Administration and treatment of immune-mediated diseases and biomarkers associated with immune-mediated diseases

Abstract

The present disclosure provides methods of treating an immune-mediated disease in a subject in need thereof. The present disclosure provides methods of treating atopic dermatitis in a subject in need thereof. The present disclosure provides methods of treating moderate to severe atopic dermatitis in a subject in need thereof. The present disclosure provides a method of treating atopic dermatitis (AD) in a subject in need thereof, the method comprises selecting a subject suffering from AD and having an elevated level relative to a control of at least one biomarker selected from the group consisting of thymus activation regulatory chemokine (TARC), interleukin-5 (IL-5), eosinophilic granulocyte count, and lactic dehydrogenase (LDH).

Description

[0001] Related applications

[0002] This application claims the rights of the following U.S. Provisional Applications filed June 20, 2023: USSN 63 / 521,985, USSN 63 / 522,039, USSN 63 / 522,098, USSN 63 / 522,784, USSN 63 / 522,822, USSN 63 / 523,284, USSN 63 / 523,284, USSN 63 / 541,111, USSN 63 / 541,102, and USSN 63 / 541,102. The following documents are incorporated herein by reference in their entirety: USSN 63 / 541,137, USSN 63 / 588,829, filed October 9, 2023; USSN 63 / 588,839, filed October 9, 2023; USSN 63 / 588,847, filed October 9, 2023; USSN 63 / 605,649, filed December 4, 2023; USSN 63 / 619,620, filed January 10, 2024; USSN 63 / 551,294, filed February 8, 2024; USSN 63 / 561,582, filed March 5, 2024; and USSN 63 / 644,282, filed May 8, 2024. Background Technology

[0003] OX40 ligand (OX40L) is a member of the TNF family and a 34 kDa type II transmembrane protein. The crystalline complex of human OX40 and OX40L is a trimer consisting of one OX40L (trimer) and three OX40 monomers. The human extracellular domain shares 42% homology with mouse OX40L.

[0004] OX40L is not constitutively expressed, but it can be induced on specialized APCs such as B cells, dendritic cells (DCs), and macrophages. Other cell types, such as Langerhans cells, endothelial cells, smooth muscle cells, mast cells, and natural killer (NK) cells, can also be induced to express OX40L. T cells can also express OX40L. The OX40L receptor OX40 is expressed on activated T cells (CD40). + and CD8+ T cells, Th2, Th1, and Th17 cells) and CD4 + FoxP3 + It is expressed on cells, even in the absence of activation. Summary of the Invention

[0005] This disclosure is based on the discovery of a method for treating a subject with an immune-mediated disease, such as atopic dermatitis, the method comprising administering to the subject an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof.

[0006] This disclosure is also based on the discovery of a method for treating immune-mediated diseases (such as atopic dermatitis) in adolescent subjects, the method comprising administering to the subject an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof.

[0007] In one aspect, a method is provided for treating an immune-mediated disease in a subject of need, the method comprising administering to the subject an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 42, the HCDR2 of SEQ ID NO: 44 and the HCDR3 of SEQ ID NO: 46, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 56, the LCDR2 of SEQ ID NO: 58 and the LCDR3 of SEQ ID NO: 60, wherein the subject receives a dose directly every 12 weeks (Q12W) without prior dose administration every 4 weeks (Q4W). With regard to the statement in this article that “the subject receives a dose directly every 12 weeks (Q12W) without prior dose administration every 4 weeks (Q4W),” we include the following meaning: at the start of treatment, the subject receives a first dose, and thereafter receives subsequent doses every 12 weeks (e.g., the first dose is received at week 0, the second dose at week 12, the third dose at week 24, etc.). Therefore, the subject can receive a dose every 12 weeks from the start of treatment (i.e., directly every 12 weeks from the start of treatment).

[0008] In one aspect, a method is provided for treating an immune-mediated disease in a subject of need, the method comprising administering to the subject an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 36, the HCDR2 of SEQ ID NO: 38 and the HCDR3 of SEQ ID NO: 40, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 50, the LCDR2 of SEQ ID NO: 52 and the LCDR3 of SEQ ID NO: 54, wherein the subject receives a dose directly every 12 weeks (Q12W) without prior dose administration every 4 weeks (Q4W). The OX40L antibody or its antigen-binding fragment may comprise: a variable heavy (VH) domain comprising the amino acid sequence of SEQ ID NO: 34, or at least 80% (e.g., at least 85%) of the same VH domain amino acid sequence as SEQ ID NO: 34; and / or a variable light (VL) domain comprising the amino acid sequence of SEQ ID NO: 48, or at least 80% (e.g., at least 85%, 90%, or 95%) of the same VL domain as SEQ ID NO: 48. Therefore, the OX40L antibody or its antigen-binding fragment may comprise: a VH domain comprising the amino acid sequence of SEQ ID NO: 34; and a VL domain comprising the amino acid sequence of SEQ ID NO: 48. Similarly, antibodies defined by reference to the above CDR or the above VH and / or VL domains may comprise a heavy chain and a light chain, the heavy chain amino acid sequence comprising the sequence of SEQ ID NO: 62, and the light chain amino acid sequence comprising the sequence of SEQ ID NO: 64. It should be understood that antibodies defined by the above CDR, the above VH and / or VL domains, or the above heavy chain and / or light chain sequences may also include an IgG4 constant region, optionally wherein the constant region is IgG4-PE (SEQ ID NO: 128). The OX40L antibody or its antigen-binding fragment may be an OX40L antagonist.On the other hand, a method for treating atopic dermatitis in a subject of need is provided, the method comprising administering to the subject an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 42, the HCDR2 of SEQ ID NO: 44 and the HCDR3 of SEQ ID NO: 46, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 56, the LCDR2 of SEQ ID NO: 58 and the LCDR3 of SEQ ID NO: 60, wherein the subject receives a dose directly every 12 weeks (Q12W) without prior dose administration every 4 weeks (Q4W).

[0009] On the other hand, a method for treating atopic dermatitis in a subject of need is provided, the method comprising administering to the subject an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 36, the HCDR2 of SEQ ID NO: 38 and the HCDR3 of SEQ ID NO: 40, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 50, the LCDR2 of SEQ ID NO: 52 and the LCDR3 of SEQ ID NO: 54, wherein the subject receives a dose directly every 12 weeks (Q12W) without prior dose administration every 4 weeks (Q4W). The OX40L antibody or its antigen-binding fragment may comprise: a variable heavy (VH) domain comprising the amino acid sequence of SEQ ID NO: 34, or at least 80% (e.g., at least 85%) of the VH domain amino acid sequence identical to SEQ ID NO: 34; and / or a variable light (VL) domain comprising the amino acid sequence of SEQ ID NO: 48, or at least 80% (e.g., at least 85%, 90%, or 95%) of the VL domain identical to SEQ ID NO: 48. Therefore, the OX40L antibody or its antigen-binding fragment may comprise: a VH domain comprising the amino acid sequence of SEQ ID NO: 34; and a VL domain comprising the amino acid sequence of SEQ ID NO: 48. Similarly, antibodies defined by reference to the above CDR or the above VH and / or VL domains may comprise a heavy chain and a light chain, the heavy chain amino acid sequence comprising the sequence of SEQ ID NO: 62, and the light chain amino acid sequence comprising the sequence of SEQ ID NO: 64. It should be understood that antibodies defined by the above CDR, the above VH and / or VL domains, or the above heavy chain and / or light chain sequences may also include an IgG4 constant region, optionally wherein the constant region is IgG4-PE (SEQ ID NO:128). The OX40L antibody or its antigen-binding fragment may be an OX40L antagonist.

[0010] In some exemplary embodiments, the antibody or its antigen-binding fragment is anilidelimab or a variant thereof. In some exemplary embodiments, the antibody is anilidelimab. In some exemplary embodiments, the antibody or its antigen-binding fragment is administered via a pre-filled syringe, a pen delivery device, or an autoinjector.

[0011] In some exemplary embodiments, the subject receives an initial dose of about 500 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 250 mg of the antibody or its antigen-binding fragment.

[0012] In some exemplary embodiments, the subject receives an initial dose of about 250 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 250 mg of the antibody or its antigen-binding fragment.

[0013] In some exemplary embodiments, the subject receives an initial dose of about 125 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 125 mg of the antibody or its antigen-binding fragment.

[0014] In some exemplary embodiments, the subject receives an initial dose of about 62.5 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 62.5 mg of the antibody or its antigen-binding fragment.

[0015] Whenever the terms “about 500 mg,” “about 250 mg,” “about 125 mg,” and “about 62.5 mg” are used in this article, we include the meanings of “500 mg,” “250 mg,” “125 mg,” and “62.5 mg,” respectively.

[0016] In some exemplary embodiments, each second dose is administered every 12 weeks (Q12W). In some exemplary embodiments, each second dose is administered every 12 weeks (Q12W), or administered until the patient has achieved vIGA O / 1, or has clear or substantially clear skin, or has achieved EAS175 or has achieved EASI90. For example, the subject may receive an initial dose of about 500 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 250 mg of the antibody or its antigen-binding fragment, wherein the second doses are administered every 12 weeks (Q12W).

[0017] In some exemplary embodiments, the subject receives a dose directly every 12 weeks from the start of treatment. In some exemplary embodiments, the subject receives a dose directly every 12 weeks without prior dose administration every 4 weeks.

[0018] In some alternative exemplary embodiments, each second dose is administered every 4 weeks (Q4W) during a 24-week period, and then every 12 weeks (Q12W).

[0019] In some alternative exemplary embodiments, each second dose is administered every 4 weeks (Q4W) during a 24-week period, or each second dose is administered Q4W until the patient has achieved vIGA O / 1, or has clear or substantially clear skin, or has achieved EASI-75 or has achieved EASI-90.

[0020] In some exemplary embodiments, the atopic dermatitis is moderate to severe. In some exemplary embodiments, the moderate to severe atopic dermatitis is not adequately controlled by topical prescription therapy or systemic therapy, or such therapies are not desirable. For the purposes of "not adequately controlled by systemic therapy" herein, it should be understood that we include systemic therapies intended to treat a condition (e.g., atopic dermatitis) other than the anti-OX40L antibody or its antigen-binding fragment described herein.

[0021] In some exemplary embodiments, the subject's Eczema Area Surface Index (EASI) score is reduced. In some exemplary embodiments, the EASI score is selected from the group consisting of EASI-75, EASI-90, and EASI-100.

[0022] In some exemplary embodiments, the subject’s Investigator Global Assessment (IGA) score is reduced.

[0023] In some exemplary embodiments, the subject’s peak pruritus digital rating scale (PP-NRS) score is reduced.

[0024] In some exemplary embodiments, the subject’s skin pain digital rating scale (SP-NRS) score is reduced.

[0025] In some exemplary embodiments, the subject’s Sleep Disorders Digital Rating Scale (SD-NRS) score is reduced.

[0026] In some exemplary embodiments, the subject's Dermatology Quality of Life Index (DLQI) score decreased. For the purposes of the context of EASI, IGA, PP-NRS, SP-NRS, SD-NRS, and DLQI scores herein, we include the meaning that the score decreased relative to the subject's pre-treatment score after treatment with an anti-OX40 ligand (OX40L) antibody or its antigen-binding fragment.

[0027] In some exemplary embodiments, the subject's Hospital Anxiety and Depression Scale (HADS) score improved. With respect to "the subject's score improved," we include the following meaning: after treating the subject by administering an anti-OX40 ligand (OX40L) antibody or its antigen-binding fragment, the subject's score improved relative to its pre-treatment score.

[0028] In some exemplary embodiments, the subject is administered a formulation comprising a 125 mg / mL amotelimab solution provided in a pre-filled syringe, which delivers 250 mg of amotelimab in 2 mL injections.

[0029] On the other hand, a method for treating an immune-mediated disease in an adolescent subject in need is provided, the method comprising administering to the adolescent subject an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 42, the HCDR2 of SEQ ID NO: 44 and the HCDR3 of SEQ ID NO: 46, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 56, the LCDR2 of SEQ ID NO: 58 and the LCDR3 of SEQ ID NO: 60.

[0030] On the other hand, a method for treating an immune-mediated disease in an adolescent subject in need is provided, the method comprising administering to the adolescent subject an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or the antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 36, the HCDR2 of SEQ ID NO: 38 and the HCDR3 of SEQ ID NO: 40, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 50, the LCDR2 of SEQ ID NO: 52 and the LCDR3 of SEQ ID NO: 54. The OX40L antibody or its antigen-binding fragment may comprise: a variable heavy (VH) domain comprising the amino acid sequence of SEQ ID NO: 34, or at least 80% (e.g., at least 85%) of the VH domain amino acid sequence identical to SEQ ID NO: 34; and / or a variable light (VL) domain comprising the amino acid sequence of SEQ ID NO: 48, or at least 80% (e.g., at least 85%, 90%, or 95%) of the VL domain identical to SEQ ID NO: 48. Therefore, the OX40L antibody or its antigen-binding fragment may comprise: a VH domain comprising the amino acid sequence of SEQ ID NO: 34; and a VL domain comprising the amino acid sequence of SEQ ID NO: 48. Similarly, antibodies defined by reference to the above CDR or the above VH and / or VL domains may comprise a heavy chain and a light chain, the heavy chain amino acid sequence comprising the sequence of SEQ ID NO: 62, and the light chain amino acid sequence comprising the sequence of SEQ ID NO: 64. It should be understood that antibodies defined by the above CDR, the above VH and / or VL domains, or the above heavy chain and / or light chain sequences may also include an IgG4 constant region, optionally wherein the constant region is IgG4-PE (SEQ ID NO: 128). The OX40L antibody or its antigen-binding fragment may be an OX40L antagonist.

[0031] In some exemplary embodiments, the antibody or its antigen-binding fragment is anitolide or a variant thereof. In some exemplary embodiments, the antibody is anitolide.

[0032] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered via a pre-filled syringe, a pen delivery device, or an autoinjector.

[0033] In some exemplary embodiments, the adolescent subject has a weight ranging from about 25 kg to about 40 kg.

[0034] In some exemplary embodiments, the adolescent subject receives an initial dose of about 250 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 125 mg of the antibody or its antigen-binding fragment.

[0035] In some exemplary embodiments, each second dose is administered every 4 weeks (Q4W) during a 24-week period, or each second dose is administered Q4W until the patient has achieved vIGA O / 1, or has clear or nearly clear skin, or has achieved EAS175 or has achieved EASI90.

[0036] In some exemplary embodiments, during a 24-week period, a second dose is administered every 4 weeks (Q4W) after the initial dose, and then each subsequent second dose is administered every 12 weeks (Q12W).

[0037] In some exemplary embodiments, each dose is administered Q12W. In some exemplary embodiments, the subject receives the dose Q12W from the start of treatment. In some exemplary embodiments, the subject receives the dose directly Q12W without prior dose administration in Q4W. For example, the adolescent subject may receive an initial dose of about 250 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 125 mg of the antibody or its antigen-binding fragment, wherein the second dose is administered every 12 weeks (Q12W).

[0038] In some exemplary embodiments, the subject is 12 years of age or older (e.g., the subject is 12-17 years of age).

[0039] In some exemplary embodiments, the atopic dermatitis is moderate to severe. In some exemplary embodiments, the moderate to severe atopic dermatitis is not adequately controlled or is not desirable with topical or systemic therapies.

[0040] In some exemplary embodiments, the subject's Eczema Area Surface Index (EASI) score is reduced. In some exemplary embodiments, the EASI score is selected from the group consisting of EASI-75, EASI-90, and EASI-100.

[0041] In some exemplary embodiments, the subject’s Investigator Global Assessment (IGA) score is reduced.

[0042] In some exemplary embodiments, the subject’s peak pruritus digital rating scale (PP-NRS) score is reduced.

[0043] In some exemplary embodiments, the subject’s skin pain digital rating scale (SP-NRS) score is reduced.

[0044] In some exemplary embodiments, the subject’s Sleep Disorders Digital Rating Scale (SD-NRS) score is reduced.

[0045] In some exemplary embodiments, the subject’s Dermatology Quality of Life Index (DLQI) score is reduced.

[0046] In some exemplary embodiments, the subject's Hospital Anxiety and Depression Scale (HADS) score improved.

[0047] In some exemplary embodiments, the subject weighs 25 kg or more but less than 40 kg, and the subject is administered a formulation comprising a 62.5 mg / mL amotelimab solution provided in a pre-filled syringe, which delivers 125 mg of amotelimab in 2 mL injections. In some exemplary embodiments, the subject weighs 25 kg or more but less than 40 kg, and the subject is administered a formulation comprising a 125 mg / mL amotelimab solution provided in a pre-filled syringe, which delivers 125 mg of amotelimab in 1 mL injections.

[0048] On the other hand, a method for treating atopic dermatitis in an adolescent subject in need is provided, the method comprising administering to the adolescent subject an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 42, the HCDR2 of SEQ ID NO: 44 and the HCDR3 of SEQ ID NO: 46, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 56, the LCDR2 of SEQ ID NO: 58 and the LCDR3 of SEQ ID NO: 60.

[0049] On the other hand, a method for treating atopic dermatitis in an adolescent subject in need is provided, the method comprising administering to the adolescent subject an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 36, the HCDR2 of SEQ ID NO: 38 and the HCDR3 of SEQ ID NO: 40, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 50, the LCDR2 of SEQ ID NO: 52 and the LCDR3 of SEQ ID NO: 54. The OX40L antibody or its antigen-binding fragment may comprise: a variable heavy (VH) domain comprising the amino acid sequence of SEQ ID NO: 34, or at least 80% (e.g., at least 85%) of the VH domain amino acid sequence identical to SEQ ID NO: 34; and / or a variable light (VL) domain comprising the amino acid sequence of SEQ ID NO: 48, or at least 80% (e.g., at least 85%, 90%, or 95%) of the VL domain identical to SEQ ID NO: 48. Therefore, the OX40L antibody or its antigen-binding fragment may comprise: a VH domain comprising the amino acid sequence of SEQ ID NO: 34; and a VL domain comprising the amino acid sequence of SEQ ID NO: 48. Similarly, antibodies defined by reference to the above CDR or the above VH and / or VL domains may comprise a heavy chain and a light chain, the heavy chain amino acid sequence comprising the sequence of SEQ ID NO: 62, and the light chain amino acid sequence comprising the sequence of SEQ ID NO: 64. It should be understood that antibodies defined by the above CDR, the above VH and / or VL domains, or the above heavy chain and / or light chain sequences may also include an IgG4 constant region, optionally wherein the constant region is IgG4-PE (SEQ ID NO: 128). The OX40L antibody or its antigen-binding fragment may be an OX40L antagonist.

[0050] In some exemplary embodiments, the antibody or its antigen-binding fragment is anitolide or a variant thereof. In some exemplary embodiments, the antibody is anitolide.

[0051] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered via a pre-filled syringe, a pen delivery device, or an autoinjector.

[0052] In some exemplary embodiments, the adolescent subject has a weight ranging from about 25 kg to about 40 kg.

[0053] In some exemplary embodiments, the adolescent subject receives an initial dose of about 250 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 125 mg of the antibody or its antigen-binding fragment.

[0054] In some exemplary embodiments, each second dose is administered every 4 weeks (Q4W) during a 24-week period, or each second dose is administered Q4W until the patient has achieved vIGA O / 1, or has clear or nearly clear skin, or has achieved EAS175 or has achieved EASI90.

[0055] In some exemplary embodiments, during a 24-week period, a second dose is administered every 4 weeks (Q4W) after the initial dose, and then each subsequent second dose is administered every 12 weeks (Q12W).

[0056] In some exemplary embodiments, each dose is administered Q12W. In some exemplary embodiments, the subject receives the dose Q12W from the start of treatment. In some exemplary embodiments, the subject receives the dose directly Q12W without prior dose administration in Q4W. For example, the adolescent subject may receive an initial dose of about 250 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 125 mg of the antibody or its antigen-binding fragment, wherein the second dose is administered every 12 weeks (Q12W).

[0057] In some exemplary embodiments, the subject is 12 years of age or older (e.g., the subject is 12-17 years of age).

[0058] In some exemplary embodiments, the atopic dermatitis is moderate to severe. In some exemplary embodiments, the moderate to severe atopic dermatitis is not adequately controlled or is not desirable with topical or systemic therapies.

[0059] In some exemplary embodiments, the subject's Eczema Area Surface Index (EASI) score is reduced. In some exemplary embodiments, the EASI score is selected from the group consisting of EASI-75, EASI-90, and EASI-100.

[0060] In some exemplary embodiments, the subject’s Investigator Global Assessment (IGA) score is reduced.

[0061] In some exemplary embodiments, the subject’s peak pruritus digital rating scale (PP-NRS) score is reduced.

[0062] In some exemplary embodiments, the subject’s skin pain digital rating scale (SP-NRS) score is reduced.

[0063] In some exemplary embodiments, the subject’s Sleep Disorders Digital Rating Scale (SD-NRS) score is reduced.

