Methods of treating atopic dermatitis with multispecific antibodies having specificity for il4r-a and il-31

Abstract

A method of treating moderate to severe atopic dermatitis (AD) in a patient by administering a bi-specific, tetravalent IgG4 antibody that binds to both the IL4 receptor alpha IL-4Rα and IL-31, at an initial dose and subsequent doses in order for the patient to respond to the antibody and meet one or more of the clinical endpoints.

Description

METHODS OF TREATING ATOPIC DERMATITIS WITH MULTISPECIFIC ANTIBODIES HAVING SPECIFICITY FOR IL-4Ra AND IL-31CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 736,088 filed on December 19, 2024, U.S. Provisional Application No. 63 / 793,360 filed on April 23, 2025, and U.S. Provisional Application No. 63 / 841,529 filed on July 7, 2025, the disclosures of each of which are hereby incorporated by reference in their entireties.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. The XML copy, created on November 29, 2025, is named JBI6971PCT-SL.xml and is 28.1 KB in size.FIELD OF THE INVENTION

[0003] The present invention is directed to methods of treating moderate to severe atopic dermatitis (AD) in a patient by administering a bi-specific, tetravalent IgG4 antibody that binds to both the IL4 receptor alpha (IL-4Ra) and IL-31. It relates to doses and dosing regimens, uses and methods for administration of a bi-specific antibody and specific pharmaceutical compositions of an antibody.BACKGROUND OF THE INVENTION

[0004] The interleukin-4 receptor subunit IL-4Ra, herein also referred to as IL-4R or IL4R binds interleukin 4 (IL-4) either upon direct interaction with the common cytokine receptor gamma chain (yc) in type I receptor complexes, or in association with IL-13Ral in type II receptorcomplexes. This IL-4R / IL-13Ral receptor complex can bind interleukin 4 (IL-4) as well as interleukin 13 (IL-13) to regulate IgE antibody production in B cells. IL-4 binding to IL-4R is further known to activate macrophages and to promote differentiation of type 2 helper T-cells (Th2-cells), leading to Th2-driven inflammation. IL-4 and / or IL-13 binding to IL-4Ra / ycand / or IL-4R / IL-13Ral leads to the activation of Janus kinase (JAK)l, JAK2, signal transducer and activator of transcription (STAT)l, STAT3, STAT6, and STAT dimerization, which in turn induces the transcription of specific genes.

[0005] Several monoclonal antibodies, which reduce or block IL-4R-mediated signaling by either binding the cytokines IL-4 and / or IL- 13 or to the IL-4R, have been described in the prior art for the treatment of such diseases. For example, dupilumab (Dupixent®) developed by Regeneron Pharmaceuticals and Sanofi Genzyme, which bind to and antagonizes IL-4R, has been approved for the treatment of moderate-to-severe atopic dermatitis, chronic rhinosinusitis with nasal polyposis (CRSwNP), asthma, chronic obstructive pulmonary disease (COPD), and eosinophilic esopagitis.

[0006] Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intense pruritus (e. g., severe itch) and by scaly and dry eczematous lesions. Severe disease can be extremely disabling due to major psychological problems, significant sleep loss, and impaired quality of life, leading to high socioeconomic costs. AD often begins in childhood before age 5 and may persist in adulthood.

[0007] AD is a common chronic inflammatory skin disorder with a lifetime prevalence of up to 20%. It is characterized by skin-barrier disruption and immune dysregulation (largely mediated by Type 2 immune responses). Many patients also suffer from atopic comorbidities including allergic asthma, allergic rhinoconjunctivitis, and food allergies. Clinically, AD is characterized by xerosis, erythematous crusted eruption (dermatosis), lichenification, an impaired skin barrier, and intense pruritus with a fluctuating course. Pruritus-induced scratching may cause mechanical damage to skin, which may in turn enhance inflammatory reactions and worsen pruritus (itchscratch cycle).

[0008] The burden of AD is extensive and significantly impacts the lives of patient caregivers and family members, with pruritus reported as the most bothersome symptom. Patients withmoderate to severe AD have a high prevalence of social dysfunction and sleep impairment, which are directly related to the severity of the disease.

[0009] The baseline therapeutic approach to AD primarily consists of trigger avoidance, skin hydration with bathing, use of emollients, and anti-inflammatory therapies consisting predominantly of TCS. In many patients, treatment with TCS provides some measure of symptomatic relief but does not adequately control the disease. In patients with persistent moderate to severe disease that is not responding adequately to TCS, guidelines outline several step-up therapeutic options. These currently include topical calcineurin inhibitors (TCIs), phototherapy, and immunosuppressive agents such as oral corticosteroids, cyclosporine, azathioprine, methotrexate, as well as the more recently introduced biologies targeting IL-4, IL- 13, or their receptors and small molecule JAK inhibitors that interfere with downstream signaling of these pathways.

[0010] Most treatment options, however, offer only temporary, incomplete symptom relief. Moreover, many patients with moderate-to-severe AD become resistant to treatment by topical corticosteroids or by calcineurin inhibitors. Therefore, more targeted therapies for the treatment and / or prevention of moderate to severe AD are needed.SUMMARY OF THE INVENTION

[0011] The aspects, advantageous features and preferred embodiments of the present invention summarized in the following items, respectively alone or in combination, further contribute to solving the object of the invention:

[0012] Provided herein is a method of treating moderate to severe atopic dermatitis (AD) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an IL-4Ra x IL-31 antibody or antigen binding fragment thereof, that binds to both IL-4Ra and IL-31 , wherein the IL-4Ra x IL-31 antibody comprises one or two binding domains, which specifically bind to IL-4Ra (IL-4Ra-BD) and one or two binding domains, which specifically bind to IL-31 (IL-31 -BD).

[0013] The disclosure provided herein also provides the following non-limiting embodiments.A method of treating moderate to severe atopic dermatitis (AD) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an IL-4Ra x IL- 31 antibody or antigen binding fragment thereof, that binds to both IL-4Ra and IL-31, wherein the IL-4Ra x IL-31 antibody comprises one or two binding domains, which specifically bind to IL-4Ra (IL-4Ra-BD) and one or two binding domains, which specifically bind to IL-31 (IL-31-BD); wherein a. each IL-4Ra-BDs comprises i. the HCDR1 sequence of SEQ ID NO: 1, ii. the HCDR2 sequences of SEQ ID NO: 2, iii. the HCDR3 sequence of SEQ ID NO: 3, iv. the LCDR1 sequence of SEQ ID NO: 4, v. the LCDR2 sequence of SEQ ID NO: 5, and vi. the LCDR3 sequences of SEQ ID NO: 6; and b. each IL-31 -BDs comprises i. the HCDR1 sequence of SEQ ID NO: 11 , ii. the HCDR2 sequence of SEQ ID NO: 12, iii. the HCDR3 sequences of SEQ ID NO: 13, iv. the LCDR1 sequence of SEQ ID NO: 14, v. the LCDR2 sequence of SEQ ID NO: 15, and vi. the LCDR3 sequences of SEQ ID NOs: 16; and wherein in HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 are according to the AHo delineation. The method of embodiment 1 , wherein a. the one or two binding domains, which specifically bind to IL-4Ra each each comprise a first heavy chain variable region (VH1) comprising an amino acid sequence which is at least 90%, or at least 95%, or at least 98%, at least 99%, or 100% identical to SEQ ID NO: 7, or 9 and a first light chain variable domain (VL1) comprising an amino acid sequence which is at least 90%, or at least 95%, or at least 98%, at least 99%, or 100% identical to SEQ ID NO: 8, 10, 25 or 27; andb. the one or two binding domains, which specifically bind to IL-31 each comprise a second heavy chain variable region (VH2) comprising an amino acid sequence which is at least 90%, or at least 95%, or at least 98%, at least 99%, or 100% identical to SEQ ID NO: 17 and a second light chain variable domain (VL2) comprising an amino acid sequence which is at least 90%, or at least 95%, or at least 98%, at least 99%, or 100% identical to SEQ ID NO: 18 or 28. method of embodiment 2, wherein a. the one or two binding domains, which specifically bind to IL-4Ra each comprise a VH1 comprising an amino acid sequence of SEQ ID NO: 7 and a VL1 comprising an amino acid sequence of SEQ ID NO: 25; and b. the one or two binding domains, which specifically bind to IL-31 each comprise a VH2 comprising an amino acid sequence of SEQ ID NO: 17 and a VL2 comprising an amino acid sequence of SEQ ID NO: 28. method of embodiment 2, wherein a. the one or two binding domains, which specifically bind to IL-4Ra each comprise a VH1 comprising an amino acid sequence of SEQ ID NO: 9 and a VL1 comprising an amino acid sequence of SEQ ID NO: 27; and b. the one or two binding domains, which specifically bind to IL-31 each comprise a VH2 comprising an amino acid sequence of SEQ ID NO: 17 and a VL2 comprising an amino acid sequence of SEQ ID NO: 28. method of embodiment 2, wherein a. the one or two binding domains, which specifically bind to IL-4Ra each comprise a VH1 comprising an amino acid sequence of SEQ ID NO: 7 and a VL1 comprising an amino acid sequence of SEQ ID NO: 8; and b. the one or two binding domains, which specifically bind to IL-31 each comprise a VH2 comprising an amino acid sequence of SEQ ID NO: 17 and a VL2 comprising an amino acid sequence of SEQ ID NO: 18.The method of embodiment 5, wherein the VL1 further comprises an amino acid sequence of SEQ ID NO: 26 and the VL2 further comprises an amino acid sequence of SEQ ID NO: 29. The method of embodiment 2, wherein a. the one or two binding domains, which specifically bind to IL-4Ra each comprise a VH1 comprising an amino acid sequence of SEQ ID NO: 9 and a VL1 comprising an amino acid sequence of SEQ ID NO: 10; and b. the one or two binding domains, which specifically bind to IL-31 comprise a VH2 comprising an amino acid sequence of SEQ ID NO: 17 and a VL2 comprising an amino acid sequence of SEQ ID NO: 18. The method of embodiment 7, wherein the VL1 further comprises an amino acid sequence of SEQ ID NO: 26 and the VL2 further comprises an amino acid sequence of SEQ ID NO: 29. The method of any of the preceding embodiments, wherein the one or two binding domains, which specifically bind to IL-4Ra comprise a Fab or a single chain variable fragment (scFv). The method of embodiment 9 wherein the one or two binding domains, which specifically bind to IL-4Ra comprise a Fab. The method of any of the preceding embodiments, wherein the one or two binding domains, which specifically bind to IL-31 comprise a Fab or a single chain variable fragment (scFv). The method of embodiment 11 wherein the one or two binding domains, which specifically bind to IL-31 comprise a scFv. The method of any one of embodiments 1-12, wherein the one or two binding domains, which specifically bind to IL-4Ra comprise a Fab and the one or two binding domains, which specifically bind to IL-31 comprise a scFv.The method of embodiment 13, wherein the scFv is in the VH2-linker2-VL2 orientation or in the VL2-linker2-VH2 orientation. The method of embodiment 14, wherein the scFv is in the VL2-linker2-VH2 orientation, and wherein the linker2 comprises or consists essentially of an amino acid sequence of SEQ ID NO: 19. The method of any one of embodiments 1-15, wherein the IL-4Ra x IL-31 antibody comprises two IL-4Ra-BDs and two IL-31-BDs. The method of embodiment 16, wherein the IL-4Ra x IL-31 antibody further comprises an immunoglobulin (Ig) heavy chain constant region, or a fragment of an Ig heavy chain constant region and an immunoglobulin (Ig) light chain constant region, or a fragment of an Ig light chain constant region. The method of embodiment 17, wherein immunoglobulin (Ig) heavy chain constant region is an IgGl isotype, and IgG2 isotype, or an IgG4 isotype. The method of embodiment 18, wherein immunoglobulin (Ig) heavy chain constant region is an IgG4 isotype. The method of embodiment 19, wherein the IL-4Ra x IL-31 antibody is in a Morisson-L format or in a Morrisson-H format. The method of embodiment 20, wherein the IL-4Ra x IL-31 antibody is in a Morrisson-H formatThe method of embodiment 21, wherein the scFv is fused to the C-terminus of the heavy chain constant region with a linkerl comprising or consisting essentially of an amino acid sequence of SEQ ID NO: 20. The method of any one of the foregoing embodiments, wherein the IL-4Ra x IL-31 antibody comprises a. two heavy chains, wherein each heavy chain comprises an amino acid sequence at least 90% identical, or at least 95%, or at least 98%, at least 99%, or 100% identical to SEQ ID NO: 21; and b. two light chains, wherein each light chain comprises an amino acid sequence at least 90% identical, or at least 95%, or at least 98%, at least 99%, or 100% identical to SEQ ID NO: 22. The method of embodiment 23, wherein the IL-4Ra x IL-31 antibody comprises a. two heavy chains, wherein each heavy chain comprising an amino acid sequence of SEQ ID NO: 21; and b. two light chains (LC), wherein each light chain comprises an amino acid sequence of SEQ ID NO: 22. The method of any one of embodiments 1-22, wherein the IL-4Ra x IL-31 antibody comprises a. two heavy chains, wherein each heavy chain comprises an amino acid sequence at least 90% identical, or at least 95%, or at least 98%, at least 99%, or 100% identical to SEQ ID NO: 23; and b. two light chains, wherein each light chain comprises an amino acid sequence at least 90% identical, or at least 95%, or at least 98%, at least 99%, or 100% identical to SEQ ID NO: 24. The method of embodiment 25, wherein the IL-4Ra x IL-31 antibody comprisesa. two heavy chains (HC), wherein each heavy chain comprises an amino acid sequence of SEQ ID NO: 23; and b. two light chains (LC), wherein each light chain comprises an amino acid sequence of SEQ ID NO: 24. A method of treating moderate to severe atopic dermatitis (AD) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an IL-4Ra and x IL-31 antibody or antigen binding fragment thereof, wherein the IL-4Ra x IL-31 antibody comprises two binding domains, which specifically bind to IL-4Ra and two binding domains, which specifically bind to IL-31 ; wherein the IL-4Ra x IL-31 antibody comprises a. a first heavy chain variable domain (VH1) comprising an amino acid sequence of SEQ ID NO: 7 b. a first heavy chain variable domain (VL1) comprising an amino acid sequence of SEQ ID NO: 25 c. a second heavy chain variable domain (VH2) comprising an amino acid sequence of SEQ ID NO: 17 d. a second heavy chain variable domain (VL2) comprising an amino acid sequence of SEQ ID NO: 28 A method of treating moderate to severe atopic dermatitis (AD) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an IL-4Ra and x IL-31 antibody or antigen binding fragment thereof, wherein the IL-4Ra x IL-31 antibody comprises two binding domains, which specifically bind to IL-4Ra and two binding domains, which specifically bind to IL-31 ; wherein the IL-4Ra x IL-31 antibody comprises a. two heavy chains, each heavy chain comprising an amino acid sequence of SEQ ID NO: 21; and b. two light chains, each light chain comprising an amino acid sequence SEQ ID NO:22.The method of any one of the preceding embodiments, wherein the method comprises administering to the patient an initial dose of the IL-4Ra x IL-31 antibody, wherein the initial dose is at least about 150 mg or 174 mg. The method of embodiment 29, wherein the initial dose is between at least about 150 mg and about 700 mg, for example about 150 mg, about 174 mg, about 200 mg, about 250 mg, about 300 mg, about 348 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg or about 696 mg. The method of embodiment 30, wherein the initial dose is about 348 mg. The method of embodiment 28, wherein the initial dose is about 696 mg. The method of any one of embodiments 29-32, wherein the method further comprises administering a dose of the IL-4Ra x IL-31 antibody after the initial dose, wherein the dose of the IL-4Ra x IL-31 antibody administered after the initial dose is equal or lower than the initial dose. The method of embodiment 33, wherein the dose of the IL-4Ra x IL-31 antibody administered after the initial dose is between about 150 mg and about 700 mg. The method of embodiment 34, wherein the initial dose and the dose administered after the initial dose is about 696 mg. The method of embodiment 34, wherein the initial dose is about 600 mg or about 696 mg and the dose administered after the initial dose is about 300 mg or about 348 mg. The method of embodiment 34, wherein the initial dose is about 600 mg and the dose administered after the initial dose is about 450 mg.The method of embodiment 34, wherein the initial dose is about 300 mg or about 348 mg and the dose administered after the initial dose is about 150 mg or about 174 mg. The method of any one of embodiments 29-38, wherein the dose administered after the initial dose is administered once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks, preferably once every 2 weeks. The method of any one of embodiments 29-39, wherein the initial dose is administered once and the dose administered after the initial dose is administered once every 2 weeks. The method of embodiment 40, wherein the initial dose is administered once and the dose administered after the initial dose is administered once every 2 weeks through week 22. The method of embodiment 41, wherein the initial dose is administered once and the dose administered after the initial dose is administered about 2 weeks after the initial dose, about 4 weeks after the initial dose, about 6 weeks after the initial dose, about 8 weeks after the initial dose, about 10 weeks after the initial dose, about 12 weeks after the initial dose, about 14 weeks after the initial dose, about 16 weeks after the initial dose, about 18 weeks after the initial dose, about 20 weeks after the initial dose, and about 22 weeks after the initial dose. The method of any one of embodiments 29-42, wherein a. the initial dose is between about 150 mg and about 700 mg; and b. the dose administered after the initial dose is i. administered about 2 weeks after the initial dose, about 4 weeks after the initial dose, about 6 weeks after the initial dose, about 8 weeks after the initial dose, bout 10 weeks after the initial dose, about 12 weeks after the initial dose, about 14 weeks after the initial dose, about 16 weeks after the initial dose, about 18 weeks after the initial dose, about 20 weeks after the initial dose, and about 22 weeks after the initial dose,ii. is between about 150 mg and about 700 mg; and iii. is equal or lower than the initial dose. The method of any one of embodiments 29-43, wherein the initial dose and the dose administered after the initial dose are a flat dose. The method of any one of embodiments 29-44, wherein the initial dose and the dose administered after the initial dose are administered subcutaneously. A method of treating moderate to severe atopic dermatitis (AD) in a patient in need thereof, wherein the method comprises administering to the patient an initial dose of the IL-4Ra x IL- 31 antibody, followed by a dose of the IL-4Ra x IL-31 antibody administered after the initial dose, wherein a. the initial dose is between at least about 150 mg and about 700 mg; b. the dose administered after the initial dose is between about 150 mg and about 700 mg; c. the dose administered after the initial dose is administered once every 2 weeks; d. the dose administered after the initial dose is administered is administered through week 22; e. the dose administered after the initial dose is equal or lower than the initial dose; f. the initial dose and the dose administered after the initial dose are administered subcutaneously; and g. the IL-4Ra x IL-31 antibody comprises two heavy chains and two light chains, wherein each heavy chain and each light chain comprise an amino acid sequence of SEQ ID NO: 21 and 22, respectively. The method of any one of the foregoing embodiments, wherein the patient is a responder or demonstrated improvement to the administration of the IL-4Ra x IL-31 antibody by being identified as meeting a clinical endpoint.The method of embodiment 47, wherein the clinical endpoint is measured through about 12 weeks, through about 16 weeks, through about 24 weeks, and / or through about 36 weeks after administration of the initial dose. The method of embodiments 47 or 48, wherein the clinical endpoints measured through about 12 weeks after the initial dose are compared to patients treated with placebos. The method of embodiments 47 or 48, wherein the clinical endpoint measured through about 12 weeks, through about 16 weeks, through about 24 weeks, and / or through about 36 weeks are compared to patients treated with dupilumab. The method of embodiment 49, wherein the clinical endpoint measured through about 12 weeks as compared to patients being treated with placebo, is: a. Eczema Area and Severity Index (EASI) 75 at week 12, b. EASI 90 at week 12; c. EASI 100 at week 12; d. vIGA-AD score of 0 and a reduction from baseline of >2 points at Week 12; e. validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of 0 or 1 and a reduction from baseline of >2 points at Week 12; f. percent change from baseline in the EASI total score at Week 12; g. >4-point improvement (reduction) in Skin Pain numeric(al) rating scale (NRS) from baseline to Week 12; h. percent change from baseline in Peak Pruritus Numeric(al) Rating Scale (PP- NRS) at Week 12; i. percent change from baseline in Skin Pain NRS at Week 12; j. percent change from baseline in the score of Item 2 of the AD Sleep Scale at Week 12; or k. >4-point improvement (reduction) in PP-NRS from baseline through Week 12.The method of embodiment 50, wherein the clinical endpoint measured through about 16 weeks as compared to patients being treated with dupilumab, is: a. EASI 75 at Week 16; b. EASI 90 at Week 16; c. EASI 100 at Week 16; d. vIGA-AD score of 0 or 1 and a reduction from baseline of >2 points at Week 16; e. vIGA-AD score of 0 and a reduction from baseline of >2 points at Week 16; f. percent change from baseline in the EASI total score at Week 16; g. >4-point improvement (reduction) in Skin Pain NRS from baseline at Week 16; h. Percent change from baseline in PP-NRS at Week 16; i. Percent change from baseline in Skin Pain NRS at Week 16; or j. Percent change from baseline in the score of Item 2 of the AD Sleep Scale at Week 16. The method of embodiment 50, wherein the clinical endpoint measured through about 24 weeks, as compared to patients being treated with dupilumab, is a. >4-point improvement (reduction) in PP-NRS from baseline through Week 24; b. EASI 75 at Week 24; c. EASI 90 at Week 24; d. EASI 100 at Week 24; e. vIGA-AD score of 0 or 1 and a reduction from baseline of >2 points at Week 24; f. vIGA-AD score of 0 and a reduction from baseline of >2 points at Week 24; g. Percent change from baseline in the EASI total score at Week 24; h. >4-point improvement (reduction) in Skin Pain NRS from baseline at Week 24; i. Percent change from baseline in PP-NRS at Week 24; j. Percent change from baseline in Skin Pain NRS at Week 24; or k. Percent change from baseline in the score of Item 2 of the AD Sleep Scale at Week 24. The method of any one of embodiments 47-53, wherein the clinical endpoints, relative to placebo through week 12 or relative to dupilumab through week 24, are based on the assessment of additional timepoints selected from the group consisting of Eczema Area andSeverity Index (EASI), EASI 75, EASI 90, EASI 100, EASI %cfb (percent change from baseline), validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD), vIGA- AD (0,1) and >2 improvement, vIGA-AD (0) and >2 improvement, Body Surface Area (BSA), BSA cfb (change from baseline), Peak Pruritus Numeric Rating Scale (PP-NRS), PP-NRS %cfb, PP-NRS (0, 1), EASI 90 and PP-NRS (0,1), Skin Pain Numeric Rating Scale (SP-NRS), SP-NRS >4 improvement, SP-NRS %cfb, AD sleep scale Item 1 cfb, AD sleep scale Item 2 %cfb, AD sleep scale Item 2 >2 improvement, AD sleep scale Item 3 cfb, Patient-Oriented Eczema Measure (POEM), POEM %cfb, POEM >4 improvement, Hospital Anxiety and Depression Scale (HADS), HADS-A %cfb, HADS-A <8, HADS-D %cfb, HADS-D <8, Dermatological Life Quality Index (DLQI), DLQI (0, 1), DLQI >4 improvement, DLQI cfb, Patient-reported Outcomes Measurement Information System-29 (PROMIS-29), PROMIS-29 by domain cfb, PROMIS-29 physical / mental composite cfb, Asthma Control Questionnaire - 5 (ACQ-5), ACQ-5 %cfb, ACQ-5 >0.5 improvement, Digital Nocturnal Scratch and Sleep Wrist- worn Device. The method of embodiment 47, wherein the clinical endpoint is the frequency and type of Adverse Events (AE) and Serious Adverse Events (SAEs) The method of embodiment 47, wherein the clinical endpoint is the concentration of the IL- 4Ra x IL-31 antibody over time or the titer of anti-drug antibody (ADA) to the IL-4Ra x IL- 31 antibody. The method of embodiment 47, wherein the clinical endpoint is changes in cellular and molecular biomarkers in skin and blood from baseline over time. The method of embodiment 47, wherein the clinical endpoint is changes from baseline over time in Asthma Control Questionnaire - 5 (ACQ-5) score in patients with concomitant medical history of asthma.The method of any one of the preceding embodiments, wherein the patient is 18 years of age or older. The method of any one of the preceding embodiments, wherein the patient has chronic atopic dermatitis, according to American Academy of Dermatology Consensus Criteria with onset of symptoms at least 1 year prior to screening visit as determined by the investigator through participant interview and / or review of the medical history. The method of any one of the preceding embodiments, wherein the patient has an adverse event of special interest (EASI) score >16 at the Screening and Baseline Visits. The method of any one of the preceding embodiments, wherein the patient has a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score >3 at the Screening and Baseline Visits. The method of any one of the preceding embodiments, wherein the patient has >10% Body Surface Area (BSA) of atopic dermatitis involvement at the Screening and Baseline Visits. The method of any one of the preceding embodiments, wherein the patient has a baseline Peak Pruritus Numeric(al) Rating Scale (PP-NRS) average score of >4. The method of any one of the preceding embodiments, wherein the patient has documented history (within 6 months before screening) of either inadequate response or inadvisability to topical treatments, or inadequate response to systemic therapies (within 12 months before screening). The method of any one of the preceding embodiments, wherein the patient has applied a moisturizer at least once daily for at least 7 days before the Baseline Visit.The method of any one of the preceding embodiments, wherein the patient does not have active skin disease other than atopic dermatitis (AD) including eczema herpeticum, molluscum contagiosum, impetigo, psoriasis or has any other ongoing significant skin condition including skin infections, that could interfere with efficacy assessments. The method of any one of the preceding embodiments, wherein the patient has not received prior administration of the IL-4Ra x IL-31 antibody. The method of any one of the preceding embodiments, wherein the patient has not received prior treatment with: a. agents that deplete B cells (alemtuzumab, ocrelizumab, or rituximab) 26 weeks prior to the first administration of the IL-4Ra x IL-31 antibody through end of study; b. any immunomodulating biologic therapy that could affect AD including but not limited to dupilumab, tralokinumab, lebrikizumab, nemolizumab, natalizumab, belimumab, abatacept, visilizumab, or any experimental or investigational therapy 12 weeks or 5 half-lives, whichever is longer, prior to the first administration of the IL- 4Ra x IL-31 antibody through end of study; c. Systemic immunomodulating / immunosuppressive treatments including but not limited to corticosteroids (oral or parenteral), methotrexate, cyclosporine A, azathioprine, JAK inhibitors, 4 weeks prior to the first administration of the IL-4Ra x IL-31 antibody through end of study; d. Phototherapy 4 weeks prior to the first administration of the Il-4Ra x IL-31 antibody through end of study; e. Systemic medications that could affect AD evaluations including, but not limited to acitretin, retinoids, herbal treatments, or traditional medicines (eg, Korean or Chinese) 4 weeks prior to the first administration of the IL-4Ra x IL-31 antibody through end of study; f. Nonbiologic experimental therapies or investigational agents 4 weeks prior to the first administration of the IL-4Ra x IL-31 antibody through end of study;g. Topical medications / treatments that could affect AD evaluations including, but not limited to Corticosteroids, calcineurin inhibitors, JAK inhibitors, PDE4 inhibitors, prescription moisturizers, herbal treatments or traditional medicines (eg, Korean or Chinese) 1 weeks prior to the first administration of the IL-4Ra x IL-31 antibody through end of study; h. Live virus or live bacterial vaccination 12 weeks (or longer if required per vaccine package insert) prior to the first administration of the IL-4Ra x IL-31 antibody through end of study and for 90 days after receiving the last dose of the IL-4Ra x IL- 31 antibody. The method of any one of the preceding embodiments, wherein the antibody is in a composition formulation comprising 125.6 mM sucrose, 20 mM (L-)arginine hydrochloride, 66.6 mM Glycine, 30 mM (L)-histidine, and 0.02% (w / v) poloxamer 188; wherein the formulation is about pH 6.0. A method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 600 mg of an IL-4Ra x IL-31 antibody that binds to both IL-4Ra and IL-31, (ii) a 300 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 300 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 300 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 300 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 300 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 300 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 300 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 300 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 300 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 300 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 300 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 7and SEQ ID NO: 25, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively , and the patient is a responder to the antibody by being identified as meeting a clinical endpoint. A method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 696 mg of an IL-4Ra x IL-31 antibody that binds to both IL-4Ra and IL-31, (ii) a 348 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 348 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 348 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 348 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 348 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 348 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 348 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 348 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 348 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 348 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 348 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 25, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint. A method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 300 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 150 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 150 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 150 mg subcutaneous dose of the antibody about 6 weeks after theinitial dose, (v) a 150 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 150 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 150 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 150 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 150 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 150 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 150 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 150 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 25, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint. A method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 348 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 174 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 174 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 174 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 174 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 174 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 174 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 174 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 174 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 174 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 174 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 174 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 25,respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint. A method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 600 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 600 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 600 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 600 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 600 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 600 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 600 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 600 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 600 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 600 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 600 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 600 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 25, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint. A method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 696 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 696 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 696 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 696 mg subcutaneous dose of the antibody about 6 weeks after theinitial dose, (v) a 696 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 696 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 696 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 696 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 696 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 696 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 696 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 696 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 25, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint. A method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 696 mg of an IL-4Ra x IL-31 antibody that binds to both IL-4Ra and IL-31, (ii) a 348 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 348 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 348 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 348 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 348 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 348 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 348 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 348 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 348 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 348 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 348 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises two heavy chains, each heavy chain comprising an amino acid sequence of SEQ ID NO: 21 and two light chains, each light chain comprisingan amino acid sequence SEQ ID NO: 22 and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint. A method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 348 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 174 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 174 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 174 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 174 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 174 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 174 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 174 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 174 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 174 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 174 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 174 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises two heavy chains, each heavy chain comprising an amino acid sequence of SEQ ID NO: 21 and two light chains, each light chain comprising an amino acid sequence SEQ ID NO: 22, and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint. A method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 696 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 696 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 696 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 696 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 696 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 696 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 696 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 696 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 696mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 696 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 696 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 696 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises two heavy chains, each heavy chain comprising an amino acid sequence of SEQ ID NO: 21 and two light chains, each light chain comprising an amino acid sequence SEQ ID NO: 22 and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint. Use of an IL-4Ra x IL-31 antibody that binds to both IL-4Ra and IL-31 for the treatment of moderate to severe atopic dermatitis in a patient, wherein the antibody comprises one or two binding domains, which specifically bind to IL-4Ra (IL-4Ra-BD), and one or two binding domains, which specifically bind to IL-31 (IL-31 -BD), wherein a. each of said IL-4Ra-BDs comprise i. the HCDR1 sequence of SEQ ID NO: 1, ii. the HCDR2 sequences of SEQ ID NO: 2, iii. the HCDR3 sequence of SEQ ID NO: 3, iv. the LCDR1 sequence of SEQ ID NO: 4, v. the LCDR2 sequence of SEQ ID NO: 5, and vi. the LCDR3 sequences of SEQ ID NO: 6; and b. each of said IL-31 -BDs comprises i. the HCDR1 sequence of SEQ ID NO: 11 , ii. the HCDR2 sequence of SEQ ID NO: 12, iii. the HCDR3 sequences of SEQ ID NO: 13, iv. the LCDR1 sequence of SEQ ID NO: 14, v. the LCDR2 sequence of SEQ ID NO: 15, and vi. the LCDR3 sequences of SEQ ID NOs: 16; and wherein the patient is deemed a responder to the antibody.The use of the antibody in embodiment 79, wherein the antibody is administered at an initial dose, a dose about 2 weeks after the initial dose, a dose about 4 weeks after the initial dose, a dose about 6 weeks after the initial dose, a dose about 8 weeks after the initial dose, a dose about 10 weeks after the initial dose, a dose about 12 weeks after the initial dose, a dose about 14 weeks after the initial dose, a dose about 16 weeks after the initial dose, a dose about 18 weeks after the initial dose, a dose about 20 weeks after the initial dose, and a dose about 22 weeks after the initial dose. The use of the antibody in embodiment 80, wherein the initial dose and the doses after the initial dose are about 600 mg or about 696 mg of the antibody. The use of the antibody in embodiment 80, wherein the initial dose is about 600 mg or about 696 mg of antibody and the doses after the initial dose are about 300 mg or about 348 mg of the antibody. The use of the antibody in embodiment 80, wherein the initial dose is about 300 mg or about 348 mg of antibody and the doses after the initial dose are about 150 mg or about 174 mg of the antibody. The use of the antibody of any one of embodiments 78-83, wherein the antibody is administered subcutaneously. The use of the antibody in embodiment 84, wherein the clinical endpoint is selected from the group consisting of: a. >4-point improvement (reduction) in PP-NRS from baseline through Week 24; b. EASI 75 at Week 24; c. EASI 90 at Week 24; d. EASI 100 at Week 24; e. vIGA-AD score of 0 or 1 and a reduction from baseline of >2 points at Week 24; f. vIGA-AD score of 0 and a reduction from baseline of >2 points at Week 24;g. Percent change from baseline in the EASI total score at Week 24; h. >4-point improvement (reduction) in Skin Pain NRS from baseline at Week 24; i. Percent change from baseline in PP-NRS at Week 24; j . Percent change from baseline in Skin Pain NRS at Week 24; or k. Percent change from baseline in the score of Item 2 of the AD Sleep Scale at Week 24. The use of embodiment 85, wherein the clinical endpoint is measured through about 12 weeks, through about 16 weeks, through about 24, and / or through about 36 weeks after the initial dose. The use of the antibody of any one of embodiments 78-86, wherein the antibody comprises a. a first heavy chain variable domain (VH1) comprising an amino acid sequence of SEQ ID NO: 7 b. a first heavy chain variable domain (VL1) comprising an amino acid sequence of SEQ ID NO: 25 c. a second heavy chain variable domain (VH2) comprising an amino acid sequence of SEQ ID NO: 17 d. a second heavy chain variable domain (VL2) comprising an amino acid sequence of SEQ ID NO: 28 The use of the antibody of anyone of embodiments 78-87, wherein the antibody comprises a. two heavy chains, each heavy chain comprising an amino acid sequence of SEQ ID NO: 21; and b. two light chains, each light chain comprising an amino acid sequence SEQ ID NO: 22. The use of an IL-4Ra x IL-31 antibody, wherein the antibody is in a composition formulation comprising 125.6 mM sucrose, 20 mM (L-)arginine hydrochloride, 66.6 mM Glycine, 30 mM (L)-histidine, and 0.02% (w / v) poloxamer 188; wherein the formulation is about pH 6.0.Use of an antibody binding to both IL-4Ra and IL-31 for the treatment of moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 600 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 300 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 300 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 300 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 300 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 300 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 300 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 300 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 300 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 300 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 300 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 300 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 25, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint. Use of an antibody binding to both IL-4Ra and IL-31 for the treatment of moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 696 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 348 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 348 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 348 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 348 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 348 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 348 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 348 mgsubcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 348 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 348 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 348 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 348 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 25, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint. Use of an antibody binding to both IL-4Ra and IL-31 for the treatment of moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 300 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 150 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 150 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 150 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 150 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 150 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 150 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 150 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 150 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 150 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 150 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 150 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 25, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ IDNO: 28, respectively, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint. Use of an antibody binding to both IL-4Ra and IL-31 for the treatment of moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 348 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 174 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 174 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 174 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 174 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 174 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 174 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 174 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 174 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 174 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 174 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 174 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 25, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint. Use of an antibody binding to both IL-4Ra and IL-31 for the treatment of moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 600 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 600 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 600 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 600 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 600 mgsubcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 600 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 600 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 600 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 600 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 600 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 600 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 600 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 25, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint, wherein the clinical endpoint is change from baseline in the EASI total score at about Week 12 and / or about week 16. Use of an antibody binding to both IL-4Ra and IL-31 for the treatment of moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 696 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 696 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 696 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 696 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 696 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 696 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 696 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 696 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 696 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 696 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 696 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 696 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibodycomprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 25, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint, wherein the clinical endpoint is change from baseline in the EASI total score at about Week 12 and / or about week 16. Use of an antibody binding to both IL-4Ra and IL-31 for the treatment of moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 696 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 348 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 348 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 348 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 348 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 348 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 348 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 348 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 348 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 348 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 348 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 348 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises two heavy chains, each heavy chain comprising an amino acid sequence of SEQ ID NO: 21 and two light chains, each light chain comprising an amino acid sequence SEQ ID NO: 22, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint. Use of an antibody binding to both IL-4Ra and IL-31 for the treatment of moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 348 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 174mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 174 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 174 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 174 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 174 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 174 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 174 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 174 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 174 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 174 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 174 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises two heavy chains, each heavy chain comprising an amino acid sequence of SEQ ID NO: 21 and two light chains, each light chain comprising an amino acid sequence SEQ ID NO: 22, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint. Use of an antibody binding to both IL-4Ra and IL-31 for the treatment of moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 696 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 696 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 696 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 696 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 696 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 696 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 696 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 696 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 696 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 696 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 696 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 696 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibodycomprises two heavy chains, each heavy chain comprising an amino acid sequence of SEQ ID NO: 21 and two light chains, each light chain comprising an amino acid sequence SEQ ID NO: 22, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint.DESCRIPTION OF THE DRAWINGS

