr Trp Arg Gly Asp Asp Phe Lys Asp Lys

565 570 575

Leu Asn Leu Lys Glu Ser Asp Asp Ser Val Asn Thr Glu Asp Arg Ile

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Leu Lys Pro Cys Ser Thr Pro Ser Asp Lys Leu Val Ile Asp Lys Ser

595 600 605

Val Val Asn Phe Gly Asn Val Leu Gln Glu Met Phe Thr Asp Glu Ala

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Arg Thr Gly Gln Glu Asn Asn Leu Gly Gly Glu Lys Asn Glu Tyr Val

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Thr His Pro Phe Arg Ala Asp Cys Pro Leu Gly Lys Ser Phe Glu Glu

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Leu Pro Val Ser Pro Glu Ile Pro Pro Arg Lys Ser Gln Tyr Leu Arg

660 665 670

Ser Arg Met Pro Glu Gly Thr Cys Leu Glu Ala Glu Glu Gln Leu Leu

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Val Ser Gly Gln Ser Leu Glu Ser Leu Ala Pro Asp His Val Arg Glu

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Ala Ala Ala Pro Asn Pro Tyr Leu Lys Asn Ser Val Thr Thr Arg Glu

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Phe Leu Val Ser Gln Lys Leu Pro Glu His Thr Lys Gly Glu Val

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Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

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Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

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Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe

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Gln Asp Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr

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Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

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Ala Arg Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly

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Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

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Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala

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Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

145 150 155 160

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

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Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

180 185 190

Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys

210 215 220

Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu

260 265 270

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser

290 295 300

Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile

325 330 335

Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

340 345 350

Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser

385 390 395 400

Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg

405 410 415

Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

<210> 6

<211> 214

<212> PRT

<213> Artificial Sequence

<220>

<223> Nemolizumab light chain amino acid sequence

<400> 6

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Asp Ile Tyr Ser Phe

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asn Ala Gln Thr Glu Ala Gln Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His His Tyr Asp Ser Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

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