[0064] In some exemplary embodiments, the subject’s Dermatology Quality of Life Index (DLQI) score is reduced.

[0065] In some exemplary embodiments, the subject's Hospital Anxiety and Depression Scale (HADS) score improved.

[0066] In some exemplary embodiments, the subject weighs 25 kg or more and less than 40 kg, and the subject is administered a formulation comprising a 62.5 mg / mL amotelimab solution provided in a prefilled syringe that delivers 125 mg of amotelimab in 2 mL injections.

[0067] In some exemplary embodiments, the subject weighs 25 kg or more and less than 40 kg, and the subject is administered a formulation comprising a 125 mg / mL amotelimab solution provided in a prefilled syringe that delivers 125 mg of amotelimab in 1 mL injection.

[0068] On the other hand, a method for treating an immune-mediated disease in a subject of need is provided, the method comprising administering to the subject an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 42, the HCDR2 of SEQ ID NO: 44 and the HCDR3 of SEQ ID NO: 46, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 56, the LCDR2 of SEQ ID NO: 58 and the LCDR3 of SEQ ID NO: 60, wherein the subject has a weight ranging from about 25 kg to about 40 kg.

[0069] On the other hand, a method for treating an immune-mediated disease in a subject of need is provided, the method comprising administering to the subject an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 36, the HCDR2 of SEQ ID NO: 38 and the HCDR3 of SEQ ID NO: 40, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 50, the LCDR2 of SEQ ID NO: 52 and the LCDR3 of SEQ ID NO: 54, wherein the subject has a weight ranging from about 25 kg to about 40 kg. The OX40L antibody or its antigen-binding fragment may comprise: a variable heavy (VH) domain comprising the amino acid sequence of SEQ ID NO: 34, or at least 80% (e.g., at least 85%) of the VH domain amino acid sequence identical to SEQ ID NO: 34; and / or a variable light (VL) domain comprising the amino acid sequence of SEQ ID NO: 48, or at least 80% (e.g., at least 85%, 90%, or 95%) of the VL domain identical to SEQ ID NO: 48. Therefore, the OX40L antibody or its antigen-binding fragment may comprise: a VH domain comprising the amino acid sequence of SEQ ID NO: 34; and a VL domain comprising the amino acid sequence of SEQ ID NO: 48. Similarly, antibodies defined by reference to the above CDR or the above VH and / or VL domains may comprise a heavy chain and a light chain, the heavy chain amino acid sequence comprising the sequence of SEQ ID NO: 62, and the light chain amino acid sequence comprising the sequence of SEQ ID NO: 64. It should be understood that antibodies defined by the above CDR, the above VH and / or VL domains, or the above heavy chain and / or light chain sequences may also include an IgG4 constant region, optionally wherein the constant region is IgG4-PE (SEQ ID NO: 128). The OX40L antibody or its antigen-binding fragment may be an OX40L antagonist.

[0070] In some exemplary embodiments, the antibody or its antigen-binding fragment is anitolide or a variant thereof. In some exemplary embodiments, the antibody is anitolide.

[0071] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered via a pre-filled syringe, a pen delivery device, or an autoinjector.

[0072] In some exemplary embodiments, the adolescent subject receives an initial dose of about 250 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 125 mg of the antibody or its antigen-binding fragment.

[0073] In some exemplary embodiments, each second dose is administered every 4 weeks (Q4W) during a 24-week period, or each second dose is administered Q4W until the patient has achieved vIGA O / 1, or has clear or nearly clear skin, or has achieved EAS175 or has achieved EASI90.

[0074] In some exemplary embodiments, during a 24-week period, a second dose is administered every 4 weeks (Q4W) after the initial dose, and then each subsequent second dose is administered every 12 weeks (Q12W).

[0075] In some exemplary embodiments, each dose is administered Q12W. In some exemplary embodiments, the subject receives the dose Q12W from the start of treatment. In some exemplary embodiments, the subject receives the dose directly Q12W without prior dose administration in Q4W. For example, the adolescent subject may receive an initial dose of about 250 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 125 mg of the antibody or its antigen-binding fragment, wherein the second dose is administered every 12 weeks (Q12W).

[0076] In some exemplary embodiments, the subject is 12 years of age or older (e.g., the subject is 12-17 years of age).

[0077] In some exemplary embodiments, the atopic dermatitis is moderate to severe. In some exemplary embodiments, the moderate to severe atopic dermatitis is not adequately controlled or is not desirable with topical or systemic therapies.

[0078] In some exemplary embodiments, the subject's Eczema Area Surface Index (EASI) score is reduced. In some exemplary embodiments, the EASI score is selected from the group consisting of EASI-75, EASI-90, and EASI-100.

[0079] In some exemplary embodiments, the subject’s Investigator Global Assessment (IGA) score is reduced.

[0080] In some exemplary embodiments, the subject’s peak pruritus digital rating scale (PP-NRS) score is reduced.

[0081] In some exemplary embodiments, the subject’s skin pain digital rating scale (SP-NRS) score is reduced.

[0082] In some exemplary embodiments, the subject’s Sleep Disorders Digital Rating Scale (SD-NRS) score is reduced.

[0083] In some exemplary embodiments, the subject’s Dermatology Quality of Life Index (DLQI) score is reduced.

[0084] In some exemplary embodiments, the subject's Hospital Anxiety and Depression Scale (HADS) score improved.

[0085] In some exemplary embodiments, the subject weighs 25 kg or more and less than 40 kg, and the subject is administered a formulation comprising a 62.5 mg / mL amotelimab solution provided in a prefilled syringe that delivers 125 mg of amotelimab in 2 mL injections.

[0086] In some exemplary embodiments, the subject weighs 25 kg or more and less than 40 kg, and the subject is administered a formulation comprising a 125 mg / mL amotelimab solution provided in a prefilled syringe that delivers 125 mg of amotelimab in 1 mL injection.

[0087] On the other hand, a method for treating atopic dermatitis in a subject in need is provided, the method comprising administering to the subject an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 42, the HCDR2 of SEQ ID NO: 44 and the HCDR3 of SEQ ID NO: 46, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 56, the LCDR2 of SEQ ID NO: 58 and the LCDR3 of SEQ ID NO: 60, wherein the subject has a weight ranging from about 25 kg to about 40 kg.

[0088] On the other hand, a method for treating atopic dermatitis in a subject in need is provided, the method comprising administering to the subject an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 36, the HCDR2 of SEQ ID NO: 38 and the HCDR3 of SEQ ID NO: 40, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 50, the LCDR2 of SEQ ID NO: 52 and the LCDR3 of SEQ ID NO: 54, wherein the subject has a weight ranging from about 25 kg to about 40 kg. The OX40L antibody or its antigen-binding fragment may comprise: a variable heavy (VH) domain comprising the amino acid sequence of SEQ ID NO: 34, or at least 80% (e.g., at least 85%) of the VH domain amino acid sequence identical to SEQ ID NO: 34; and / or a variable light (VL) domain comprising the amino acid sequence of SEQ ID NO: 48, or at least 80% (e.g., at least 85%, 90%, or 95%) of the VL domain identical to SEQ ID NO: 48. Therefore, the OX40L antibody or its antigen-binding fragment may comprise: a VH domain comprising the amino acid sequence of SEQ ID NO: 34; and a VL domain comprising the amino acid sequence of SEQ ID NO: 48. Similarly, antibodies defined by reference to the above CDR or the above VH and / or VL domains may comprise a heavy chain and a light chain, the heavy chain amino acid sequence comprising the sequence of SEQ ID NO: 62, and the light chain amino acid sequence comprising the sequence of SEQ ID NO: 64. It should be understood that antibodies defined by the above CDR, the above VH and / or VL domains, or the above heavy chain and / or light chain sequences may also include an IgG4 constant region, optionally wherein the constant region is IgG4-PE (SEQ ID NO: 128). The OX40L antibody or its antigen-binding fragment may be an OX40L antagonist.

[0089] In some exemplary embodiments, the antibody or its antigen-binding fragment is anitolide or a variant thereof. In some exemplary embodiments, the antibody is anitolide.

[0090] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered via a pre-filled syringe, a pen delivery device, or an autoinjector.

[0091] In some exemplary embodiments, the adolescent subject receives an initial dose of about 250 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 125 mg of the antibody or its antigen-binding fragment.

[0092] In some exemplary embodiments, each second dose is administered every 4 weeks (Q4W) during a 24-week period, or each second dose is administered Q4W until the patient has achieved vIGA O / 1, or has clear or nearly clear skin, or has achieved EAS175 or has achieved EASI90.

[0093] In some exemplary embodiments, during a 24-week period, a second dose is administered every 4 weeks (Q4W) after the initial dose, and then each subsequent second dose is administered every 12 weeks (Q12W).

[0094] In some exemplary embodiments, each dose is administered Q12W. In some exemplary embodiments, the subject receives the dose Q12W from the start of treatment. In some exemplary embodiments, the subject receives the dose directly Q12W without prior dose administration in Q4W. For example, the adolescent subject may receive an initial dose of about 250 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 125 mg of the antibody or its antigen-binding fragment, wherein the second dose is administered every 12 weeks (Q12W).

[0095] In some exemplary embodiments, the subject is 12 years of age or older (e.g., the subject is 12-17 years of age).

[0096] In some exemplary embodiments, the atopic dermatitis is moderate to severe. In some exemplary embodiments, the moderate to severe atopic dermatitis is not adequately controlled or is not desirable with topical or systemic therapies.

[0097] In some exemplary embodiments, the subject's Eczema Area Surface Index (EASI) score is reduced. In some exemplary embodiments, the EASI score is selected from the group consisting of EASI-75, EASI-90, and EASI-100.

[0098] In some exemplary embodiments, the subject’s Investigator Global Assessment (IGA) score is reduced.

[0099] In some exemplary embodiments, the subject’s peak pruritus digital rating scale (PP-NRS) score is reduced.

[0100] In some exemplary embodiments, the subject’s skin pain digital rating scale (SP-NRS) score is reduced.

[0101] In some exemplary embodiments, the subject’s Sleep Disorders Digital Rating Scale (SD-NRS) score is reduced.

[0102] In some exemplary embodiments, the subject’s Dermatology Quality of Life Index (DLQI) score is reduced.

[0103] In some exemplary embodiments, the subject's Hospital Anxiety and Depression Scale (HADS) score improved.

[0104] In some exemplary embodiments, the subject weighs 25 kg or more and less than 40 kg, and the subject is administered a formulation comprising a 62.5 mg / mL amotelimab solution provided in a prefilled syringe that delivers 125 mg of amotelimab in 2 mL injections.

[0105] In some exemplary embodiments, the subject weighs 25 kg or more and less than 40 kg, and the subject is administered a formulation comprising a 125 mg / mL amotelimab solution provided in a prefilled syringe that delivers 125 mg of amotelimab in 1 mL injection.

[0106] This disclosure is also based on the discovery of biomarkers associated with atopic dermatitis.

[0107] This disclosure relates to the use of at least one or all of a biomarker selected from the group consisting of TARC, IL-5, eosinophil count and LDH in the treatment of an immune-mediated disease, such as atopic dermatitis (AD), in a subject in need.

[0108] This disclosure relates to the use of at least one or all of a biomarker selected from the group consisting of IL-5, TARC, eosinophil chemokine-3, total IgE, IL-13, IL-17A, IL-22 and eosinophil count in the treatment of an immune-mediated disease, such as asthma, in a subject in need.

[0109] This disclosure relates to the use of at least one or all of the biomarkers selected from the group consisting of IL-17A, IL-13 and IL-31 in the treatment of immune-mediated diseases (such as interstitial lung disease-systemic sclerosis (ILD-SSc)) in subjects in need.

[0110] This disclosure relates to the use of at least one or all of the biomarkers selected from the group consisting of IL-5, IL-22 and TARC in the treatment of subjects in need of immune-mediated diseases such as systemic sclerosis (SSc).

[0111] This disclosure relates to the use of at least one or all of a biomarker selected from the group consisting of IL-17A, IL-13, IL-31 and periosteal protein in the treatment of an immune-mediated disease (such as SSc) in a subject in need.

[0112] This disclosure relates to the use of the biomarker IL-17A in the treatment of immune-mediated diseases, such as hidradenitis suppurativa (HS), in subjects in need.

[0113] This disclosure relates to the use of at least one or all of the biomarkers selected from the group consisting of IL-13, IL-22, IL-17A and IL-31 in the treatment of immune-mediated diseases (such as alopecia areata (AA)) in subjects in need.

[0114] This disclosure relates to the use of at least one or all of the biomarkers selected from the group consisting of IL-17A, IL-22, IL-5 and IL-13 in the treatment of an immune-mediated disease (such as celiac disease) in a subject in need.

[0115] This disclosure relates to the use of at least one or all of the biomarkers selected from the group consisting of IL-17A, IL-22 and IL-13 in the treatment of an immune-mediated disease (such as celiac disease) in a subject in need.

[0116] In the context of “use of biomarkers” in the treatment of immune-mediated diseases or atopic dermatitis, we include the implication of using biomarkers to select subjects for treatment and / or monitor treatment efficacy.

[0117] On another front, a method is provided for treating an immune-mediated disease in a subject of need, comprising administering to the subject an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof in an amount that effectively reduces the level of at least one biomarker selected from the group consisting of TARC, IL-5, eosinophil count, and LDH, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 42, HCDR2 of SEQ ID NO: 44, and HCDR3 of SEQ ID NO: 46, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 56, LCDR2 of SEQ ID NO: 58, and LCDR3 of SEQ ID NO: 60. In one embodiment, the anti-OX40L antibody or an antigen-binding fragment thereof is administered to the subject in an amount that effectively reduces the level of all biomarkers selected from the group consisting of TARC, IL-5, eosinophil count, and LDH.

[0118] On another front, a method is provided for treating an immune-mediated disease in a subject of need, comprising administering to the subject an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof in an amount that effectively reduces the level of at least one biomarker selected from the group consisting of TARC, IL-5, eosinophil count, and LDH, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 36, HCDR2 of SEQ ID NO: 38, and HCDR3 of SEQ ID NO: 40, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 50, LCDR2 of SEQ ID NO: 52, and LCDR3 of SEQ ID NO: 54. In one embodiment, the anti-OX40L antibody or an antigen-binding fragment thereof is administered to the subject in an amount that effectively reduces the level of all biomarkers selected from the group consisting of TARC, IL-5, eosinophil count, and LDH.

[0119] The OX40L antibody or its antigen-binding fragment may comprise: a variable heavy (VH) domain comprising the amino acid sequence of SEQ ID NO: 34, or at least 80% (e.g., at least 85%) of the VH domain amino acid sequence identical to SEQ ID NO: 34; and / or a variable light (VL) domain comprising the amino acid sequence of SEQ ID NO: 48, or at least 80% (e.g., at least 85%, 90%, or 95%) of the VL domain identical to SEQ ID NO: 48. Therefore, the OX40L antibody or its antigen-binding fragment may comprise: a VH domain comprising the amino acid sequence of SEQ ID NO: 34; and a VL domain comprising the amino acid sequence of SEQ ID NO: 48. Similarly, antibodies defined by reference to the above CDR or the above VH and / or VL domains may comprise a heavy chain and a light chain, the heavy chain amino acid sequence comprising the sequence of SEQ ID NO: 62, and the light chain amino acid sequence comprising the sequence of SEQ ID NO: 64. It should be understood that antibodies defined by the above CDR, the above VH and / or VL domains, or the above heavy chain and / or light chain sequences may also include an IgG4 constant region, optionally wherein the constant region is IgG4-PE (SEQ ID NO:128). The OX40L antibody or its antigen-binding fragment may be an OX40L antagonist.

[0120] In one embodiment, the method results in a reduction in the level of at least one biomarker in the subject, for example, relative to the level of at least one biomarker prior to administration of an anti-OX40 ligand (OX40L) antibody or its antigen-binding fragment.

[0121] On the other hand, a method for treating an immune-mediated disease in a subject of need is provided, the method comprising selecting a subject suffering from an immune-mediated disease and having elevated levels relative to a control of at least one biomarker selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count and lactate dehydrogenase (LDH), and administering to the subject an effective amount of an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 42, HCDR2 of SEQ ID NO: 44 and HCDR3 of SEQ ID NO: 46, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 56, LCDR2 of SEQ ID NO: 58 and LCDR3 of SEQ ID NO: 60. In one embodiment, subjects with elevated levels relative to controls of all biomarkers selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count, and lactate dehydrogenase (LDH). For the purposes of “elevated biomarker levels relative to controls” as used herein, we include the meaning of increased biomarker levels relative to biomarker levels from subjects without immune-mediated diseases.

[0122] On the other hand, a method for treating an immune-mediated disease in a subject of need is provided, the method comprising selecting a subject suffering from an immune-mediated disease and having elevated levels relative to a control of at least one biomarker selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count and lactate dehydrogenase (LDH), and administering to the subject an effective amount of an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 36, HCDR2 of SEQ ID NO: 38 and HCDR3 of SEQ ID NO: 40, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 50, LCDR2 of SEQ ID NO: 52 and LCDR3 of SEQ ID NO: 54. In one embodiment, subjects with elevated levels relative to controls of all biomarkers selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count, and lactate dehydrogenase (LDH) were selected.

[0123] The OX40L antibody or its antigen-binding fragment may comprise: a variable heavy (VH) domain comprising the amino acid sequence of SEQ ID NO: 34, or at least 80% (e.g., at least 85%) of the VH domain amino acid sequence identical to SEQ ID NO: 34; and / or a variable light (VL) domain comprising the amino acid sequence of SEQ ID NO: 48, or at least 80% (e.g., at least 85%, 90%, or 95%) of the VL domain identical to SEQ ID NO: 48. Therefore, the OX40L antibody or its antigen-binding fragment may comprise: a VH domain comprising the amino acid sequence of SEQ ID NO: 34; and a VL domain comprising the amino acid sequence of SEQ ID NO: 48. Similarly, antibodies defined by reference to the above CDR or the above VH and / or VL domains may comprise a heavy chain and a light chain, the heavy chain amino acid sequence comprising the sequence of SEQ ID NO: 62, and the light chain amino acid sequence comprising the sequence of SEQ ID NO: 64. It should be understood that antibodies defined by the above CDR, the above VH and / or VL domains, or the above heavy chain and / or light chain sequences may also include an IgG4 constant region, optionally wherein the constant region is IgG4-PE (SEQ ID NO:128). The OX40L antibody or its antigen-binding fragment may be an OX40L antagonist.

[0124] In another aspect, a method for treating atopic dermatitis (AD) in a subject of need is provided, the method comprising administering to the subject an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof in an amount that effectively reduces the level of at least one biomarker selected from the group consisting of TARC, IL-5, eosinophil count, and LDH, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 42, the HCDR2 of SEQ ID NO: 44, and the HCDR3 of SEQ ID NO: 46, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 56, the LCDR2 of SEQ ID NO: 58, and the LCDR3 of SEQ ID NO: 60. In one embodiment, the anti-OX40L antibody or an antigen-binding fragment thereof is administered to the subject in an amount that effectively reduces the level of all biomarkers selected from the group consisting of TARC, IL-5, eosinophil count, and LDH.

[0125] In another aspect, a method for treating atopic dermatitis (AD) in a subject of need is provided, the method comprising administering to the subject an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof in an amount that effectively reduces the level of at least one biomarker selected from the group consisting of TARC, IL-5, eosinophil count, and LDH, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 36, HCDR2 of SEQ ID NO: 38, and HCDR3 of SEQ ID NO: 40, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 50, LCDR2 of SEQ ID NO: 528, and LCDR3 of SEQ ID NO: 54. In one embodiment, the anti-OX40L antibody or an antigen-binding fragment thereof is administered to the subject in an amount that effectively reduces the level of all biomarkers selected from the group consisting of TARC, IL-5, eosinophil count, and LDH.

[0126] The OX40L antibody or its antigen-binding fragment may comprise: a variable heavy (VH) domain comprising the amino acid sequence of SEQ ID NO: 34, or at least 80% (e.g., at least 85%) of the VH domain amino acid sequence identical to SEQ ID NO: 34; and / or a variable light (VL) domain comprising the amino acid sequence of SEQ ID NO: 48, or at least 80% (e.g., at least 85%, 90%, or 95%) of the VL domain identical to SEQ ID NO: 48. Therefore, the OX40L antibody or its antigen-binding fragment may comprise: a VH domain comprising the amino acid sequence of SEQ ID NO: 34; and a VL domain comprising the amino acid sequence of SEQ ID NO: 48. Similarly, antibodies defined by reference to the above CDR or the above VH and / or VL domains may comprise a heavy chain and a light chain, the heavy chain amino acid sequence comprising the sequence of SEQ ID NO: 62, and the light chain amino acid sequence comprising the sequence of SEQ ID NO: 64. It should be understood that antibodies defined by the above CDR, the above VH and / or VL domains, or the above heavy chain and / or light chain sequences may also include an IgG4 constant region, optionally wherein the constant region is IgG4-PE (SEQ ID NO:128). The OX40L antibody or its antigen-binding fragment may be an OX40L antagonist.