[0014] FIG. 1 shows the schematic representation of the IgG4 Morrison-H format (left) and Morrison-L format (right) with labeled subdomain nomenclature. Linker sequences connecting the Fv domains (light grey) consist of (G4S) modules of different repetitions (two modules in between constant regions and scFv domains and 4 modules in between VL2 and VH2).DETAILED DESCRIPTION OF THE INVENTION

[0015] The disclosed methods can be understood more readily by reference to the following detailed description. It is to be understood that the disclosed methods are not limited to the specific methods described and / or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed methods. All patents published patent applications and publications cited herein are incorporated by reference as if set fourth fully herein.Definitions

[0016] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this invention pertains. Other specifically defined terms are to be construed in a manner consistent with the definitions provided herein.

[0017] Various terms relating to aspects of the description are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definitions provided herein.

[0018] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a cell” includes a combination of two or more cells, and the like.

[0019] The term “about” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of up to ±10% from the specified value, as such variations are appropriate to perform the disclosed methods. Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0020] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0021] Unless otherwise indicated, the term “at least” preceding a series of elements is to be understood to refer to every element in the series. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the invention.

[0022] The transitional terms “comprising.” “consisting essentially of,” and “consisting of’ are intended to connote their generally accepted meanings in the patent vernacular; that is, (i) “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; (ii) “consisting of’ excludes any element, step, or ingredient not specified in the claim; and (iii)“consisting essentially of’ limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention. Embodiments described in terms of the phrase “comprising” (or its equivalents) also provide as embodiments those independently described in terms of “consisting of’ and “consisting essentially of.”

[0023] It should also be understood that the terms “approximately,” “generally,” “substantially” and like terms, used herein when referring to a dimension or characteristic of a component of the preferred invention, indicate that the described dimension / characteristic is not a strict boundary or parameter and does not exclude minor variations therefrom that are functionally the same or similar, as would be understood by one having ordinary skill in the art. At a minimum, such references that include a numerical parameter would include variations that, using mathematical and industrial principles accepted in the art (e.g., rounding, measurement or other systematic errors, manufacturing tolerances, etc.), would not vary the least significant digit.

[0024] The term “antibody” is meant in a broad sense and includes immunoglobulin molecules including monoclonal antibodies including murine, human, humanized and chimeric monoclonal antibodies, antigen binding fragments, multispecific antibodies, such as bispecific, trispecific, tetraspecific, dimeric, tetrameric or multimeric antibodies, single chain antibodies, domain antibodies and any other modified configuration of the immunoglobulin molecule that comprises an antigen binding site of the required specificity. “Antibodies” and the like, as used herein, includes whole antibodies or single chains thereof; and any antigen-binding fragment (i. e., “antigen-binding portion”) or single chains thereof; and molecules comprising antibody CDRs, VH regions or VL regions (including without limitation multispecific antibodies).

[0025] “Full length antibodies” are comprised of two heavy chains (HC) and two light chains (LC) inter-connected by disulfide bonds as well as multimers thereof (e.g. IgM). Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (comprised of domains CHI, hinge, CH2 and CH3). Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL). The VH and the VL may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FR). Each VH and VL is composed of three CDRsand four FR segments, arranged from amino-to-carboxy -terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.

[0026] Immunoglobulins may be assigned to five major classes, IgA, IgD, IgE, IgG and IgM, depending on the heavy chain constant domain amino acid sequence. IgA and IgG are further sub-classified as the isotypes IgAl, IgA2, IgGl, IgG2, IgG3 and IgG4. Antibody light chains of any vertebrate species may be assigned to one of two clearly distinct types, namely kappa (K) and lambda (X), based on the amino acid sequences of their constant domains.

[0027] The term “immunoglobulin Fc region” or “Fc region”, as used herein, is used to define a C-terminal region of an immunoglobulin heavy chain constant region, i. e. the CH2 and CH3 domains of the heavy chain constant regions. The term “Fc region” may include native-sequence Fc regions and variant Fc regions, i. e. Fc regions that are engineered to exhibit certain desired properties, such as for example altered Fc receptor binding function, reduced or suppressed arm exchange, and / or increased serum half-life. “Fc polypeptide” of a dimeric Fc refers to one of the two polypeptide forming the dimeric Fc domain. For example, an Fc polypeptide of a dimeric IgG Fc comprises an IgG CH2 and an IgG CH3 constant domain sequence).

[0028] The term “IgG region”, as used herein, refers to the heavy and light chain of an immunoglobulin G, i. e. the Fc region, as defined above, and the Fab region, consisting of the VL, VH, CL and CHI domains. The term “IgG region” includes native-sequence Ig regions, such as human IgGl , lgG2 (lgG2A, lgG2B), lgG3 and lgG4, as well as engineered IgG regions, which exhibit certain desired properties, as for example the properties define above for the Fc region. The term “functional IgG region”, as used herein, refers to an IgG region comprising a functional Fc region.

[0029] The VH and the VL regions may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FR). Each VH and VL is composed of three CDRs and four FR segments, arranged from amino-to- carboxy -terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. “Complementarity determining regions” (CDR) are antibody regions that bind an antigen. There are three CDRs in the VH (HCDR1, HCDR2, HCDR3) and three CDRs in the VL (LCDR1, LCDR2, LCDR3). CDRs may be defined using various delineations such as Kabat (Wu et al. (1970) J Exp Med 132: 211-50; Kabat et al., Sequences of Proteins of Immunological Interest,5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia et al. (1987) J Mol Biol 196: 901-17), IMGT (Lefranc et al. (2003) Dev Comp Immunol 27: 55-77), AbM (Martin and Thornton J Bmol Biol 263: 800-15, 1996) and AHo (Honegger & Pliickthun, J. Mol. Biol. 309 (2001) 657-670). The correspondence between the various delineations and variable region numbering is described (see e.g., Lefranc et al. (2003) Dev Comp Immunol 27: 55-77; Honegger and Pluckthun, J Mol Biol (2001) 309:657-70; International ImMunoGeneTics (IMGT) database). Available programs such as abYsis by UCL Business PLC may be used to delineate CDRs. The term “CDR”, “HCDR1”, “HCDR2”, “HCDR3”, “LCDR”, “LCDR2” and “LCDR3” as used herein includes CDRs defined by any of the methods described supra, Kabat, Chothia, IMGT, AbM, and AHo unless otherwise explicitly stated in the specification.

[0030] In the context of the present invention, the numbering system suggested by Honegger & Pluckthun (“AHo”) is used (Honegger & Pluckthun, J. Mol. Biol. 309 (2001) 657-670), unless specifically mentioned otherwise. In particular, the following residues are defined as CDRs according to AHo numbering scheme: LCDR1 (also referred to as CDR-L1): L24-L42; LCDR2 (also referred to as CDR-L2): L58-L72; LCDR3 (also referred to as CDR-L3): L107-L138; HCDR1 (also referred to as CDR-H1): H27-H42; HCDR2 (also referred to as CDR-H2): H57- H76; HCDR3 (also referred to as CDR-H3): H108-H138.

[0031] Antibodies used in the present invention include, but are not limited to, full length antibodies, antigen binding fragments, chimeric, human and humanized antibodies.

[0032] “Antigen binding fragment”, “antigen binding domain” or “binding domain” refers to a portion of the protein that binds an antigen, or to one or more fragments of an intact antibody that retain the ability to specifically bind to a given antigen (e. g., IL-4Ra, IL-31). Antigen binding fragments may be synthetic, enzymatically obtainable or genetically engineered polypeptides and include portions of an immunoglobulin that bind an antigen, such as the VH, the VL, the VH and the VL, Lab, Lab', L(ab')2, Ld and Fv fragments, domain antibodies (dAb) consisting of one VH domain or one VL domain, shark variable IgNAR domains, camelized VH domains, VHH domains, minimal recognition units consisting of the amino acid residues that mimic the CDRs of an antibody, such as FR3-CDR3-FR4 portions, the HCDR1, the HCDR2 and / or the HCDR3 and the LCDR1, the LCDR2 and / or the LCDR3, alternative scaffolds thatbind an antigen, and multispecific proteins comprising the antigen binding fragments. Antigen binding fragments (such as VH and VL) may be linked together via a synthetic linker to form various types of single antibody designs where the VH / VL domains may pair intramolecularly, or intermolecularly in those cases when the VH and VL domains are expressed by separate single chains, to form a monovalent antigen binding domain, such as single chain Fv (scFv) or diabody.

[0033] Antigen binding fragments may also be conjugated to other antibodies, proteins, antigen binding fragments or alternative scaffolds which may be monospecific or multispecific to engineer bispecific and multispecific proteins. Preferably, the binding domains of the antibodies used in the present invention are independently of each other selected from a Fab fragment, an Fv fragment, a dsFv fragment and a single-chain Fv fragment (scFv). In particular embodiments, the binding domains of the antibodies used in the present invention are independently of each other selected from a Fab fragment and a single-chain Fv fragment (scFv). In other particular embodiments, the VL and VH domains of the scFv fragment are stabilized by an interdomain disulfide bond, in particular said VH domain comprises a single cysteine residue in position 51 (AHo numbering) and said VL domain comprises a single cysteine residue in position 141 (AHo numbering).

[0034] “Single chain Fv” or “scFv” refers to a fusion protein comprising at least one antibody fragment comprising a light chain variable region (VL) and at least one antibody fragment comprising a heavy chain variable region (VH), wherein the VL and the VH are contiguously linked via a polypeptide linker, and capable of being expressed as a single chain polypeptide. Unless specified, as used herein, a scFv may have the VL and VH variable regions in either order, e.g., with respect to the N-terminal and C-terminal ends of the polypeptide, the scFv may comprise VL-linker-VH or may comprise VH-linker-VL.

[0035] “(scFv)2” or “tandem scFv” or “bis-scFv” fragments refers to a fusion protein comprising two light chain variable region (VL) and two heavy chain variable region (VH), wherein the two VL and the two VH regions are contiguously linked via polypeptide linkers, and capable of being expressed as a single chain polypeptide. The two VL and two VH regions fused by peptide linkers form a bivalent molecule VLA-hnker-VHA-linker-VLB-linker-VHB to form two binding sites, capable of binding two different antigens or epitopes concurrently.

[0036] “dAb” or “dAb fragment” refers to an antibody fragment composed of a VH domain (Ward et al., Nature 341 :544 546 (1989)).

[0037] “Fab” or “Fab fragment” refers to an antibody fragment composed of VH, CHI, VL and CL domains.

[0038] “F(ab')2” or “F(ab')2 fragment” refers to an antibody fragment containing two Fab fragments connected by a disulfide bridge in the hinge region.

[0039] “Fd” or “Fd fragment” refers to an antibody fragment composed of VH and CHI domains.

[0040] “Fv” or “Fv fragment” refers to an antibody fragment composed of the VH and the VL domains from a single arm of the antibody. Fv fragments lack the constant regions of Fab (CHI and CL) regions. The VH and VL in Fv fragments are held together by non-covalent interactions.

[0041] “Human antibody” refers to an antibody that is optimized to have minimal immune response when administered to a human subject. Variable regions of human antibody are derived from human immunoglobulin sequences. If human antibody contains a constant region or a portion of the constant region, the constant region is also derived from human immunoglobulin sequences. Human antibody comprises heavy and light chain variable regions that are “derived from” sequences of human origin if the variable regions of the human antibody are obtained from a system that uses human germline immunoglobulin or rearranged immunoglobulin genes. Such exemplary systems are human immunoglobulin gene libraries displayed on phage, and transgenic non-human animals such as mice or rats carrying human immunoglobulin loci.“Human antibody” typically contains amino acid differences when compared to the immunoglobulins expressed in humans due to differences between the systems used to obtain the human antibody and human immunoglobulin loci, introduction of somatic mutations or intentional introduction of substitutions into the frameworks or CDRs, or both. Typically, “human antibody” is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical in amino acid sequence to an amino acid sequence encoded by human germline immunoglobulin or rearranged immunoglobulin genes. In some cases, “human antibody” may contain consensus framework sequences derived from human framework sequence analyses, for example as described in Knappik et al., (2000) J Mol Biol 296:57-86, or a synthetic HCDR3 incorporated into humanimmunoglobulin gene libraries displayed on phage, for example as described in Shi et al., (2010) J Mol Biol 397:385-96, and in Int. Patent Publ. No. W02009 / 085462. Antibodies in which at least one CDR is derived from a non-human species are not included in the definition of “human antibody”.