[0127] In one embodiment, the method results in a reduction in the level of at least one biomarker in the subject, for example, relative to the level of at least one biomarker prior to administration of an anti-OX40 ligand (OX40L) antibody or its antigen-binding fragment.

[0128] On the other hand, a method for treating atopic dermatitis (AD) in a subject in need is provided, the method comprising selecting a subject suffering from AD and having elevated levels relative to a control of at least one biomarker selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count and lactate dehydrogenase (LDH), and administering to the subject an effective amount of an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 42, the HCDR2 of SEQ ID NO: 44 and the HCDR3 of SEQ ID NO: 46, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 56, the LCDR2 of SEQ ID NO: 58 and the LCDR3 of SEQ ID NO: 60. In one embodiment, subjects with elevated levels of all biomarkers selected relative to controls, comprising the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count, and lactate dehydrogenase (LDH), are selected. For the purposes of “elevated biomarker levels relative to controls” as used herein, we include the meaning of increased biomarker levels relative to biomarker levels from subjects without atopic dermatitis.

[0129] On the other hand, a method for treating atopic dermatitis (AD) in a subject in need is provided, the method comprising selecting a subject suffering from AD and having elevated levels relative to a control of at least one biomarker selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count and lactate dehydrogenase (LDH), and administering to the subject an effective amount of an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 36, the HCDR2 of SEQ ID NO: 38 and the HCDR3 of SEQ ID NO: 40, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 50, the LCDR2 of SEQ ID NO: 52 and the LCDR3 of SEQ ID NO: 54. In one embodiment, subjects with elevated levels relative to controls of all biomarkers selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count, and lactate dehydrogenase (LDH) were selected.

[0130] The OX40L antibody or its antigen-binding fragment may comprise: a variable heavy (VH) domain comprising the amino acid sequence of SEQ ID NO: 34, or at least 80% (e.g., at least 85%) of the VH domain amino acid sequence identical to SEQ ID NO: 34; and / or a variable light (VL) domain comprising the amino acid sequence of SEQ ID NO: 48, or at least 80% (e.g., at least 85%, 90%, or 95%) of the VL domain identical to SEQ ID NO: 48. Therefore, the OX40L antibody or its antigen-binding fragment may comprise: a VH domain comprising the amino acid sequence of SEQ ID NO: 34; and a VL domain comprising the amino acid sequence of SEQ ID NO: 48. Similarly, antibodies defined by reference to the above CDR or the above VH and / or VL domains may comprise a heavy chain and a light chain, the heavy chain amino acid sequence comprising the sequence of SEQ ID NO: 62, and the light chain amino acid sequence comprising the sequence of SEQ ID NO: 64. It should be understood that antibodies defined by the above CDR, the above VH and / or VL domains, or the above heavy chain and / or light chain sequences may also include an IgG4 constant region, optionally wherein the constant region is IgG4-PE (SEQ ID NO:128). The OX40L antibody or its antigen-binding fragment may be an OX40L antagonist.

[0131] In another aspect, a method is provided for treating an immune-mediated disease in a subject of need, the method comprising administering to the subject an effective amount of an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 42, HCDR2 of SEQ ID NO: 44 and HCDR3 of SEQ ID NO: 46, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 56, LCDR2 of SEQ ID NO: 58 and LCDR3 of SEQ ID NO: 60; and reducing the level of at least one biomarker selected from TARC, IL-5, eosinophil count, LDH, or combinations thereof. In one embodiment, the levels of all biomarkers selected from TARC, IL-5, eosinophil count, and LDH are reduced.

[0132] On the other hand, a method is provided for treating an immune-mediated disease in a subject of need, the method comprising administering to the subject an effective amount of an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 36, HCDR2 of SEQ ID NO: 38 and HCDR3 of SEQ ID NO: 40, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 50, LCDR2 of SEQ ID NO: 52 and LCDR3 of SEQ ID NO: 54; and reducing the level of at least one biomarker selected from TARC, IL-5, eosinophil count, LDH, or combinations thereof. In one embodiment, the levels of all biomarkers selected from TARC, IL-5, eosinophil count, and LDH are reduced.

[0133] The OX40L antibody or its antigen-binding fragment may comprise: a variable heavy (VH) domain comprising the amino acid sequence of SEQ ID NO: 34, or at least 80% (e.g., at least 85%) of the VH domain amino acid sequence identical to SEQ ID NO: 34; and / or a variable light (VL) domain comprising the amino acid sequence of SEQ ID NO: 48, or at least 80% (e.g., at least 85%, 90%, or 95%) of the VL domain identical to SEQ ID NO: 48. Therefore, the OX40L antibody or its antigen-binding fragment may comprise: a VH domain comprising the amino acid sequence of SEQ ID NO: 34; and a VL domain comprising the amino acid sequence of SEQ ID NO: 48. Similarly, antibodies defined by reference to the above CDR or the above VH and / or VL domains may comprise a heavy chain and a light chain, the heavy chain amino acid sequence comprising the sequence of SEQ ID NO: 62, and the light chain amino acid sequence comprising the sequence of SEQ ID NO: 64. It should be understood that antibodies defined by the above CDR, the above VH and / or VL domains, or the above heavy chain and / or light chain sequences may also include an IgG4 constant region, optionally wherein the constant region is IgG4-PE (SEQ ID NO:128). The OX40L antibody or its antigen-binding fragment may be an OX40L antagonist.

[0134] On the other hand, a method for treating an immune-mediated disease in a subject of need is provided, the method comprising selecting a subject suffering from an immune-mediated disease and having elevated levels relative to a control of at least one biomarker selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count, and lactate dehydrogenase (LDH), and administering to the subject an effective amount of an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof to reduce the level of at least one biomarker selected from TARC, IL-5, eosinophil count, LDH, or combinations thereof, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 42, HCDR2 of SEQ ID NO: 44, and HCDR3 of SEQ ID NO: 46, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 56, LCDR2 of SEQ ID NO: 58, and LCDR3 of SEQ ID NO: 60. In one embodiment, a subject exhibiting elevated levels relative to a control of at least one biomarker selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count, and lactate dehydrogenase (LDH) is selected, and the subject is administered an anti-OX40L antibody or an antigen-binding fragment thereof to reduce the level of at least one biomarker selected from TARC, IL-5, eosinophil count, and LDH. In a further embodiment, a subject exhibiting elevated levels relative to a control of at least one biomarker selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count, and lactate dehydrogenase (LDH) is selected, and the subject is administered an anti-OX40L antibody or an antigen-binding fragment thereof to reduce the level of all biomarkers selected from TARC, IL-5, eosinophil count, and LDH.

[0135] On the other hand, a method for treating an immune-mediated disease in a subject of need is provided, the method comprising selecting a subject suffering from an immune-mediated disease and having elevated levels relative to a control of at least one biomarker selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count, and lactate dehydrogenase (LDH), and administering to the subject an effective amount of an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof to reduce the level of at least one biomarker selected from TARC, IL-5, eosinophil count, LDH, or combinations thereof, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 36, HCDR2 of SEQ ID NO: 38, and HCDR3 of SEQ ID NO: 40, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 50, LCDR2 of SEQ ID NO: 52, and LCDR3 of SEQ ID NO: 54. In one embodiment, a subject exhibiting elevated levels relative to a control of at least one biomarker selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count, and lactate dehydrogenase (LDH) is selected, and the subject is administered an anti-OX40L antibody or an antigen-binding fragment thereof to reduce the level of at least one biomarker selected from TARC, IL-5, eosinophil count, and LDH. In a further embodiment, a subject exhibiting elevated levels relative to a control of at least one biomarker selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count, and lactate dehydrogenase (LDH) is selected, and the subject is administered an anti-OX40L antibody or an antigen-binding fragment thereof to reduce the level of all biomarkers selected from TARC, IL-5, eosinophil count, and LDH.

[0136] The OX40L antibody or its antigen-binding fragment may comprise: a variable heavy (VH) domain comprising the amino acid sequence of SEQ ID NO: 34, or at least 80% (e.g., at least 85%) of the VH domain amino acid sequence identical to SEQ ID NO: 34; and / or a variable light (VL) domain comprising the amino acid sequence of SEQ ID NO: 48, or at least 80% (e.g., at least 85%, 90%, or 95%) of the VL domain identical to SEQ ID NO: 48. Therefore, the OX40L antibody or its antigen-binding fragment may comprise: a VH domain comprising the amino acid sequence of SEQ ID NO: 34; and a VL domain comprising the amino acid sequence of SEQ ID NO: 48. Similarly, antibodies defined by reference to the above CDR or the above VH and / or VL domains may comprise a heavy chain and a light chain, the heavy chain amino acid sequence comprising the sequence of SEQ ID NO: 62, and the light chain amino acid sequence comprising the sequence of SEQ ID NO: 64. It should be understood that antibodies defined by the above CDR, the above VH and / or VL domains, or the above heavy chain and / or light chain sequences may also include an IgG4 constant region, optionally wherein the constant region is IgG4-PE (SEQ ID NO:128). The OX40L antibody or its antigen-binding fragment may be an OX40L antagonist.

[0137] On the other hand, a method for treating atopic dermatitis (AD) in a subject of need is provided, the method comprising administering to the subject an effective amount of an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 42, HCDR2 of SEQ ID NO: 44 and HCDR3 of SEQ ID NO: 46, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 56, LCDR2 of SEQ ID NO: 58 and LCDR3 of SEQ ID NO: 60; and reducing the level of at least one biomarker selected from TARC, IL-5, eosinophil count, LDH, or combinations thereof. In one embodiment, the levels of all biomarkers selected from TARC, IL-5, eosinophil count, and LDH are reduced.

[0138] In another aspect, a method for treating atopic dermatitis (AD) in a subject of need is provided, the method comprising administering to the subject an effective amount of an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 36, HCDR2 of SEQ ID NO: 38 and HCDR3 of SEQ ID NO: 40, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 50, LCDR2 of SEQ ID NO: 52 and LCDR3 of SEQ ID NO: 54; and reducing the level of at least one biomarker selected from TARC, IL-5, eosinophil count, LDH, or combinations thereof. In one embodiment, the levels of all biomarkers selected from TARC, IL-5, eosinophil count, and LDH are reduced.

[0139] The OX40L antibody or its antigen-binding fragment may comprise: a variable heavy (VH) domain comprising the amino acid sequence of SEQ ID NO: 34, or at least 80% (e.g., at least 85%) of the VH domain amino acid sequence identical to SEQ ID NO: 34; and / or a variable light (VL) domain comprising the amino acid sequence of SEQ ID NO: 48, or at least 80% (e.g., at least 85%, 90%, or 95%) of the VL domain identical to SEQ ID NO: 48. Therefore, the OX40L antibody or its antigen-binding fragment may comprise: a VH domain comprising the amino acid sequence of SEQ ID NO: 34; and a VL domain comprising the amino acid sequence of SEQ ID NO: 48. Similarly, antibodies defined by reference to the above CDR or the above VH and / or VL domains may comprise a heavy chain and a light chain, the heavy chain amino acid sequence comprising the sequence of SEQ ID NO: 62, and the light chain amino acid sequence comprising the sequence of SEQ ID NO: 64. It should be understood that antibodies defined by the above CDR, the above VH and / or VL domains, or the above heavy chain and / or light chain sequences may also include an IgG4 constant region, optionally wherein the constant region is IgG4-PE (SEQ ID NO:128). The OX40L antibody or its antigen-binding fragment may be an OX40L antagonist.

[0140] On the other hand, a method for treating atopic dermatitis (AD) in a subject in need is provided, the method comprising selecting a subject suffering from AD and having elevated levels relative to a control of at least one biomarker selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count and lactate dehydrogenase (LDH), and administering to the subject an effective amount of an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 42, the HCDR2 of SEQ ID NO: 44 and the HCDR3 of SEQ ID NO: 46, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 56, the LCDR2 of SEQ ID NO: 58 and the LCDR3 of SEQ ID NO: 60. In one embodiment, subjects with elevated levels relative to controls of all biomarkers selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count, and lactate dehydrogenase (LDH) were selected.

[0141] On the other hand, a method for treating atopic dermatitis (AD) in a subject in need is provided, the method comprising selecting a subject suffering from AD and having elevated levels relative to a control of at least one biomarker selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count and lactate dehydrogenase (LDH), and administering to the subject an effective amount of an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 36, the HCDR2 of SEQ ID NO: 38 and the HCDR3 of SEQ ID NO: 40, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 50, the LCDR2 of SEQ ID NO: 52 and the LCDR3 of SEQ ID NO: 54. In one embodiment, subjects with elevated levels relative to controls of all biomarkers selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count, and lactate dehydrogenase (LDH) were selected.

[0142] The OX40L antibody or its antigen-binding fragment may comprise: a variable heavy (VH) domain comprising the amino acid sequence of SEQ ID NO: 34, or at least 80% (e.g., at least 85%) of the VH domain amino acid sequence identical to SEQ ID NO: 34; and / or a variable light (VL) domain comprising the amino acid sequence of SEQ ID NO: 48, or at least 80% (e.g., at least 85%, 90%, or 95%) of the VL domain identical to SEQ ID NO: 48. Therefore, the OX40L antibody or its antigen-binding fragment may comprise: a VH domain comprising the amino acid sequence of SEQ ID NO: 34; and a VL domain comprising the amino acid sequence of SEQ ID NO: 48. Similarly, antibodies defined by reference to the above CDR or the above VH and / or VL domains may comprise a heavy chain and a light chain, the heavy chain amino acid sequence comprising the sequence of SEQ ID NO: 62, and the light chain amino acid sequence comprising the sequence of SEQ ID NO: 64. It should be understood that antibodies defined by the above CDR, the above VH and / or VL domains, or the above heavy chain and / or light chain sequences may also include an IgG4 constant region, optionally wherein the constant region is IgG4-PE (SEQ ID NO:128). The OX40L antibody or its antigen-binding fragment may be an OX40L antagonist.

[0143] In another aspect, a method for reducing biomarkers in a subject suffering from atopic dermatitis (AD) is provided, the method comprising administering to the subject an effective amount of an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 42, HCDR2 of SEQ ID NO: 44, and HCDR3 of SEQ ID NO: 46, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 56, LCDR2 of SEQ ID NO: 58, and LCDR3 of SEQ ID NO: 60; wherein the biomarker is selected from TARC, IL-5, eosinophil count, and LDH. In one embodiment, the levels of all biomarkers selected from TARC, IL-5, eosinophil count, and LDH are reduced.

[0144] In another aspect, a method for reducing biomarkers in a subject suffering from atopic dermatitis (AD) is provided, the method comprising administering to the subject an effective amount of an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 36, HCDR2 of SEQ ID NO: 38, and HCDR3 of SEQ ID NO: 40, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 50, LCDR2 of SEQ ID NO: 52, and LCDR3 of SEQ ID NO: 54; wherein the biomarker is selected from TARC, IL-5, eosinophil count, and LDH. In one embodiment, the levels of all biomarkers selected from TARC, IL-5, eosinophil count, and LDH are reduced.

[0145] The OX40L antibody or its antigen-binding fragment may comprise: a variable heavy (VH) domain comprising the amino acid sequence of SEQ ID NO: 34, or at least 80% (e.g., at least 85%) of the VH domain amino acid sequence identical to SEQ ID NO: 34; and / or a variable light (VL) domain comprising the amino acid sequence of SEQ ID NO: 48, or at least 80% (e.g., at least 85%, 90%, or 95%) of the VL domain identical to SEQ ID NO: 48. Therefore, the OX40L antibody or its antigen-binding fragment may comprise: a VH domain comprising the amino acid sequence of SEQ ID NO: 34; and a VL domain comprising the amino acid sequence of SEQ ID NO: 48. Similarly, antibodies defined by reference to the above CDR or the above VH and / or VL domains may comprise a heavy chain and a light chain, the heavy chain amino acid sequence comprising the sequence of SEQ ID NO: 62, and the light chain amino acid sequence comprising the sequence of SEQ ID NO: 64. It should be understood that antibodies defined by the above CDR, the above VH and / or VL domains, or the above heavy chain and / or light chain sequences may also include an IgG4 constant region, optionally wherein the constant region is IgG4-PE (SEQ ID NO:128). The OX40L antibody or its antigen-binding fragment may be an OX40L antagonist.

[0146] In another aspect, a method is provided for reducing biomarkers in subjects with atopic dermatitis (AD), the method comprising selecting a subject with AD and having elevated levels relative to a control of at least one biomarker selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count and lactate dehydrogenase (LDH), and administering to the subject an effective amount of an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 42, HCDR2 of SEQ ID NO: 44 and HCDR3 of SEQ ID NO: 46, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 56, LCDR2 of SEQ ID NO: 58 and LCDR3 of SEQ ID NO: 60. In one embodiment, subjects with elevated levels relative to controls of all biomarkers selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count, and lactate dehydrogenase (LDH) were selected.

[0147] In another aspect, a method is provided for reducing biomarkers in subjects with atopic dermatitis (AD), the method comprising selecting a subject with AD and having elevated levels relative to a control of at least one biomarker selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count and lactate dehydrogenase (LDH), and administering to the subject an effective amount of an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 36, HCDR2 of SEQ ID NO: 38 and HCDR3 of SEQ ID NO: 40, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 50, LCDR2 of SEQ ID NO: 52 and LCDR3 of SEQ ID NO: 54. In one embodiment, subjects with elevated levels relative to controls of all biomarkers selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count, and lactate dehydrogenase (LDH) were selected.

[0148] The OX40L antibody or its antigen-binding fragment may comprise: a variable heavy (VH) domain comprising the amino acid sequence of SEQ ID NO: 34, or at least 80% (e.g., at least 85%) of the VH domain amino acid sequence identical to SEQ ID NO: 34; and / or a variable light (VL) domain comprising the amino acid sequence of SEQ ID NO: 48, or at least 80% (e.g., at least 85%, 90%, or 95%) of the VL domain identical to SEQ ID NO: 48. Therefore, the OX40L antibody or its antigen-binding fragment may comprise: a VH domain comprising the amino acid sequence of SEQ ID NO: 34; and a VL domain comprising the amino acid sequence of SEQ ID NO: 48. Similarly, antibodies defined by reference to the above CDR or the above VH and / or VL domains may comprise a heavy chain and a light chain, the heavy chain amino acid sequence comprising the sequence of SEQ ID NO: 62, and the light chain amino acid sequence comprising the sequence of SEQ ID NO: 64. It should be understood that antibodies defined by the above CDR, the above VH and / or VL domains, or the above heavy chain and / or light chain sequences may also include an IgG4 constant region, optionally wherein the constant region is IgG4-PE (SEQ ID NO:128). The OX40L antibody or its antigen-binding fragment may be an OX40L antagonist.

[0149] In another aspect, a method is provided for reducing biomarkers in a subject suffering from an immune-mediated disease, the method comprising administering to the subject an effective amount of an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 42, HCDR2 of SEQ ID NO: 44, and HCDR3 of SEQ ID NO: 46, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 56, LCDR2 of SEQ ID NO: 58, and LCDR3 of SEQ ID NO: 60; wherein the biomarker is selected from TARC, IL-5, eosinophil count, and LDH. In one embodiment, the levels of all biomarkers selected from TARC, IL-5, eosinophil count, and LDH are reduced. In another aspect, a method is provided for reducing biomarkers in a subject suffering from an immune-mediated disease, the method comprising administering to the subject an effective amount of an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 36, HCDR2 of SEQ ID NO: 38, and HCDR3 of SEQ ID NO: 40, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 50, LCDR2 of SEQ ID NO: 52, and LCDR3 of SEQ ID NO: 54; wherein the biomarker is selected from TARC, IL-5, eosinophil count, and LDH. In one embodiment, the levels of all biomarkers selected from TARC, IL-5, eosinophil count, and LDH are reduced.

[0150] The OX40L antibody or its antigen-binding fragment may comprise: a variable heavy (VH) domain comprising the amino acid sequence of SEQ ID NO: 34, or at least 80% (e.g., at least 85%) of the VH domain amino acid sequence identical to SEQ ID NO: 34; and / or a variable light (VL) domain comprising the amino acid sequence of SEQ ID NO: 48, or at least 80% (e.g., at least 85%, 90%, or 95%) of the VL domain identical to SEQ ID NO: 48. Therefore, the OX40L antibody or its antigen-binding fragment may comprise: a VH domain comprising the amino acid sequence of SEQ ID NO: 34; and a VL domain comprising the amino acid sequence of SEQ ID NO: 48. Similarly, antibodies defined by reference to the above CDR or the above VH and / or VL domains may comprise a heavy chain and a light chain, the heavy chain amino acid sequence comprising the sequence of SEQ ID NO: 62, and the light chain amino acid sequence comprising the sequence of SEQ ID NO: 64. It should be understood that antibodies defined by the above CDR, the above VH and / or VL domains, or the above heavy chain and / or light chain sequences may also include an IgG4 constant region, optionally wherein the constant region is IgG4-PE (SEQ ID NO:128). The OX40L antibody or its antigen-binding fragment may be an OX40L antagonist.

[0151] In another aspect, a method is provided for reducing biomarkers in subjects with immune-mediated diseases, the method comprising selecting a subject with AD and having elevated levels of at least one biomarker selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count and lactate dehydrogenase (LDH) relative to a control, and administering to the subject an effective amount of an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 42, HCDR2 of SEQ ID NO: 44 and HCDR3 of SEQ ID NO: 46, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 56, LCDR2 of SEQ ID NO: 58 and LCDR3 of SEQ ID NO: 60. In one embodiment, subjects with elevated levels relative to controls of all biomarkers selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count, and lactate dehydrogenase (LDH) were selected.

[0152] In another aspect, a method is provided for reducing biomarkers in subjects with immune-mediated diseases, the method comprising selecting a subject with AD and having elevated levels of at least one biomarker selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count and lactate dehydrogenase (LDH) relative to a control, and administering to the subject an effective amount of an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 36, HCDR2 of SEQ ID NO: 38 and HCDR3 of SEQ ID NO: 40, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 50, LCDR2 of SEQ ID NO: 52 and LCDR3 of SEQ ID NO: 54. In one embodiment, subjects with elevated levels relative to controls of all biomarkers selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count, and lactate dehydrogenase (LDH) were selected.

[0153] The OX40L antibody or its antigen-binding fragment may comprise: a variable heavy (VH) domain comprising the amino acid sequence of SEQ ID NO: 34, or at least 80% (e.g., at least 85%) of the VH domain amino acid sequence identical to SEQ ID NO: 34; and / or a variable light (VL) domain comprising the amino acid sequence of SEQ ID NO: 48, or at least 80% (e.g., at least 85%, 90%, or 95%) of the VL domain identical to SEQ ID NO: 48. Therefore, the OX40L antibody or its antigen-binding fragment may comprise: a VH domain comprising the amino acid sequence of SEQ ID NO: 34; and a VL domain comprising the amino acid sequence of SEQ ID NO: 48. Similarly, antibodies defined by reference to the above CDR or the above VH and / or VL domains may comprise a heavy chain and a light chain, the heavy chain amino acid sequence comprising the sequence of SEQ ID NO: 62, and the light chain amino acid sequence comprising the sequence of SEQ ID NO: 64. It should be understood that antibodies defined by the above CDR, the above VH and / or VL domains, or the above heavy chain and / or light chain sequences may also include an IgG4 constant region, optionally wherein the constant region is IgG4-PE (SEQ ID NO:128). The OX40L antibody or its antigen-binding fragment may be an OX40L antagonist.

[0154] In the various embodiments disclosed herein, the antibody or its antigen-binding fragment is anilidelimab or a variant thereof. In some embodiments, the antibody is anilidelimab.

[0155] In the various embodiments disclosed herein, the method results in a reduction in the level of at least one biomarker selected from TARC, IL-5, eosinophil count, LDH, or combinations thereof relative to the baseline level of the corresponding biomarker in the subject prior to administration of an effective amount of anti-OX40 ligand (OX40L) antibody or its antigen-binding fragment.

[0156] In the various embodiments disclosed herein, the effective amount of the anti-OX40 ligand (OX40L) antibody or its antigen-binding fragment ranges from 50 mg to 500 mg.

[0157] In the various embodiments disclosed herein, the effective amount of the anti-OX40 ligand (OX40L) antibody or its antigen-binding fragment is about 62.5 mg, 125 mg, 250 mg or 500 mg.

[0158] In the various embodiments disclosed herein, the subject receives an initial dose of about 500 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 250 mg of the antibody or its antigen-binding fragment.

[0159] In the various embodiments disclosed herein, the subject receives an initial dose of about 250 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 250 mg of the antibody or its antigen-binding fragment.

[0160] In the various embodiments disclosed herein, the subject receives an initial dose of about 250 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 125 mg of the antibody or its antigen-binding fragment.

[0161] In the various embodiments disclosed herein, the subject receives an initial dose of about 125 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 125 mg of the antibody or its antigen-binding fragment.

[0162] In the various embodiments disclosed herein, the subject receives an initial dose of about 62.5 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 62.5 mg of the antibody or its antigen-binding fragment.

[0163] In the various embodiments disclosed herein, each second dose may be administered every 4 weeks (Q4W) over a 24-week period.

[0164] In the various embodiments disclosed herein, the first second dose is administered every 4 weeks (Q4W) after the initial dose until week 24, and each subsequent second dose is administered every 12 weeks (Q12W).

[0165] In the various embodiments disclosed herein, including those involving specific biomarkers, each dose is administered Q12W. In some exemplary embodiments, the subject receives the dose Q12W at the start of treatment. In some exemplary embodiments, the subject receives the dose directly Q12W without prior dose administration Q4W. For example, an adult subject may receive an initial dose of about 500 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 250 mg of the antibody or its antigen-binding fragment, wherein the second dose is administered every 12 weeks (Q12W). In another example, an adolescent subject may receive an initial dose of about 250 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 125 mg of the antibody or its antigen-binding fragment, wherein the second dose is administered every 12 weeks (Q12W).

[0166] In the various embodiments disclosed herein, the antibody or its antigen-binding fragment is administered via a pre-filled syringe, pen delivery device, or autoinjector.

[0167] In the various embodiments disclosed herein, the subject is treated with the antibody or its antigen-binding fragment for a duration of approximately 4 to approximately 24 weeks.

[0168] In the various embodiments disclosed herein, the subject was treated with the antibody or its antigen-binding fragment for a duration of approximately 4 weeks, 16 weeks, 24 weeks, or 52 weeks.

[0169] In the various embodiments disclosed herein, the atopic dermatitis is moderate to severe atopic dermatitis.

[0170] In the various embodiments disclosed herein, the moderate to severe atopic dermatitis is not adequately controlled or is not desirable with topical or systemic therapies.

[0171] On the other hand, a method for treating atopic dermatitis (AD) in a subject of need is provided, the method comprising selecting a subject with elevated levels of biomarkers, wherein the biomarkers are selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count and lactate dehydrogenase (LDH), and administering to the subject an anti-OX40 ligand (OX40L) antibody or antigen and its binding fragment, wherein the antibody or its antigen-binding fragment comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 42, HCDR2 of SEQ ID NO: 44 and HCDR3 of SEQ ID NO: 46, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 56, LCDR2 of SEQ ID NO: 58 and LCDR3 of SEQ ID NO: 60. In one embodiment, subjects with elevated levels relative to controls of all biomarkers selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count, and lactate dehydrogenase (LDH) were selected.

[0172] On the other hand, a method for treating atopic dermatitis (AD) in a subject of need is provided, the method comprising selecting a subject with elevated levels of biomarkers, wherein the biomarkers are selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count and lactate dehydrogenase (LDH), and administering to the subject an anti-OX40 ligand (OX40L) antibody or antigen or its binding fragment, wherein the antibody or its antigen-binding fragment comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 36, HCDR2 of SEQ ID NO: 38 and HCDR3 of SEQ ID NO: 40, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 50, LCDR2 of SEQ ID NO: 52 and LCDR3 of SEQ ID NO: 54. In one embodiment, subjects with elevated levels relative to controls of all biomarkers selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count, and lactate dehydrogenase (LDH) were selected.

[0173] The OX40L antibody or its antigen-binding fragment may comprise: a variable heavy (VH) domain comprising the amino acid sequence of SEQ ID NO: 34, or at least 80% (e.g., at least 85%) of the VH domain amino acid sequence identical to SEQ ID NO: 34; and / or a variable light (VL) domain comprising the amino acid sequence of SEQ ID NO: 48, or at least 80% (e.g., at least 85%, 90%, or 95%) of the VL domain identical to SEQ ID NO: 48. Therefore, the OX40L antibody or its antigen-binding fragment may comprise: a VH domain comprising the amino acid sequence of SEQ ID NO: 34; and a VL domain comprising the amino acid sequence of SEQ ID NO: 48. Similarly, antibodies defined by reference to the above CDR or the above VH and / or VL domains may comprise a heavy chain and a light chain, the heavy chain amino acid sequence comprising the sequence of SEQ ID NO: 62, and the light chain amino acid sequence comprising the sequence of SEQ ID NO: 64. It should be understood that antibodies defined by the above CDR, the above VH and / or VL domains, or the above heavy chain and / or light chain sequences may also include an IgG4 constant region, optionally wherein the constant region is IgG4-PE (SEQ ID NO:128). The OX40L antibody or its antigen-binding fragment may be an OX40L antagonist.

[0174] In some exemplary embodiments, the method results in a reduction in the level of at least one biomarker in the subject relative to a control (e.g., relative to the level of at least one biomarker prior to administration of an anti-OX40 ligand (OX40L) antibody or its antigen-binding fragment).

[0175] In some exemplary embodiments, the antibody or its antigen-binding fragment is anitolide or a variant thereof. In some exemplary embodiments, the antibody is anitolide.

[0176] In some exemplary embodiments, the effective amount of the anti-OX40 ligand (OX40L) antibody or its antigen-binding fragment ranges from 50 mg to 500 mg. In some exemplary embodiments, the effective amount of the anti-OX40 ligand (OX40L) antibody or its antigen-binding fragment is about 62.5 mg, 125 mg, 250 mg, or 500 mg.

[0177] In some exemplary embodiments, the subject receives an initial dose of about 250 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 125 mg of the antibody or its antigen-binding fragment.

[0178] In some exemplary embodiments, the subject receives an initial dose of about 500 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 250 mg of the antibody or its antigen-binding fragment.

[0179] In some exemplary embodiments, the subject receives an initial dose of about 250 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 250 mg of the antibody or its antigen-binding fragment.

[0180] In some exemplary embodiments, the subject receives an initial dose of about 125 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 125 mg of the antibody or its antigen-binding fragment.

[0181] In some exemplary embodiments, the subject receives an initial dose of about 62.5 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 62.5 mg of the antibody or its antigen-binding fragment.

[0182] In some exemplary embodiments, each second dose is administered every 4 weeks (Q4W).

[0183] In some exemplary embodiments, each dose is administered Q12W. In some exemplary embodiments, the subject receives the dose Q12W from the start of treatment. In some exemplary embodiments, the subject receives the dose directly Q12W without prior dose administration Q4W. For example, an adult subject may receive an initial dose of about 500 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 250 mg of the antibody or its antigen-binding fragment, wherein the second dose is administered every 12 weeks (Q12W). In another example, an adolescent subject may receive an initial dose of about 250 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 125 mg of the antibody or its antigen-binding fragment, wherein the second dose is administered every 12 weeks (Q12W).

[0184] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered via a pre-filled syringe, a pen delivery device, or an autoinjector.

[0185] In some exemplary embodiments, the atopic dermatitis is moderate to severe. In some exemplary embodiments, the moderate to severe atopic dermatitis is not adequately controlled with topical or systemic therapy, or where topical or systemic therapy is not desirable.

[0186] In some exemplary embodiments, the subject's EASI score is reduced. In some exemplary embodiments, the EASI score is selected from the group consisting of EASI-75, EASI-90, and EASI-100.

[0187] In some exemplary embodiments, the subject's IGA score is reduced.

[0188] In some exemplary embodiments, the subject's PP-NRS score is reduced.

[0189] In some exemplary embodiments, the subject's SP-NRS score is reduced.

[0190] In some exemplary embodiments, the subject's SD-NRS score is reduced.

[0191] In some exemplary embodiments, the subject's DLQI score is reduced.

[0192] In some exemplary embodiments, the subject's HADS score is improved.

[0193] In some exemplary embodiments, the level of at least one biomarker selected from the group consisting of TARC, IL-5, eosinophil count and LDH is reduced in the subject.

[0194] On the other hand, a method is provided for reducing biomarkers in a subject suffering from atopic dermatitis (AD), the method comprising administering to the subject an effective amount of an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 42, HCDR2 of SEQ ID NO: 44, and HCDR3 of SEQ ID NO: 46, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 56, LCDR2 of SEQ ID NO: 58, and LCDR3 of SEQ ID NO: 60, wherein the biomarker is selected from TARC, IL-5, eosinophil count, and LDH. In one embodiment, the levels of all biomarkers selected from TARC, IL-5, eosinophil count, and LDH are reduced.

[0195] On the other hand, a method is provided for reducing biomarkers in a subject suffering from atopic dermatitis (AD), the method comprising administering to the subject an effective amount of an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 36, HCDR2 of SEQ ID NO: 38, and HCDR3 of SEQ ID NO: 40, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 50, LCDR2 of SEQ ID NO: 52, and LCDR3 of SEQ ID NO: 54, wherein the biomarker is selected from TARC, IL-5, eosinophil count, and LDH. In one embodiment, the levels of all biomarkers selected from TARC, IL-5, eosinophil count, and LDH are reduced.

[0196] The OX40L antibody or its antigen-binding fragment may comprise: a variable heavy (VH) domain comprising the amino acid sequence of SEQ ID NO: 34, or at least 80% (e.g., at least 85%) of the VH domain amino acid sequence identical to SEQ ID NO: 34; and / or a variable light (VL) domain comprising the amino acid sequence of SEQ ID NO: 48, or at least 80% (e.g., at least 85%, 90%, or 95%) of the VL domain identical to SEQ ID NO: 48. Therefore, the OX40L antibody or its antigen-binding fragment may comprise: a VH domain comprising the amino acid sequence of SEQ ID NO: 34; and a VL domain comprising the amino acid sequence of SEQ ID NO: 48. Similarly, antibodies defined by reference to the above CDR or the above VH and / or VL domains may comprise a heavy chain and a light chain, the heavy chain amino acid sequence comprising the sequence of SEQ ID NO: 62, and the light chain amino acid sequence comprising the sequence of SEQ ID NO: 64. It should be understood that antibodies defined by the above CDR, the above VH and / or VL domains, or the above heavy chain and / or light chain sequences may also include an IgG4 constant region, optionally wherein the constant region is IgG4-PE (SEQ ID NO:128). The OX40L antibody or its antigen-binding fragment may be an OX40L antagonist.

[0197] In some exemplary embodiments, the method results in a reduction in the level of at least one biomarker in the subject relative to a control (e.g., relative to the level of at least one biomarker prior to administration of an anti-OX40 ligand (OX40L) antibody or its antigen-binding fragment).

[0198] In some exemplary embodiments, the antibody or its antigen-binding fragment is anitolide or a variant thereof. In some exemplary embodiments, the antibody is anitolide.

[0199] In some exemplary embodiments, the method results in a reduction in the level of at least one biomarker selected from TARC, IL-5, eosinophil count, and LDH, or combinations thereof, relative to the baseline level of the corresponding biomarker in the subject prior to administration of an effective amount of anti-OX40L antibody or its antigen-binding fragment.

[0200] In some exemplary embodiments, the effective amount of the anti-OX40L antibody or its antigen-binding fragment ranges from 50 mg to 500 mg. In some exemplary embodiments, the effective amount of the anti-OX40L antibody or its antigen-binding fragment is about 62.5 mg, 125 mg, 250 mg, or 500 mg.

[0201] In some exemplary embodiments, the subject receives an initial dose of about 250 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 125 mg of the antibody or its antigen-binding fragment.

[0202] In some exemplary embodiments, the subject receives an initial dose of about 500 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 250 mg of the antibody or its antigen-binding fragment.

[0203] In some exemplary embodiments, the subject receives an initial dose of about 250 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 250 mg of the antibody or its antigen-binding fragment.

[0204] In some exemplary embodiments, the subject receives an initial dose of about 125 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 125 mg of the antibody or its antigen-binding fragment.

[0205] In some exemplary embodiments, the subject receives an initial dose of about 62.5 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 62.5 mg of the antibody or its antigen-binding fragment.

[0206] In some exemplary embodiments, each second dose is administered every Q4W.

[0207] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered via a pre-filled syringe, a pen delivery device, or an autoinjector.

[0208] In some exemplary embodiments, the atopic dermatitis is moderate to severe. In some exemplary embodiments, the moderate to severe atopic dermatitis is not adequately controlled with topical or systemic therapy, or where topical or systemic therapy is not desirable.

[0209] In some exemplary embodiments, the subject's EASI score is reduced. In some exemplary embodiments, the EASI score is selected from the group consisting of EASI-75, EASI-90, and EASI-100.

[0210] In some exemplary embodiments, the subject's IGA score is reduced.

[0211] In some exemplary embodiments, the subject's PP-NRS score is reduced.

[0212] In some exemplary embodiments, the subject's SP-NRS score is reduced.

[0213] In some exemplary embodiments, the subject's SD-NRS score is reduced.

[0214] In some exemplary embodiments, the subject's DLQI score is reduced.

[0215] In some exemplary embodiments, the subject's HADS score is improved.

[0216] On the other hand, a method for treating an immune-mediated disease in a subject of need is provided, the method comprising administering to the subject an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 42, the HCDR2 of SEQ ID NO: 44 and the HCDR3 of SEQ ID NO: 46, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 56, the LCDR2 of SEQ ID NO: 58 and the LCDR3 of SEQ ID NO: 60, and wherein the immune-mediated disease is selected from the group consisting of: atopic dermatitis (AD), asthma, interstitial lung disease-systemic sclerosis (ILD-SSc), systemic sclerosis (SSc), hidradenitis suppurativa (HS), alopecia areata (AA) and celiac disease.

[0217] On the other hand, a method for treating an immune-mediated disease in a subject of need is provided, the method comprising administering to the subject an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 36, HCDR2 of SEQ ID NO: 38 and HCDR3 of SEQ ID NO: 40, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 50, LCDR2 of SEQ ID NO: 52 and LCDR3 of SEQ ID NO: 54, and wherein the immune-mediated disease is selected from the group consisting of: atopic dermatitis (AD), asthma, interstitial lung disease-systemic sclerosis (ILD-SSc), systemic sclerosis (SSc), hidradenitis suppurativa (HS), alopecia areata (AA) and celiac disease. The OX40L antibody or its antigen-binding fragment may comprise: a variable heavy (VH) domain comprising the amino acid sequence of SEQ ID NO: 34, or at least 80% (e.g., at least 85%) of the same VH domain amino acid sequence as SEQ ID NO: 34; and / or a variable light (VL) domain comprising the amino acid sequence of SEQ ID NO: 48, or at least 80% (e.g., at least 85%, 90%, or 95%) of the same VL domain as SEQ ID NO: 48. Therefore, the OX40L antibody or its antigen-binding fragment may comprise: a VH domain comprising the amino acid sequence of SEQ ID NO: 34; and a VL domain comprising the amino acid sequence of SEQ ID NO: 48. Similarly, antibodies defined by reference to the above CDR or the above VH and / or VL domains may comprise a heavy chain and a light chain, the heavy chain amino acid sequence comprising the sequence of SEQ ID NO: 62, and the light chain amino acid sequence comprising the sequence of SEQ ID NO: 64. It should be understood that antibodies defined by the above CDR, the above VH and / or VL domains, or the above heavy chain and / or light chain sequences may also include an IgG4 constant region, optionally wherein the constant region is IgG4-PE (SEQ ID NO: 128). The OX40L antibody or its antigen-binding fragment may be an OX40L antagonist.

[0218] In some exemplary embodiments, the immune-mediated disease is Alzheimer's disease (AD). In some exemplary embodiments, the immune-mediated disease is asthma. In some exemplary embodiments, the immune-mediated disease is ILD-SSc. In some exemplary embodiments, the immune-mediated disease is SSc. In some exemplary embodiments, the immune-mediated disease is HS. In some exemplary embodiments, the immune-mediated disease is AA. In some exemplary embodiments, the immune-mediated disease is celiac disease. In some exemplary embodiments, systemic therapy is not desirable.

[0219] In some exemplary embodiments, the method results in a reduction in the level of at least one biomarker in the subject relative to a control (e.g., relative to the level of at least one biomarker prior to administration of an anti-OX40 ligand (OX40L) antibody or its antigen-binding fragment).

[0220] In some exemplary embodiments, the antibody or its antigen-binding fragment is anitolide or a variant thereof. In some exemplary embodiments, the antibody is anitolide.

[0221] In some exemplary embodiments, the method results in a reduction in the level of at least one biomarker selected from TARC, IL-5, eosinophil count, and LDH, or any combination thereof, relative to the baseline level of the corresponding biomarker in the subject prior to administration of an effective amount of anti-OX40L antibody or its antigen-binding fragment.

[0222] In some exemplary embodiments, the effective amount of the anti-OX40L antibody or its antigen-binding fragment ranges from 50 mg to 500 mg. In some exemplary embodiments, the effective amount of the anti-OX40L antibody or its antigen-binding fragment is about 62.5 mg, 125 mg, 250 mg, or 500 mg. In some exemplary embodiments, the effective amount of the anti-OX40L antibody or its antigen-binding fragment is 62.5 mg, 125 mg, 250 mg, or 500 mg.