[0042] The term “humanized” antibody (or antigen-binding fragment thereof), as used herein, refers to an antibody in which at least one CDR is derived from non-human species and at least one framework is derived from human immunoglobulin sequences. Humanized antibody may include substitutions in the frameworks so that the frameworks may not be exact copies of expressed human immunoglobulin or human immunoglobulin germline gene sequences. An humanized antibody (or antigen-binding fragment thereof) retains the reactivity of a non-human antibody while being less immunogenic in humans. This can be achieved, for instance, by retaining the non-human CDR regions and replacing the remaining parts of the antibody with their human counterparts ( / . e., the constant region as well as the framework portions of the variable region). Additional framework region modifications may be made within the human framework sequences as well as within the CDR sequences derived from the germline of another mammalian species. The humanized antibodies of the invention may include amino acid residues not encoded by human sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo, or a conservative substitution to promote stability or manufacturing).

[0043] The term “chimeric antibody” (or antigen-binding fragment thereof), as used herein, refers to an antibody molecule (or antigen-binding fragment thereof) in which (a) the constant region, or a portion thereof, is altered, replaced or exchanged so that the antigen-binding site (variable region) is linked to a constant region of a different or altered class, effector function and / or species; or (b) the variable region, or a portion thereof, is altered, replaced or exchanged with a variable region having a different or altered antigen specificity. For example, a mouse antibody can be modified by replacing its constant region with the constant region from a human immunoglobulin. Due to the replacement with a human constant region, the chimeric antibody can retain its specificity in recognizing the antigen while having reduced antigenicity in human as compared to the original mouse antibody.

[0044] Suitably, the antibodies of the invention are isolated antibodies. The term “isolated antibody”, as used herein, refers to an antibody that is substantially free of other antibodies having different antigenic specificities (e. g., an isolated antibody that specifically binds IL-4Ra and IL-31 is substantially free of antibodies that specifically bind antigens other than IL-4Ra and IL-31. Moreover, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0045] The term “multispecific antibody” as used herein, refers to an antibody that binds to two or more different epitopes on at least two or more different targets (e. g., IL-4Ra and IL-31). Suitably, the multispecific antibodies used in the method of the invention comprise one or two IL-4Ra-BDs. Particularly, the multispecific antibodies used in the method of the invention comprise two IL-4Ra-BD. Suitably, the multispecific antibodies used in the method of the invention comprise one or two IL-31-BDs. Particularly, the multispecific antibodies used in the method of the invention comprise two IL-31-BD. Suitably, the multispecific antibodies used in the method of the invention comprise two IL-4Ra-BDs and to IL-31-BDs.

[0046] In some embodiments, the multispecific antibodies used in the method of the invention are bispecific.

[0047] The term “bispecific antibody” as used herein, refers to a molecule (such as an antibody) that specifically binds two distinct antigens or two distinct epitopes within the same antigen. The bispecific molecule may have cross-reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca cynomolgus (cynomolgus, cyno) or Pan troglodytes, or may bind an epitope that is shared between two or more distinct antigens. In the context of the present invention, bispecific refers to an antibody that binds to at least two different epitopes on two different targets (e. g., IL-4Ra and IL-31).

[0048] In the context of the present invention, the term “binding domain” or “BD” used in the present invention” relates to a binding domain as such, i. e. independent of a multispecific context, and, in particular, to a binding domain comprised in a multispecific construct, e. g. one of the binding domains comprised in a bispecific, trispecific or tetraspecific construct. Suitably, the binding domains of the multispecific antibodies used in the invention are selected from the group consisting of: a Fab, an Fv, a dsFv and an scFv. Suitably, the binding domains of themultispecific antibodies used in the invention are operably linked. The binding domains of the multispecific antibodies of the invention are capable of binding to their respective antigens or receptors simultaneously. The term “simultaneously”, as used in this connection refers to the simultaneous binding of at least one of the IL-4Ra-BDs and at least one of the IL-31-BDs. The multispecific antibodies of the present invention comprising one or two IL-4Ra-BDs and one or two IL-31-BDs, wherein said one or two IL-4Ra-BDs, and said one or two IL-31-BDs are operably linked to each other.

[0049] The term “epitope” means a protein determinant capable of specific binding to an antibody. Epitopes usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually have specific three-dimensional structural characteristics, as well as specific charge characteristics. “Conformational” and “linear” epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents.

[0050] The term “operably linked”, as used herein, indicates that two molecules (e. g., polypeptides, domains, binding domains) are attached in a way that each molecule retains functional activity. Two molecules can be “operably linked” whether they are attached directly or indirectly (e. g., via a linker, via a moiety, via a linker to a moiety). The term “linker” refers to a peptide or other moiety that is optionally located between binding domains or antibody fragments used in the invention. A number of strategies may be used to covalently link molecules together. These include, but are not limited to, polypeptide linkages between N- and C-termini of proteins or protein domains, linkage via disulfide bonds, and linkage via chemical cross-linking reagents. In one aspect of this embodiment, the linker is a peptide bond, generated by recombinant techniques or peptide synthesis. Choosing a suitable linker for a specific case where two polypeptide chains are to be connected depends on various parameters, including but not limited to the nature of the two polypeptide chains (e. g., whether they naturally oligomerize), the distance between the N- and the C-termini to be connected if known, and / or the stability of the linker towards proteolysis and oxidation. Furthermore, the linker may contain amino acid residues that provide flexibility.

[0051] In the context of the present invention, the term “polypeptide linker” refers to a linker consisting of a chain of amino acid residues linked by peptide bonds that is connecting twodomains, each being attached to one end of the linker. The polypeptide linker should have a length that is adequate to link two molecules in such a way that they assume the correct conformation relative to one another so that they retain the desired activity. In particular embodiments, the polypeptide linker has a continuous chain of between 2 and 30 amino acid residues (e. g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, or 30 amino acid residues). In addition, the amino acid residues selected for inclusion in the polypeptide linker should exhibit properties that do not interfere significantly with the activity of the polypeptide. Thus, the linker peptide on the whole should not exhibit a charge that would be inconsistent with the activity of the polypeptide, or interfere with internal folding, or form bonds or other interactions with amino acid residues in one or more of the monomers that would seriously impede the binding of receptor monomer domains. In particular embodiments, the polypeptide linker is non-structured polypeptide. Useful linkers include glycine-serine, or GS linkers. By “Gly-Ser” or “GS” linkers is meant a polymer of glycines and serines in series (including, for example, (Gly-Ser)n, (GSGGS)n (GGGGS)n and (GGGS)n, where n is an integer of at least one), glycine-alanine polymers, alanine-serine polymers, and other flexible linkers such as the tether for the shaker potassium channel, and a large variety of other flexible linkers, as will be appreciated by those in the art. Glycine-serine polymers are preferred since oligopeptides comprising these amino acids are relatively unstructured, and therefore may be able to serve as a neutral tether between components. Secondly, serine is hydrophilic and therefore able to solubilize what could be a globular glycine chain. Third, similar chains have been shown to be effective in joining subunits of recombinant proteins such as single-chain antibodies.

[0052] In the context of the present disclosure, “linker2” or “Linker L2” specifically refers to the linker used to connect the IL-31 variable heavy and light chains (VH2 and VL2) in the VL2- Linker2-VH2 orientation to create an scFv. Linker2 may comprise, consist of and / or consist essentially of the ammo acid sequence of SEQ ID NO: 19 (GGGGSGGGGSGGGGSGGGGS).

[0053] In the context of the present disclosure, “linkerl”or “Linker LI” refers to a linker that further connects the C-termini of the IgG constant region or a fragment thereof to the VL2 of the IL-31 binding domain. Linkerl may comprise, consist of and / or consist essentially of the amino acid sequence of SEQ ID NO: 20 (GGGGSGGGGS).

[0054] The term “IL-4R“ or “IL-4Ra” refers in particular to human IL-4Ra with UniProt ID number P24394. Particularly, the multispecific antibodies used in the method of the invention comprise one or two IL-4Ra Binding Domains (IL-4Ra-BDs) that target human and Cynomolgus (Macaca fascicularis) IL-4Ra. More particularly, the multispecific antibody of the invention comprises one or two IL-4Ra-BDs that targets human, Cynomolgus (Macaca fascicularis) and Marmoset (Callithrix jacchus) IL-4Ra.

[0055] The term “IL31” or “IL-31” refers in particular to human IL-31 with UniProt ID number Q6EBC2. Suitably, the IL-31 Binding Domain (IL-31-BD) of the multispecific antibodies of the invention targets IL-31 , in particular human IL-31 as shown in UniProt ID number Q6EBC2. Particularly, the multispecific antibodies of the invention comprise one or two IL-31-BDs that target human and cynomolgus (Macaca fascicularis) IL-31.

[0056] “Specifically binds,” “specific binding,” “specifically binding” or “binds” refer to a proteinaceous molecule binding to an antigen or an epitope within the antigen with greater affinity than for other antigens. Typically, the proteinaceous molecule binds to the antigen or the epitope within the antigen with an equilibrium dissociation constant (KD) of about 1 x 10-7M or less, for example about 5x10-8M or less, about 1 x 10-8M or less, about 1 x 10-9M or less, about 1 x 1 CT10M or less, about 1 x 10-11M or less, or about 1 x 10-12M or less, typically with the KD that is at least one hundred fold less than its KD for binding to a non-specific antigen (e.g., BSA, casein). In the context of the prostate neoantigens described here, “specific binding” refers to binding of the proteinacous molecule to the prostate neoantigen without detectable binding to a wild-type protein the neoantigen is a variant of.

[0057] The term “IL-4Ra x IL-31 antibody”, or “IL4RxIL-31 antibody” and the like refer to an antibody that binds IL-4Ra and IL-31 and that comprises at least one binding domain (IL-4Ra- BD) specifically binding IL-4Ra and at least one binding domain (IL-31 -BD) specifically binding IL-31. The domains specifically binding IL-4Ra and IL-31 are typically VH / VL pairs. The domains specifically binding to IL-4Ra are typically referred herein as VH1 / VL1 pairs. The domains specifically binding to IL-31 are typically referred herein as VH2 / VL2 pairs.

[0058] “Subject” includes any human or nonhuman animal. “Nonhuman animal” includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats,horses, cows, chickens, amphibians, reptiles, etc. The terms “subject” and “patient” can be used interchangeably herein.

[0059] “Therapeutically effective amount” or “effective amount” used interchangeably herein, refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. A therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of a therapeutic or a combination of therapeutics to elicit a desired response in the individual. Example indicators of an effective therapeutic or combination of therapeutics that include, for example, improved wellbeing of the patient, reduction of a tumor burden, arrested or slowed growth of a tumor, reduction in PSA levels, and / or absence of metastasis of cancer cells to other locations in the body.

[0060] “Treat,” “treating” or “treatment” of a disease or disorder such as cancer refers to accomplishing one or more of the following: reducing the severity and / or duration of the disorder, inhibiting worsening of symptoms characteristic of the disorder being treated, limiting or preventing recurrence of the disorder in subjects that have previously had the disorder, or limiting or preventing recurrence of symptoms in subjects that were previously symptomatic for the disorder.

[0061] “dose” refers to a dose of the active agent that is administered to a subject to treat a disease. A dose may be administered at a regular dosing interval on a repetitive basis (e.g. weekly (i.e. once a week), once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks etc.). A dose can be an initial dose, or a dose administered after the initial dose. The “initial dose” can also be known as a “loading dose.” When the pre- clinical and clinical studies were developed and / or initiated, the assumed absorptivity constant for IL-4Ra x IL-31 antibody was 2.05 (mg / mLj^cm’1. The calculated and experimentally verified theoretical absorptivity constant is about 1.76 (mg / mLj^cnT1. As a result, the target IL- 4Ra x IL-31 antibody doses tested in the nonclinical toxicology, Phase 1 and Phase 2b studies are consistently about 16% higher.

[0062] “Plat dose” refers to a dose that is administered to a subject without correction for the subject’s specific body weight or body surface area. A flat dose, sometimes referred to as a fixed dose, is therefore provided as an absolute amount of the agent (e.g., mg drug), and not as aweight-based amount that accounts for the subject’s specific weight (e.g. pg / kg or pg drug per kg body weight). For example, a subject weighing 65 kg may be administered the same flat dose in milligrams as a subject weighing 85 kg. A flat dose may be administered according to a predefined class or category of body weight but is not modified according to the subject’s specific weight. For example, a “Flat Dose A” may be administered if a patient is greater than a predefined threshold weight, whereas a different “Flat Dose B” may be administered if the patent is less than the pre-defined threshold weight.

[0063] As used herein, the term "atopic dermatitis" (AD) refers to a kind of autoimmune skin diseases, accompanied by skin abscess, eczema, itchiness. Although both environmental and genetic factors are known to be involved in the onset of atopic dermatitis, pathogenesis has not been clearly elucidated. In the present invention, atopic dermatitis may be used interchangeably with "AD".

[0064] The term “moderate to severe atopic dermatitis (AD)” refers to AD that has been present for at least 1 year, as determined by a physician through patient interview and / or review of the medical history. Patients usually have a history of inadequate response to treatment for AD with topical medications or for whom topical treatments are otherwise medically inadvisable, an EASI score >16, an IGA score >3, and an involved percent BSA >10% at both screening and at baseline, a baseline PP-NRS average score of >4, and without a history of primary failure or intolerance to IL-4Ra, IL-4, and / or IL- 13 inhibitors.

[0065] As used herein, the term “adverse event” (AE) refers to any untoward medical occurrence in a patient administered a pharmaceutical product and which does not necessarily have a causal relationship with the treatment.IL-4Ra x IL-31 antibody

[0066] Provided herein is a method of treating moderate to severe atopic dermatitis (AD) in a patient in need thereof, wherein the method comprises administering a therapeutically effective amount an IL-4Ra x IL-31 antibody or antigen binding fragment thereof, that binds to both IL- 4Ra and IL-31.

[0067] In some embodiments, the method of treating moderate to severe atopic dermatitis (AD) in a patient in need thereof, comprises administering to the patient a therapeutically effective amount of an IL-4Ra x IL-31 antibody or antigen binding fragment thereof, that binds to both IL-4Ra and IL-31 , wherein the IL-4Ra x IL-31 antibody comprises one or two binding domains, which specifically bind to IL-4Ra (IL-4Ra-BD) and one or two binding domains, which specifically bind to IL-31 (IL-31-BD); wherein a. each IL-4Ra-BDs comprises i. the HCDR1 sequence of SEQ ID NO: 1, ii. the HCDR2 sequences of SEQ ID NO: 2, iii. the HCDR3 sequence of SEQ ID NO: 3, iv. the LCDR1 sequence of SEQ ID NO: 4, v. the LCDR2 sequence of SEQ ID NO: 5, and vi. the LCDR3 sequences of SEQ ID NO: 6; and b. each IL-31 -BDs comprises i. the HCDR1 sequence of SEQ ID NO: 11 , ii. the HCDR2 sequence of SEQ ID NO: 12, iii. the HCDR3 sequences of SEQ ID NO: 13, iv. the LCDR1 sequence of SEQ ID NO: 14, v. the LCDR2 sequence of SEQ ID NO: 15, and vi. the LCDR3 sequences of SEQ ID NOs: 16.

[0068] In some embodiments, the one or two binding domains, which specifically bind to IL- 4Ra each comprise a first heavy chain variable region (VH1) comprising an amino acid sequence which is at least 90%, or at least 95%, or at least 98%, at least 99%, or 100% identical to SEQ ID NO: 7, or 9 and a first light chain variable domain (VL1) comprising an amino acid sequence which is at least 90%, or at least 95%, or at least 98%, at least 99%, or 100% identical to SEQ ID NO: 8, 10, 25 or 27.

[0069] In some embodiments, the one or two binding domains, which specifically bind to IL-31 each comprise a second heavy chain variable region (VH2) comprising an amino acid sequence which is at least 90%, or at least 95%, or at least 98%, at least 99%, or 100% identical to SEQ IDNO: 17 and a second light chain variable domain (VL2) comprising an amino acid sequence which is at least 90%, or at least 95%, or at least 98%, at least 99%, or 100% identical to SEQ ID NO: 18 or 28.

[0070] In some embodiments, the one or two IL-4Ra-BDs which specifically bind to IL-4Ra each, each comprise a first heavy chain variable region (VH1) of SEQ ID NO: 7 or 9 and a first light chain variable domain (VL1) of SEQ ID NO: 8 or 10; and the IL-31-BDs comprise a second heavy chain variable region (VH2) of SEQ ID NO: 17 and a second light chain variable domain (VL2) of SEQ ID NO: 18.

[0071] In some embodiments, the IL-4Ra-BDs comprise a first heavy chain variable region (VH1) of SEQ ID NO: 7 and a first light chain variable domain (VL1) of SEQ ID NO: 8; and the IL-31-BDs comprise a second heavy chain variable region (VH2) of SEQ ID NO: 17 and a second light chain variable domain (VL2) of SEQ ID NO: 18.

[0072] In some embodiments, the IL-4Ra-BDs comprise a first heavy chain variable region (VH1) of SEQ ID NO: 9 and a first light chain variable domain (VL1) of SEQ ID NO: 10; and the IL-31 -BDs comprise a second binding domain comprises a first heavy chain variable region (VH2) of SEQ ID NO: 17 and a second light chain variable domain (VL2) of SEQ ID NO: 18.

[0073] In some embodiments, the IL-4Ra-BDs comprise a first heavy chain variable region (VH1) comprising an amino acid sequence of SEQ ID NO: 7 or 9 and a first light chain variable domain (VL1) comprising an amino acid sequence of SEQ ID NO: 8 or 10; and the IL-31 -BDs comprise a second heavy chain variable region (VH2) comprising an amino acid sequence of SEQ ID NO: 17 and a second light chain variable domain (VL2) comprising an amino acid sequence of SEQ ID NO: 18.

[0074] In some embodiments, the IL-4Ra-BDs comprise a first heavy chain variable region (VH1) comprising an amino acid sequence of SEQ ID NO: 7 and a first light chain variable domain (VL1) comprising an amino acid sequence of SEQ ID NO: 8; and the IL-31 -BDs comprise a second heavy chain variable region (VH2) comprising an amino acid sequence of SEQ ID NO: 17 and a second light chain variable domain (VL2) comprising an amino acid sequence of SEQ ID NO: 18.

[0075] In some embodiments, the IL-4Ra-BDs comprise a first heavy chain variable region (VH1) comprising an amino acid sequence of SEQ ID NO: 9 and a first light chain variabledomain (VL1) comprising an amino acid sequence of SEQ ID NO: 10; and the IL-31-BDs comprise a second binding domain comprises a first heavy chain variable region (VH2) comprising an amino acid sequence of SEQ ID NO: 17 and a second light chain variable domain (VL2) comprising an amino acid sequence of SEQ ID NO: 18.

[0076] In some embodiments, the IL-4Ra-BDs comprise a first heavy chain variable region (VH1) of SEQ ID NO: 7 and a first light chain variable domain (VL1) of SEQ ID NO: 8 further comprising a framework 4 of SEQ ID NO: 26; and the IL-31-BDs comprise a second heavy chain variable region (VH2) of SEQ ID NO: 17 and a second light chain variable domain (VL2) of SEQ ID NO: 18 further comprising a framework 4 of SEQ ID NO: 29.

[0077] In some embodiments, the IL-4Ra-BDs comprise a first heavy chain variable region (VH1) of SEQ ID NO: 9 and a first light chain variable domain (VL1) of SEQ ID NO: 10 further comprising a framework 4 of SEQ ID NO: 26; and the IL-31-BDs comprise a second binding domain comprises a first heavy chain variable region (VH2) of SEQ ID NO: 17 and a second light chain variable domain (VL2) of SEQ ID NO: 18 further comprising a framework 4 of SEQ ID NO: 29.

[0078] In some embodiments, the IL-4Ra-BDs comprise a first heavy chain variable region (VH1) of SEQ ID NO: 7 and a first light chain variable domain (VL1) of SEQ ID NO: 25; and the IL-31-BDs comprise a second heavy chain variable region (VH2) of SEQ ID NO: 17 and a second light chain variable domain (VL2) of SEQ ID NO: 28.

[0079] In some embodiments, the IL-4Ra-BDs comprise a first heavy chain variable region (VH1) of SEQ ID NO: 9 and a first light chain variable domain (VL1) of SEQ ID NO: 27; and the IL-31 -BDs comprise a second heavy chain variable region (VH2) of SEQ ID NO: 17 and a second light chain variable domain (VL2) of SEQ ID NO: 28.

[0080] In some embodiments, the IL-4Ra x IL-31 antibody comprises(a) a first heavy chain variable domain (VH1) of SEQ ID NO: 7;(b) a first light chain variable domain (VL1) of SEQ ID NO: 8, further comprising a framework 4 of SEQ ID NO: 26;(c) a second heavy chain variable domain (VH2) of SEQ ID NO: 17; and(d) a second light chain variable domain (VL2) of SEQ ID NO: 18, further comprising a framework 4 of SEQ ID NO: 29.

[0081] In some embodiments, the IL-4Ra x IL-31 antibody comprises(a) a first heavy chain variable domain (VH1) of SEQ ID NO: 7;(b) a first light chain variable domain (VL1) of SEQ ID NO: 25;(c) a second heavy chain variable domain (VH2) of SEQ ID NO: 17; and(d) a second light chain variable domain (VL2) of SEQ ID NO: 28.

[0082] In some embodiments, the IL-4Ra x IL-31 antibody comprises(a) a first heavy chain variable domain (VH1) of SEQ ID NO: 9;(b) a first light chain variable domain (VL1) of SEQ ID NO: 10, further comprising a framework 4 of SEQ ID NO: 26;(c) a second heavy chain variable domain (VH2) of SEQ ID NO: 17; and(d) a second light chain variable domain (VL2) of SEQ ID NO: 18, further comprising a framework 4 of SEQ ID NO: 29.

[0083] In some embodiments, the IL-4Ra x IL-31 antibody comprises(a) a first heavy chain variable domain (VH1) of SEQ ID NO: 9;(b) a first light chain variable domain (VL1) of SEQ ID NO: 27;(c) a second heavy chain variable domain (VH2) of SEQ ID NO: 17; and(d) a second light chain variable domain (VL2) of SEQ ID NO: 28.

[0084] In some embodiments, the one or two binding domains, which specifically bind to IL- 4Ra each comprise a Fab or a single chain variable fragment (scFv).

[0085] In some embodiments, the one or two binding domains, which specifically bind to IL- 4Ra each comprise a Fab.

[0086] In some embodiments, the one or two binding domains, which specifically bind to IL-31 each comprise a Fab or a scFv.

[0087] In some embodiments, the one or two binding domains, which specifically bind to IL-31 each comprise a scFv.

[0088] In some embodiments, the IL-4Ra x IL-31 antibody comprises two IL-4Ra-BDs and twoIL-31-BDs.

[0089] In some embodiments, the IL-4Ra-BD comprises a Fab or a single chain variable fragment (scFv).

[0090] In some embodiments, the IL-4Ra-BD comprises a Fab.

[0091] In some embodiments, the IL-31-BD comprises a Fab or a single chain variable fragment (scFv).

[0092] In some embodiments, the IL-31 -BD comprises a scFv.

[0093] In some embodiments, the two binding domains, which specifically bind to IL-4Ra comprise a Fab and the two binding domains, which specifically bind to IL-31 comprise a scFv.

[0094] In some embodiments, the IL-31-BDs comprise the VH2 and VL2 of SEQ ID NO: 17 and 18, respectively, wherein the VH2 and VL2 form a scFv comprising, from the N-terminus to the C-terminus a VH2-linker(L2)-VL2 or VL2-linker(L2)-VH2, preferably a VL2-linker(L2)-VH2.

[0095] In some embodiments, the IL-31-BDs comprise the VH2 and VL2 of SEQ ID NO: 17 and 18, respectively, wherein the VH2 and VL2 form a scFv comprising, from the N-terminus to the C-terminus a VL2-linker(L2)-VH2.

[0096] In some embodiments, the linker L2 is a peptide of 10-40 amino acids, more particularly 15-30 amino acids, and most particularly 20-25 amino acids. In particular embodiments, said linker L2 comprises one or more units of four (4) glycine amino acid residues and one (1) serine amino acid residue (GGGGS)n, wherein n=l, 2, 3, 4, 5, 6, 7 or 8, particularly n=4.

[0097] In some embodiments, the linker L2 comprises or consists of the amino acid sequence of SEQ ID NO: 19 (GGGGSGGGGSGGGGSGGGGS).

[0098] In some embodiments, the IL-31-BDs comprise the VH2 and VL2 of SEQ ID NO: 17 and 18, respectively, wherein the VH2 and VL2 form a scFv comprising, from the N-terminus to the C-terminus a VL2-linker(L2)-VH2, wherein the linker L2 comprises or consists of the amino acid sequence of SEQ ID NO: 19.

[0099] In some embodiments, the IL-31-BDs comprise the VH2 and VL2 of SEQ ID NO: 17 and 18, respectively, wherein the VH2 and VL2 form a scFv comprising, from the N-terminus to the C-terminus a VH2-linker(L2)-VL2 or VL2-linker(L2)-VH2, preferably a VL2-linker(L2)-VH2, wherein VL2 further comprises the framework 4 of SEQ ID NO: 29 (FGTGTKVTVLG) and the linker L2 comprises the SEQ ID NO: 19 .