[0223] In some exemplary embodiments, the subject receives an initial dose of about 250 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 125 mg of the antibody or its antigen-binding fragment.

[0224] In some exemplary embodiments, the subject receives an initial dose of about 500 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 250 mg of the antibody or its antigen-binding fragment.

[0225] In some exemplary embodiments, the subject receives an initial dose of about 250 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 250 mg of the antibody or its antigen-binding fragment.

[0226] In some exemplary embodiments, the subject receives an initial dose of about 125 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 125 mg of the antibody or its antigen-binding fragment.

[0227] In some exemplary embodiments, the subject receives an initial dose of about 62.5 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 62.5 mg of the antibody or its antigen-binding fragment.

[0228] In some exemplary embodiments, each second dose Q4W is administered.

[0229] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered via a pre-filled syringe, a pen delivery device, or an autoinjector.

[0230] In some exemplary embodiments, the atopic dermatitis is moderate to severe. In some exemplary embodiments, the moderate to severe atopic dermatitis is not adequately controlled with topical or systemic therapy, or where topical or systemic therapy is not desirable.

[0231] In some exemplary embodiments, the subject's EASI score is reduced. In some exemplary embodiments, the EASI score is selected from the group consisting of EASI-75, EASI-90, and EASI-100.

[0232] In some exemplary embodiments, the subject's IGA score is reduced.

[0233] In some exemplary embodiments, the subject's PP-NRS score is reduced.

[0234] In some exemplary embodiments, the subject's SP-NRS score is reduced.

[0235] In some exemplary embodiments, the subject's SD-NRS score is reduced.

[0236] In some exemplary embodiments, the subject's DLQI score is reduced.

[0237] In some exemplary embodiments, the subject's HADS score is improved.

[0238] In some exemplary embodiments, the level of at least one biomarker selected from the group consisting of TARC, IL-5, eosinophil count and LDH is reduced in the subject.

[0239] On the other hand, a method for treating atopic dermatitis in a subject of need is provided, the method comprising administering to the subject an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 42, the HCDR2 of SEQ ID NO: 44, and the HCDR3 of SEQ ID NO: 46, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 56, the LCDR2 of SEQ ID NO: 58, and the LCDR3 of SEQ ID NO: 60, wherein efficacy is maintained at week 28 after discontinuation of treatment or at week 32 after final administration of the antibody or antigen-binding fragment to the subject. For the purposes of “maintaining efficacy at week 28 after discontinuation of treatment or at week 32 after final administration of the antibody or antigen-binding fragment” herein, we include the meaning of maintaining efficacy 28 or 32 weeks after final administration of the antibody or antigen-binding fragment to the subject.

[0240] On the other hand, a method for treating atopic dermatitis in a subject in need is provided, the method comprising administering to the subject an anti-OX40 ligand (OX40L) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity-determining region (HCDR) 1 of SEQ ID NO: 36, the HCDR2 of SEQ ID NO: 38 and the HCDR3 of SEQ ID NO: 40, and the light chain complementarity-determining region (LCDR) 1 of SEQ ID NO: 50, the LCDR2 of SEQ ID NO: 52 and the LCDR3 of SEQ ID NO: 54, wherein efficacy is maintained at week 28 after discontinuation of treatment or at week 32 after the final administration of the antibody or antigen-binding fragment thereof to the subject. The OX40L antibody or its antigen-binding fragment may comprise: a variable heavy (VH) domain comprising the amino acid sequence of SEQ ID NO: 34, or at least 80% (e.g., at least 85%) of the VH domain amino acid sequence identical to SEQ ID NO: 34; and / or a variable light (VL) domain comprising the amino acid sequence of SEQ ID NO: 48, or at least 80% (e.g., at least 85%, 90%, or 95%) of the VL domain identical to SEQ ID NO: 48. Therefore, the OX40L antibody or its antigen-binding fragment may comprise: a VH domain comprising the amino acid sequence of SEQ ID NO: 34; and a VL domain comprising the amino acid sequence of SEQ ID NO: 48. Similarly, antibodies defined by reference to the above CDR or the above VH and / or VL domains may comprise a heavy chain and a light chain, the heavy chain amino acid sequence comprising the sequence of SEQ ID NO: 62, and the light chain amino acid sequence comprising the sequence of SEQ ID NO: 64. It should be understood that antibodies defined by the above CDR, the above VH and / or VL domains, or the above heavy chain and / or light chain sequences may also include an IgG4 constant region, optionally wherein the constant region is IgG4-PE (SEQ ID NO: 128). The OX40L antibody or its antigen-binding fragment may be an OX40L antagonist.

[0241] In some exemplary embodiments, each dose is administered Q12W. In some exemplary embodiments, the subject receives the dose Q12W from the start of treatment. In some exemplary embodiments, the subject receives the dose directly Q12W without prior dose administration Q4W. For example, an adult subject may receive an initial dose of about 500 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 250 mg of the antibody or its antigen-binding fragment, wherein the second dose is administered every 12 weeks (Q12W). In another example, an adolescent subject may receive an initial dose of about 250 mg of the antibody or its antigen-binding fragment, followed by one or more second doses of about 125 mg of the antibody or its antigen-binding fragment, wherein the second dose is administered every 12 weeks (Q12W).

[0242] In some exemplary embodiments, the subject is a vIGA 0 / 1 responder and maintains vIGA 0 / 1 response efficacy, or the subject is an AESI 75 responder and maintains EASI 75 response efficacy. In some exemplary embodiments, the subject is a vIGA 0 / 1 responder and maintains vIGA 0 / 1 response efficacy. In some exemplary embodiments, the subject is an AESI 75 responder and maintains EASI 75 efficacy.

[0243] In some exemplary embodiments, the subject did not experience a treatment-induced adverse event (TEAE).

[0244] On the other hand, a method for treating atopic dermatitis in a subject in need is provided, the method comprising administering anilidelimab to the subject, wherein the subject receives a dose directly every 12 weeks (Q12W) without prior dose administration every 4 weeks (Q4W), and wherein the subject receives an initial dose of about 500 mg of anilidelimab, followed by one or more second doses of about 250 mg of anilidelimab.

[0245] On the other hand, a method for treating atopic dermatitis in an adolescent subject in need is provided, the method comprising administering animotrimalab to the adolescent subject, wherein the adolescent subject receives an initial dose of about 250 mg of animotrimalab, followed by one or more second doses of about 125 mg of animotrimalab, and wherein the subject receives the dose from the start of treatment Q12W.

[0246] On the other hand, a method for treating atopic dermatitis in a subject in need is provided, the method comprising administering anilide to the subject, wherein the subject has a weight ranging from about 25 kg to about 40 kg, wherein the subject receives an initial dose of about 250 mg of anilide, followed by one or more second doses of about 125 mg of anilide, and wherein the subject receives the doses from the start of treatment Q12W.

[0247] On the other hand, a method is provided for treating atopic dermatitis (AD) in a subject in need, the method comprising administering animotriumab to the subject, wherein the subject receives a direct dose every 12 weeks (Q12W) without prior dose administration every 4 weeks (Q4W), wherein the subject receives an initial dose of about 500 mg of animotriumab, followed by one or more second doses of about 250 mg of animotriumab, and wherein the method results in a reduction in the level of at least one biomarker in the subject relative to a control (e.g., relative to the level of the at least one biomarker before administration of animotriumab).

[0248] On the other hand, a method for treating atopic dermatitis (AD) in a subject of need is provided, the method comprising administering anilidelimab to the subject, wherein the subject receives a direct dose every 12 weeks (Q12W) without prior dose administration every 4 weeks (Q4W), wherein the subject receives an initial dose of about 500 mg of anilidelimab, followed by one or more second doses of about 250 mg of anilidelimab, and reducing the level of at least one biomarker selected from thymic activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count and lactate dehydrogenase (LDH), or combinations thereof.

[0249] On the other hand, a method for reducing biomarkers in subjects with atopic dermatitis (AD) is provided, the method comprising administering anilideumab to the subject, the subject receiving a direct dose every 12 weeks (Q12W) without prior dose administration every 4 weeks (Q4W), wherein the subject receives an initial dose of approximately 500 mg of anilideumab, followed by one or more second doses of approximately 250 mg of anilideumab, and wherein the biomarker is selected from thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count, and lactate dehydrogenase (LDH).

[0250] On the other hand, a method for treating atopic dermatitis (AD) in a subject in need is provided, the method comprising selecting a subject suffering from AD and having elevated levels relative to a control of at least one biomarker selected from the group consisting of: thymus activation-regulated chemokine (TARC), interleukin-5 (IL-5), eosinophil count and lactate dehydrogenase (LDH), and administering anilidelimab to the subject, wherein the subject receives a dose directly every 12 weeks (Q12W) without prior dose administration every 4 weeks (Q4W), and wherein the subject receives an initial dose of about 500 mg of anilidelimab, followed by one or more second doses of about 250 mg of anilidelimab.

[0251] On the other hand, a method for treating atopic dermatitis (AD) in a subject in need is provided, the method comprising administering animotriumab to the subject, wherein the subject receives a dose directly every 12 weeks (Q12W) without prior dose administration every 4 weeks (Q4W), and wherein the subject receives an initial dose of about 500 mg of animotriumab, followed by one or more second doses of about 250 mg of animotriumab.

[0252] On the other hand, a method for treating atopic dermatitis (AD) in a subject in need is provided, the method comprising administering anilidelimab to the subject, wherein the subject receives a dose directly every 12 weeks (Q12W) without prior dose administration every 4 weeks (Q4W), and wherein the subject receives an initial dose of about 500 mg of anilidelimab, followed by one or more second doses of about 250 mg of anilidelimab.

[0253] On the other hand, a method for treating asthma in a subject in need is provided, the method comprising administering amotilimab to the subject, wherein the subject receives a dose directly every 12 weeks (Q12W) without prior dose administration every 4 weeks (Q4W), and wherein the subject receives an initial dose of about 500 mg of amotilimab, followed by one or more second doses of about 250 mg of amotilimab.

[0254] On the other hand, a method is provided for treating interstitial lung disease-systemic sclerosis in a subject in need, the method comprising administering animotriumab to the subject, wherein the subject receives a dose directly every 12 weeks (Q12W) without prior dose administration every 4 weeks (Q4W), and wherein the subject receives an initial dose of about 500 mg of animotriumab, followed by one or more second doses of about 250 mg of animotriumab.

[0255] On the other hand, a method for treating systemic sclerosis in a subject in need is provided, the method comprising administering animotriumab to the subject, wherein the subject receives a dose directly every 12 weeks (Q12W) without prior dose administration every 4 weeks (Q4W), and wherein the subject receives an initial dose of about 500 mg of animotriumab, followed by one or more second doses of about 250 mg of animotriumab.

[0256] On the other hand, a method for treating hidradenitis suppurativa in a subject in need is provided, the method comprising administering animotriumab to the subject, wherein the subject receives a dose directly every 12 weeks (Q12W) without prior dose administration every 4 weeks (Q4W), and wherein the subject receives an initial dose of about 500 mg of animotriumab, followed by one or more second doses of about 250 mg of animotriumab.

[0257] On the other hand, a method for treating alopecia areata in a subject in need is provided, the method comprising administering amotelimab to the subject, wherein the subject receives a dose directly every 12 weeks (Q12W) without prior dose administration every 4 weeks (Q4W), and wherein the subject receives an initial dose of about 500 mg of amotelimab, followed by one or more second doses of about 250 mg of amotelimab.

[0258] On the other hand, a method for treating celiac disease in a subject in need is provided, the method comprising administering amotilimab to the subject, wherein the subject receives a dose directly every 12 weeks (Q12W) without prior dose administration every 4 weeks (Q4W), and wherein the subject receives an initial dose of about 500 mg of amotilimab, followed by one or more second doses of about 250 mg of amotilimab.

[0259] On the other hand, a method for treating atopic dermatitis in a subject in need is provided, the method comprising administering anilidelimab to the subject, wherein the subject receives a direct dose every 12 weeks (Q12W) without prior dose administration every 4 weeks (Q4W), and wherein the subject receives an initial dose of about 500 mg of anilidelimab, followed by one or more second doses of about 250 mg of anilidelimab, and wherein efficacy is maintained at week 28 after discontinuation of treatment or at week 32 after final administration of anilidelimab. Attached Figure Description

[0260] The accompanying drawings, which are incorporated herein and form part of this specification, illustrate exemplary embodiments of the present disclosure and, together with the general description given above and the detailed description given below, serve to explain the features of the present disclosure.

[0261] Figure 1 The main inclusion and exclusion criteria for the STREAM-AD study are described.

[0262] Figure 2 The main analytical details of the STREAM-AD study are described.

[0263] Figure 3 The baseline demographic data for the STREAM-AD study is depicted.

[0264] Figure 4 The baseline disease characteristics of the STREAM-AD study were described.

[0265] Figure 5 The primary endpoint at week 16 was depicted: EASI, change relative to baseline % (LS mean).

[0266] Figure 6 The key secondary endpoint was characterized: EASI-75 over time, for patients.

[0267] Figure 7 The key secondary endpoint was depicted: IGA 0 / 1 over time, for patients.

[0268] Figure 8 The key secondary endpoint was characterized as a time-varying PP-NRS ≥ 4 in patients.

[0269] Figure 9 This is a comparison of key efficacy results from week 16 and week 24.

[0270] Figure 10 This is a PopPK / EASI model that extends to Q12W after an induction period using a loading dose. Comparable effects were observed for all three simulated doses. The effect lasted for more than 24 weeks after the last dose, with the highest dose maintaining the effect for an even longer period (with less impact in the case of missed doses).

[0271] Figure 11 This is a PopPK / EASI model for direct Q12W. Only minor differences were observed between the two dosing regimens (125 / 62.5 mg Q12W and 500 / 250 mg Q2W). The effect lasted for more than 24 weeks after the last dose, with a longer duration of action at the highest dose (less impact in the event of a missed dose).

[0272] Figure 12 A summary of the Ph 2b endpoints is described.

[0273] Figure 13The Ph 2bSTREAM-AD experimental design, showing Part 1 (weeks 0 to 24) and Part 2 (weeks 24 to 52), is described.

[0274] Figure 14 The study depicted the emotelimab C-maximum (left panel) and AUC4W (right panel) in atopic dermatitis participants after the first dose (week 1) and the last dose (week 20) ​​following Q4W administration (10th, 25th, 50th, 75th and 90th percentiles and individual values).

[0275] Figure 15 The study depicted emotelimab homeostatic exposure (AUC4W) (10th, 25th, 50th, 75th and 90th percentiles and individual values) in participants with atopic dermatitis classified by baseline weight category (left panel) and moderate to severe atopic dermatitis (right panel) in each dose group.

[0276] Figure 16 The predicted AUC12W and C were highest (10th, 25th, 50th, 75th and 90th percentiles and individual values) of AD participants from the KY1005-CT05 / DRI17366 (STREAM-AD) study after 24 weeks—0–12 week interval (top) and 12–24 week interval (bottom)—compared to 250 mg Q12W (with a 500 mg loading dose) versus 62.5 mg Q4W (without a loading dose) and 250 mg Q4W (with a 500 mg loading dose) (n=301).

[0277] Figure 17 The representation of the final PopPK model is schematically depicted.

[0278] Figure 18 The final group PK and PopPK / EASI models are schematically represented.

[0279] Figure 19 The percentage change in EASI score relative to baseline (at week 24) was plotted for both responders and non-responders using 250 mg Q12W (with a 500 mg loading dose) for 24 weeks (simulating 2000 participants: 1200 responders and 800 non-responders). Non-responders: top data line; Responders: bottom data line; Responders + Non-responders: middle data line.

[0280] Figure 20Simulations of two doses with a Q12W dosing interval (125 mg loading dose + 62.5 mg maintenance dose and 500 mg loading dose + 250 mg maintenance dose) are depicted. The median and 10th and 90th percentiles of the simulation with a cohort of 200 virtual patients are shown. 125 / 62.5 mg, top data line; 500 / 250 mg, bottom data line.

[0281] Figure 21 A legend for the path diagram is shown schematically.

[0282] Figure 22 A pharmacokinetic model of amotelimab is schematically depicted.

[0283] Figure 23 Pharmacokinetic models for anti-IL-13 antibody (antibody Y) and anti-IL-4 receptor antibody (antibody X) are schematically depicted. Drugs from both PK models are treated within the models as total drug, free drug, and bound drug (bound to the drug target) in concentration units.

[0284] Figure 24 A schematic model of drug-target binding is depicted. Mature dendritic cells (DCs) are mature dendritic cells within lymphatic compartments that express OX40L.

[0285] Figure 25 The generation of biomarkers is illustrated schematically.

[0286] Figure 26 Cell migration and the initiation of helper T cells are schematically depicted.

[0287] Figure 27 A schematic model of drug-target binding in the skin is depicted.

[0288] Figure 28 The activation and life cycle of Th2 cells in the skin compartment are schematically depicted. DC = dendritic cells, Treg = regulatory T cells.

[0289] Figure 29 The activation and life cycle of Th22 cells in the skin compartment are schematically depicted. DC = dendritic cells, Treg = regulatory T cells.

[0290] Figure 30 The activation and life cycle of Treg cells in the skin compartment are schematically depicted. Treg ChK = chemokines that attract Tregs; DC = dendritic cells; Treg = regulatory T cells.

[0291] Figure 31The activation and life cycle of mast cells in skin compartments are schematically depicted.

[0292] Figure 32 The maturation and life cycle of mast cells in skin compartments are schematically depicted.

[0293] Figure 33 The life cycle of keratinocytes is schematically depicted.

[0294] Figure 34 The generation and elimination of mediators in the skin are schematically depicted.

[0295] Figure 35 The process of generating and controlling itching is illustrated schematically. KC = keratinocytes, MC = mast cells.

[0296] Figure 36 The sequence of calculations and controls for barrier function and keratinocyte quality is schematically depicted. CC = keratinocyte, KC = keratinocyte, MC = mast cell.

[0297] Figure 37 The sequence for calculating clinical outcome scores is illustrated schematically. DC = dendritic cells, MC = mast cells.

[0298] Figure 38 Amotrilimab exposure following a loading dose at Q4W, segmented by body weight, is depicted, and the AUC after the loading dose is shown. 4W (Top Figure) and C after loading dose 最大 (Base map).

[0299] Figure 39 Amotriumab exposure was depicted following a loading dose at Q4W, segmented by body weight, and steady-state AUC after the loading dose was shown. 4W (Top Figure) and steady-state C after loading dose 最大 (Base map).

[0300] Figure 40 Amotriumab exposure following a loading dose at Q12W, segmented by body weight, was depicted, and the AUC after the loading dose was shown. 12W (Top Figure) and C after loading dose 最大 (Base map).

[0301] Figure 41 Amotriumab exposure was depicted following a loading dose at Q12W, segmented by body weight, and steady-state AUC after the loading dose was shown. 12W (Top Figure) and steady-state C after loading dose 最大 (Base map).

[0302] Figures 42A to 42B The efficacy assessment of treatment based on the biomarker TARC is described.

[0303] Figures 43A to 43B The efficacy assessment of LDH treatment based on biomarkers was described.

[0304] Figures 44A to 44B This paper describes the evaluation of treatment efficacy based on the biomarker eosinophil count.

[0305] Figures 45A to 45B The efficacy assessment of treatment based on the biomarker IL-5 was described.

[0306] Figures 46A to 46B A treatment efficacy assessment model for TARC was described.

[0307] Figure 47 A treatment efficacy evaluation model for LDH was described.

[0308] Figure 48 A model for evaluating the therapeutic effect of blood eosinophils was described.

[0309] Figure 49 The diagram illustrates how emotelimab modulated all measured biomarkers at week 24, with the highest observed efficacy among Th2 / Th22 biomarkers. Median changes from baseline were measured at week 24 for IgE, iL-13, IL-17A, IL-22, TARC, LDH, and eosinophils.

[0310] Figure 50 The treatment efficacy assessment model is illustrated using the Th2-related biomarker IL-13.

[0311] Figure 51 The treatment efficacy assessment model is illustrated using the Th2-related biomarker IL-31.

[0312] Figure 52 A model for evaluating treatment efficacy is illustrated: Th2-related biomarker eosinophil chemokine-3.

[0313] Figure 53 The treatment efficacy assessment model is illustrated: IL-17A.

[0314] Figure 54 The treatment efficacy assessment model is illustrated: IL-22.

[0315] Figure 55 The treatment efficacy assessment model is illustrated: IgE.

[0316] Figure 56The treatment efficacy assessment model is illustrated using the Th2-related biomarker IL-13.

[0317] Figure 57 The treatment efficacy assessment model is illustrated using the Th2-related biomarker IL-31.

[0318] Figure 58 The treatment efficacy assessment model is illustrated using the Th2-related biomarker IL-5.

[0319] Figure 59 A model for evaluating treatment efficacy is illustrated: Th2-related biomarker eosinophil chemokine-3.