[0100] In some embodiments, the IL-31-BDs comprise the VH2 and VL2 of SEQ ID NO: 17 and 18, respectively, wherein the VH2 and VL2 form a scFv comprising, from the N-terminus to theC-terminus a VL2-linker(L2)-VH2, wherein VL2 further comprises the framework 4 of SEQ ID NO: 29 (FGTGTKVTVLG) and the linker L2 comprises the SEQ ID NO: 19.

[0101] In some embodiments, the IL-31-BDs comprise the VH2 and VL2 of SEQ ID NO: 17 and 28, respectively, wherein the VH2 and VL2 form a scFv comprising, from the N-terminus to the C-terminus a VL2-linker(L2)-VH2, and wherein the linker L2 comprises or consists of the amino acid sequence of SEQ ID NO: 19.

[0102] In some embodiments, the IL-4Ra x IL-31 antibody comprises an immunoglobulin (Ig) heavy chain constant region (comprised of domains CHI, hinge, CH2 and CH3), or a fragment of an Ig heavy chain constant region and an immunoglobulin (Ig) light chain constant region (CL), or a fragment of an Ig light chain constant region.

[0103] In some embodiments, the immunoglobulin (Ig) heavy chain constant region is an IgGl isotype, and IgG2 isotype, or an IgG4 isotype.

[0104] In some embodiments, the immunoglobulin (Ig) heavy chain constant region is an IgG4 isotype.

[0105] In some embodiments, the IL-4Ra x IL-31 antibody comprises an immunoglobulin Fc region.

[0106] In some embodiments, the IL-4Ra x IL-31 antibody used in the method of the invention is in a Morisson-L format or in a Morrisson -H format.

[0107] The Morrison-L and Morrison-H formats used in the present invention are tetravalent and bispecific molecular formats bearing an IgGFc region, in particular an IgG4 Fc region. Two highly stable scFv binding domains, wherein the light chain comprises Vk FR1 to FR3 in combination with a VAFR4 (X-cap), herein also called A- cap scFv, are fused via a linker LI to the heavy chain (Morrison-H) or light chain (Morrison-L) C-termini (FIG. 1). In a special embodiment of the invention, the IL-4Ra x IL-31 antibodies have a Morrison-H format, as defined above.

[0108] In some embodiments, the IL-4Ra x IL-31 antibody is in a Morrisson-H format.

[0109] In some embodiments, the IL-4Ra x IL-31 antibody is in a Morrisson-L format.

[0110] In some embodiments, the IL-4Ra-BDs are located in the Fab arms, and the IL-31-BDs are located in the scFv part of the Morrison format.

[0111] In some embodiments, the IL-4Ra-BDs are located in the Fab arms, and the IL-31-BDs are located in the scFv part of the Morrison-H format.

[0112] In some embodiments, the IL-4Ra-BDs are located in the Fab arms, and the IL-31-BDs are located in the scFv part of the Morrison-L format.

[0113] In some embodiments, the scFv comprising the IL-31-BD is fused to the C-termini of the heavy chain constant region.

[0114] In some embodiments, scFv is fused to the C-termini of the Fc with a linker LI.

[0115] In some embodiments, the linker LI is a peptide of 2-30 amino acids, more particularly 5-25 amino acids, and most particularly 10-20 amino acids. In some embodiments, the linker LI comprises one or more units of four (4) glycine amino acid residues and one (1) serine amino acid residue (GGGGS)n, wherein n= 1,2, 3, 4 or 5, particularly n=2.

[0116] In some embodiments, scFv is fused to the C-termini of the Fc with a linker LI of SEQ ID NO: 20 (GGGGSGGGGS).

[0117] In some embodiments, the scFv comprising the IL-31-BD is fused to the C-termini of the heavy chain constant region via a linker LI (GGGGSGGGGS; SEQ ID NO: 20).

[0118] In some embodiments, the IL-31-BDs comprise the VH2 and VL2 of SEQ ID NO: 17 and 28, respectively, wherein the VH2 and VL2 form a scFv comprising, from the N-terminus to the C-terminus a VL2-linker(L2)-VH2, wherein the linker L2 comprises or consists of the amino acid sequence of SEQ ID NO: 19 (GGGGSGGGGS GGGGSGGGGS) and wherein the scFv is fused to the C-termini of the Fc with a linker LI of SEQ ID NO: 20 (GGGGSGGGGS).

[0119] In some embodiments, the IL-31-BDs comprise the VH2 and VL2 of SEQ ID NO: 17 and 28, respectively, wherein the VH2 and VL2 form a scFv comprising, from the N-terminus to the C-terminus a VL2-linker(L2)-VH2, wherein the linker L2 comprises or consists of the amino acid sequence of SEQ ID NO: 19 (GGGGSGGGGS GGGGSGGGGS) and wherein the scFv is fused to the C-termini of the heavy chain constant region with a linker LI of SEQ ID NO: 20 (GGGGSGGGGS).

[0120] In some embodiments, the Ig heavy chain constant region comprises the Fc silencing mutation (L234A / L235A / D265S); wherein the numbering of the amino acid mutations is according to the EU index.

[0121] In some embodiments, the Ig heavy chain constant region comprises the half-life extension mutations S252Y / S254T / T256E wherein the numbering of the amino acid mutations is according to the EU index.

[0122] In some embodiments, the IL-4Ra x IL-31 antibody comprises a heavy chain (HC), and a light chain (LC) having amino acid sequences at least 90% identical, or at least 95%, or at least 98%, at least 99%, or 100% identical to SEQ ID NO: 21, and SEQ ID NO: 22, respectively, preferably, the HC, and LC comprise the amino acid sequences of SEQ ID NO: 21, and SEQ ID NO: 22, respectively.

[0123] In some embodiments, the IL-4Ra x IL-31 antibody comprises a heavy chain (HC), and a light chain (LC) having amino acid sequences comprising the amino acid sequences of SEQ ID NO: 21, and SEQ ID NO: 22, respectively.

[0124] In some embodiments, the IL-4Ra x IL-31 antibody comprises two heavy chains (HC), and two light chains (LC) having amino acid sequences at least 90% identical, or at least 95%, or at least 98%, at least 99%, or 100% identical to SEQ ID NO: 21, and SEQ ID NO: 22, respectively; preferably, the HCs, and LCs comprise the amino acid sequences of SEQ ID NO: 21, and SEQ ID NO: 22, respectively.

[0125] In some embodiments, the IL-4Ra x IL-31 antibody comprises two heavy chains (HC), and two light chains (LC) comprising the amino acid sequences of SEQ ID NO: 21, and SEQ ID NO: 22, respectively.

[0126] In some embodiments, the IL-4Ra x IL-31 antibody comprises a heavy chain (HC), and a light chain (LC) having amino acid sequences at least 90% identical, or at least 95%, or at least 98%, at least 99%, or 100% identical to SEQ ID NO: 23, and SEQ ID NO: 24, respectively; preferably, the HC, and LC comprise the amino acid sequences of SEQ ID NO: 23, and SEQ ID NO: 24, respectively.

[0127] In some embodiments, the IL-4Ra x IL-31 antibody comprises a heavy chain (HC), and a light chain (LC) comprising the amino acid sequences of SEQ ID NO: 23, and SEQ ID NO: 24, respectively.

[0128] In some embodiments, the IL-4Ra x IL-31 antibody comprises two heavy chains (HC), and two light chains (LC) comprising amino acid sequences at least 90% identical, or at least 95%, or at least 98%, at least 99%, or 100% identical to SEQ ID NO: 23, and SEQ ID NO: 24,respectively; preferably, the HCs, and LCs comprise the amino acid sequences of SEQ ID NO: 23, and SEQ ID NO: 24, respectively.

[0129] In some embodiments, the IL-4Ra x IL-31 antibody comprises two heavy chains (HC), and two light chains (LC) comprising the amino acid sequences of SEQ ID NO: 23, and SEQ ID NO: 24, respectively.

[0130] In some embodiments, the method of the invention comprises any of the IL-4Ra x IL-31 antibodies described in WO2022 / 136669, the entire content of which is incorporated herein by reference.Dosing

[0131] The IL-4Ra x IL-31 antibody or the antigen binding fragment thereof used in the method of the disclosure is administered at a dose to treat moderate to acute atopic dermatitis (AD) in a subject. The inventors have found that certain doses may be suitable for treatment of moderate to acute atopic dermatitis.

[0132] Accordingly, in some embodiments, the method comprises administering to the patient in need thereof an initial dose of the IL-4Ra x IL-31 antibody, wherein the initial dose is at least about 150 mg or about 174 mg.

[0133] Accordingly, in some embodiments, the method comprises administering to the patient in need thereof an initial dose of the IL-4Ra x IL-31 antibody, wherein the initial dose is at least about 300 mg.

[0134] Accordingly, in some embodiments, the method comprises administering to the patient in need thereof an initial dose of the IL-4Ra x IL-31 antibody, wherein the initial dose is at least about 600 mg or about 696 mg.

[0135] In some embodiments, the initial dose is between about 150 mg and about 700 mg, for example about 150 mg, about 174 mg, about 200 mg, about 250 mgs, about 300 mg, about 348 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg or about 696 mg.

[0136] In some embodiments, the initial dose is about 150mg.

[0137] In some embodiments, the initial dose is about 174 mg.

[0138] In some embodiments, the initial dose is about 300 mg.

[0139] In some embodiments, the initial dose is about 348 mg.

[0140] In some embodiments, the initial dose is about 600 mg.

[0141] In some embodiments, the initial dose is about 696 mg.

[0142] In some embodiments, the method further comprises administering a dose of the IL-4Ra x IL-31 antibody after the initial dose, wherein the dose of the IL-4Ra x IL-31 antibody administered after the initial dose is equal or lower than the initial dose.

[0143] In some embodiments, the dose of the IL-4Ra x IL-31 antibody administered after the initial dose is between about 150 mg and about 700 mg.

[0144] In some embodiments, the initial dose is about 600 mg and the dose administered after the initial dose is about 150 mg, about 174 mg, about 200 mg, about 250 mgs, about 300 mg, about 348 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg or about 696 mg.

[0145] In some embodiments, the initial dose is about 300 mg or about 348 mg and the dose administered after the initial dose is about 150 mg, about 174 mg, about 200 mg, about 250 mg, about 300 mg or about 348 mg.

[0146] In some embodiments, the initial dose and the dose administered after the initial dose is about 600 mg or about 696 mg.

[0147] In some embodiments, the initial dose is about 600 mg or 696 mg and the dose administered after the initial dose is about 300 mg or 348 mg.

[0148] In some embodiments, the initial dose is about 696 mg and the dose administered after the initial dose is about 348 mg or 450 mg.

[0149] In some embodiments, the initial dose is about 300 mg or 348 mg and the dose administered after the initial dose is about 150 mg or 174 mg.

[0150] The initial dose of the IL-4Ra x IL-31 antibody and the dose of the IL-4Ra x IL-31 antibody administered after the initial dose may be a flat dose, as defined herein. Flat dosing may provide advantages compared to dosing according to body weight, such as reduced preparation time, and simpler administration and manufacturing.

[0151] In some embodiments, the initial dose and the dose administered after the initial dose are a flat dose.

[0152] In some embodiments, the initial dose is a flat dose of at least about 150 mg.

[0153] In some embodiments, the initial dose is a flat dose of between about 150 mg and about 700 mg, for example a flat dose of about 150 mg, a flat dose of about 174 mg, a flat dose of about 200 mg, a flat dose of about 250 mgs, a flat dose of about 300 mg, a flat dose of about 348 mg, a flat dose of about 350 mg, a flat dose of about 400 mg, a flat dose of about 450 mg, a flat dose of about 500 mg, a flat dose of about 550 mg, a flat dose of about 600 mg or a flat dose of about 696 mg.

[0154] In some embodiments, the initial dose is a flat dose of about 300 mg or 348 mg.

[0155] In some embodiments, the initial dose is a flat dose of about 600 mg or 696 mg.

[0156] In some embodiments, the dose of the IL-4Ra x IL-31 antibody administered after the initial dose of the IL-4xIL-31 antibody is a flat dose that is equal or lower than the initial dose.

[0157] In some embodiments, the dose of the IL-4Ra x IL-31 antibody administered after the initial dose is a flat dose of between about 150 mg and about 700 mg.

[0158] In some embodiments, the initial dose of the IL-4a x IL-31 antibody is a flat dose of about 600 mg or 696 mg and the dose administered after the initial dose is a flat dose of about 150 mg, about 174 mg, about 200 mg, about 250 mgs, about 300 mg, about 348 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg or about 696 mg.

[0159] In some embodiments, the initial dose is a flat dose of about 300 mg and the dose administered after the initial dose is a flat dose of about 150 mg, about 200 mg, about 250 mgs, about 300 mg or about 348 mg.

[0160] In some embodiments, the initial dose and the dose administered after the initial dose is a flat dose of about 600 mg or 696 mg.

[0161] In some embodiments, the initial dose is a flat dose of about 600 mg or 696 mg and the dose administered after the initial dose is a flat dose of about 300 mg or 348 mg.

[0162] In some embodiments, the initial dose is a flat dose of about 600 mg or 696 mg and the dose administered after the initial dose is a flat dose of about 450 mg.

[0163] In some embodiments, the initial dose is a flat dose of about 300 mg or 348 mg and the dose administered after the initial dose is a flat dose of about 150 mg or 174 mg.Administration frequency

[0164] In some embodiments, the dose administered after the initial dose is administered at regular dosing interval on a repetitive basis (e.g. weekly (i.e. once a week), once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks etc.), preferably once every 2 weeks.

[0165] In some embodiments, the initial dose is administered once and the dose administered after the initial dose is administered once every one to six weeks, for example, once a week, once every two weeks, once every three weeks, once every four weeks, once every five week or once every six weeks.

[0166] In some embodiments, the initial dose is administered once and the dose administered after the initial dose is administered once every 2 weeks.

[0167] In some embodiments, the initial dose is administered once and the dose administered after the initial dose is administered once every 2 weeks through week 22.

[0168] In some embodiments, the initial dose is administered once and the dose administered after the initial dose is administered about 2 weeks after the initial dose, about 4 weeks after the initial dose, about 6 weeks after the initial dose, about 8 weeks after the initial dose, about 10 weeks after the initial dose, about 12 weeks after the initial dose, about 14 weeks after the initial dose, about 16 weeks after the initial dose, about 18 weeks after the initial dose, about 20 weeks after the initial dose, and about 22 weeks after the initial dose.

[0169] In some embodiments, the method of treating moderate to severe atopic dermatitis comprises administering an initial dose of the IL-4Ra x IL-31 antibody and administering a dose of the IL-4Ra x IL-31 antibody after the initial dose, wherein the initial dose is between about 150 mg and about 700 mg; and the dose administered after the initial dose is a. administered about 2 weeks after the initial dose, about 4 weeks after the initial dose, about 6 weeks after the initial dose, about 8 weeks after the initial dose, bout 10 weeks after the initial dose, about 12 weeks after the initial dose, about 14 weeks after the initial dose, about 16 weeks after the initial dose, about 18 weeks after the initial dose, about 20 weeks after the initial dose, and about 22 weeks after the initial dose,b. is between about 150 mg and about 700 mg; and c. is equal or lower than the initial dose.

[0170] In some embodiments, the method of treating moderate to severe atopic dermatitis comprises administering an initial dose of the IL-4Ra x IL-31 antibody and administering a dose of the IL-4Ra x IL-31 antibody after the initial dose, wherein the initial dose is administered once and is a flat dose of about 600 mg or about 696 mg; and the dose administered after the initial dose is a flat dose of about 600 mg or 696 mg and is administered about 2 weeks after the initial dose, about 4 weeks after the initial dose, about 6 weeks after the initial dose, about 8 weeks after the initial dose, bout 10 weeks after the initial dose, about 12 weeks after the initial dose, about 14 weeks after the initial dose, about 16 weeks after the initial dose, about 18 weeks after the initial dose, about 20 weeks after the initial dose, and about 22 weeks after the initial dose.

[0171] In some embodiments, the method of treating moderate to severe atopic dermatitis comprises administering an initial dose of the IL-4Ra x IL-31 antibody and administering a dose of the IL-4Ra x IL-31 antibody after the initial dose, wherein the initial dose is administered once and is a flat dose of about 600 mg or about 696 mg; and the dose administered after the initial dose is a flat dose of about 450 mg and is administered about 2 weeks after the initial dose, about 4 weeks after the initial dose, about 6 weeks after the initial dose, about 8 weeks after the initial dose, bout 10 weeks after the initial dose, about 12 weeks after the initial dose, about 14 weeks after the initial dose, about 16 weeks after the initial dose, about 18 weeks after the initial dose, about 20 weeks after the initial dose, and about 22 weeks after the initial dose.

[0172] In some embodiments, the method of treating moderate to severe atopic dermatitis comprises administering an initial dose of the IL-4Ra x IL-31 antibody and administering a dose of the IL-4Ra x IL-31 antibody after the initial dose, wherein the initial dose is administered once and is a flat dose of about 600 mg or about 696 mg; and the dose administered after the initial dose is a flat dose of about 300 mg or about 348 mg and is administered about 2 weeks after the initial dose, about 4 weeks after the initial dose, about 6 weeks after the initial dose, about 8 weeks after the initial dose, bout 10 weeks after the initial dose, about 12 weeks after the initial dose, about 14 weeks after the initial dose, about 16 weeks after the initial dose, about 18weeks after the initial dose, about 20 weeks after the initial dose, and about 22 weeks after the initial dose.

[0173] In some embodiments, the method of treating moderate to severe atopic dermatitis comprises administering an initial dose of the IL-4Ra x IL-31 antibody and administering a dose of the IL-4Ra x IL-31 antibody after the initial dose, wherein the initial dose is administered once and is a flat dose of about 300 mg or about 348 mg; and the dose administered after the initial dose is a flat dose of about 150 mg or about 174 mg and is administered about 2 weeks after the initial dose, about 4 weeks after the initial dose, about 6 weeks after the initial dose, about 8 weeks after the initial dose, bout 10 weeks after the initial dose, about 12 weeks after the initial dose, about 14 weeks after the initial dose, about 16 weeks after the initial dose, about 18 weeks after the initial dose, about 20 weeks after the initial dose, and about 22 weeks after the initial dose.Route of administration

[0174] The methods of the instant invention include any route of administration of the antibody of the present invention that achieves the intended purpose. Any suitable route of administration considered appropriate by a person of skill in the art can be used to administer the antibody or a pharmaceutical composition including the antibody used in the method of treatment of the disclosure. For example, administration may be accomplished by a number of different routes including, subcutaneous route (for example subcutaneous).

[0175] In some embodiments, the IL-4Ra x IL-31 antibody used in the methods of the disclosure is administered using the subcutaneous route of administration.

[0176] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject a therapeutically effective amount of an IL-4Ra x IL-31 antibody comprising a first antigen binding domain that binds specifically to IL-4Ra, and a second antigen binding domain that binds specifically to IL-31, wherein the IL-4Ra x IL-31 antibody comprises a heavy chain (HC) of SEQ ID NO: 21 and a light chain (LC) of SEQ ID NO: 22; and wherein the IL-4Ra x IL-31 antibody is administered to the subject subcutaneously.

[0177] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject a therapeutically effective amount of an IL-4Ra x IL-31 antibody comprising a first antigen binding domain that binds specifically to IL-4Ra, and a second antigen binding domain that binds specifically to IL-31, wherein the IL-4Ra x IL-31 antibody comprises two heavy chains (HC) wherein each heavy chain comprises an amino acid sequence of SEQ ID NO: 21 and two light chains (LC) wherein each heavy chain comprises an amino acid sequence of SEQ ID NO: 22; and wherein the IL-4Ra x IL-31 antibody is administered to the subject subcutaneously.

[0178] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject a therapeutically effective amount of an IL-4Ra x IL-31 antibody comprising a first antigen binding domain that binds specifically to IL-4Ra, and a second antigen binding domain that binds specifically to IL-31, wherein the IL-4Ra x IL-31 antibody comprises a heavy chain (HC) of SEQ ID NO: 23 and a light chain (LC) of SEQ ID NO: 24; and wherein the IL-4Ra x IL-31 antibody is administered to the subject subcutaneously.

[0179] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject a therapeutically effective amount of an IL-4Ra x IL-31 antibody comprising a first antigen binding domain that binds specifically to IL-4Ra, and a second antigen binding domain that binds specifically to IL-31, wherein the IL-4Ra x IL-31 antibody comprises two heavy chains (HC) wherein each heavy chain comprises an amino acid sequence of SEQ ID NO: 23 and two light chains (LC) wherein each heavy chain comprises an amino acid sequence of SEQ ID NO: 24; and wherein the IL-4Ra x IL-31 antibody is administered to the subject subcutaneously.

[0180] In some embodiments, the IL-4Ra x IL-31 antibody used in the methods of the disclosure is administered to the subject subcutaneously at an initial dose between about 150 mg and about 700 mg.

[0181] In some embodiments, the IL-4Ra x IL-31 antibody used in the methods of the disclosure is administered to the subject subcutaneously at a dose administered after the initial dose between about 150 mg and about 700 mg.

[0182] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject an initial dose of an IL-4Ra x IL-31 and administering to the subject a dose of the IL-4Ra x IL- 31 after the initial dose, wherein a. the IL-4Ra x IL-31 antibody comprises a heavy chain (HC) of SEQ ID NO: 21 and a light chain (LC) of SEQ ID NO: 22; b. the initial dose is administered once and is between about 150 mg and about 700 mg; c. the dose administered after the initial dose of the IL-4Ra x IL-31 antibody is administered once every two weeks, is between about 150 mg and about 700 mg, and is equal or lower than the initial dose; and d. the initial dose and dose administered after the initial dose are administered subcutaneously.

[0183] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject an initial dose of an IL-4Ra x IL-31 and administering to the subject a dose of the IL-4Ra x IL- 31 after the initial dose, wherein a. the IL-4Ra x IL-31 antibody comprises a heavy chain (HC) of SEQ ID NO: 23 and a light chain (LC) of SEQ ID NO: 24; b. the initial dose is administered once and is between about 150 mg and about 700 mg; c. the dose administered after the initial dose of the IL-4Ra x IL-31 antibody is administered once every two weeks, is between about 150 mgs and about 700 mgs, and is equal or lower than the initial dose; and d. the initial dose and dose administered after the initial dose are administered subcutaneously.

[0184] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject an initial dose of an IL-4Ra x IL-31 and administering to the subject a dose of the IL-4Ra x IL- 31 after the initial dose, whereina. the IL-4Ra x IL-31 antibody comprises a heavy chain (HC) of SEQ ID NO: 21 and a light chain (LC) of SEQ ID NO: 22; b. the initial dose is administered once subcutaneously at a flat dose of about 600 mg; and c. the dose administered after the initial dose of the IL-4Ra x IL-31 antibody is administered once every two weeks, subcutaneously at a flat dose of about 600 mg.

[0185] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject an initial dose of an IL-4Ra x IL-31 and administering to the subject a dose of the IL-4Ra x IL- 31 after the initial dose, wherein a. the IL-4Ra x IL-31 antibody comprises a heavy chain (HC) of SEQ ID NO: 21 and a light chain (LC) of SEQ ID NO: 22; b. the initial dose is administered once subcutaneously at a flat dose of about 696 mg; and c. the dose administered after the initial dose of the IL-4Ra x IL-31 antibody is administered once every two weeks, subcutaneously at a flat dose of about 696 mg.

[0186] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject an initial dose of an IL-4Ra x IL-31 antibody and administering to the subject a dose of the IL- 4Ra x IL-31 antibody after the initial dose, wherein a. the IL-4Ra x IL-31 antibody comprises a heavy chain (HC) of SEQ ID NO: 21 and a light chain (LC) of SEQ ID NO: 22; b. the initial dose is administered once subcutaneously at a flat dose of about 600 mg; and c. the dose administered after the initial dose of the IL-4Ra x IL-31 antibody is administered once every two weeks, subcutaneously at a flat dose of about 450 mg.

[0187] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject an initial dose of an IL-4Ra x IL-31 antibody and administering to the subject a dose of the IL- 4Ra x IL-31 antibody after the initial dose, wherein a. the IL-4Ra x IL-31 antibody comprises a heavy chain (HC) of SEQ ID NO: 21 and a light chain (LC) of SEQ ID NO: 22; b. the initial dose is administered once subcutaneously at a flat dose of about 600 mg; and c. the dose administered after the initial dose of the IL-4Ra x IL-31 antibody is administered once every two weeks, subcutaneously at a flat dose of about 450 mgs.

[0188] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject an initial dose of an IL-4Ra x IL-31 antibody and administering to the subject a dose of the IL- 4Ra x IL-31 after the initial dose, wherein a. the IL-4Ra x IL-31 antibody comprises a heavy chain (HC) of SEQ ID NO: 21 and a light chain (LC) of SEQ ID NO: 22; b. the initial dose is administered once subcutaneously at a flat dose of about 600 mg; and c. the dose administered after the initial dose of the IL-4Ra x IL-31 antibody is administered once every two weeks, subcutaneously at a flat dose of about 300.