[0320] Figure 60 The treatment efficacy assessment model is illustrated: Th17 / 22 related biomarker: IL-17A.

[0321] Figure 61 The treatment efficacy assessment model is illustrated: Th17 / 22 related biomarker: IL-22.

[0322] Figure 62 The biomarker IgE associated with the treatment of atopic dermatitis is illustrated.

[0323] Figure 63 The illustration shows that anitolimab modulates all measured biomarkers, with the highest observed effect on Th2 / Th22 biomarkers.

[0324] Figure 64 This is a table showing the biomarkers TARC, IgE, eosinophils, and eosinophil chemokine-3 regulated by emotelimab.

[0325] Figure 65 The treatment efficacy assessment model is illustrated: IL-22.

[0326] Figure 66 The treatment efficacy assessment model is illustrated: IL-17A.

[0327] Figures 67A to 67B The treatment efficacy assessment model is illustrated: IL-13.

[0328] Figure 68 A table depicting the distribution of respondents from Part 1 who entered Part 2 of the STREAM-AD trial is presented.

[0329] Figure 69 It is a table depicting the baseline demographic and disease characteristics of the Part 1 (general population) and Part 2 (respondents) populations at week 0.

[0330] Figure 70 This is a table depicting the baseline disease characteristics at week 24 when the sample is rerandomized.

[0331] Figure 71 This table depicts the maintenance of IGA 0 / 1 response in participants who were IGA 0 / 1 respondents at week 24 at week 52 (28 weeks after treatment cessation). *Non-responder imputation (NRI) analysis: All participants who were IGA 0 / 1 respondents at the rerandomization visit were included. Patients who discontinued treatment due to lack of efficacy or received emergency medications or prohibited medications / procedures affecting efficacy on or after the rerandomization date or first-dose date and before the corresponding time point in Part 2 were considered non-responders. Patients who received emergency medications or prohibited medications / procedures affecting efficacy in Part 1 were not considered non-responders. Patients with missing data were considered non-responders. **Treatment policy analysis: All participants who were IGA 0 / 1 respondents at the rerandomization visit were included. Patients with missing data were considered non-responders.

[0332] Figure 72 This table depicts the maintenance of EASI-75 response in participants who were EASI-75 responders at week 24 at week 52 (28 weeks after treatment cessation). *Non-responder imputation (NRI) analysis: All participants who were EASI-75 responders at the rerandomization visit were included. Patients who discontinued treatment due to lack of efficacy or received emergency medications or prohibited medications / procedures affecting efficacy on or after the rerandomization date or first-dose date and before the corresponding time point in Part 2 were considered non-responders. Patients who received emergency medications or prohibited medications / procedures affecting efficacy in Part 1 were not considered non-responders. Patients with missing data were considered non-responders. **Treatment policy analysis: All participants who were EASI-75 responders at the rerandomization visit were included. Patients with missing data were considered non-responders.

[0333] Figure 73This table depicts the maintenance of IGA 0 / 1 and / or EASI-75 responses in participants who were IGA 0 / 1 and / or EASI-75 responders at week 52 (28 weeks after treatment cessation). *Non-responder imputation (NRI) analysis: All participants who were IGA 0 / 1 and / or EASI-75 responders at the re-randomization visit were included. Patients who discontinued treatment due to lack of efficacy or received emergency medications or prohibited medications / procedures affecting efficacy on or after the re-randomization date or first-dose date and before the corresponding time point in Part 2 were considered non-responders. Patients who received emergency medications or prohibited medications / procedures affecting efficacy in Part 1 were not considered non-responders. Patients with missing data were considered non-responders. **Treatment policy analysis: All participants who were IGA 0 / 1 and / or EASI-75 responders at the re-randomization visit were included. Patients with missing data were considered non-responders.

[0334] Figure 74 The durability of EASI-75 response after treatment cessation is illustrated graphically. Percentages are based on the number of patients achieving EASI-75 at re-randomization (week 24), calculated for patients who did not experience an event from re-randomization to the date of the first event or censoring date. The censoring date is week 68 + 1 day (EOS), calculated as the number of patients who experienced an event divided by the total number of patient years for that event. Lost time is censored when emergency medications are used and / or when contraindicated medications / procedures affecting efficacy are selected, or when the study is suspended / completed (whichever is earlier). In STREAM-AD, participants who received emergency care in Part 1 are able to proceed to Part 2.

[0335] Figure 75 This table describes the overall tolerability of anitolide and its acceptable safety profile in the combined dose groups for the Part 2 safety population (weeks 0 to 52). *For participants entering Part 2, data from Part 1 + Part 2 are shown. Treatment with anitolide continued until week 52 (last dose given at week 48), with SFU until week 68. Data cutoff was when the last participant reached week 52. However, the data presented include some participants who remained for up to 68 weeks. **TEAEs are included during treatment with anitolide in Part 1 and during treatment with placebo in Part 2. 3 This includes patients with nasopharyngitis and pharyngitis.

[0336] Figure 76This is a table summarizing anti-drug antibody (ADA) data from week 0 to week 68. All ADA occurring after treatment was identified as treatment-induced ADA. *Alimtamarab treatment continued until week 52 (with the last dose given at week 48), followed by SFU until week 68. Data cutoff was when the last participant reached week 52. However, the data presented include some participants who remained for up to 68 weeks.

[0337] Figure 77 The illustration depicts the maintenance of durable clinical responses (IGA 0 / 1 and EASI-75) with treatment (combined dose groups). LLOQ; lowest level of quantitation. a Data from a multi-dose escalation study in healthy subjects showed that emotelimab at concentrations ≤4 µg / mL had no effect on KLH immunity. b NRI: Patients who discontinued treatment / received emergency medications / contraindicated medications or procedures affecting efficacy due to lack of efficacy on or after the rerandomization date / first dose date and before the corresponding time point in Part 2 are considered non-responders. Patients who received emergency medications / contraindicated medications or procedures affecting efficacy during Part 1 are not considered non-responders. Patients with missing data are considered non-responders. c All data (treatment policy): Patients with missing data are considered non-responders.

[0338] Figure 78 The diagram illustrates the effect of serum elemotriumab reaching negligible levels. a However, it maintains a sustained clinical response even after drug discontinuation. LLOQ; minimum level of quantification. a Data from a multi-dose escalation study in healthy subjects showed that emotelimab at concentrations ≤4 µg / mL had no effect on KLH immunity. b NRI: Patients who discontinued treatment / received emergency medications / contraindicated medications or procedures affecting efficacy due to lack of efficacy on or after the rerandomization date / first dose date and before the corresponding time point in Part 2 are considered non-responders. Patients who received emergency medications / contraindicated medications or procedures affecting efficacy during Part 1 are not considered non-responders. Patients with missing data are considered non-responders. c All data (treatment policy): Patients with missing data are considered non-responders.

[0339] Figure 79The diagram illustrates that TARC levels (Th2) remained suppressed after elemotriumab was cleared from serum. For EASI-75 and / or IGA 0 / 1 responders entering Part 2, the fold change (± CI) of biomarkers relative to baseline was repeatedly measured using a mixed model up to week 52 (all data with baseline and assessment of at least one evaluable biomarker between week 24 and week 52). Mean values ​​for the continued elemotriumab group and the discontinued elemotriumab group were estimated using a single model.

[0340] Figure 80 The illustration depicts the continued suppression of eosinophil levels (Th2) after elemotriumab clearance from serum. For EASI-75 and / or IGA 0 / 1 responders entering Part 2, the fold change (± CI) of biomarkers relative to baseline was repeatedly measured using a mixed model up to week 52 (all data with baseline and assessment of at least one evaluable biomarker between week 24 and week 52). Mean values ​​for the continued elemotriumab group and the discontinued elemotriumab group were estimated using a single model.

[0341] Figure 81 The diagram illustrates the continued suppression of IL-22 levels (Th22) after elemotriumab clearance from serum. For EASI-75 and / or IGA 0 / 1 responders entering Part 2, the fold change (± CI) of biomarkers relative to baseline was repeatedly measured using a mixed model up to week 52 (all data with baseline and assessment of at least one evaluable biomarker between week 24 and week 52). Mean values ​​for the continued elemotriumab group and the discontinued elemotriumab group were estimated using a single model.

[0342] Figure 82 A to Figure 82H graphically depicts the fold change (± CI) of AD-related biomarkers relative to baseline during Part 1 for all patients and Part 2 (right) for clinical responders. (A) TARC; (B) IgE; (C) IL-13; (D) IL-31; (E) IL-22; (F) IL-17A; (G) LDH; (H) Blood eosinophils. Clinical responders were all patients with baseline and at least one post-baseline biomarker result (Part 1) and at least one biomarker result between weeks 24 and 52 in Part 2. Concentrations below the lower limit of quantitation (LLOQ) were imputed as ½ LLOQ. Placebo (n: Part 1 = 75, Part 2 = 15), gray solid circle; 250 mg (+LD) amotilimab (n: Part 1 = 75, Part 2 = 13), blue solid circle; 250 mg amotilimab (n: Part 1 = 74, Part 2 = 12), red solid triangle; 125 mg amotilimab (n: Part 1 = 75, Part 2 = 12), green solid rhombus; 62.5 mg amotilimab (n: Part 1 = 78, Part 2 = 7), yellow solid square; 250 mg (+LD) discontinued (n=34), blue open dashed circle; 250 mg discontinued (n=28), orange open dashed triangle; 125 mg discontinued (n=32), green open dashed rhombus; 62.5 mg amotilimab (n=32 ... red solid triangle; 250 mg (+LD) discontinued (n=34), red solid triangle; 250 mg (+LD) discontinued (n=34), red solid circle; 250 mg (+LD) discontinued (n=34), red solid circle; 250 mg (+LD) discontinued (n=34), red solid circle; 250 mg (+LD) discontinued (n=34), red solid circle; 250 mg (+LD) discontinued (n=34), red solid circle; 250 mg (+LD) discontinued (n=34), red solid circle; 250 mg (+LD) discontinued (n=34), red solid mg discontinuation (n=34), yellow open dashed square. Detailed Implementation

[0343] Embodiments of this disclosure provide methods for treating immune-mediated diseases or atopic dermatitis, wherein a subject receives a dose directly every 12 weeks (Q12W) without prior dose administration every 4 weeks (Q4W); methods for treating immune-mediated diseases or atopic dermatitis in adolescent subjects; and methods for treating immune-mediated diseases or atopic dermatitis involving specific biomarkers.

[0344] definition

[0345] The following lists definitions of various terms used to describe the embodiments disclosed herein. These definitions apply to the terminology used throughout this specification and claims, unless otherwise limited, either individually or as part of a larger group, in particular.

[0346] Unless otherwise defined, all scientific and technical terms used herein shall have the meanings commonly understood by one of ordinary skill in the art. Furthermore, unless the context requires otherwise, singular terms shall include plural terms, and plural terms shall include singular terms. Generally, the terminology and techniques used in conjunction with the cell and tissue culture, molecular biology, and protein and oligonucleotide or polynucleotide chemistry and hybridization described herein are well-known and commonly used terminology and techniques in the art.

[0347] As used herein and in the appended claims, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” include plural references. Thus, for example, references to “molecule” optionally include combinations of two or more such molecules, etc. The word “or” as used herein is inclusive.

[0348] As used herein, the terms “about” or “approximately” will be understood by those skilled in the art and will vary to some extent depending on the context in which they are used. When referring to measurable values ​​(such as quantity, duration, etc.), the terms “about” or “approximately” mean to cover a variation of ±20%, ±15%, or ±10% (inclusive) relative to a specified value, as such variation is appropriate for performing the disclosed methods.

[0349] As used in this specification and claims, the terms “comprising” (and any form of inclusion, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of inclusion, such as “includes” and “include)”), or “containing” (and any form of containing, such as “contains” and “contain)”) are inclusive or open-ended and do not exclude additional elements or method steps not listed.

[0350] As used herein, the term "consistently of" refers to those elements required for a given embodiment. This term allows for the presence of elements that do not materially affect the basic, novel, or functional features of the embodiment.

[0351] The abbreviation “eg” originates from the Latin “exempli gratia” and is used in this text to indicate a non-restrictive instance. Therefore, the abbreviation “eg” is synonymous with the term “for example”.

[0352] As used herein, the term "amino acid" includes alanine (Ala or A); arginine (Arg or R); asparagine (Asn or N); aspartic acid (Asp or D); cysteine ​​(Cys or C); glutamine (Gin or Q); glutamic acid (Glu or E); glycine (Gly or G); histidine (His or H); isoleucine (lie or I); leucine (Leu or L); lysine (Lys or K); methionine (Met or M); phenylalanine (Phe or F); proline (Pro or P); serine (Ser or S); threonine (Thr or T); tryptophan (Trp or W); tyrosine (Tyr or Y); and valine (Val or V). Non-traditional amino acids are also within the scope of this disclosure and include ortholeucine, ornithine, orvaline, homoserine, and other amino acid residue analogs, such as those described in Ellman et al., Meth. Enzymol. 202:301-336 (1991). To generate such non-naturally occurring amino acid residues, procedures can be used as described by Noren et al. (Science 244:182, 1989) and Ellman et al., ibid. In short, these procedures involve chemically activating repressive tRNA with non-naturally occurring amino acid residues, followed by in vitro transcription and translation of the RNA. The introduction of non-traditional amino acids can also be achieved using peptide chemistry known in the art. As used herein, the term "polar amino acid" includes amino acids with a net zero charge but a non-zero partial charge in different portions of their side chains (e.g., M, F, W, S, Y, N, Q, C). These amino acids can participate in both hydrophobic and electrostatic interactions. As used herein, the term "charged amino acid" includes amino acids that may have a non-zero net charge on their side chains (e.g., R, K, H, E, D). These amino acids can participate in both hydrophobic and electrostatic interactions.

[0353] As used herein, the term "conservative amino acid substitution" refers to an amino acid substitution resulting from replacing one amino acid with another amino acid having similar structure and / or chemical properties, such as replacing leucine with isoleucine or valine, replacing aspartic acid with glutamic acid, or replacing threonine with serine. Therefore, "conservative substitution" of a particular amino acid sequence refers to the substitution of amino acids that are not critical to peptide activity, or the substitution of amino acids with other amino acids having similar properties (e.g., acidic, basic, positively or negatively charged, polar or nonpolar, etc.) such that even if a critical amino acid is substituted, the peptide's activity (i.e., its ability to cross the blood-brain barrier (BBB)) is not reduced. Conservative substitutions of functionally similar amino acids are well known in the art. For example, the following six groups each contain amino acids that are conservedly substituted for each other: 1) alanine (A), serine (S), threonine (T); 2) aspartic acid (D), glutamic acid (E); 3) asparagine (N), glutamine (Q); 4) arginine (R), lysine (K); 5) isoleucine (I), leucine (L), methionine (M), valine (V); and 6) phenylalanine (F), tyrosine (Y), tryptophan (W). (See also Creighton, Proteins, WH Freeman and Company (1984), which is incorporated herein by reference in its entirety.) In some embodiments, alterations, additions, or deletions of individual amino acids or small percentages of amino acids may also be considered “conserved substitutions” if the change does not reduce the activity of the peptide. Insertions or deletions are typically in the range of about 1 to 5 amino acids. The selection of conserved amino acids can be based on the position of the amino acid to be substituted in the peptide, for example, if the amino acid is external to the peptide and exposed to the solvent, or internal to the peptide and not exposed to the solvent.

[0354] In alternative embodiments, the amino acid to replace the existing amino acid can be selected based on its position in the solvent (i.e., its exposure to the solvent, compared to an internally located amino acid that is not exposed to the solvent, if the amino acid is exposed to the solvent or present on the outer surface of the peptide or polypeptide). Such conservative selection of amino acid substitutions is well known in the art, for example as disclosed in Dordo et al., J. Mol Biol, 1999, 217, 721-739, Taylor et al., J. Theor. Biol. 119 (1986); 205-218, and S. French and B. Robson, J. Mol. Evol., 19 (1983) 171. Therefore, conserved amino acid substitutions suitable for the amino acids outside the protein or peptide (i.e., amino acids exposed to the solvent) can be selected, for example, but not limited to, the following substitutions can be used: replacing Y with F, replacing T with S or K, replacing P with A, replacing E with D or Q, replacing N with D or G, replacing R with K, replacing G with N or A, replacing T with S or K, replacing D with N or E, replacing I with L or V, replacing F with Y, replacing S with T or A, replacing R with K, replacing G with N or A, replacing K with R, and replacing A with S, K, or P.

[0355] In alternative embodiments, conservative amino acid substitutions suitable for amino acids within the protein or peptide may also be selected. For example, conservative substitutions suitable for amino acids within the protein or peptide (i.e., amino acids not exposed to the solvent) may be used, such as, but not limited to, the following conservative substitutions: wherein Y is replaced by F, T by A or S, I by L or V, W by Y, M by L, N by D, G by A, T by A or S, D by N, I by L or V, F by Y or L, S by A or T, and A by S, G, T, or V. In some embodiments, non-conservative amino acid substitutions are also covered within the terminology of the variants.

[0356] As used herein, the term "administration" means the dispensing, delivery, or administration of an active compound (i.e., an antibody or its antigen-binding fragment) in a pharmaceutical formulation to a subject via any suitable route for delivering the active compound to a subject. Examples of routes of administration include, but are not limited to, subcutaneous, intravenous (e.g., intravenous injection and intravenous infusion, such as via a central venous access), intramuscular, oral, nasal, and pulmonary administration.

[0357] As used herein, the term "antibody" generally refers to an immunoglobulin molecule and its multimers (e.g., IgM) consisting of four polypeptide chains, two heavy (H) chains, and two light (L) chains linked by disulfide bonds; however, immunoglobulin molecules consisting only of heavy chains (i.e., lacking light chains) are also included within the definition of the term "antibody." Each heavy chain contains a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region contains three domains: CH1, CH2, and CH3. Each light chain includes a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region contains one domain (CL1). The VH and VL regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs), which are interspersed with more conserved regions called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0358] As used herein, the terms “antagonistic antibody” or “antagonist antibody” are used equivalently herein and include antibodies capable of inhibiting and / or neutralizing the biological signaling activity of OX40, for example by blocking or substantially reducing the binding of OX40 to OX40 ligand (OX40L), and thus inhibiting or reducing OX40-triggered signaling pathways and / or inhibiting or reducing OX40-mediated cellular responses such as lymphocyte proliferation, cytokine expression, or lymphocyte survival.

[0359] Unless otherwise specifically indicated, the term “antibody” as used herein should be understood to encompass the complete antibody molecule and its antigen-binding fragment. As used herein, the term “antigen-binding portion” or “antigen-binding fragment” (or simply “antibody portion” or “antibody fragment”) of an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to a target antigen, such as human OX40L or its epitopes.

[0360] As used herein, the term "antibody fragment" refers to a polypeptide that contains at least one immunoglobulin variable domain or an immunoglobulin variable domain sequence and specifically binds to a given antigen. An antibody fragment may include an antibody or a polypeptide containing an antigen-binding domain of an antibody. In some embodiments, an antibody fragment may include a monoclonal antibody or a polypeptide containing an antigen-binding domain of a monoclonal antibody. For example, an antibody may contain a heavy (H) chain variable region (abbreviated herein as VH) and an OX40L (L) chain variable region (abbreviated herein as VL). In another instance, an antibody contains two heavy (H) chain variable regions and two OX40L (L) chain variable regions. The term "antibody fragment" encompasses antigen-binding fragments of antibodies (e.g., single-chain antibodies, Fab and sFab fragments, F(ab')2, Fd fragments, Fv fragments, scFv and domain antibody (dAb) fragments (see, for example, deWildt et al., Eur J. Immunol., 1996; 26(3):629-39; which is incorporated herein by reference in its entirety)) as well as complete antibodies. Antibodies can possess the structural characteristics of IgA, IgG, IgE, IgD, IgM (and their subtypes and combinations). Antibodies can originate from any source, including mice, rabbits, pigs, rats, and primates (human and non-human primates), as well as primate-derived antibodies. Antibodies also include microantibodies, humanized antibodies, chimeric antibodies, etc.

[0361] As used herein, "antibody variable domain" refers to the portion of the antibody molecule's OX40L and heavy chain, including the amino acid sequence of the complementarity-determining regions (CDRs; i.e., CDR1, CDR2, and CDR3) and framework regions (FRs). VH refers to the variable domain of the heavy chain. VL refers to the variable domain of the light chain. According to the methods used in this disclosure, the amino acid positions assigned to CDRs and FRs can be defined according to Kabat (Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md., 1987 and 1991)) or according to IMGT nomenclature.

[0362] As used herein, the term "antibody binding site" refers to a polypeptide or domain that contains one or more CDRs of an antibody and is capable of binding an antigen. For example, a polypeptide may contain CDR3 (e.g., HCDR3). For example, a polypeptide may contain CDRs 1 and 2 (e.g., HCDR1 and 2) or CDRs 1-3 (e.g., HCDR1-3) of variable antibody domains. In one instance, the antibody binding site is provided by a single variable domain (e.g., a VH or VL domain). In another instance, the binding site contains a VH / VL pair or two or more such pairs.