[0189] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject an initial dose of an IL-4Ra x IL-31 antibody and administering to the subject a dose of the IL- 4Ra x IL-31 after the initial dose, wherein a. the IL-4Ra x IL-31 antibody comprises a heavy chain (HC) of SEQ ID NO: 21 and a light chain (LC) of SEQ ID NO: 22; b. the initial dose is administered once subcutaneously at a flat dose of about 696 mg; andc. the dose administered after the initial dose of the IL-4Ra x IL-31 antibody is administered once every two weeks, subcutaneously at a flat dose of about 348 mg.

[0190] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject an initial dose of an IL-4Ra x IL-31 antibody and administering to the subject a dose of the IL- 4Ra x IL-31 antibody after the initial dose, wherein a. the IL-4Ra x IL-31 antibody comprises a heavy chain (HC) of SEQ ID NO: 21 and a light chain (LC) of SEQ ID NO: 22; b. the initial dose is administered once subcutaneously at a flat dose of about 300 mg; and c. the dose administered after the initial dose of the IL-4Ra x IL-31 antibody is administered once every two weeks, subcutaneously at a flat dose of about 150 mg.

[0191] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject an initial dose of an IL-4Ra x IL-31 antibody and administering to the subject a dose of the IL- 4Ra x IL-31 antibody after the initial dose, wherein a. the IL-4Ra x IL-31 antibody comprises a heavy chain (HC) of SEQ ID NO: 21 and a light chain (LC) of SEQ ID NO: 22; b. the initial dose is administered once subcutaneously at a flat dose of about 348 mg; and c. the dose administered after the initial dose of the IL-4Ra x IL-31 antibody is administered once every two weeks, subcutaneously at a flat dose of about 174 mg.

[0192] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject an initial dose of an IL-4Ra x IL-31 antibody and administering to the subject a dose of the IL- 4Ra x IL-31 antibody after the initial dose, whereina. the IL-4Ra x IL-31 antibody comprises a heavy chain (HC) of SEQ ID NO: 23 and a light chain (LC) of SEQ ID NO: 24; b. the initial dose is administered once subcutaneously at a flat dose of about 600 mg; and c. the dose administered after the initial dose of the IL-4Ra x IL-31 antibody is administered once every two weeks, subcutaneously at a flat dose of about 600 mg.

[0193] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject an initial dose of an IL-4Ra x IL-31 antibody and administering to the subject a dose of the IL- 4Ra x IL-31 antibody after the initial dose, wherein a. the IL-4Ra x IL-31 antibody comprises a heavy chain (HC) of SEQ ID NO: 23 and a light chain (LC) of SEQ ID NO: 24; b. the initial dose is administered once subcutaneously at a flat dose of about 696 mg; and c. the dose administered after the initial dose of the IL-4Ra x IL-31 antibody is administered once every two weeks, subcutaneously at a flat dose of about 696 mg.

[0194] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject an initial dose of an IL-4Ra x IL-31 antibody and administering to the subject a dose of the IL- 4Ra x IL-31 antibody after the initial dose, wherein a. the IL-4Ra x IL-31 antibody comprises a heavy chain (HC) of SEQ ID NO: 23 and a light chain (LC) of SEQ ID NO: 24; b. the initial dose is administered once subcutaneously at a flat dose of about 696 mg; and c. the dose administered after the initial dose of the IL-4Ra x IL-31 antibody is administered once every two weeks, subcutaneously at a flat dose of about 450 mg.

[0195] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject an initial dose of an IL-4Ra x IL-31 antibody and administering to the subject a dose of the IL- 4Ra x IL-31 antibody after the initial dose, wherein a. the IL-4Ra x IL-31 antibody comprises a heavy chain (HC) of SEQ ID NO: 23 and a light chain (LC) of SEQ ID NO: 24; b. the initial dose is administered once subcutaneously at a flat dose of about 600 mg; and c. the dose administered after the initial dose of the IL-4Ra x IL-31 antibody is administered once every two weeks, subcutaneously at a flat dose of about 300 mg.

[0196] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject an initial dose of an IL-4Ra x IL-31 antibody and administering to the subject a dose of the IL- 4Ra x IL-31 antibody after the initial dose, wherein a. the IL-4Ra x IL-31 antibody comprises a heavy chain (HC) of SEQ ID NO: 23 and a light chain (LC) of SEQ ID NO: 24; b. the initial dose is administered once subcutaneously at a flat dose of about 696 mg; and c. the dose administered after the initial dose of the IL-4Ra x IL-31 antibody is administered once every two weeks, subcutaneously at a flat dose of about 348 mg.

[0197] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject an initial dose of an IL-4Ra x IL-31 antibody and administering to the subject a dose of the IL- 4Ra x IL-31 antibody after the initial dose, wherein a. the IL-4Ra x IL-31 antibody comprises a heavy chain (HC) of SEQ ID NO: 23 and a light chain (LC) of SEQ ID NO: 24; b. the initial dose is administered once subcutaneously at a flat dose of about 300 mg; andc. the dose administered after the initial dose of the IL-4Ra x IL-31 antibody is administered once every two weeks, subcutaneously at a flat dose of about 150 mg.

[0198] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject an initial dose of an IL-4Ra x IL-31 antibody and administering to the subject a dose of the IL- 4Ra x IL-31 antibody after the initial dose, wherein a. the IL-4Ra x IL-31 antibody comprises a heavy chain (HC) of SEQ ID NO: 23 and a light chain (LC) of SEQ ID NO: 24; b. the initial dose is administered once subcutaneously at a flat dose of about 348 mg; and c. the dose administered after the initial dose of the IL-4Ra x IL-31 antibody is administered once every two weeks, subcutaneously at a flat dose of about 174 mg.

[0199] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject an initial dose of an IL-4Ra x IL-31 and administering to the subject a dose of the IL-4Ra x IL- 31 after the initial dose, wherein a. the IL-4Ra x IL-31 antibody comprises two heavy chains (HC) and two light chains (LC) comprising the amino acid sequence of SEQ ID NO: 21 and SEQ ID NO: 22, respectively; b. the initial dose is administered once and is between about 150 mg and about 700 mg; c. the dose administered after the initial dose of the IL-4Ra x IL-31 antibody is administered once every two weeks, is between about 150 mg and about 700 mg, and is equal or lower than the initial dose; and d. the initial dose and dose administered after the initial dose are administered subcutaneously.

[0200] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subjectan initial dose of an IL-4Ra x IL-31 and administering to the subject a dose of the IL-4Ra x IL- 31 after the initial dose, wherein a. the IL-4Ra x IL-31 antibody comprises two heavy chains (HC) and two light chains (LC) comprising the amino acid sequence of SEQ ID NO: 23 and SEQ ID NO: 24, respectively; b. the initial dose is administered once and is between about 150 mg and about 700 mg; c. the dose administered after the initial dose of the IL-4Ra x IL-31 antibody is administered once every two weeks, is between about 150 mg and about 700 mg, and is equal or lower than the initial dose; and d. the initial dose and dose administered after the initial dose are administered subcutaneously.

[0201] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject an initial dose of an IL-4Ra x IL-31 and administering to the subject a dose of the IL-4Ra x IL- 31 after the initial dose, wherein a. the IL-4Ra x IL-31 antibody comprises two heavy chains (HC) and two light chains (LC) comprising the amino acid sequence of SEQ ID NO: 21 and SEQ ID NO: 22, respectively; b. the initial dose is administered once and is a flat dose of about 696 mg; c. the dose administered after the initial dose of the IL-4Ra x IL-31 antibody is administered once every two weeks, is a flat dose of about 696 mg; and d. the initial dose and dose administered after the initial dose are administered subcutaneously.

[0202] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject an initial dose of an IL-4Ra x IL-31 and administering to the subject a dose of the IL-4Ra x IL- 31 after the initial dose, whereina. the IL-4Ra x IL-31 antibody comprises two heavy chains (HC) and two light chains (LC) comprising the amino acid sequence of SEQ ID NO: 23 and SEQ ID NO: 24, respectively; b. the initial dose is administered once and is a flat dose of about 696 mg; c. the dose administered after the initial dose of the IL-4Ra x IL-31 antibody is administered once every two weeks, is a flat dose of about 696 mg; and d. the initial dose and dose administered after the initial dose are administered subcutaneously.

[0203] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject an initial dose of an IL-4Ra x IL-31 and administering to the subject a dose of the IL-4Ra x IL- 31 after the initial dose, wherein a. the IL-4Ra x IL-31 antibody comprises two heavy chains (HC) and two light chains (LC) comprising the amino acid sequence of SEQ ID NO: 21 and SEQ ID NO: 22, respectively; b. the initial dose is administered once and is a flat dose of about 696 mg; c. the dose administered after the initial dose of the IL-4Ra x IL-31 antibody is administered once every two weeks, is a flat dose of about 348 mg; and d. the initial dose and dose administered after the initial dose are administered subcutaneously.

[0204] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject an initial dose of an IL-4Ra x IL-31 and administering to the subject a dose of the IL-4Ra x IL- 31 after the initial dose, wherein a. the IL-4Ra x IL-31 antibody comprises two heavy chains (HC) and two light chains (LC) comprising the amino acid sequence of SEQ ID NO: 23 and SEQ ID NO: 24, respectively; b. the initial dose is administered once and is a flat dose of about 696 mg; c. the dose administered after the initial dose of the IL-4Ra x IL-31 antibody is administered once every two weeks, is a flat dose of about 348 mg; andd. the initial dose and dose administered after the initial dose are administered subcutaneously

[0205] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject an initial dose of an IL-4Ra x IL-31 and administering to the subject a dose of the IL-4Ra x IL- 31 after the initial dose, wherein a. the IL-4Ra x IL-31 antibody comprises two heavy chains (HC) and two light chains (LC) comprising the amino acid sequence of SEQ ID NO: 21 and SEQ ID NO: 22, respectively; b. the initial dose is administered once and is a flat dose of about 348 mg; c. the dose administered after the initial dose of the IL-4Ra x IL-31 antibody is administered once every two weeks, is a flat dose of about 174 mg; and d. the initial dose and dose administered after the initial dose are administered subcutaneously.

[0206] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a human subject, wherein the method comprises administering to the subject an initial dose of an IL-4Ra x IL-31 and administering to the subject a dose of the IL-4Ra x IL- 31 after the initial dose, wherein a. the IL-4Ra x IL-31 antibody comprises two heavy chains (HC) and two light chains (LC) comprising the amino acid sequence of SEQ ID NO: 23 and SEQ ID NO: 24, respectively; b. the initial dose is administered once and is a flat dose of about 348 mg; c. the dose administered after the initial dose of the IL-4Ra x IL-31 antibody is administered once every two weeks, is a flat dose of about 174 mg; and d. the initial dose and dose administered after the initial dose are administered subcutaneouslyTreatment of moderate to severe atopic dermatitis

[0207] In some embodiments the administration of the IL-4Ra x IL-31 antibody or antigen binding fragment thereof according to the methods disclosed herein may lead to safe and effective outcomes for subjects in need of treatment for moderate to severe atopic dermatitis.

[0208] In one aspect, the method of the present invention comprises administering to a patient in need thereof of an IL-4Ra x IL-31 antibody at a therapeutically effective dose and at administration intervals wherein the method improves, stabilizes or reduces a symptom associated with atopic dermatitis compared to patient treated with placebo.

[0209] In one aspect, the method of the present invention comprises administering to a patient in need thereof of an IL-4Ra x IL-31 antibody at a therapeutically effective dose and at administration intervals wherein the method improves, stabilizes or reduces a symptom associated with atopic dermatitis compared to patient treated with standard of care.

[0210] In one aspect, the method of the present invention comprises administering to a patient in need thereof of an IL-4Ra x IL-31 antibody at a therapeutically effective dose and at administration intervals wherein the method improves, stabilizes or reduces a symptom associated with atopic dermatitis compared to patient treated with dupilumab.

[0211] In some embodiments, the patient has moderate to acute atopic dermatitis.

[0212] In some embodiments, the patient is a responder or demonstrated improvement to the administration of the IL-4Ra xIL-31 antibody by being identified as meeting a clinical endpoint.

[0213] In some embodiments, the clinical endpoint is measured through about 12 weeks, through about 16 weeks, through about 24, and / or through about 36 weeks after the initial dose.

[0214] In some embodiments, the clinical endpoints measured through about 12 weeks after the initial dose are compared to patients treated with placebos.

[0215] In some embodiments, the clinical endpoint measured through about 12 weeks, through about 16 weeks, through about 24 weeks, and / or through about 36 weeks are compared to patients treated with dupilumab.

[0216] In some embodiments, the clinical endpoint measured through about 12 weeks as compared to patients being treated with placebo, is: a. Eczema Area and Severity Index (EASI) 75 at week 12,b. EASI 90 at week 12; c. EASI 100 at week 12; d. vIGA-AD score of 0 and a reduction from baseline of >2 points at Week 12; e. validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of 0 or 1 and a reduction from baseline of >2 points at Week 12; f. percent change from baseline in the EASI total score at Week 12; g. >4-point improvement (reduction) in Skin Pain numeric(al) rating scale (NRS) from baseline to Week 12; h. percent change from baseline in Peak Pruritus Numeric(al) Rating Scale (PP- NRS) at Week 12; i. percent change from baseline in Skin Pain NRS at Week 12; j. percent change from baseline in the score of Item 2 of the AD Sleep Scale at Week 12; or k. >4-point improvement (reduction) in PP-NRS from baseline through Week 12.

[0217] In some embodiments, the clinical endpoint measured through about 16 weeks as compared to patients being treated with dupilumab, is: a. EASI 75 at Week 16; b. EASI 90 at Week 16; c. EASI 100 at Week 16; d. vIGA-AD score of 0 or 1 and a reduction from baseline of >2 points at Week 16; e. vIGA-AD score of 0 and a reduction from baseline of >2 points at Week 16; f. percent change from baseline in the EASI total score at Week 16; g. >4-point improvement (reduction) in Skin Pain NRS from baseline at Week 16; h. Percent change from baseline in PP-NRS at Week 16; i. Percent change from baseline in Skin Pain NRS at Week 16; or j. Percent change from baseline in the score of Item 2 of the AD Sleep Scale at Week 16.

[0218] In some embodiments, the clinical endpoint measured through about 24 weeks, as compared to patients being treated with dupilumab, is a. >4-point improvement (reduction) in PP-NRS from baseline through Week 24 b. EASI 75 at Week 24;c. EASI 90 at Week 24; d. EASI 100 at Week 24; e. vIGA-AD score of 0 or 1 and a reduction from baseline of >2 points at Week 24; f. vIGA-AD score of 0 and a reduction from baseline of >2 points at Week 24; g. Percent change from baseline in the EASI total score at Week 24; h. >4-point improvement (reduction) in Skin Pain NRS from baseline at Week 24; i. Percent change from baseline in PP-NRS at Week 24; j. Percent change from baseline in Skin Pain NRS at Week 24; or k. Percent change from baseline in the score of Item 2 of the AD Sleep Scale at Week 24.

[0219] In some embodiments, the clinical endpoints, relative to placebo through week 12 or relative to dupilumab through week 24, are based on the assessment of additional timepoints for EASI, vIGA-AD, BSA, PP NRS, Skin Pam NRS, AD Sleep Scale, POEM, HADS, DLQI, PROMIS-29, Digital Nocturnal Scratch and Sleep Wrist-worn Device.

[0220] In some embodiments, the clinical endpoint is the frequency and type of Adverse Events (AE) and Serious Adverse Events (SAEs).

[0221] In some embodiments, the clinical endpoint is the concentration of the IL-4Ra x IL-31 antibody over time or the titer of anti-drug antibody (ADA) to the IL-4Ra x IL-31 antibody.

[0222] In some embodiments, the clinical endpoint is changes in cellular and molecular biomarkers in skin and blood from baseline over time.

[0223] In some embodiments, the clinical endpoint is changes from baseline over time in Asthma Control Questionnaire - 5 (ACQ-5) score in patients with concomitant medical history of asthma.

[0224] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 600 mg of an IL-4Ra x IL-31 antibody that binds to both IL-4Ra and IL-31, (ii) a 300 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 300 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 300 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 300 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 300 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 300 mgsubcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 300 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 300 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 300 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 300 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 300 mg subcutaneous dose of the antibody about 22 weeks after the initial dose; wherein the antibody comprises a IL-4Ra binding domain (IL-4Ra-BD) comprising a first heavy chain variable region (VH1) and a first light chain variable region (VL1) having the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 8, respectively; and a IL-31 binding domain (IL-31-BD) comprising a second heavy chain variable region (VH2) and a second light chain variable region (VL2) having the amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 18, respectively, and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

[0225] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 600 mg of an IL-4Ra x IL-31 antibody that binds to both IL-4Ra and IL-31, (ii) a 450 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 450 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 450 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 450 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 450 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 450 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 450 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 450 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 450 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 450 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 450 mg subcutaneous dose of the antibody about 22 weeks after the initial dose; wherein the antibody comprises a IL-4Ra binding domain (IL-4Ra-BD) comprising a first heavy chain variable region (VH1) and a first light chain variable region (VL1) having the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 8, respectively; and a IL-31 binding domain (IL-31-BD) comprising a second heavy chain variable region (VH2) and a second light chain variable region (VL2) havingthe amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 18, respectively, and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

[0226] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 300 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 150 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 150 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 150 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 150 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 150 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 150 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 150 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 150 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 150 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 150 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 150 mg subcutaneous dose of the antibody about 22 weeks after the initial dose; wherein the antibody comprises a IL-4Ra binding domain (IL-4Ra-BD) comprising a first heavy chain variable region (VH1) and a first light chain variable region (VL1) having the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 8, respectively; and a IL-31 binding domain (IL-31-BD) comprising a second heavy chain variable region (VH2) and a second light chain variable region (VL2) having the amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 18, respectively, and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

[0227] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 600 mg of an antibody that binds to both IL-4Ra and IL-31 , (ii) a 600 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 600 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 600 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 600 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 600 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 600 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 600 mg subcutaneous dose of the antibody about 14 weeks after the initialdose, (ix) a 600 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 600 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 600 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 600 mg subcutaneous dose of the antibody about 22 weeks after the initial dose; wherein the antibody comprises a IL-4Ra binding domain (IL-4Ra-BD) comprising a first heavy chain variable region (VH1) and a first light chain variable region (VL1) having the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 8, respectively; and a IL-31 binding domain (IL-31-BD) comprising a second heavy chain variable region (VH2) and a second light chain variable region (VL2) having the amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 18, respectively, and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

[0228] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 600 mg of an IL-4Ra x IL-31 antibody that binds to both IL-4Ra and IL-31, (ii) a 300 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 300 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 300 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 300 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 300 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 300 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 300 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 300 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 300 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 300 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 300 mg subcutaneous dose of the antibody about 22 weeks after the initial dose; wherein the antibody comprises a IL-4Ra binding domain (IL-4Ra-BD) comprising a first heavy chain variable region (VH1) and a first light chain variable region (VL1) having the amino acid sequences of SEQ ID NO: 9 and SEQ ID NO: 10, respectively; and a IL-31 binding domain (IL-31-BD) comprising a second heavy chain variable region (VH2) and a second light chain variable region (VL2) having the amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 18, respectively, and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

[0229] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 600 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 450 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 450 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 450 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 450 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 450 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 450 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 450 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 450 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 450 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 450 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 450 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a IL-4Ra binding domain (IL-4Ra-BD) comprising a first heavy chain variable region (VH1) and a first light chain variable region (VL1) having the amino acid sequences of SEQ ID NO: 9 and SEQ ID NO: 10, respectively; and a IL-31 binding domain (IL-31-BD) comprising a second heavy chain variable region (VH2) and a second light chain variable region (VL2) having the amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 18, respectively, and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

[0230] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 300 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 150 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 150 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 150 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 150 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 150 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 150 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 150 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 150 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 150 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 150 mgsubcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 150 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a IL-4Ra binding domain (IL-4Ra-BD) comprising a first heavy chain variable region (VH1) and a first light chain variable region (VL1) having the amino acid sequences of SEQ ID NO: 9 and SEQ ID NO: 10, respectively; and a IL-31 binding domain (IL-31-BD) comprising a second heavy chain variable region (VH2) and a second light chain variable region (VL2) having the amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 18, respectively, and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

[0231] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 600 mg of an antibody that binds to both IL-4Ra and IL-31 , (ii) a 600 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 600 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 600 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 600 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 600 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 600 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 600 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 600 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 600 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 600 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 600 mg subcutaneous dose of the antibody about 22 weeks after the initial dose; wherein the antibody comprises a IL-4Ra binding domain (IL-4Ra-BD) comprising a first heavy chain variable region (VH1) and a first light chain variable region (VL1) having the amino acid sequences of SEQ ID NO: 9 and SEQ ID NO: 10, respectively; and a IL-31 binding domain (IL-31-BD) comprising a second heavy chain variable region (VH2) and a second light chain variable region (VL2) having the amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 18, respectively, and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

[0232] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 696 mg of an IL-4Ra x IL-31 antibody that binds to both IL-4Ra and IL-31, (ii) a 348mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 348 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 348 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 348 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 348 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 348 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 348 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 348 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 348 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 348 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 348 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 25, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

[0233] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 348 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 174 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 174 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 174 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 174 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 174 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 174 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 174 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 174 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 174 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 174 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 174 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1)comprising an amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 25, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

[0234] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 696 mg of an antibody that binds to both IL-4Ra and IL-31 , (ii) a 696 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 696 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 696 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 696 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 696 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 696 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 696 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 696 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 696 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 696 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 696 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 25, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

[0235] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 696 mg of an IL-4Ra x IL-31 antibody that binds to both IL-4Ra and IL-31, (ii) a 348 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 348 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 348 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 348 mgsubcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 348 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 348 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 348 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 348 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 348 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 348 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 348 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises two heavy chains, each heavy chain comprising an amino acid sequence of SEQ ID NO: 21 and two light chains, each light chain comprising an amino acid sequence SEQ ID NO: 22 and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

[0236] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 348 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 174 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 174 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 174 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 174 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 174 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 174 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 174 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 174 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 174 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 174 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 174 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises two heavy chains, each heavy chain comprising an amino acid sequence of SEQ ID NO: 21 and two light chains, each light chain comprising an amino acid sequence SEQ ID NO: 22, and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

[0237] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 696 mg of an antibody that binds to both IL-4Ra and IL-31 , (ii) a 696 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 696 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 696 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 696 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 696 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 696 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 696 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 696 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 696 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 696 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 696 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises two heavy chains, each heavy chain comprising an amino acid sequence of SEQ ID NO: 21 and two light chains, each light chain comprising an amino acid sequence SEQ ID NO: 22 and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

[0238] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 696 mg of an IL-4Ra x IL-31 antibody that binds to both IL-4Ra and IL-31, (ii) a 348 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 348 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 348 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 348 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 348 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 348 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 348 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 348 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 348 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 348 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 348 mgsubcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 9 and SEQ ID NO: 27, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

[0239] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 348 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 174 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 174 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 174 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 174 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 174 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 174 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 174 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 174 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 174 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 174 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 174 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 9 and SEQ ID NO: 27, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

[0240] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 696 mg of an antibody that binds to both IL-4Ra and IL-31 , (ii) a 696 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 696 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 696 mg subcutaneous dose of the antibodyabout 6 weeks after the initial dose, (v) a 696 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 696 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 696 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 696 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 696 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 696 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 696 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 696 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 9 and SEQ ID NO: 27, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

[0241] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 696 mg of an IL-4Ra x IL-31 antibody that binds to both IL-4Ra and IL-31, (ii) a 348 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 348 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 348 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 348 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 348 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 348 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 348 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 348 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 348 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 348 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 348 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises two heavy chains, each heavy chain comprising an amino acid sequence of SEQ ID NO: 23 and two light chains, each light chain comprising an amino acid sequence SEQ ID NO:24 and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

[0242] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 348 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 174 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 174 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 174 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 174 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 174 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 174 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 174 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 174 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 174 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 174 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 174 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises two heavy chains, each heavy chain comprising an amino acid sequence of SEQ ID NO: 23 and two light chains, each light chain comprising an amino acid sequence SEQ ID NO: 24, and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

[0243] In some embodiments, the disclosure comprises a method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 696 mg of an antibody that binds to both IL-4Ra and IL-31 , (ii) a 696 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 696 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 696 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 696 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 696 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 696 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 696 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 696 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 696 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 696 mgsubcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 696 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises two heavy chains, each heavy chain comprising an amino acid sequence of SEQ ID NO: 23 and two light chains, each light chain comprising an amino acid sequence SEQ ID NO: 24 and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

[0244] The disclosed method can comprise the exemplary treatment schedules provided in Table 1.Table 1. Exemplary treatment schedule

[0245] In some embodiments, the patient is 18 years of age or older.