[0363] As used herein, “OX40L antagonistic antibody” or “OX40L antagonist antibody” refers to an antibody or its antigen-binding fragment that can inhibit and / or neutralize the biological signaling activity of OX40L, for example by blocking or substantially reducing the binding of OX40 to OX40L.

[0364] As used in this article, a "buffer" is a chemical reagent that can absorb a certain amount of acid or base without undergoing a strong change in pH.

[0365] As used herein, the term "cell" means a cell in vitro, outside the body, or in vivo. In some embodiments, an outside cell may be a portion of a tissue sample excised from an organism, such as a mammal. In some embodiments, an outside cell may be a cell in a cell culture. In some embodiments, an in vivo cell is a cell that is alive in an organism, such as a mammal.

[0366] As used herein, the term "dosage" refers to the specified amount or quantity of a drug taken or recommended to be taken at a particular time. As used herein, it is typically expressed in mg of the antibody or a fragment thereof. Alternatively, it may be expressed in mg / kg, taking into account the patient's weight. "Daily dose" refers to the total amount administered to an individual over a single 24-hour day.

[0367] As used herein, the term "administration" refers to the administration of a specific amount, quantity, and frequency of a drug over a specified period of time. Administration implies duration. A "administration regimen" is a treatment plan for administering a drug over a period of time.

[0368] As used herein, the terms “improve,” “improving,” or “improvement,” or their grammatical variations, used in relation to behavior, refer to the ability in subjects (including humans or non-human animals) to achieve a measurable improvement in performance related to the task used to test these behaviors.

[0369] As used herein, “injection” refers to a means of administration and encompasses, for example, IV and subcutaneous injections. An IV injection may be referred to as an infusion. It is also used herein to refer to administration in which the substance is administered by injection, such as in the phrase “one or more induction period injections.” Each injection will involve the administration of a dose of the antibody or a fragment thereof.

[0370] As used herein, an "injection device" refers to a device designed for administering an injection, which includes the step of temporarily fluidly coupling the injection device to a person's tissue (typically subcutaneous tissue). An injection further includes administering a volume of aqueous medication to the tissue and dissociating or removing the injection device from the tissue. In some embodiments, the injection device may be an intravenous device or an IV device, which are types of injection devices used when the target tissue is blood within the circulatory system (e.g., blood in a vein). Common, but not limiting, examples of injection devices are needles and syringes.

[0371] As used herein, "instructions for use" refers to written, printed, or graphic content displayed directly on the container of an article of manufacture, such as written material displayed on a vial containing a pharmaceutically active agent, or details of the formulation and use of a product of interest contained in a kit containing a formulation of interest. Instructions for use describe the treatment method intended to be administered or performed.

[0372] As used herein, the terms “isolated antibody” or “purified antibody” refer to an antibody that, due to its origin or derived origin, has one to four of the following characteristics: (1) it does not associate with the naturally associated components that are present in their native state; (2) it contains no or substantially no other proteins from the same species; (3) it is expressed by cells from a different species; or (4) it is not present in nature. An isolated antibody is substantially free of other antibodies with different antigen specificities.

[0373] As used herein, when referring to antibodies, the term "formulation" means a combination of an antibody and a pharmaceutically acceptable excipient comprising at least one buffer, at least one stabilizer, at least one surfactant, at least one chelating agent, and wherein the pH is as defined. As used herein, the term "formulation" may be used interchangeably with the term "composition".

[0374] As used herein, “monoclonal antibody” means an antibody obtained from a substantially homogeneous group of antibodies, i.e., the individual antibodies comprising that group are identical except for the possible presence of naturally occurring mutations in small quantities. Monoclonal antibodies are highly specific, targeting a single antigenic site. Furthermore, each monoclonal antibody targets a single determinant on an antigen, unlike polyclonal antibody formulations which typically contain different antibodies targeting different determinants (epitopes). The modifier “monoclonal” indicates that the antibody’s properties are obtained from a substantially homogeneous group of antibodies and should not be construed as requiring the antibody to be produced by any particular method. For example, monoclonal antibodies used according to this disclosure can be prepared by a hybridoma method first described in Kohler and Milstein, 1975, Nature 256:495, or by a recombinant DNA method such as that described in U.S. Patent No. 4,816,567. Monoclonal antibodies can also be isolated from phage libraries generated using, for example, techniques described in McCafferty et al., 1990, Nature 348:552-554. As used herein, a “humanized” antibody refers to a form of non-human (e.g., murine) antibody that is a chimeric immunoglobulin, immunoglobulin chain, or fragment thereof (such as the Fv, Fab, Fab', F(ab')2, or other antigen-binding sequence of an antibody) containing a minimal sequence derived from a non-human immunoglobulin. In an exemplary embodiment, the humanized antibody is a human immunoglobulin (recipient antibody) in which residues of the recipient’s CDR are replaced by residues of a CDR from a non-human species (donor antibody) (such as a mouse, rat, or rabbit) having the desired specificity, affinity, and capability. Humanized antibodies may include residues not found in the recipient antibody or in the introduced CDR or framework sequence but included to further refine and optimize antibody performance.

[0375] As used herein, the terms “level” and “levels” are used interchangeably with the terms “concentration” and “concentrations”.

[0376] As used herein, the terms “patient” or “subject” or “animal” or “host” refer to mammals. A subject can be a human, but can also be a mammal requiring veterinary treatment, such as livestock (e.g., dogs, cats, etc.), farm animals (e.g., cattle, sheep, poultry, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0377] The terms “peptide” or “polypeptide” are used interchangeably herein and refer to a compound consisting of about 2 to about 90 amino acid residues (including terminal values), wherein the amino group of one amino acid is linked to the carboxyl group of another amino acid via a peptide bond. Peptides can be derived from or removed from natural proteins, for example, by enzymatic or chemical cleavage, or can be prepared using conventional peptide synthesis techniques (e.g., solid-phase synthesis) or molecular biology techniques (see Sambrook et al., MOLECULAR CLONING: LAB. MANUAL (Cold Spring Harbor Press, Cold Spring Harbor, NY, 1989)). A “peptide” may contain any suitable L- and / or D-amino acids, such as common α-amino acids (e.g., alanine, glycine, valine), non-α-amino acids (e.g., β-alanine, 4-aminobutyric acid, 6-aminohexanoic acid, sarcosine, pepsinic acid), and unusual amino acids (e.g., citrulline, homocitrulline, homoserine, ortholeucine, orthovaline, ornithine). The amino, carboxyl, and / or other functional groups on a peptide can be free (e.g., unmodified) or protected with suitable protecting groups. Suitable protecting groups for amino and carboxyl groups, and methods for adding or removing protecting groups, are known in the art. See, for example, Green and Wuts, Protecting Grops in Organic Synthesis (John Wiley and Sons, 1991). The functional groups of a peptide can also be derivatized (e.g., alkylated) using methods known in the art.

[0378] As used herein, the terms "pharmaceutical formulation" or "pharmaceutical preparation" refer to a preparation in a form that enables the biological activity of the active ingredient to be effective. "Pharmaceutical formulation" and the term "pharmaceutical preparation" refer to mixtures or structures comprising different chemical combinations of active pharmaceutical ingredients to form a final pharmaceutical product, such as sterile products, solutions, powders, emulsions, capsules, tablets, granules, topical preparations, and non-conventional products (such as semi-solid or sustained-release preparations, liquids, etc.). Pharmaceutical formulations are prepared according to a specific procedure ("formulation"). The resulting pharmaceutical product varies depending on the route of administration. As used herein, when referring to antibodies, the term "formulation" means describing a combination of an antibody with a pharmaceutically acceptable excipient comprising at least one buffer, at least one stabilizer, at least one surfactant, at least one chelating agent, and wherein the pH is as defined.

[0379] The term “pharmaceutical formulation” is interchangeable with the term “pharmaceutical composition,” which further refers to a combination of an active agent and a pharmaceutically acceptable carrier (e.g., a carrier commonly used in the pharmaceutical industry). The phrase “pharmaceutically acceptable” is used herein to refer to compounds, materials, compositions, or formulations and / or dosage forms that are suitable for use in human and animal tissues to the extent of proper medical judgment without causing excessive toxicity, irritation, allergic responses, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0380] As used herein, the term "pharmaceuticalally acceptable excipient" (mediator, additive) refers to those active ingredients used that can be safely administered to a subject to provide an effective dose. As used herein, the terms "excipient" or "carrier" refer to inert substances that are commonly used as diluents, mediators, preservatives, binders, or stabilizers in pharmaceuticals. As used herein, the term "diluent" refers to a pharmaceutically acceptable (safe and non-toxic for human administration) solvent that can be used to prepare the aqueous formulations described herein. Exemplary diluents include, but are not limited to, sterile water and water for sterile injection (BWFI).

[0381] As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or carrier (such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material) that relates to carrying or transporting a compound useful in this disclosure into or to a subject so that it can perform its intended function. Typically, such constructs carry or deliver from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense that it is compatible with other components of the formulation, including compounds useful in this disclosure, and is harmless to the subject. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; astragalus powder; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer; and other non-toxic and compatible substances used in pharmaceutical formulations.

[0382] As used herein, the term "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, absorption delay agents, etc., that are compatible with the activity of the compounds useful in this disclosure and are physiologically acceptable to a subject. In some cases, supplemental active compounds may also be incorporated into the pharmaceutical formulation. "Pharmaceutically acceptable carrier" may further include pharmaceutically acceptable salts of the compounds disclosed herein. Other additional ingredients that may be included in the pharmaceutical formulation are known in the art and described, for example, in Remington's Pharmaceutical Sciences (Genaro, editor, Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0383] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral salts or organic acid salts of basic residues such as amines; alkali metal salts or organic salts of acidic residues such as carboxylic acids; and so on. Pharmaceutically acceptable salts of this disclosure include, for example, conventional non-toxic salts of parent compounds formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of this disclosure can be synthesized from parent compounds containing a basic or acidic moiety using conventional chemical methods. Typically, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water, in an organic solvent, or in a mixture of both; typically, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is used. The phrase "pharmaceutically acceptable salt" is not limited to a single salt or a 1:1 salt. For example, "pharmaceutically acceptable salt" also includes disalts, such as dihydrochlorides. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0384] As used herein, when referring to polypeptides of this disclosure, the terms “part,” “fragment,” “variant,” “derivative,” and “analyte” include any polypeptide that retains at least some of the biological activities (e.g., antigen binding) described herein.

[0385] As used herein, the term "immune-mediated disease" includes the meaning of "hOX40L-mediated disease" or "hOX40L-mediated condition," which are used interchangeably and include reference to any disease or condition that is wholly or partially caused by or is a result of hOX40L. In some embodiments, hOX40L is aberrantly (e.g., highly) expressed on the cell surface. In some embodiments, hOX40L may be aberrantly upregulated in a particular cell type. In other embodiments, normal, aberrant, or excessive cell signaling is caused by the binding of hOX40L to an hOX40L ligand. In some embodiments, the hOX40L ligand is, for example, OX40 expressed on the cell surface. Immune-mediated diseases may be selected from autoimmune diseases or conditions, systemic inflammatory diseases or conditions, or transplant rejection.

[0386] As used herein, the terms “prevent” or “prevention” mean that if a symptom or disease does not occur, there is no development of a symptom or disease, or if a symptom or disease has already developed, there is no further development of a symptom or disease. The ability to prevent some or all of the symptoms associated with a symptom or disease is also considered.

[0387] As used herein, the terms “treat,” “treatment,” “treating,” or “improvement” refer to a therapeutic action aimed at reversing, alleviating, improving, suppressing, slowing, or stopping the progression or severity of a condition associated with a disease or symptom. The term “treatment” includes reducing or alleviating at least one side effect or symptom of a condition, disease, or symptom. Treatment is generally considered “effective” if one or more symptoms or clinical markers are reduced. Alternatively, treatment is considered “effective” if the progression of the disease is reduced or stopped. That is, “treatment” includes not only improvement in symptoms or markers but also stopping or at least slowing the progression or worsening of symptoms compared to the expected symptoms without treatment. Beneficial or desired clinical outcomes include, but are not limited to: relief of one or more symptoms, reduction of disease severity, stabilization (i.e., no worsening) of the disease state, delay or slowing of disease progression, improvement or mitigation of the disease state, remission (whether partial or complete) and / or a reduction in mortality, whether detectable or undetectable. The term “treatment” for a disease also includes relief of the symptoms or side effects of the disease (including palliative care). Complete cure is not considered for treatment to be effective. This method may also include a cure in some respects.

[0388] As used herein, the term “mg / kg” refers to the dose of a substance administered to an individual in milligrams per kilogram of individual body weight.

[0389] As used herein, “packaging” refers to how components are organized and / or constrained into units suitable for dispensing and / or use. Packaging may include, for example, boxes, bags, syringes, ampoules, vials, tubes, clamshell packaging, barriers and / or containers for maintaining sterility, labels, etc.

[0390] As used herein, the term “recombinant antibody” is intended to include all antibodies prepared, expressed, produced, or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into host cells, antibodies isolated from a recombinant human antibody library, antibodies isolated from or prepared from animals (e.g., mice) transfected with human immunoglobulin genes, and such recombinant human antibodies may be subject to in vitro mutagenesis.

[0391] As used herein, “reconstitute” or “sterile formulation” refers to the preparation of a pharmaceutical product in an environment free from bacteria, viruses, or any other potentially infectious microorganisms. Sterile formulation is used for preparations to be administered via IV, injection, or direct eye contact.

[0392] As used herein, the phrases “systemic administration,” “systemic administration,” “peripheral administration,” and “peripheral administration” refer to the administration of a compound, drug, or other material, rather than direct administration to a target tissue (e.g., the nervous system), so that it enters the animal’s system and thus undergoes metabolism and other similar processes, such as subcutaneous administration.

[0393] As used herein, the terms “sequence identity,” “identity percentage,” “homology percentage,” or, for example, “80% identical to…”, refer to the degree to which sequences are identical on a nucleotide-by-nucleotide or amino acid-by-amino acid basis within a comparison window. Therefore, the “sequence identity percentage” can be calculated by comparing two optimally aligned sequences within a comparison window, determining the number of positions in which identical nucleic acid bases (e.g., A, T, C, G, I) or identical amino acid residues (e.g., Ala, Pro, Ser, Thr, Gly, Val, Leu, Ile, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gln, Cys, and Met) appear in both sequences to produce the number of matching positions, dividing the number of matching positions by the total number of positions in the comparison window (i.e., the window size), and multiplying the result by 100 to produce the sequence identity percentage.

[0394] The calculation of sequence similarity or sequence identity between sequences (these terms are used interchangeably herein) can be performed as follows. To determine the percentage of identity between two amino acid sequences or two nucleic acid sequences, sequences can be aligned for optimal comparison purposes (e.g., vacancies can be introduced in one or both of the first and second amino acid or nucleic acid sequences for optimal alignment, and non-homologous sequences can be ignored for comparison purposes). In some embodiments, the length of the reference sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, 60%, or at least 70%, 80%, 90%, 100% of the length of a reference sequence. The amino acid residues or nucleotides at the corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, the molecules are identical at that position.

[0395] In some embodiments, the length of the reference sequence compared for comparison purposes is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% the same as SEQ ID NO: 42 (HCDR1). In some embodiments, the length of the reference sequence compared for comparison purposes is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% the same as SEQ ID NO: 44 (HCDR2). In some embodiments, the length of the reference sequence compared for comparison purposes is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% the same as SEQ ID NO: 46 (HCDR3). In some embodiments, the length of the reference sequence compared for comparison purposes is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% the same as SEQ ID NO: 56 (LCDR1). In some embodiments, the length of the reference sequence compared for comparison purposes is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% the same as SEQ ID NO: 58 (LCDR2). In some embodiments, the length of the reference sequence compared for comparison purposes is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% the same as SEQ ID NO: 60 (LCDR3).

[0396] In some embodiments, the length of the reference sequence compared for comparison purposes is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% the same as SEQ ID NO: 34 (VH). In some embodiments, the length of the reference sequence compared for comparison purposes is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% the same as SEQ ID NO: 48 (VL).

[0397] In some embodiments, the length of the reference sequence compared for comparison purposes is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% the same as SEQ ID NO: 62 (HC). In some embodiments, the length of the reference sequence compared for comparison purposes is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% the same as SEQ ID NO: 64 (LC).

[0398] The percentage of identity between two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps and the length of each gap. This function needs to be introduced for optimal alignment of the two sequences.

[0399] Sequence comparison and determination of the percentage of identity between two sequences can be achieved using mathematical algorithms. In some embodiments, the percentage of identity between two amino acid sequences is determined using the Needleman and Wunsch (1970, J. Mol. Biol. 48: 444-453) algorithm in the GAP program, which is incorporated in the GCG software package, using a Blossum 62 matrix or a PAM250 matrix and vacancy weights of 16, 14, 12, 10, 8, 6, or 4 and length weights of 1, 2, 3, 4, 5, or 6. In yet another exemplary embodiment, the percentage of identity between two nucleotide sequences is determined using the GAP program in the GCG software package, using an NWSgapdna.CMP matrix and vacancy weights of 40, 50, 60, 70, or 80 and length weights of 1, 2, 3, 4, 5, or 6. Another set of exemplary parameters includes a Blossum 62 scoring matrix, where the vacancy penalty is 12, the vacancy extension penalty is 4, and the frameshift vacancy penalty is 5. The percentage of identity between two amino acid or nucleotide sequences can also be determined using the algorithm of E. Meyers and W. Miller (1989, Cabios, 4: 11-17), which has been incorporated into the ALIGN program (version 2.0), using the PAM120 weighted residue table, vacancy length penalty 12, and vacancy penalty 4.

[0400] For example, the peptide sequences described herein can be used as "query sequences" to search public databases, thereby, for example, identifying other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul et al., (1990, J.Mol.Biol, 215: 403-10). A BLAST nucleotide search can be performed using the NBLAST program (score=100, word length=12) to obtain nucleotide sequences homologous to the nucleic acid molecules of this disclosure. A BLAST protein search can be performed using the XBLAST program (score=50, word length=3) to obtain amino acid sequences homologous to the protein molecules of this disclosure. For vacancy-free alignments for comparative purposes, vacancy-free BLASTs, such as those by Altschul et al. (Nucleic Acids Res.25:3389-3402, 1997), can be utilized. When using BLAST procedures and BLAST procedures with available slots, the default parameters of the corresponding procedures (e.g., XBLAST and NBLAST) can be used.

[0401] Definitions of commonly used terms in cell biology and molecular biology can be found in: *The Merck Manual of Diagnosis and Therapy*, 19th edition, published by Merck Research Laboratories, 2006 (ISBN 0-911910-19-0); *The Encyclopedia of Molecular Biology*, edited by Robert S. Porter et al., published by Blackwell Science Ltd., 1994 (ISBN 0-632-02182-9); *Genes X*, published by Jones & Bartlett Publishing, 2009 (ISBN-10: 0763766321); *Molecular Biology and Biotechnology: a Comprehensive Desk Reference*, edited by Kendrew et al., published by VCH Publishers, Inc., 1995 (ISBN 1-56081-569-8); and *Current Protocols in Protein Sciences*, 2009. Wiley Intersciences, Coligan et al., editors.

[0402] Unless otherwise specified, use standard procedures, such as those described below: Sambrook et al., *Molecular Cloning: A Laboratory Manual* (4th edition), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, USA (2012); Davis et al., *Basic Methods in Molecular Biology*, Elsevier Science Publishing, Inc., New York, USA (1995); or *Methods in Enzymology: Guide to Molecular Cloning Techniques*, Volume 152, edited by SLBerger and AR Kimmel, Academic Press Inc., San Diego, USA (1987); *Current Protocols in Protein Science* (CPPS) (edited by John E. Coligan et al., John Wiley and Sons, Inc.), *Current Protocols in Cell Biology* (CPCB) (edited by Juan S. Bonifacino et al., John Wiley and Sons, Inc.), and *Culture of Animal Cells: A Manual of Basic Technique* by R. Ian Freshney, published by [Publisher Name Missing]. Wiley-Liss, 5th edition (2005), Animal Cell Culture Methods (Methods in Cell Biology, Vol. 57, edited by Jennie P. Mather and David Barnes, Academic Press, 1st edition, 1998), these references are incorporated into this article in their entirety by citation.

[0403] Other terms are defined within the description of the various embodiments of this disclosure.

[0404] When aspects or embodiments of this disclosure are described in accordance with Markush groups or other alternative groupings, this disclosure covers not only the entire group listed as a whole, but also each member of the group individually and all possible subgroups of the main group, as well as the main group lacking one or more of its members. This disclosure also contemplates the express exclusion of one or more of any of the group members in the claims.