[0246] In some embodiments, the patient has chronic atopic dermatitis, according to American Academy of Dermatology Consensus Criteria with onset of symptoms at least 1 year prior to screening visit as determined by the investigator through participant interview and / or review of the medical history

[0247] In some embodiments, the patient has an adverse event of special interest (EASI) score >16 at the Screening and Baseline Visits.

[0248] In some embodiments, the patient has a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score >3 at the Screening and Baseline Visits.

[0249] In some embodiments, the patient has >10% Body Surface Area (BSA) of atopic dermatitis involvement at the Screening and Baseline Visits.

[0250] In some embodiments, the patient has a baseline Peak Pruritus Numeric(al) Rating Scale (PP-NRS) average score of >4. In some embodiments, the patient has documented history(within 6 months before screening) of either inadequate response or inadvisability to topical treatments, or inadequate response to systemic therapies (within 12 months before screening).

[0251] In some embodiments, the patient has applied a moisturizer at least once daily for at least 7 days before the Baseline Visit.

[0252] In some embodiments, the patient does not have active skin disease other than atopic dermatitis (AD) including eczema herpeticum, molluscum contagiosum, impetigo, psoriasis or has any other ongoing significant skin condition including skin infections, that could interfere with efficacy assessments.

[0253] In some embodiments, the patient has not received prior administration of the IL-4Ra x IL-31 antibody.

[0254] In some embodiments, the patient has not received prior treatment with: a. agents that deplete B cells (alemtuzumab, ocrelizumab, or rituximab) 26 weeks prior to the first administration of IL-4Ra x IL-31 antibody through end of study; b. any immunomodulating biologic therapy that could affect AD including but not limited to dupilumab, tralokinumab, lebrikizumab, nemolizumab, natalizumab, belimumab, abatacept, visilizumab, or any experimental or investigational therapy 12 weeks or 5 half-lives, whichever is longer, prior to the first administration of the IL- 4Ra x IL-31 antibody through end of study; c. Systemic immunomodulating / immunosuppressive treatments including but not limited to corticosteroids (oral or parenteral), methotrexate, cyclosporine A, azathioprine, JAK inhibitors, 4 weeks prior to the first administration of the Il-4Ra xIL-31 antibody through end of study; d. Phototherapy 4 weeks prior to the first administration of the Il-4RaxIL-31 antibody through end of study; e. Systemic medications that could affect AD evaluations including, but not limited to acitretin, retinoids, herbal treatments, or traditional medicines (eg, Korean or Chinese) 4 weeks prior to the first administration of the IL-4RaxIL-31 antibody through end of study; f. Nonbiologic experimental therapies or investigational agents 4 weeks prior to the first administration of the IL-4Ra x IL-31 antibody through end of study;g. Topical medications / treatments that could affect AD evaluations including, but not limited to Corticosteroids, calcineurin inhibitors, JAK inhibitors, PDE4 inhibitors, prescription moisturizers, herbal treatments or traditional medicines (eg, Korean or Chinese) 1 weeks prior to the first administration of the IL-4RxIL-31 antibody through end of study; h. Live virus or live bacterial vaccination 12 weeks (or longer if required per vaccine package insert) prior to the first administration of the IL-4a x IL-31 antibody through end of study and for 90 days after receiving the last dose of the IL-4a x IL-31 antibody.

[0255] In some embodiments, the patient has not experienced primary efficacy failure (no response within 16 weeks) or an adverse event (AE) requiring discontinuation related to agents (eg, severe ocular surface disease, dupilumab-associated facial redness) inhibiting IL-4Ra, IL-4, and / or IL- 13 signaling (eg, dupilumab, lebrikizumab, or tralokinumab).Compositions

[0256] The IL-4Ra x IL-31 antibody or antigen binding fragment thereof can be administered in pharmaceutical a composition that include an effective amount of the antibody or antigen binding fragment thereof, and one or more pharmaceutically acceptable carriers or excipients, which can be formulated by methods known to those skilled in the art.

[0257] Acceptable carriers and excipients in the pharmaceutical compositions are nontoxic to recipients at the dosages and concentrations employed. Acceptable carriers and excipients may include buffers, antioxidants, preservatives, polymers, amino acids, and carbohydrates. In some embodiments, the pharmaceutical composition further comprises one or more excipients. In some embodiments, the one or more excipients include, but are not limited to a buffering agent, a sugar, a surfactant, a chelator, or any combination thereof.

[0258] Pharmaceutical compositions for injection can be formulated using a sterile solution or any pharmaceutically acceptable liquid as a vehicle. Pharmaceutically acceptable vehicles include, but are not limited to, sterile water, physiological saline, and cell culture media (e.g., Dulbecco’s Modified Eagle Medium (DMEM), a-Modified Eagles Medium (a-MEM), L-12medium). Formulation methods are known in the art, see e.g., Banga (ed.) Therapeutic Peptides and Proteins: Formulation, Processing and Delivery Systems (2nd ed.) Taylor & Francis Group, CRC Press (2006).

[0259] In some embodiments, the IL-4Ra x IL-31 antibody or antigen binding fragment thereof useful for a method of the application can be packaged in one or more kits, which can optionally contain instructions for use.

[0260] In some embodiments, the IL-4Ra x IL-31 antibody or antigen binding fragment thereof can be administered in pharmaceutical a composition comprising a formulation comprising 125.6 mM sucrose, 20 mM (L-)arginine hydrochloride, 66.6 mM Glycine, 30 mM (L)-histidine, and 0.02% (w / v) poloxamer 188; wherein the formulation is about pH 6.0.EXAMPLESExample 1: Sequence and structure of IL-4Ra x IL-31 antibody

[0261] The IL-4Ra x IL-31 antibodies (i.e. anti-IL-4Ra / anti-IL-31 antibody) PRO2198 and PRO2199 are described in WO2022136669 which is incorporate by reference herein. The IL- 4Ra x IL-31 antibodies comprises a first domain that binds IL-4Ra (in the format of a Fab) and a second domain that binds IL-31R (in format of an scFv).

[0262] The IL-4Ra x IL-31 antibodies PRO2198 and PRO2199 are in the Morrison-H format.

[0263] The Morrison format (also IgG-(scFv)2 format) is a bivalent and bispecific IgG-based molecular format comprising an Fc region and two scFv domains that are either fused via linkers to the C-termini of the heavy chains, commonly referred to as Morrison-H format , or that are fused via linkers to the C-termini of the light chains, commonly referred to as Morrison-L format (FIG. 1).

[0264] The IL-4Ra binding domain is in Fab format. The IL-31 binding domain is in highly stable A- capped scFv format (Table 2). The scFv comprises a linker polypeptide (linker2) (SEQ ID NO: 19; GGGGSGGGGSGGGGSGGGGS) between the VL and the VH. The scFv domains are fused to the C-termini of the heavy chain with a linker polypeptide (linkerl) of SEQ ID NO: 20 (GGGGSGGGGS) (Momson-H).

[0265] The amino acid sequences of the IL-4Ra x IL-31 antibodies PRO2198 and PRO2199 are shown in Table 3-7. CDR sequences are defined according to the AHo numbering.Table 2: IL-4Ra x IL-31 antibody (PRO2198 and PRO2199) in IgG4 Morrison-H formatTable 3. Sequences of the IL-4Ra binding domain of the IL-4Ra x IL-31R antibody PRO2198Table 4. Sequences of the IL-4Ra binding domain of the IL-4Ra x IL-31R antibody PRO2199Table 4. Sequences of the IL-31 binding domain of the IL-4Ra x IL-31R antibody PRO2198 and PRO2199.Table 5. Sequences of the HC and LC of the IL-4Ra x IL-31R antibody PRO2198.Table 6. Sequences of the HC and LC of the IL-4Ra x IL-31R antibody PRO2199.Example 2. Nonclinical StudiesPharmacologic Profile

[0266] In vitro studies have demonstrated high-affinity binding of the IL-4Ra x IL-31 antibody (PRO2198 of example 1) to its 2 human-target proteins, IL-4Ra and IL-31, and that binding to both targets can occur concomitantly without impact on potency. The IL-4Ra x IL-31 antibody potently inhibits IL-4a, IL-13, and IL-31-induced signaling in reporter based cellular experiments. In addition, the dual antagonism of IL-4Ra x IL-31 antibody has been shown to be effective in the inhibition of CCL2 release from bronchial epithelial cells following stimulation with the combination of IL-4Ra and IL-31 , to a greater extent than the inhibition of a single pathway such as that elicited by the IL-4R antagonist dupilumab. The IL-4Ra x IL-31 antibody potently inhibits the IL-4a and IL- 13 -driven activation of primary immune cells implicated in the pathology of AD, as demonstrated- by the inhibition of TARC (CCL17) release from human and cynomolgus monkey whole blood assays, and the inhibition of CD23 (FcsRII) upregulation from human primary B cells and monocytes. FcyR binding has been demonstrated, as anticipated for an IgG4 molecule however, no detectable antibody-dependent cytotoxicity and complementdependent cytotoxicity activity has been observed.

[0267] In vitro studies demonstrate the cross-reactivity of IL-4Ra x IL-31 antibody to cynomolgus IL-4Ra and IL-31 with similar affinity and functional potency as that of IL-4Ra x IL-31 antibody to its human-target proteins. This has been demonstrated in a range of assays including surface plasmon resonance, reporter cell assays, and primary cell assays. Limited cross-reactivity has been demonstrated for other potential toxicological species such as dog, pig, rat, and mouse, therefore justifying cynomolgus monkey as the only relevant species to assess the toxicological effects of the IL-4Ra x IL-31 antibody.

[0268] Ex vivo studies using human skin punch biopsies have demonstrated the ability of IL- 4Ra x IL-31 antibody to inhibit the dysregulation of gene expression induced by IL-4a, IL-13, and IL-31.

[0269] In vivo studies have shown that IL-4Ra x IL-31 antibody inhibits IL-31 -driven pruritus in a cynomolgus monkey model of itch behavior.Safety Pharmacology

[0270] Separate safety pharmacology studies were not conducted with IL-4Ra x IL-31 antibody. However, cardiovascular, respiratory, and central nervous system safety pharmacology endpoints were incorporated into the design of the 4-week and 6-month repeat-dose GLP toxicology studies conducted in cynomolgus monkeys (see below).Toxicology

[0271] A 4-week repeated-dose GLP toxicology study in cynomolgus monkeys has shown that doses up to 125 mg / kg (SC and IV) of IL-4Ra x IL-31 antibody administered weekly for a total of 5 doses were well tolerated with no noted treatment-related adverse toxicities, including assessment of cardiovascular, central nervous system, and respiratory function. The highest administered dose of 125 mg / kg in monkeys is therefore regarded as the NOEL of that study. In the 6-month repeat-dose GLP toxicology study in cynomolgus monkeys, there were no IL-4Ra x IL-31 antibody-related adverse findings at once weekly SC or IV doses up to 125 mg / kg. Non- adverse IL-4Ra x IL-31 antibody-related increase in liver / gallbladder weights with no microscopic correlate was observed at 25 and 125 mg / kg SC at the end of dosing but was not observed in the recovery animals. The moribundity and adverse clinical observations in 1 female at 125 mg / kg SC (clinical signs started on Day 99 with animal euthanized on Day 180) were considered likely related to ADA-mediated immune reaction and not directly related to IL-4Ra x IL-31 antibody, based on the presence of high levels of ADA with complete loss of exposure to IL-4Ra x IL-31 antibody at the time of occurrence, the nature of clinical observations and injection site microscopic findings with associated clinical pathology parameter changes, and the lack of other direct-target organ toxicities. AD As directed against IL-4Ra x IL-31 antibody, a humanized antibody, in cynomolgus monkeys do not predict the occurrence of AD As in humans. Based on these results, the NOAEL was considered to be at the highest dose tested, 125 mg / kg SC and IV At the NOAEL, the Day 183 sex-combined mean AUC0-168hr was487,000 pg*h / mL for the IV route, and the mean AUC0-168hr was 389,000 pg*h / mL, and the mean Cmax was 2940 pg / mL for the SC route (safety multiples of 33x and 35x, relative to the projected human AUC and Cmax at the highest proposed Phase 2 SC dose of 600 mg q2w, respectively).

[0272] In addition, a soluble in vitro cytokine release assay was conducted and demonstrated lack of detectable cytokine release from human whole blood from multiple donors at doses of IL- 4Ra x IL-31 antibody up to 100 pg / well. In the in vitro tissue cross-reactivity study, no unexpected binding was noted in the normal human and cynomolgus monkey tissues.Pharmacokinetic Profile

[0273] PK analysis in cynomolgus monkeys dosed via SC and IV administration in the 4-week GLP toxicology study indicate a ti / 2 of 7 to 10 days at doses >5 mg / kg IV and >5 mg / kg SC, and a Tmax of approximately 72 hours at doses of 125 mg / kg SC. A non-linear PK profile is observed in monkeys and most likely this is due to TMDD, as seen for other anti-IL-4R antibodies such as dupilumab.

[0274] No notable or consistent sex differences were observed for exposure to IL-4Ra x IL-31 antibody in the 6month GLP toxicology study. Following weekly administration via the SC route in cynomolgus monkeys, mean Cmax and AUC values increased with increasing dose in an approximately dose-proportional manner between study Days 1 and 183. The estimated absolute bioavailability after a 125 mg / kg SC dose was similar between males and females and increased over time with %F of 53.1% and 79.9% for males and 63.2% and 86.2% for females on Days 1 and 183, respectively.

[0275] As to be expected for a humanized protein administered to cynomolgus monkeys, some animals in the GLP toxicology studies developed AD As towards IL-4Ra x IL-31 antibody, which in some cases reduced or eliminated long-term exposure. However, in both GLP-toxicology studies, a relevant number of animals remained ADA negative and demonstrated exposure to study drug until end of the study.Example 3. A Phase 1 randomized, double-blind, placebo-controlled study that evaluates the safety, tolerability, and PK of IL-4Ra x IL-31 antibody in healthy participants and participants with moderate to severe Atopic Dermatitis (AD)

[0276] This is a first-in-human randomized, double-blind, placebo-controlled study that evaluates the safety, tolerability, and PK of IL-4Ra x IL-31 antibody (PRO2198 of example 1) inhealthy participants and participants with moderate to severe AD. The study is summarized inTable 7.Table 7.

[0277] While all Parts have completed dosing, the study is considered ongoing (until CSR is finalized) at the time of filing. The preliminary results, including safety, tolerability, PK, and PD data, are summarized below.Safety and tolerability

[0278] At the time of filing, in Parts A and C, IL-4Ra x IL-31 antibody was generally safe and well tolerated. No SAEs, severe AEs, or deaths have occurred. The most common TRAE is administration site conditions or reaction (erythema, pain, or discomfort) in 6 participants.

[0279] At the time of filing, in Part B, based on the results in Cohort Bl, IL-4Ra x IL-31 antibody was well tolerated after multiple doses. There were 2 TRAEs in 1 participant who developed both non-disseminated herpes zoster and oral herpes; the patient had a history of similar episodes for both events and both events completely resolved within 5 days of standard antiviral therapy. Based on preliminary blinded results for Cohort B2, there were 13 TRAEs in 3 patients including 1 SAE. The participant with the SAE reported reactive respiratory distresssyndrome (Preferred Term) on Day 25, 2 days after receiving the final injection administration. The participant was admitted to the hospital, and the SAE was resolved following overnight treatment and observation. The participant did not have a medical history of asthma.

[0280] No other clinically significant safety trends were observed in vital signs, physical examinations, ECG, or safety laboratories in all Parts of the study at the time of filing. Overall, administration of IL-4Ra x IL-31 antibody or placebo in multiple SC administrations was safe and well tolerated.Efficacy

[0281] At the time of filing, part B of the ongoing Phase 1 study includes 2 cohorts of multiple SC administrations of IL-4Ra x IL-31 antibody in participants with moderate to severe AD (Table 7). The primary objectives are safety, tolerability, and PK assessed on Day 29 EOT. Exploratory endpoints evaluated changes in EASI, PP-NRS, Skin Pain NRS, or PROMIS-SRI-8a from baseline. At the time of filing, preliminary data from Cohort Bl treated participants and placebo show a numerical improvement in EASI scores at Day 29 EOT, with similar trends in PP-NRS, Skin Pain NRS, and PROMIS-SRI-8a. At the time of filing, cohort B2 is still blinded at the time of protocol development.Exploratory Biomarker

[0282] At the time of filing, preliminary exploratory biomarker analysis supports IL-4Ra x IL-31 antibody binding to IL-4Ra in humans. Serum IL-4 level was transiently increased following IL- 4Ra x IL-31 antibody treatment in healthy participants (Parts A and C) in a dose-dependent manner and participants with moderate to severe AD (Part B). No increase was observed in participants who received a placebo among the unblinded cohorts. In Part B among participants with AD, no treatment-related change in serum TARC or IgE levels was observed. IL-31 was not measured.Human Pharmacokinetics

[0283] Preliminary pharmacokinetic data from SAD and MAD of the Phase 1 study are summarized below.

[0284] At the time of filing, following a single SC administration of 12 to 1035 mg of IL-4Ra x IL-31 antibody (Part A) in non- Asian healthy participants, median peak plasma concentrations were reached approximately 5 to 7 days post dose. The exposure (Cmax and AUC) appeared to increase in a greater than proportional manner at low doses (<348 mg) due to target-mediated drug disposition. In contrast, at higher doses, Cmax and AUC increase in a close to proportional manner. The terminal half-life varied from 88 hours (348 mg and 460 mg doses) to 143 hours (696 mg and 1044 mg doses). PK data observed in Japanese healthy participants were similar to non- Asian healthy participants (Part A, Cohorts A4J to A6J).

[0285] Upon repeated doses administered in weekly dosing intervals, some accumulation of the drug (2.5fold for Cmaxand 3.8-fold for AUC) is observed. The exposure to IL-4Ra x IL-31 antibody in AD participants tended to be lower than that in healthy adults and there is considerable inter-participant variability for exposure (Part B, Cohorts Bl and B2). Steady state concentrations are expected to be reached approximately by Week 10 (6thdose) following q2w dosing regimen.Example 4. A Phase 2b Clinical studies Multicenter, Randomized, Double-blind, Placebo- and Active-controlled, Dose-ranging Study of the IL-4Ra x IL-31 antibody for the Treatment of Participants with Moderate to Severe Atopic Dermatitis.

[0286] This is a Phase 2b, Multicenter, Randomized, Double-blind, Placebo- and Active- controlled, Dose-ranging Study to Evaluate the Efficacy and Safety of the IL-4Ra x IL-31 antibody (of example 1, PRO2198) for the Treatment of Participants with Moderate to Severe Atopic Dermatitis.

[0287] The IL-4Ra x IL-31 antibody is a first-in-class bispecific, tetravalent, humanized antibody in an IgG4-scFv fusion format targets inhibits IL-4Ra (Type I and Type II receptors) and IL-31 in a bivalent manner (with the single-chain anti-IL-31 Fv fragment fused to the C- termini of both IgG4 heavy chains, also referred to as Morrison-H format) as describe in Example 1.OVERALL DESIGN

[0288] This is a Phase 2b randomized, double-blind, placebo- and active-controlled, doseranging, parallel, multicenter, interventional study in adults with moderate to severe AD. The participant population will be comprised of adults >18 years of age, with AD that is moderate to severe, and has been present for at least 1 year before the first administration of study intervention, as determined by the investigator through patient interview and / or review of the medical history. Participants must also have a history of inadequate response to treatment for AD with topical medications or for whom topical treatments are otherwise medically inadvisable, an EASI score >16, an IGA score >3, and an involved percent BSA >10% at both screening and at baseline, a baseline PP-NRS average score of >4, and without a history of primary failure or intolerance to IL-4Ra, IL-4, and / or IL- 13 inhibitors. Participants must agree to apply moisturizers at least once daily for at least 7 days before randomization and continue the treatment throughout the study.

[0289] Participants are randomized in this study in a 2:2:2: 1 : 1 ratio into 1 of 5 treatment arms with dupilumab, IL-4Ra x IL-31 antibody (696 mg q2w), IL-4Ra x IL-31 antibody (696 mg initial dose followed by 348 mg q2w), IL-4Ra x IL-31 antibody (348 mg initial dose followed by 174 mg q2w), or placebo, respectively. Participants randomized to placebo will be switched to receive IL-4Ra x IL-31 antibody (696 mg q2w) after 12 weeks of treatment. Randomization will be stratified by severity of disease (moderate [vIGA-AD=3] or severe [vIGA-AD=4]) and geographic region (Asia, Eastern Europe / Latin America, Rest of World). Participants with moderate AD (vIGA-AD=3) will comprise a maximum of approximately 65% of the study population, and participants with a history of exposure to IL-4Ra, IL-4, and / or IL- 13 inhibitors will comprise a maximum of approximately 15% of the study population.

[0290] A target of approximately 240 participants will be enrolled in this study.

[0291] The total duration of the study is approximately 37 weeks and includes up to 5 -week screening period, a 12- week placebo-controlled period, a 24-week active-comparator-controlled period to run concurrently with the placebo comparison, and an 8-week safety follow-up period.

[0292] Participants will be randomized in this study in a 2:2:2: 1 : 1 ratio into 1 of 5 treatment groups with dupilumab, IL-4Ra x IL-31 antibody, or placebo administered subcutaneously:• Group A: Dupilumab SC 600 mg initial dose followed by 300 mg q2w for 24 weeks• Group B: IL-4Ra x IL-31 antibody SC: 696 mg q2w for 24 weeks• Group C: IL-4Ra x IL-31 antibody SC: 696 mg initial dose followed by 348 mg q2w for 24 weeks• Group D: IL-4Ra x IL-31 antibody SC: 348 mg initial dose followed by 174 mg q2w for 24 weeks• Group E: Placebo SC q2w for 12 weeks, then switch to receive IL-4Ra x IL-31 antibody SC 696 mg q2w for another 12 weeks

[0293] Efficacy, safety, PK, immunogenicity, and biomarkers will be assessed. An optional pharmacogenomic blood sample will be collected from participants who consent to the collection of these samples (where local regulations permit).Active comparator

[0294] The Active Comparator, Dupilumab (DUPIXENT, Regeneron Pharmaceuticals, Inc.) is a human monoclonal IgG4 antibody that inhibits IL-4 and IL- 13 signaling by specifically binding to the IL-4Ra subunit shared by the IL-4 and IL- 13 receptor complexes. Dupilumab inhibits IL-4 signaling via the Type I receptor and both IL-4 and IL- 13 signaling through the Type II receptor.

[0295] Dupilumab was selected as the active comparator for this study because it has demonstrated efficacy in patients with moderate to severe AD and serves as a useful efficacy benchmark.

[0296] Dupilumab has been approved for treatment of moderate to severe AD in the adult and pediatric populations in the US, Canada, EU, United Kingdom, Japan, and a number of other countries / territories worldwide.STUDY POPULATION

[0297] The inclusion and exclusion criteria for enrolling participants in this study are described below.Inclusion Criteria1. >18 years of age (or at least the legal age of consent in the jurisdiction in which the study is taking place) at the time of informed consent.Type of Participant and Disease Characteristic(s)2. Be otherwise healthy on the basis of physical examination, medical history, vital signs, and 12-lead ECG performed at screening. Any abnormalities must be consistent with the underlying illness in the study population and this determination must be recorded in the participant's source documents and initialed by the investigator.3. Meets all the following disease activity criteria: a. Chronic AD, according to American Academy of Dermatology Consensus Criteria (Eichenfield 2014) with onset of symptoms at least 1 year prior to screening visit as determined by the investigator through participant interview and / or review of the medical history. b. EASI score >16 at the Screening and Baseline Visits; c. vIGA-AD score >3 at the Screening and Baseline Visits; d. >10% BSA of AD involvement at the Screening and Baseline Visits; e. Baseline PP-NRS average score of >4 (Section 8.2.1.1). f. Documented history (within 6 months before screening) of either inadequate response or inadvisability to topical treatments, or inadequate response to systemic therapies (within 12 months before screening) g. Participant has applied a moisturizer at least once daily for at least 7 days before the Baseline Visit.Exclusion criteria

[0298] Any potential participant who meets any of the following criteria will be excluded from participating in the study:Medical Conditions1. Active skin disease other than AD including eczema herpeticum, molluscum contagiosum, impetigo, psoriasis or has any other ongoing significant skin conditionincluding skin infections, that, according to the investigator, could interfere with efficacy assessments. Concomitant keratosis pilaris or ichthyosis vulgaris associated with AD may not need to be exclusionary Current diagnosis or signs or symptoms of severe, progressive, or uncontrolled renal, cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, psychiatric, or metabolic disturbances. Had major surgery (eg, requiring general anesthesia and hospitalization), within 8 weeks before screening, or will not have fully recovered from surgery, or has such surgery planned during the time the participant is expected to participate in the study. Has a transplanted organ (with exception of a corneal transplant >12 weeks before the first administration of study intervention). Uncontrolled chronic disease that might require bursts of oral corticosteroids including co-morbid severe uncontrolled asthma (eg, history of >2 asthma exacerbations within the last 12 months requiring systemic [oral and / or parenteral] corticosteroid treatment or hospitalization for >24 hours). History of drug or alcohol abuse within 1 year before screening. In the investigator’s opinion, any clinically significant laboratory results from the chemistry, hematology, or urinalysis tests obtained at the screening visit. History of chronic or recurrent infectious disease, including but not limited to chronic renal infection, chronic chest infection (eg, bronchiectasis, untreated latent tuberculosis), recurrent urinary tract infection (recurrent pyelonephritis or chronic non remitting cystitis), fungal infection (mucocutaneous candidiasis), mycobacterial infection, or open, draining, or infected skin wounds, or ulcers. History of an infected joint prosthesis or has received antibiotics for a suspected infection of a joint prosthesis, if that prosthesis has not been removed or replaced. Known or suspected immunodeficiency, including history of invasive opportunistic infections (eg, active TB, nontuberculous mycobacterial infection, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystis, aspergillosis, HIV) or otherwise recurrent infections of abnormal frequency or prolonged duration despite infection resolution, suggesting an immune-compromised status, as judged by the investigator.11. Serious infection (eg, disseminated herpes zoster, sepsis, pneumonia, or pyelonephritis), or has been hospitalized or received IV antibiotics for an infection during the 8 weeks before screening.12. Recent case of eczema herpeticum, herpes zoster within 8 weeks before screening, or history of recurrent eczema herpeticum.13. Diagnosed active parasitic infection or at high risk of parasitic infection, unless treated with antihelminth therapy prior to randomization.14. History of being HIV antibody-positive, HIV test positive, or tests positive for HIV at screening.15. Tests positive for HBV or HCV infection at screening or known liver cirrhosis.16. Current malignancy or history of malignancy within 5 years before screening (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, which is considered cured with no evidence of recurrence for at least 3 months prior to the first administration of study intervention and with minimal risk of recurrence).17. History of lymphoproliferative disease, including lymphoma; a history of monoclonal gammopathy of undetermined significance; or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy or splenomegaly.18. Patient with Prior / Concomitant Therapy as show in Table 8, or patent who has previously received IL-4Ra x IL-31 antibody.Table 8.24. Experienced primary efficacy failure (no response within 16 weeks) or an AE requiring discontinuation related to agents (eg, severe ocular surface disease, dupilumab-associated facial redness) inhibiting IL-4Ra, IL-4, and / or IL- 13 signaling (eg, dupilumab, lebrikizumab, or tralokinumab).25. Has known hypersensitivity to dupilumab or its excipients.26. Has known hypersensitivity to any biologic medication or known allergies, or clinically significant reactions to murine, chimeric, human proteins, mAbs, or antibody fragments.STUDY INTERVENTIONS

[0299] Study interventions are described in Table 9.Table 9.OBJECTIVES AND ENDPOINTS

[0300] Primary, secondary and other endpoints are shown in Table 10.Table 10.EFFICACY ASSESSMENT

[0301] Patient-reported outcome(s) (PROs) and Investigator assessments will be used to assess efficacy in this study.Patient-reported Outcomes

[0302] At least 4 PP-NRS 24-hour assessments are required within 7 days before randomization to support eligibility and prior to Week 12, Week 16, and Week 24 to support analyses.

[0303] Peak Pruritis Numerical Rating Scale (PP-NRS) - The PP-NRS is a single item asking participants to assess their worst itch over the past 24 hours. There are 11 response categories, ranging from 0 (no itch) to 10 (worst itch imaginable). This item is administered daily throughout the trial.

[0304] Atopic Dermatitis Symptom Scale Skin Pain Numeric Rating Scale (Skin Pain NRS) - The Skin Pain NRS is a single item asking participants to assess their worst skin pain over the past 24 hours. There are 11 response categories, ranging from 0 (no pain) to 10 (worst pain imaginable). This item is administered daily throughout the trial.

[0305] Atopic Dermatitis Sleep Scale (AD Sleep Scale) - The AD Sleep Scale is a validated 3- item PRO instrument to capture self-reported impact of itch on sleep disturbance each day, including difficulty falling asleep, number of night-time awakenings, and difficulty falling back asleep after waking during the previous night. This item is administered daily throughout the trial. Each AD Sleep Scale item is scored individually. For Items 1 and 3, participants are asked to select a score ranging from 0 (not at all) to 4 (very difficult). For Item 2, participants select the number of times they woke up each night, ranging from 0 to 29 times. Participants only answer Item 3 if their answer to Item 2 is greater than 0.

[0306] Patient-oriented Outcome Measure (POEM) - The POEM is a 7-item validated questionnaire used in clinical practice and clinical trials to assess disease symptoms in children and adult. The recall period for all items is over the last week. The format is a response to 7 items (dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) based on frequency during the past week (ie, 0 = no days, 1 = 1 to 2 days, 2 = 3 to 4 days, 3 = 5 to 6 days, and 4 = every day) with a scoring system of 0 to 28; the total score reflects disease-related morbidity and a higher score indicates greater severity.

[0307] Hospital Anxiety and Depression Scale (HADS) - The HADS consists of 2 subscales, 1 measuring anxiety and 1 measuring depression, which are scored separately. The recall period for all items is the past week. Each subscale contains 7 items, with responses ranging from 0 to 3. For each subscale, the responses are summed to arrive at a total score ranging from 0 to 21.

[0308] Dermatology Life Quality Index (DLQI) - The DLQI is a dermatology-specific Health- related Quality of Life (HRQoL) instrument designed to assess the impact of the disease on a participant’s HRQoL. It is a 10 item questionnaire that assesses HRQoL over the past week and in addition to evaluating overall HRQoL. It is used to assess 6 different aspects that may affect quality of life: symptoms and feelings, daily activities, leisure, work or school performance, personal relationships, and treatment. The total score ranges from 0 to 30 with a higher score indicating greater impact on HRQoL.

[0309] Patient-reported Outcomes Measurement Information System-29 (PROMIS -29) - The PROMIS-29 v2.1 is a 29-item generic HRQoL survey, assessing each of the 7 PROMIS domains (depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and ability to participate in social roles and activities) with 4 questions for each domain. There is also one 11 -point rating scale for pain intensity. The recall period for all items is the past 7 days. The PROMIS-29 uses 5-point Likert scale ranging from 1 to 5 for the 7 health domains and a numerical rating scale that ranges from 0 (No pain) to 10 (Worst pain imaginable) for the pain intensity item. The domain scores are standardized T-scores with a mean of 50 and a SD of 10. Higher scores on anxiety, depression, fatigue, sleep disturbance, and pain interference indicate more severe symptoms. Higher scores on physical function and social participation indicate better health outcomes

[0310] Patient Global Impression of Severity (PGIS) - APGIS anchor item is a selfadministered, single item of patients’ impression of symptom severity or frequency. Three PGIS items will be administered, 1 asking about the severity of itch during sleep hours, another asking about the severity of scratch during sleep hours, and a third asking about frequency of sleep interruptions due to scratch. The recall period for the PGIS is the past 7 days. Higher PGIS scores indicate more severe / frequent symptoms. The PGIS items will be used as anchors in validation of digital assessment of nocturnal scratch and sleep analysis.

[0311] Patient Global Impression of Change (PGIC) - A PGIC anchor item is a selfadministered, single item of patients’ impression of change in symptom severity or frequency. Two PGIC items will be administered, 1 asking about the change in severity of itch during sleep hours, and a second asking about the change in severity of scratch during sleep hours. The recall period for the PGIC is since the first study visit. Higher PGIC scores indicate more improvement in symptoms. The PGIC items will be used as anchors in validation of digital assessment of nocturnal scratch and sleep analysis.

[0312] Asthma Control Questionnaire - 5 (ACQ-5) - The ACQ-5 is a self-administered questionnaire consisting of 5 items, each with 7 response categories ranging from 0 to 6. The ACQ-5 is scored by computing the average of the 5 items. The final score ranges from 0 (well- controlled) to 6 (extremely poorly controlled).

[0313] Digital Assessments of Nocturnal Scratch and Sleep - The most common symptom of AD is pruritus, or itch. A common reaction to the itch sensation is to scratch the affected area, which results in additional inflammation and disruption of the skin barrier. Furthermore, scratch often occurs during sleep hours (“nocturnal”) and disrupts patients’ sleep and reduces the quality of life of patients as well as caregivers. A recent study found that the action of scratching was a top burdensome symptom; and >85% of adults with AD, and caregivers of children with AD, considered it valuable that a new treatment reduces nocturnal scratching.

[0314] In this study, nocturnal scratch and sleep quality will be monitored with a wrist- worn device in the study participant’s normal sleeping environment. Participants will be provided with 2 wrist-worn devices at screening together with instructions for use. Both will be worn during sleep to capture scratch movements involving either wrist. During the day, 1 device will be worn on the non-dominant hand. These digital devices will measure wrist movement via an accelerometer and may also measure angular velocity (via gyroscope), heart rate (via photoplethysmography), and skin temperature. The sensor-based measurements will be combined to derive scratch and sleep metrics.

[0315] Where the device is available, digital nocturnal scratch and sleep assessments are part of the study procedures but can be opted out of: 1) if the patient has known severe reactions to wrist band components (ie, standard band contains silicone, stainless steel hardware, and glass fiber polyamide blend buckle, which have been tested for conforming to the standards of ISO 10993 for biocompatibility) or; 2) if in the opinion of the investigator, wearing of wrist bands would exacerbate disease manifestations (eg, lesions on the wrists). Additionally, the participant may discontinue the nocturnal scratch assessment but remain in the study if they experience wristband related AEs (such as contact irritation or contact dermatitis).Clinician-reported Outcomes

[0316] Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) - The vIGA- AD™ developed by Eh Lilly and Company is an assessment instrument used in clinical studies to rate the severity of AD, based on a 5-point scale ranging from 0 (clear) to 4 (severe; Simpson 2020). The IGA score is selected using the morphological descriptors that best describe theoverall appearance of the AD lesions at a given time point. The Investigator Global Assessment (iGA) score will be assessed at time points according to the Schedule of Activities.

[0317] Eczema Area and Severity Index (EASI) - The EASI is a validated measure used in clinical practice and clinical trials to assess the severity and extent of AD. The EASI is a composite index with scores ranging from 0 to 72. Four AD disease characteristics (erythema, thickness [induration, papulation, edema], scratching [excoriation], and lichenification) will each be assessed for severity by the investigator or designee on a scale of “0” (absent) through “3” (severe). In addition, the area of AD involvement will be assessed as a percentage by body area of head, trunk, upper limbs, and lower limbs, and converted to a score of 0 to 6. In each body region, the area is expressed as 0, 1 (1% to 9%), 2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), or 6 (90% to 100%). The EASI will be collected at time points according to the So A.

[0318] Body Surface Area (BSA) - StatBSA affected by AD will be derived from data collected as part of the EASI assessment. In general, the BSA assessment estimates the extent of disease or skin involvement with respect to AD and is expressed as a percentage of total body surface. BSA will be determined by the investigator or designee using the patient palm = 1% rule. Assessors must be trained and certified by the Sponsor prior to conducting this assessment.STATISTICAL METHODSSample Size

[0319] This study is designed to enroll approximately a total of 240 participants to have sufficient power to detect superiority of IL-4Ra x IL-31 antibody versus placebo on the primary endpoint of the proportion of participants achieving improvement of 75% or greater in the EASI total score (EASI 75) at Week 12. Given a 2:1 randomization ratio of the 696 mg IL-4Ra x IL-31 antibody group versus placebo group, and assuming a placebo EASI 75 response of 15% and at least 50% for the 696 mg IL-4Ra x IL-31 antibody dose group, a sample size of 60:30 will provide a power of >92% to detect superiority of IL-4Ra x IL-31 antibody over placebo at a 1- sided significance level of 2.5%.

[0320] The sample size was also selected to have an adequate precision for estimating the difference in EASI 75 response rates at Week 16 between each of the IL-4Ra x IL-31 antibody 348 mg and 696 mg q2w groups versus the dupilumab group. To illustrate the precision that the sample size of the trial offers for this objective, the 95% Cis of the observed difference (denoted by delta) in proportions of EASI 75 responders are provided in Table 11, for various scenarios of possible outcomes. The sample size of 60 participants in each of the IL-4Ra x IL-31 antibody 348 mg, IL-4Ra x IL-31 antibody 696 mg, and dupilumab groups produces a precision of <18% based on the half- width of the 95% CI for delta, when the assumed EASI 75 response rate is 45% to 50% in the dupilumab treatment group (Table 11). The planned precision characterized by a half-width of <18% of the 95% CI is considered appropriate at this stage of clinical development.Table 11. Precision of a Range of Differences Between EASI 75 Week 16 Responders in 348 mg every 2 weeks (q2w) / 696 mg IL-4Ra x IL-31 antibody q2w Versus Dupilumab 300mg q2w Based on a 95% confidence interval (CI)Efficacy Analyses

[0321] Efficacy analysis will be performed on all randomized participants who receive at least 1 (partial) administration of study intervention and will be analyzed according to the treatment to which the participant was randomized (regardless of the treatment the participant actually received).

[0322] The primary endpoint treatment comparisons will be performed using a CMH test stratified by baseline vIGA-AD severity and region. The differences in binary endpoints betweengroups and the corresponding 95% Cis will be presented. In general, all statistical testing will be performed at a significance level of 0.05 (2-sided) unless otherwise specified. Nominal p-values will be displayed for all treatment comparisons.Safety Analyses

[0323] Safety data, including but not limited to, AEs, SAEs, infections, serious infections, mortality, changes in laboratory assessments, and changes in vital signs will be summarized. Treatment-emergent AEs will be summarized by treatment group and MedDRA system organ class and preferred terms.Primary Endpoint(s) / Estimand Analysis

[0324] The primary estimand is defined by the following 5 attributes:

[0325] Study Intervention:• IL-4Ra x IL-31 antibody SC: 696 mg q2w, 348 mg q2w (with a 696 mg initial dose), or174 mg q2w (with a 348 mg initial dose)• Placebo SC

[0326] Population: adult participants with moderate to severe AD

[0327] Variable / Endpoint: Response binary variable, where a responder is defined as a participant achieving an EASI 75 response at Week 12 who does not have intercurrent events in categories 1 or 2 (defined below). A participant with missing data will be considered a nonresponder.

[0328] Population Level Summary: Difference in the proportions of participants achieving an EASI 75 response at Week 12 between each of the IL-4Ra x IL-31 antibody groups and the placebo group.

[0329] Intercurrent Events (ICEs) and Their Corresponding Strategies as listed in Table 12.Table 12.

[0330] To assess the primary objective of superiority on the proportion of responders as defined in the primary estimand, the IL-4Ra x IL-31 antibody dose groups versus the placebo group will be tested sequentially using a CMH test stratified by baseline disease severity and region at the 1 -sided significance level of 2.5%:1. no difference between the 600 or 696 mg every 2 weeks (q2w) IL-4Ra x IL-31 antibody dose group and the placebo group2. no difference between the 300 mg or 348 mg q2w IL-4Ra x IL-31 antibody dose group and the placebo group3. no difference between the 150 mg or 174 mg q2w IL-4Ra x IL-31 antibody dose group and the placebo group

[0331] Tests lower in the hierarchy will only be tested conditional of the previous test being significant. The study will be considered positive if the test between the 696 mg IL-4Ra x IL-31 antibody group and the placebo group is significant. This analysis will be conducted on the FAS, using the primary estimand.

[0332] A supportive analysis will be performed using MCP-mod. A further supportive analysis will be performed on the EASI scores up to Week 12 over time. Treatment comparisons will be performed using a Mixed-effect Model Repeated Measure (MMRM). The MMRM will have treatment group, baseline EASI score, and stratification factors (disease severity and region) as explanatory factors. The MMRM will also include visit, treatment group by visit interaction, and baseline value by visit interaction as additional explanatory factors. Treatment differences and their associated 95% CI will be presented.Secondary Endpoint(s) / Estimand Analysis

[0333] To assess the secondary objective of evaluating the efficacy of IL-4Ra x IL-31 antibody dose groups versus dupilumab, the proportion of participants achieving EASI 75 will becompared at Week 16. This analysis will be conducted on the FAS, using the key secondary estimand (analogous to the primary estimand). For the pair- wise comparison between IL-4Ra x IL-31 antibody and dupilumab treatment groups, a Cochran-Mantel-Haenszel (CMH) test stratified by the baseline disease severity and region will be performed, reporting the 95% confidence interval (CI).

[0334] A supportive analysis will be performed on the EASI scores up to Week 16 over time, using a MRMM analogous to the supportive analysis defined for the primary endpoint analysis.

Claims

What is claimed is:

1. A method of treating moderate to severe atopic dermatitis (AD) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an IL-4Ra x IL- 31 antibody or antigen binding fragment thereof, that binds to both IL-4Ra and IL-31, wherein the IL-4Ra x IL-31 antibody comprises one or two binding domains, which specifically bind to IL-4Ra (IL-4Ra-BD) and one or two binding domains, which specifically bind to IL-31 (IL-31-BD); wherein a. each IL-4Ra-BDs comprises i. the HCDR1 sequence of SEQ ID NO: 1 , ii. the HCDR2 sequences of SEQ ID NO: 2, iii. the HCDR3 sequence of SEQ ID NO: 3, iv. the LCDR1 sequence of SEQ ID NO: 4, v. the LCDR2 sequence of SEQ ID NO: 5, and vi. the LCDR3 sequences of SEQ ID NO: 6; and a. each IL-31 -BDs comprises i. the HCDR1 sequence of SEQ ID NO: 11 , ii. the HCDR2 sequence of SEQ ID NO: 12, iii. the HCDR3 sequences of SEQ ID NO: 13, iv. the LCDR1 sequence of SEQ ID NO: 14, v. the LCDR2 sequence of SEQ ID NO: 15, and vi. the LCDR3 sequences of SEQ ID NOs: 16; and wherein in HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 are according to the AHo delineation.

2. The method of claim 1 , wherein a. the one or two binding domains, which specifically bind to IL-4Ra each each comprise a first heavy chain variable region (VH1) comprising an amino acid sequence which is at least 90%, or at least 95%, or at least 98%, at least 99%, or 100% identical to SEQ ID NO: 7, or 9 and a first light chain variable domain (VL1)comprising an amino acid sequence which is at least 90%, or at least 95%, or at least 98%, at least 99%, or 100% identical to SEQ ID NO: 8, 10, 25 or 27; and b. the one or two binding domains, which specifically bind to IL-31 each comprise a second heavy chain variable region (VH2) comprising an amino acid sequence which is at least 90%, or at least 95%, or at least 98%, at least 99%, or 100% identical to SEQ ID NO: 17 and a second light chain variable domain (VL2) comprising an amino acid sequence which is at least 90%, or at least 95%, or at least 98%, at least 99%, or 100% identical to SEQ ID NO: 18 or 28.

3. The method of claim 2, wherein a. the one or two binding domains, which specifically bind to IL-4Ra each comprise a VH1 comprising an amino acid sequence of SEQ ID NO: 7 and a VL1 comprising an amino acid sequence of SEQ ID NO: 25; and b. the one or two binding domains, which specifically bind to IL-31 each comprise a VH2 comprising an amino acid sequence of SEQ ID NO: 17 and a VL2 comprising an amino acid sequence of SEQ ID NO: 28.

4. The method of claim 2, wherein a. the one or two binding domains, which specifically bind to IL-4Ra each comprise a VH1 comprising an amino acid sequence of SEQ ID NO: 9 and a VL1 comprising an amino acid sequence of SEQ ID NO: 27; and b. the one or two binding domains, which specifically bind to IL-31 each comprise a VH2 comprising an amino acid sequence of SEQ ID NO: 17 and a VL2 comprising an amino acid sequence of SEQ ID NO: 28.

5. The method of claim 2, wherein a. the one or two binding domains, which specifically bind to IL-4Ra each comprise a VH1 comprising an amino acid sequence of SEQ ID NO: 7 and a VL1 comprising an amino acid sequence of SEQ ID NO: 8; andb. the one or two binding domains, which specifically bind to IL-31 each comprise a VH2 comprising an amino acid sequence of SEQ ID NO: 17 and a VL2 comprising an amino acid sequence of SEQ ID NO: 18.

6. The method of claim 5, wherein the VL1 further comprises an amino acid sequence of SEQ ID NO: 26 and the VL2 further comprises an amino acid sequence of SEQ ID NO: 29.

7. The method of claim 2, wherein a. the one or two binding domains, which specifically bind to IL-4Ra each comprise a VH1 comprising an amino acid sequence of SEQ ID NO: 9 and a VL1 comprising an amino acid sequence of SEQ ID NO: 10; and b. the one or two binding domains, which specifically bind to IL-31 comprise a VH2 comprising an amino acid sequence of SEQ ID NO: 17 and a VL2 comprising an amino acid sequence of SEQ ID NO: 18.

8. The method of claim 7, wherein the VL1 further comprises an amino acid sequence of SEQ ID NO: 26 and the VL2 further comprises an amino acid sequence of SEQ ID NO: 29.

9. The method of any of the preceding claims, wherein the one or two binding domains, which specifically bind to IL-4Ra comprise a Fab or a single chain variable fragment (scFv).

10. The method of claim 9 wherein the one or two binding domains, which specifically bind to IL-4Ra comprise a Fab.

11. The method of any of the preceding claims, wherein the one or two binding domains, which specifically bind to IL-31 comprise a Fab or a single chain variable fragment (scFv).

12. The method of claim 11 wherein the one or two binding domains, which specifically bind to IL-31 comprise a scFv.

13. The method of any one of claims 1-12, wherein the one or two binding domains, which specifically bind to IL-4Ra comprise a Fab and the one or two binding domains, which specifically bind to IL-31 comprise a scFv.

14. The method of claim 13, wherein the scFv is in the VH2-linker2-VL2 orientation or in the VL2-linker2-VH2 orientation.

15. The method of claim 14, wherein the scFv is in the VL2-linker2-VH2 orientation, and wherein the linker2 comprises or consists essentially of an amino acid sequence of SEQ ID NO: 19.

16. The method of any one of claims 1-15, wherein the IL-4Ra x IL-31 antibody comprises two IL-4Ra-BDs and two IL-31-BDs.

17. The method of claim 16, wherein the IL-4Ra x IL-31 antibody further comprises an immunoglobulin (Ig) heavy chain constant region, or a fragment of an Ig heavy chain constant region and an immunoglobulin (Ig) light chain constant region, or a fragment of an Ig light chain constant region.

18. The method of claim 17, wherein immunoglobulin (Ig) heavy chain constant region is an IgGl isotype, and IgG2 isotype, or an IgG4 isotype.

19. The method of claim 18, wherein immunoglobulin (Ig) heavy chain constant region is an IgG4 isotype.

20. The method of claim 19, wherein the IL-4Ra x IL-31 antibody is in a Morisson-L format or in a Morrisson-H format.

21. The method of claim 20, wherein the IL-4Ra x IL-31 antibody is in a Morrisson-H format.

22. The method of claim 21, wherein the scFv is fused to the C-terminus of the heavy chain constant region with a linkerl comprising or consisting essentially of an amino acid sequence of SEQ ID NO: 20.

23. The method of any one of the foregoing claims, wherein the IL-4Ra x IL-31 antibody comprises a. two heavy chains, wherein each heavy chain comprises an amino acid sequence at least 90% identical, or at least 95%, or at least 98%, at least 99%, or 100% identical to SEQ ID NO: 21; and b. two light chains, wherein each light chain comprises an amino acid sequence at least 90% identical, or at least 95%, or at least 98%, at least 99%, or 100% identical to SEQ ID NO: 22.

24. The method of claim 23, wherein the IL-4Ra x IL-31 antibody comprises a. two heavy chains, wherein each heavy chain comprising an amino acid sequence of SEQ ID NO: 21; and b. two light chains (LC), wherein each light chain comprises an amino acid sequence of SEQ ID NO: 22.

25. The method of any one of claims 1-22, wherein the IL-4Ra x IL-31 antibody comprises a. two heavy chains, wherein each heavy chain comprises an amino acid sequence at least 90% identical, or at least 95%, or at least 98%, at least 99%, or 100% identical to SEQ ID NO: 23; and b. two light chains, wherein each light chain comprises an amino acid sequence at least 90% identical, or at least 95%, or at least 98%, at least 99%, or 100% identical to SEQ ID NO: 24.

26. The method of claim 25, wherein the IL-4Ra x IL-31 antibody comprises a. two heavy chains (HC), wherein each heavy chain comprises an amino acid sequence of SEQ ID NO: 23; andb. two light chains (LC), wherein each light chain comprises an amino acid sequence of SEQ ID NO: 24.

27. A method of treating moderate to severe atopic dermatitis (AD) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an IL-4Ra and x IL-31 antibody or antigen binding fragment thereof, wherein the IL-4Ra x IL-31 antibody comprises two binding domains, which specifically bind to IL-4Ra and two binding domains, which specifically bind to IL-31 ; wherein the IL-4Ra x IL-31 antibody comprises a. a first heavy chain variable domain (VH1) comprising an amino acid sequence of SEQ ID NO: 7 b. a first heavy chain variable domain (VL1) comprising an amino acid sequence of SEQ ID NO: 25 c. a second heavy chain variable domain (VH2) comprising an amino acid sequence of SEQ ID NO: 17 d. a second heavy chain variable domain (VL2) comprising an amino acid sequence of SEQ ID NO: 2828. A method of treating moderate to severe atopic dermatitis (AD) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an IL-4Ra and x IL-31 antibody or antigen binding fragment thereof, wherein the IL-4Ra x IL-31 antibody comprises two binding domains, which specifically bind to IL-4Ra and two binding domains, which specifically bind to IL-31 ; wherein the IL-4Ra x IL-31 antibody comprises a. two heavy chains, each heavy chain comprising an amino acid sequence of SEQ ID NO: 21; and b. two light chains, each light chain comprising an amino acid sequence SEQ ID NO: 22.

29. The method of any one of the preceding claims, wherein the method comprises administering to the patient an initial dose of the IL-4Ra x IL-31 antibody, wherein the initial dose is at least about 150 mg or 174 mg.

30. The method of claim 29, wherein the initial dose is between at least about 150 mg and about 700 mg, for example about 150 mg, about 174 mg, about 200 mg, about 250 mg, about 300 mg, about 348 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg or about 696 mg.

31. The method of claim 30, wherein the initial dose is about 348 mg.

32. The method of claim 28, wherein the initial dose is about 696 mg.

33. The method of any one of claims 29-32, wherein the method further comprises administering a dose of the IL-4Ra x IL-31 antibody after the initial dose, wherein the dose of the IL-4Ra x IL-31 antibody administered after the initial dose is equal or lower than the initial dose.

34. The method of claim 33, wherein the dose of the IL-4Ra x IL-31 antibody administered after the initial dose is between about 150 mg and about 700 mg.

35. The method of claim 34, wherein the initial dose and the dose administered after the initial dose is about 696 mg.

36. The method of claim 34, wherein the initial dose is about 600 mg or about 696 mg and the dose administered after the initial dose is about 300 mg or about 348 mg.

37. The method of claim 34, wherein the initial dose is about 600 mg and the dose administered after the initial dose is about 450 mg.

38. The method of claim 34, wherein the initial dose is about 300 mg or about 348 mg and the dose administered after the initial dose is about 150 mg or about 174 mg.

39. The method of any one of claims 29-38, wherein the dose administered after the initial dose is administered once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks, preferably once every 2 weeks.

40. The method of any one of claims 29-39, wherein the initial dose is administered once and the dose administered after the initial dose is administered once every 2 weeks.

41. The method of claim 40, wherein the initial dose is administered once and the dose administered after the initial dose is administered once every 2 weeks through week 22.

42. The method of claim 41, wherein the initial dose is administered once and the dose administered after the initial dose is administered about 2 weeks after the initial dose, about 4 weeks after the initial dose, about 6 weeks after the initial dose, about 8 weeks after the initial dose, about 10 weeks after the initial dose, about 12 weeks after the initial dose, about 14 weeks after the initial dose, about 16 weeks after the initial dose, about 18 weeks after the initial dose, about 20 weeks after the initial dose, and about 22 weeks after the initial dose.

43. The method of any one of claims 29-42, wherein a. the initial dose is between about 150 mg and about 700 mg; and b. the dose administered after the initial dose is i. administered about 2 weeks after the initial dose, about 4 weeks after the initial dose, about 6 weeks after the initial dose, about 8 weeks after the initial dose, bout 10 weeks after the initial dose, about 12 weeks after the initial dose, about 14 weeks after the initial dose, about 16 weeks after the initial dose, about 18 weeks after the initial dose, about 20 weeks after the initial dose, and about 22 weeks after the initial dose, ii. is between about 150 mg and about 700 mg; and iii. is equal or lower than the initial dose.

44. The method of any one of claims 29-43, wherein the initial dose and the dose administered after the initial dose are a flat dose.

45. The method of any one of claims 29-44, wherein the initial dose and the dose administered after the initial dose are administered subcutaneously.

46. A method of treating moderate to severe atopic dermatitis (AD) in a patient in need thereof, wherein the method comprises administering to the patient an initial dose of the IL-4Ra x IL- 31 antibody, followed by a dose of the IL-4Ra x IL-31 antibody administered after the initial dose, wherein a. the initial dose is between at least about 150 mg and about 700 mg; b. the dose administered after the initial dose is between about 150 mg and about 700 mg; c. the dose administered after the initial dose is administered once every 2 weeks; d. the dose administered after the initial dose is administered is administered through week 22; e. the dose administered after the initial dose is equal or lower than the initial dose; f. the initial dose and the dose administered after the initial dose are administered subcutaneously; and g. the IL-4Ra x IL-31 antibody comprises two heavy chains and two light chains, wherein each heavy chain and each light chain comprise an amino acid sequence of SEQ ID NO: 21 and 22, respectively.

47. The method of any one of the foregoing claims, wherein the patient is a responder or demonstrated improvement to the administration of the IL-4Ra x IL-31 antibody by being identified as meeting a clinical endpoint.

48. The method of claim 47, wherein the clinical endpoint is measured through about 12 weeks, through about 16 weeks, through about 24 weeks, and / or through about 36 weeks after administration of the initial dose.

49. The method of claims 47 or 48, wherein the clinical endpoints measured through about 12 weeks after the initial dose are compared to patients treated with placebos.

50. The method of claims 47 or 48, wherein the clinical endpoint measured through about 12 weeks, through about 16 weeks, through about 24 weeks, and / or through about 36 weeks are compared to patients treated with dupilumab.

51. The method of claim 49, wherein the clinical endpoint measured through about 12 weeks as compared to patients being treated with placebo, is: a. improvement of 75% or greater in the Eczema Area and Severity Index score Index (EASI 75) at week 12, b. improvement of 90% or greater in the Eczema Area and Severity Index score Index (EASI 90) at week 12; c. improvement of 100% or greater in the Eczema Area and Severity Index total score (EASI 100) at week 12; d. validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of 0 and a reduction from baseline of >2 points at Week 12; e. validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of 0 or 1 and a reduction from baseline of >2 points at Week 12; f. percent change from baseline in the Eczema Area and Severity Index (EASI) total score at Week 12; g. >4-point improvement (reduction) in Skin Pain numeric(al) rating scale (NRS) from baseline to Week 12; h. percent change from baseline in Peak Pruritus Numeric(al) Rating Scale (PP- NRS) at Week 12; i. percent change from baseline in Skin Pain NRS at Week 12; j. percent change from baseline in the score of Item 2 of the AD Sleep Scale at Week 12; or k. >4-point improvement (reduction) in PP-NRS from baseline through Week 12.

52. The method of claim 50, wherein the clinical endpoint measured through about 16 weeks as compared to patients being treated with dupilumab, is: a. EASI 75 atWeek 16; b. EASI 90 atWeek 16; c. EASI lOO at Week 16; d. vIGA-AD score of 0 or 1 and a reduction from baseline of >2 points at Week 16; e. vIGA-AD score of 0 and a reduction from baseline of >2 points at Week 16; f. percent change from baseline in the EASI total score at Week 16; g. >4-point improvement (reduction) in Skin Pain NRS from baseline at Week 16; h. Percent change from baseline in PP-NRS at Week 16; i. Percent change from baseline in Skin Pain NRS at Week 16; or j. Percent change from baseline in the score of Item 2 of the AD Sleep Scale at Week 16.

53. The method of claim 50, wherein the clinical endpoint measured through about 24 weeks, as compared to patients being treated with dupilumab, is a. >4-point improvement (reduction) in PP-NRS from baseline through Week 24; b. EASI 75 at Week 24; c. EASI 90 at Week 24; d. EASI 100 at Week 24; e. vIGA-AD score of 0 or 1 and a reduction from baseline of >2 points at Week 24; f. vIGA-AD score of 0 and a reduction from baseline of >2 points at Week 24; g. Percent change from baseline in the EASI total score at Week 24; h. >4-point improvement (reduction) in Skin Pain NRS from baseline at Week 24; i. Percent change from baseline in PP-NRS at Week 24; j. Percent change from baseline in Skin Pain NRS at Week 24; or k. Percent change from baseline in the score of Item 2 of the AD Sleep Scale at Week 24.

54. The method of any one of claims 47-53, wherein the clinical endpoints, relative to placebo through week 12 or relative to dupilumab through week 24, are based on the assessment of additional timepoints selected from the group consisting of Eczema Area and Severity Index (EASI), EASI 75, EASI 90, EASI 100, EASI %cfb (percent change from baseline), validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD), vIGA-AD (0,1) and >2 improvement, vIGA-AD (0) and >2 improvement, Body Surface Area (BSA), BSA cfb (change from baseline), Peak Pruritus Numeric Rating Scale (PP-NRS), PP-NRS %cfb, PP-NRS (0, 1), EASI 90 and PP-NRS (0,1), Skin Pam Numeric Rating Scale (SP-NRS), SP- NRS >4 improvement, SP-NRS %cfb, AD sleep scale Item 1 cfb, AD sleep scale Item 2 %cfb, AD sleep scale Item 2 >2 improvement, AD sleep scale Item 3 cfb, Patient-Oriented Eczema Measure (POEM), POEM %cfb, POEM >4 improvement, Hospital Anxiety and Depression Scale (HADS), HADS-A %cfb, HADS-A<8, HADS-D %cfb, HADS-D <8, Dermatological Life Quality Index (DLQI), DLQI (0, 1), DLQI >4 improvement, DLQI cfb, Patient-reported Outcomes Measurement Information System-29 (PROMIS-29), PROMIS- 29 by domain cfb, PROMIS-29 physical / mental composite cfb, Asthma Control Questionnaire - 5 (ACQ-5), ACQ-5 %cfb, ACQ-5 >0.5 improvement, Digital Nocturnal Scratch and Sleep Wrist-worn Device.

55. The method of claim 47, wherein the clinical endpoint is the frequency and type of Adverse Events (AE) and Serious Adverse Events (S AEs).

56. The method of claim 47, wherein the clinical endpoint is the concentration of the IL-4Ra x IL-31 antibody over time or the titer of anti-drug antibody (ADA) to the IL-4Ra x IL-31 antibody.

57. The method of claim 47, wherein the clinical endpoint is changes in cellular and molecular biomarkers in skin and blood from baseline over time.

58. The method of claim 47, wherein the clinical endpoint is changes from baseline over time in Asthma Control Questionnaire - 5 (ACQ-5) score in patients with concomitant medical history of asthma.

59. The method of any one of the preceding claims, wherein the patient is 18 years of age or older.

60. The method of any one of the preceding claims, wherein the patient has chronic atopic dermatitis, according to American Academy of Dermatology Consensus Criteria with onset of symptoms at least 1 year prior to screening visit as determined by the investigator through participant interview and / or review of the medical history.

61. The method of any one of the preceding claims, wherein the patient has an adverse event of special interest (EASI) score >16 at the Screening and Baseline Visits.

62. The method of any one of the preceding claims, wherein the patient has a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score >3 at the Screening and Baseline Visits.

63. The method of any one of the preceding claims, wherein the patient has >10% Body Surface Area (BSA) of atopic dermatitis involvement at the Screening and Baseline Visits.

64. The method of any one of the preceding claims, wherein the patient has a baseline Peak Pruritus Numeric(al) Rating Scale (PP-NRS) average score of >4.

65. The method of any one of the preceding claims, wherein the patient has documented history (within 6 months before screening) of either inadequate response or inadvisability to topical treatments, or inadequate response to systemic therapies (within 12 months before screening).

66. The method of any one of the preceding claims, wherein the patient has applied a moisturizer at least once daily for at least 7 days before the Baseline Visit.

67. The method of any one of the preceding claims, wherein the patient does not have active skin disease other than atopic dermatitis (AD) including eczema herpeticum, molluscum contagiosum, impetigo, psoriasis or has any other ongoing significant skin condition including skin infections, that could interfere with efficacy assessments.

68. The method of any one of the preceding claims, wherein the patient has not received prior administration of the IL-4Ra x IL-31 antibody.

69. The method of any one of the preceding claims, wherein the patient has not received prior treatment with: a. agents that deplete B cells (alemtuzumab, ocrelizumab, or rituximab) 26 weeks prior to the first administration of the IL-4Ra x IL-31 antibody through end of study; b. any immunomodulating biologic therapy that could affect AD including but not limited to dupilumab, tralokinumab, lebrikizumab, nemolizumab, natalizumab, belimumab, abatacept, visilizumab, or any experimental or investigational therapy 12 weeks or 5 half-lives, whichever is longer, prior to the first administration of the IL- 4Ra x IL-31 antibody through end of study; c. Systemic immunomodulating / immunosuppressive treatments including but not limited to corticosteroids (oral or parenteral), methotrexate, cyclosporine A, azathioprine, JAK inhibitors, 4 weeks prior to the first administration of the IL-4Ra x IL-31 antibody through end of study; d. Phototherapy 4 weeks prior to the first administration of the Il-4Ra x IL-31 antibody through end of study; e. Systemic medications that could affect AD evaluations including, but not limited to acitretin, retinoids, herbal treatments, or traditional medicines (eg, Korean or Chinese) 4 weeks prior to the first administration of the IL-4Ra x IL-31 antibody through end of study;f. Nonbiologic experimental therapies or investigational agents 4 weeks prior to the first administration of the IL-4Ra x IL-31 antibody through end of study; g. Topical medications / treatments that could affect AD evaluations including, but not limited to Corticosteroids, calcineurin inhibitors, JAK inhibitors, PDE4 inhibitors, prescription moisturizers, herbal treatments or traditional medicines (eg, Korean or Chinese) 1 weeks prior to the first administration of the IL-4Ra x IL-31 antibody through end of study; h. Live virus or live bacterial vaccination 12 weeks (or longer if required per vaccine package insert) prior to the first administration of the IL-4Ra x IL-31 antibody through end of study and for 90 days after receiving the last dose of the IL-4Ra x IL- 31 antibody.

70. The method of any one of the preceding claims, wherein the antibody is in a composition formulation comprising 125.6 mM sucrose, 20 mM (L-)arginine hydrochloride, 66.6 mM Glycine, 30 mM (L)-histidine, and 0.02% (w / v) poloxamer 188; wherein the formulation is about pH 6.0.

71. A method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 600 mg of an IL-4Ra x IL-31 antibody that binds to both IL-4Ra and IL-31, (ii) a 300 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 300 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 300 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 300 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 300 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 300 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 300 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 300 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 300 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 300 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 300 mg subcutaneous dose of the antibody about 22 weeks after theinitial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 25, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively , and the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

72. A method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 696 mg of an IL-4Ra x IL-31 antibody that binds to both IL-4Ra and IL-31, (ii) a 348 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 348 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 348 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 348 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 348 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 348 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 348 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 348 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 348 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 348 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 348 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 25, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

73. A method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 300 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 150 mg subcutaneous dose of the antibody about 2weeks after the initial dose, (iii) a 150 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 150 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 150 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 150 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 150 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 150 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 150 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 150 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 150 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 150 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 25, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

74. A method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 348 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 174 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 174 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 174 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 174 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 174 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 174 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 174 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 174 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 174 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 174 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 174 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibodycomprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 25, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

75. A method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 600 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 600 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 600 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 600 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 600 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 600 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 600 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 600 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 600 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 600 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 600 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 600 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 25, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

76. A method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 696 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 696 mg subcutaneous dose of the antibody about 2weeks after the initial dose, (iii) a 696 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 696 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 696 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 696 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 696 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 696 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 696 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 696 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 696 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 696 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 25, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

77. A method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 696 mg of an IL-4Ra x IL-31 antibody that binds to both IL-4Ra and IL-31, (ii) a 348 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 348 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 348 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 348 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 348 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 348 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 348 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 348 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 348 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 348 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 348 mg subcutaneous dose of the antibody about 22 weeks after theinitial dose, wherein the antibody comprises two heavy chains, each heavy chain comprising an amino acid sequence of SEQ ID NO: 21 and two light chains, each light chain comprising an amino acid sequence SEQ ID NO: 22 and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

78. A method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 348 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 174 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 174 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 174 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 174 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 174 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 174 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 174 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 174 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 174 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 174 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 174 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises two heavy chains, each heavy chain comprising an amino acid sequence of SEQ ID NO: 21 and two light chains, each light chain comprising an amino acid sequence SEQ ID NO: 22, and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

79. A method of treating moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 696 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 696 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 696 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 696 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 696 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 696 mg subcutaneous dose of the antibody about 10 weeks after the initial dose,(vii) a 696 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 696 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 696 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 696 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 696 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 696 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises two heavy chains, each heavy chain comprising an amino acid sequence of SEQ ID NO: 21 and two light chains, each light chain comprising an amino acid sequence SEQ ID NO: 22 and wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

80. Use of an IL-4Ra x IL-31 antibody that binds to both IL-4Ra and IL-31 for the treatment of moderate to severe atopic dermatitis in a patient, wherein the antibody comprises one or two binding domains, which specifically bind to IL-4Ra (IL-4Ra-BD), and one or two binding domains, which specifically bind to IL-31 (IL-31 -BD), wherein a. each of said IL-4Ra-BDs comprise i. the HCDR1 sequence of SEQ ID NO: 1 , ii. the HCDR2 sequences of SEQ ID NO: 2, iii. the HCDR3 sequence of SEQ ID NO: 3, iv. the LCDR1 sequence of SEQ ID NO: 4, v. the LCDR2 sequence of SEQ ID NO: 5, and vi. the LCDR3 sequences of SEQ ID NO: 6; and b. each of said IL-31 -BDs comprises i. the HCDR1 sequence of SEQ ID NO: 11 , ii. the HCDR2 sequence of SEQ ID NO: 12, iii. the HCDR3 sequences of SEQ ID NO: 13, iv. the LCDR1 sequence of SEQ ID NO: 14, v. the LCDR2 sequence of SEQ ID NO: 15, and vi. the LCDR3 sequences of SEQ ID NOs: 16; and wherein the patient is deemed a responder to the antibody.

81. The use of the antibody in claim 80, wherein the antibody is administered at an initial dose, a dose about 2 weeks after the initial dose, a dose about 4 weeks after the initial dose, a dose about 6 weeks after the initial dose, a dose about 8 weeks after the initial dose, a dose about 10 weeks after the initial dose, a dose about 12 weeks after the initial dose, a dose about 14 weeks after the initial dose, a dose about 16 weeks after the initial dose, a dose about 18 weeks after the initial dose, a dose about 20 weeks after the initial dose, and a dose about 22 weeks after the initial dose.

82. The use of the antibody in claim 81, wherein the initial dose and the doses after the initial dose are about 600 mg or about 696 mg of the antibody.

83. The use of the antibody in claim 81, wherein the initial dose is about 600 mg or about 696 mg of antibody and the doses after the initial dose are about 300 mg or about 348 mg of the antibody.

84. The use of the antibody in claim 81, wherein the initial dose is about 300 mg or about 348 mg of antibody and the doses after the initial dose are about 150 mg or about 174 mg of the antibody.

85. The use of the antibody of any one of claims 79-84, wherein the antibody is administered subcutaneously.

86. The use of the antibody in claim 85, wherein the clinical endpoint is selected from the group consisting of: a. >4-point improvement (reduction) in PP-NRS from baseline through Week 24; b. EASI 75 at Week 24; c. EASI 90 at Week 24; d. EASI 100 at Week 24; e. vIGA- AD score of 0 or 1 and a reduction from baseline of >2 points at Week 24;f. vIGA-AD score of 0 and a reduction from baseline of >2 points at Week 24; g. Percent change from baseline in the EASI total score at Week 24; h. >4-point improvement (reduction) in Skin Pain NRS from baseline at Week 24; i. Percent change from baseline in PP-NRS at Week 24; j. Percent change from baseline in Skin Pain NRS at Week 24; or k. Percent change from baseline in the score of Item 2 of the AD Sleep Scale at Week 24.

87. The use of claim 86, wherein the clinical endpoint is measured through about 12 weeks, through about 16 weeks, through about 24, and / or through about 36 weeks after the initial dose.

88. The use of the antibody of any one of claims 79-87, wherein the antibody comprises a. a first heavy chain variable domain (VH1) comprising an amino acid sequence of SEQ ID NO: 7 b. a first heavy chain variable domain (VL1) comprising an amino acid sequence of SEQ ID NO: 25 c. a second heavy chain variable domain (VH2) comprising an amino acid sequence of SEQ ID NO: 17 d. a second heavy chain variable domain (VL2) comprising an amino acid sequence of SEQ ID NO: 2889. The use of the antibody of anyone of claims 79-88, wherein the antibody comprises a. two heavy chains, each heavy chain comprising an amino acid sequence of SEQ ID NO: 21; and b. two light chains, each light chain comprising an amino acid sequence SEQ ID NO: 22.

90. The use of an IL-4Ra x IL-31 antibody, wherein the antibody is in a composition formulation comprising 125.6 mM sucrose, 20 mM (L-)arginine hydrochloride, 66.6 mM Glycine, 30 mM (L)-histidine, and 0.02% (w / v) poloxamer 188; wherein the formulation is about pH 6.0.

91. Use of an antibody binding to both IL-4Ra and IL-31 for the treatment of moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 600 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 300 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 300 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 300 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 300 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 300 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 300 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 300 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 300 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 300 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 300 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 300 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 25, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

92. Use of an antibody binding to both IL-4Ra and IL-31 for the treatment of moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 696 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 348 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 348 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 348 mgsubcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 348 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 348 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 348 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 348 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 348 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 348 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 348 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 348 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 25, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

93. Use of an antibody binding to both IL-4Ra and IL-31 for the treatment of moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 300 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 150 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 150 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 150 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 150 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 150 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 150 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 150 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 150 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 150 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 150 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 150 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibodycomprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 25, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

94. Use of an antibody binding to both IL-4Ra and IL-31 for the treatment of moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 348 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 174 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 174 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 174 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 174 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 174 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 174 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 174 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 174 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 174 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 174 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 174 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 25, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

95. Use of an antibody binding to both IL-4Ra and IL-31 for the treatment of moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initialsubcutaneous dose of 600 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 600 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 600 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 600 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 600 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 600 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 600 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 600 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 600 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 600 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 600 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 600 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 25, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint, wherein the clinical endpoint is change from baseline in the EASI total score at about Week 12 and / or about week 16.

96. Use of an antibody binding to both IL-4Ra and IL-31 for the treatment of moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 696 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 696 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 696 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 696 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 696 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 696 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 696 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 696 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 696 mgsubcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 696 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 696 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 696 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1) comprising an amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 25, respectively, and a second heavy chain variable region (VH2) and a second light chain variable region (VL2) comprising an amino acid sequences of SEQ ID NO: 17 and SEQ ID NO: 28, respectively, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint, wherein the clinical endpoint is change from baseline in the EASI total score at about Week 12 and / or about week 16.

97. Use of an antibody binding to both IL-4Ra and IL-31 for the treatment of moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 696 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 348 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 348 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 348 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 348 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 348 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 348 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 348 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 348 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 348 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 348 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 348 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises two heavy chains, each heavy chain comprising an amino acid sequence of SEQ ID NO: 21 and two light chains, each light chain comprising an amino acid sequence SEQ ID NO: 22, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

98. Use of an antibody binding to both IL-4Ra and IL-31 for the treatment of moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 348 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 174 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 174 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 174 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 174 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 174 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 174 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 174 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 174 mg subcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 174 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 174 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 174 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises two heavy chains, each heavy chain comprising an amino acid sequence of SEQ ID NO: 21 and two light chains, each light chain comprising an amino acid sequence SEQ ID NO: 22, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

99. Use of an antibody binding to both IL-4Ra and IL-31 for the treatment of moderate to severe atopic dermatitis in a patient, comprising administering to the patient (i) an initial subcutaneous dose of 696 mg of an antibody that binds to both IL-4Ra and IL-31, (ii) a 696 mg subcutaneous dose of the antibody about 2 weeks after the initial dose, (iii) a 696 mg subcutaneous dose of the antibody about 4 weeks after the initial dose, (iv) a 696 mg subcutaneous dose of the antibody about 6 weeks after the initial dose, (v) a 696 mg subcutaneous dose of the antibody about 8 weeks after the initial dose, (vi) a 696 mg subcutaneous dose of the antibody about 10 weeks after the initial dose, (vii) a 696 mg subcutaneous dose of the antibody about 12 weeks after the initial dose, (viii) a 696 mg subcutaneous dose of the antibody about 14 weeks after the initial dose, (ix) a 696 mgsubcutaneous dose of the antibody about 16 weeks after the initial dose, (x) a 696 mg subcutaneous dose of the antibody about 18 weeks after the initial dose, (xi) a 696 mg subcutaneous dose of the antibody about 20 weeks after the initial dose, and (xii) a 696 mg subcutaneous dose of the antibody about 22 weeks after the initial dose, wherein the antibody comprises two heavy chains, each heavy chain comprising an amino acid sequence of SEQ ID NO: 21 and two light chains, each light chain comprising an amino acid sequence SEQ ID NO: 22, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint.

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