[0405] The description of embodiments in this disclosure is not intended to be exhaustive or to limit this disclosure to the precise forms disclosed. While specific embodiments and examples of this disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of this disclosure, as will be recognized by those skilled in the art. For example, while method steps or functions are presented in a given order, alternative embodiments may perform functions in a different order or may perform functions substantially in parallel. The teachings of this disclosure provided herein can be suitably applied to other procedures or methods. The various embodiments described herein can be combined to provide further embodiments. If desired, aspects of this disclosure may be modified to incorporate formulations, functions, and concepts applied in the foregoing references to provide yet another embodiment of this disclosure. Furthermore, for reasons of biological functional equivalence, some changes may be made to the protein structure without affecting the biological or chemical action in terms of type or quantity. These and other changes may be made to the detailed description of this disclosure. All such modifications are intended to be included within the scope of the appended claims.

[0406] Biomarkers associated with atopic dermatitis

[0407] Examples of AD-related biomarkers include, but are not limited to, one or any combination of IgE, thymic activation-regulated chemokine (TARC), lactate dehydrogenase (LDH), interleukin-5 (IL-5), IL-13, IL-17A, IL-22, IL-31, eosinophil chemokine-3, and eosinophil count. In some embodiments, one or more AD-related biomarkers may be detected from biological samples (e.g., blood or serum) derived from a subject.

[0408] In some embodiments, subjects experience an improvement in AD as measured by the biomarker relative to baseline (e.g., the level of the biomarker before treatment with the OX40L antibody or its antigen-binding fragment). For example, the biomarker may be one or more of IgE level, TARC level, LDH level, IL-5 level, IL-13 level, IL-17A level, IL-22 level, IL-31 level, eosinophil chemokine-3 level, and eosinophil count level. Regarding levels, we include the meaning of biomarker expression (e.g., RNA and protein levels of the biomarker). In some exemplary embodiments, TARC level is reduced relative to baseline. In some exemplary embodiments, LDH level is reduced relative to baseline. In some exemplary embodiments, total IgE level is reduced relative to baseline. In some exemplary embodiments, IL-5 level is reduced relative to baseline. In some exemplary embodiments, TARC level is reduced relative to baseline. In some exemplary embodiments, IL-13 level is reduced relative to baseline. In some exemplary embodiments, IL-17A level is reduced relative to baseline. In some exemplary embodiments, IL-22 levels are reduced relative to baseline. In some exemplary embodiments, IL-31 levels are reduced relative to baseline. In some exemplary embodiments, eosinophil chemokine-3 levels are reduced relative to baseline. In some exemplary embodiments, eosinophil levels are reduced relative to baseline. In some embodiments, improvement in AD is indicated by a reduction in AD relative to baseline at weeks 4, 12, 24, etc., after treatment. In other words, improvement in AD can be indicated by a reduction in any one or more of the following levels relative to the corresponding levels before administration of the OX40L antibody or its antigen-binding fragment at weeks 4, 12, 24, etc., after treatment: IgE level, TARC level, LDH level, IL-5 level, IL-13 level, IL-17A level, IL-22 level, IL-31 level, eosinophil chemokine-3 level, and eosinophil count.

[0409] Improvements in AD-related parameters can be expressed as percentages. For example, a score improvement of 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 100% relative to baseline.

[0410] As described above, biomarker expression or levels can be determined by detecting proteins or RNA in serum. In some embodiments, RNA samples are used to determine RNA levels (non-genetic analysis), such as the RNA levels of biomarkers; and in other embodiments, RNA samples are used for transcriptome sequencing (e.g., genetic analysis).

[0411] To determine whether AD-related parameters have “improved,” the parameters are quantified at baseline and at time points following administration of the antibody or its antigen-binding fragment or pharmaceutical composition of the present invention. For example, AD-related parameters may be measured on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, or at weeks 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 52, or longer after initial treatment with the pharmaceutical composition described herein. In some embodiments, parameters are measured daily (e.g., once or twice daily), weekly, bi-weekly, or monthly. In other embodiments, parameters are measured daily, and the average determined over a month is compared to baseline. For the AD-related parameters in this context, we include all biomarkers discussed above, as well as the meaning of AD clinical scores discussed below.

[0412] The difference between the parameter value at a specific time point after the start of treatment and the parameter value at baseline is used to determine whether AD-related parameters have “improved” (e.g., increased or decreased depending on the specific parameter measured).

[0413] Various test types

[0414] Eczema Area Surface Index (EASI)

[0415] The EASI score measures the extent (area) and severity of Alzheimer's disease (AD). Each area is calculated as severity score x area score x multiplier. A score of 0 indicates clear or absent eczema, 0.1 to 1.0 indicates almost clear eczema, 1.1 to 7 indicates mild disease, 7.1 to 21 indicates moderate disease, 21.1 to 50 indicates severe disease, and a score greater than 51 indicates very severe disease.

[0416] For the extent, four body regions were scored: 1) Head and neck (face 33% (17% on each side), neck 33% (17% front and back, and 33% scalp); 2) Trunk (including genital area, 55% front and 45% back); 3) Upper limbs (each arm 50% of the upper limb area (25% front or back of one arm); and 4) Lower limbs (including hips, 45% of each leg (22.5% front or back of one leg) and 10% hips). An area score was calculated for each of the four body regions. The area score is the percentage of skin affected by eczema in each body region. An area score of 0 = no active eczema in the region. An area score of 1 = 1-9% of the skin in the region is affected. An area score of 2 = 10-29% of the skin in the region is affected. An area score of 3 = 30-49% of the skin in the region is affected. An area score of 4 = 50-69% of the skin in the region is affected. An area score of 5 means 70-89% of the skin in that area is affected. An area score of 6 means 90-100% of the skin in that area is affected (the entire area is affected by eczema).

[0417] To assess severity, each of the four areas of the body is scored. The severity score is the sum of the intensity scores for the four signs. These four signs are: redness (erythema, inflammation);

[0418] Thickness (induration, papules, swelling – acute eczema); scratching (epidermal peeling); lichenification (wrinkled skin, deepened grooves, prurigo nodules – chronic eczema). The mean intensity of each sign in each body area was rated as: none / absent (0); mild / not noticeable (1); moderate / obvious (2); and severe (3). Half points are allowed.

[0419] EASI-75 indicates an improvement of ≥ 75% in EASI score relative to baseline. EASI-90 indicates an improvement of ≥ 90% in EASI score relative to baseline. EASI-100 indicates an improvement of 100% in EASI score relative to baseline.

[0420] Investigator Overall Assessment (IGA)

[0421] The IGA is a four-point scoring system for assessing the overall severity of Alzheimer's disease (AD) skin lesions. A score of 0 = Clear, with no signs of AD inflammation. A score of 1 = Almost clear, with only perceptible erythema and perceptible papules / infiltrations. A score of 2 = Mild disease, with mild erythema and mild papules / infiltrations. A score of 3 = Moderate disease, with moderate erythema and moderate papules / infiltrations. A score of 4 = Severe disease, with severe erythema and severe papules / infiltrations.

[0422] Peak pruritus numerical rating scale (PP-NRS)

[0423] PP-NRS is PRO, designed to measure peak or “most severe” itching over the past 24 hours based on the following question: “On a scale of 0 to 10, where 0 is ‘no itching’ and 10 is ‘the most severe itching imaginable’, how would you rate your most severe itching over the past 24 hours?”

[0424] Numerical Rating Scale for Skin Pain (SP-NRS)

[0425] SP-NRS is a PRO that measures “most severe skin pain” over the past 24 hours on an 11-subscale (0 = no pain and 10 = most severe pain imaginable).

[0426] Sleep Disorders Numerical Rating Scale (SD-NRS)

[0427] SD-NRS is a PRO that measures sleep by asking subjects to rate their sleep loss from the previous night on a scale from 0 ("no sleep loss") to 10 ("I didn't sleep at all").

[0428] Dermatology Quality of Life Index (DLQI)

[0429] DLQI, or Patient-Reported Outcome (PRO), is designed to measure a participant's skin condition-specific HRQoL. This tool contains 10 items that assess the impact of a skin condition on a participant's health-related quality of life (HRQoL) in the preceding week. These items cover symptoms, leisure activities, time spent at work / school or on vacation, interpersonal relationships (including close relationships), side effects of treatment, and emotional responses to the skin condition. It is a valid questionnaire used in clinical practice and clinical trials. The response scale is a 4-point Likert scale with 9 items (0 = "not at all", 3 = "very much"). The remaining item regarding work / study asks whether work / study is hindered, and then (if "no") the extent to which the skin condition is problematic at work / study; this item is rated on a 3-point Likert scale ("not at all" to "very much"). The overall score ranges from 0 to 30, with high scores indicating poor HRQoL.

[0430] Hospital Anxiety and Depression Scale (HADS)

[0431] The HADS is a 14-item scale, with seven items each for anxiety and depression. Each item is scored from 0 to 3. A subscale score >8 indicates anxiety or depression. Subscale scores of 8-10 are mild, 11-14 are moderate, and 15-21 are severe. Scores of 7 or lower are considered non-cases.

[0432] Atopic dermatitis score (SCORAD)

[0433] SCORAD is a clinical tool used to assess the extent and severity of Alzheimer's disease (AD) using area, intensity, and subjective symptom scores. The SCORAD score ranges from 0 to 103 and defines three levels of AD severity (i.e., SCORAD < 25 is mild, 25 ≤ SCORAD ≤ 50 is moderate, and SCORAD > 50 is severe). The total SCORAD score is A / 5 + 7B / 2 + C.

[0434] To determine the area affected, eczema-affected areas are shaded on a human anatomy diagram. The rule of 9 is used to calculate the percentage of the body area affected (A): head and neck 9%; upper limbs 9% each; lower limbs 18% each; anterior trunk 18%; posterior trunk 18%; and genitals 1%. The scores for each area are summed. The total area is designated "A", with a maximum score of 100%.

[0435] To determine the intensity, a representative area of ​​eczema was selected. Within this area, the intensity of each of the following signs was rated as none (0), mild (1), moderate (2), or severe (3): redness; swelling; oozing / scabbing; scratching; thickening of the skin (lichenification); and dryness (assessed in areas without inflammation). The intensity scores were summed to obtain a "B", with a maximum score of 18.

[0436] To determine the subjective symptoms (i.e., itching and insomnia), the patient or a relative used a visual analog scale to rate each symptom, where 0 represents no itching (or no insomnia) and 10 represents the most severe imaginable itching (or insomnia). These scores were summed to obtain a "C", with a maximum score of 20.

[0437] Application plan

[0438] According to certain embodiments, multiple doses of anti-OX40L antibody or its antigen-binding fragment can be administered to a subject over a defined time period. Such methods include sequentially administering multiple doses of anti-OX40L antibody or its antigen-binding fragment to a subject. As used herein, “sequential administration” means administering each dose of anti-OX40L antibody or its antigen-binding fragment to a subject at different time points (e.g., on different dates separated by predetermined intervals, such as hours, days, weeks, or months). Methods are provided that include sequentially administering a single initial dose of anti-OX40L antibody or its antigen-binding fragment to a patient, followed by one or more second doses of anti-OX40L antibody or its antigen-binding fragment, and optionally subsequently administering one or more third doses of anti-OX40L antibody or its antigen-binding fragment.

[0439] Methods are provided that include administering a pharmaceutical composition comprising an anti-OX40L antibody or an antigen-binding fragment thereof to a subject at a frequency of approximately four times a week, twice a week, once a week (q1w), once every two weeks (q2w is interchangeable with every other week, once every two weeks, or every q2w), once every three weeks (q3w), once every four weeks (q4w), once a month (q4w), once every five weeks (q5w), once every six weeks (q6w), once every seven weeks (q7w), once every eight weeks (q8w), once every nine weeks (q9w), once every ten weeks (q10w), once every eleven weeks (q11w), once every twelve weeks (q12w), or fewer (provided a therapeutic response is achieved).

[0440] In some embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or an antigen-binding fragment thereof, the drug may be administered once weekly in amounts of about 62.5 mg, about 125 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or an antigen-binding fragment thereof, the drug may be administered once every two weeks in amounts of about 62.5 mg, about 125 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg (every two weeks is interchangeable with every other week, every two weeks, or q2w). In other embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or an antigen-binding fragment thereof, the drug may be administered once every three weeks in amounts of about 62.5 mg, about 125 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or an antigen-binding fragment thereof, the drug may be administered once every four weeks (monthly) in amounts of about 62.5 mg, about 125 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or an antigen-binding fragment thereof, the drug may be administered once every five weeks in amounts of about 62.5 mg, about 125 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or an antigen-binding fragment thereof, the drug may be administered once every six weeks in amounts of about 62.5 mg, about 125 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or an antigen-binding fragment thereof, the drug may be administered once every eight weeks in an amount of about 62.5 mg, about 125 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or an antigen-binding fragment thereof, the drug may be administered once every twelve weeks in an amount of about 62.5 mg, about 125 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or an antigen-binding fragment thereof, the subject receives a dose of about 62.5 mg, about 125 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg once every twelve weeks from the start of treatment.In some exemplary embodiments, the administration route is subcutaneous.

[0441] In some embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or its antigen-binding fragment, the drug may be administered once weekly in doses of 62.5 mg, 125 mg, 250 mg, 300 mg, 400 mg, 500 mg, or 600 mg. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or its antigen-binding fragment, the drug may be administered once every two weeks in doses of 62.5 mg, 125 mg, 250 mg, 300 mg, 400 mg, 500 mg, or 600 mg (every two weeks is interchangeable with every other week, every two weeks, or q2w). In other embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or its antigen-binding fragment, the drug may be administered once every three weeks in doses of 62.5 mg, 125 mg, 250 mg, 300 mg, 400 mg, 500 mg, or 600 mg. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or its antigen-binding fragment, the drug may be administered once every four weeks (monthly) in doses of 62.5 mg, 125 mg, 250 mg, 300 mg, 400 mg, 500 mg, or 600 mg. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or its antigen-binding fragment, the drug may be administered once every five weeks in doses of 62.5 mg, 125 mg, 250 mg, 300 mg, 400 mg, 500 mg, or 600 mg. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or its antigen-binding fragment, the drug may be administered once every six weeks in doses of 62.5 mg, 125 mg, 250 mg, 300 mg, 400 mg, 500 mg, or 600 mg. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or its antigen-binding fragment, the drug may be administered once every eight weeks in doses of 62.5 mg, 125 mg, 250 mg, 300 mg, 400 mg, 500 mg, or 600 mg. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or its antigen-binding fragment, the drug may be administered once every twelve weeks in doses of 62.5 mg, 125 mg, 250 mg, 300 mg, 400 mg, 500 mg, or 600 mg. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or its antigen-binding fragment, the subject receives a dose of 62.5 mg, 125 mg, 250 mg, 300 mg, 400 mg, 500 mg, or 600 mg once every twelve weeks from the start of treatment. In some exemplary embodiments, the route of administration is subcutaneous.

[0442] In some embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or an antigen-binding fragment thereof, a subject may receive an initial dose of about 500 mg of the antibody or an antigen-binding fragment thereof, followed by one or more second doses of about 250 mg of the antibody or an antigen-binding fragment thereof, wherein the second doses are administered every 12 weeks (Q12W), the subject is an adult subject, and the administration is subcutaneous.

[0443] In some embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or an antigen-binding fragment thereof, a subject may receive an initial dose of about 250 mg of the antibody or an antigen-binding fragment thereof, followed by one or more second doses of about 125 mg of the antibody or an antigen-binding fragment thereof, wherein the second doses are administered every 12 weeks (Q12W), the subject is an adolescent subject, and the administration is subcutaneous.

[0444] The term “week” or “weeks” refers to a period of time of (n x 7 days) ± 3 days, such as (n x 7 days) ± 2 days, (n x 7 days) ± 1 day, or (n x 7 days), where “n” represents the number of weeks, such as 1, 2, 3, 4, 5, 6, 8, 12, or more.

[0445] The terms “initial dose,” “second dose,” and “third dose” refer to the temporal sequence of administration of the anti-OX40L antibody or its antigen-binding fragment. Thus, the “initial dose” is the dose administered at the start of the treatment regimen (also known as the “baseline dose” or “loading dose”); the “second dose” is the dose administered after the initial dose; and the “third dose” is the dose administered after the second dose. The initial, second, and third doses may all contain the same amount of the anti-OX40L antibody or its antigen-binding fragment, or they may differ in frequency of administration. However, in some embodiments, the amounts of the anti-OX40L antibody or its antigen-binding fragment contained in the initial, second, and / or third doses during treatment may differ from each other (e.g., appropriately increased or decreased). In some embodiments, two or more doses (e.g., 2, 3, 4, or 5) are administered at the start of the treatment regimen as a “loading dose,” followed by subsequent doses administered on a less frequent basis. In one embodiment, the second dose may be lower than the loading dose. For example, one or more initial doses or loading doses of an anti-OX40L antibody or its antigen-binding fragment of 62.5 mg, 125 mg, 250 mg, or 500 mg may be administered, followed by a second dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg. In one embodiment, the second dose may be equal to the initial dose / loading dose. For example, one or more initial doses / loading doses of an anti-OX40L antibody or its antigen-binding fragment of 62.5 mg, 125 mg, 250 mg, or 500 mg may be administered, followed by a second dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, respectively.

[0446] In some embodiments, the initial dose is about 50 mg to about 600 mg of anti-OX40L antibody or its antigen-binding fragment. In some embodiments, the initial dose is about 62.5 mg of anti-OX40L antibody or its antigen-binding fragment. In some embodiments, the initial dose is about 125 mg of anti-OX40L antibody or its antigen-binding fragment. In some embodiments, the initial dose is about 250 mg of anti-OX40L antibody or its antigen-binding fragment. In another embodiment, the initial dose is 500 mg of anti-OX40L antibody or its antigen-binding fragment.

[0447] In some embodiments, the second dose is about 50 mg to about 600 mg of anti-OX40L antibody or its antigen-binding fragment. In one embodiment, the second dose is about 62.5 mg of anti-OX40L antibody or its antigen-binding fragment. In one embodiment, the second dose is about 125 mg of anti-OX40L antibody or its antigen-binding fragment. In another embodiment, the second dose is about 125 mg of anti-OX40L antibody or its antigen-binding fragment. In yet another embodiment, the second dose is about 250 mg of anti-OX40L antibody or its antigen-binding fragment.

[0448] In some embodiments, the initial loading dose is about 500 mg (two injections of 250 mg), followed by a dose of about 250 mg (one injection of 250 mg) administered via Q12W.

[0449] In some embodiments, the initial loading dose is about 500 mg (two injections of 250 mg), followed by a dose of about 250 mg (one injection of 250 mg) administered Q4W, and for patients with clear or nearly clear skin at 24 weeks of treatment, a dose of about 250 mg is subsequently administered Q12W.

[0450] Treatment population

[0451] The methods described herein include administering a therapeutic composition comprising an anti-OX40L antibody or an antigen-binding fragment thereof to a subject in need. The term "subject in need" means a person or non-human animal exhibiting one or more symptoms or signs of AD, or who has been diagnosed with AD. For example, "subject in need" may include, for instance, a subject who exhibits (or has exhibited) one or more AD-related parameters prior to treatment, such as, for example, impaired EASI, impaired IGA, impaired PP-NRS, impaired SP-NRS, impaired SD-NRS, impaired DLQI, and / or impaired HADS. In various embodiments, the method can be used to treat patients in need with mild, moderate to severe (e.g., uncontrolled moderate to severe) and severe AD.

[0452] In some embodiments, “subjects in need” are selected from the group consisting of: subjects aged 18 years or older, subjects aged 12 years or older, subjects aged 12 to 17 years (12 to <18 years), subjects aged 6 to 11 years (6 to <12 years), and subjects aged 2 to 5 years (2 to <6 years). In some embodiments, “subjects in need” are selected from the group consisting of: adults, adolescents, and children. In some embodiments, “subjects in need” are selected from the group consisting of: adults aged 18 years or older, adolescents aged 12 to 17 years (12 to <18 years), children aged 6 to 11 years (6 to <12 years), and children aged 2 to 5 years (2 to <6 years). Subjects may be younger than 2 years, for example, 12 to 23 months or 6 to 11 months. In some embodiments, the weight of “subjects in need” is between about 25 kg and about 40 kg.

[0453] dose

[0454] The amount of anti-OX40 ligand (OX40L) antibody or its antigen-binding fragment administered to a subject according to the methods described herein is generally a therapeutically effective amount. As used herein, the phrase “therapeutically effective amount” means the amount of anti-OX40L antibody or its antigen-binding fragment that results in improvement of one or more AD-related parameters (as defined elsewhere herein). “Therapeutically effective amount” also includes the amount of anti-OX40L antibody or its antigen-binding fragment that inhibits, prevents, mitigates, or delays the progression of AD in a subject.

[0455] The dosage can be from 20 mg to 1000 mg. The dosage can be from 20 mg to 600 mg. The dosage can be up to 550 mg, up to 500 mg, up to 450 mg, up to 400 mg, up to 350 mg, up to 300 mg, up to 250 mg, up to 200 mg, up to 150 mg, up to 120 mg, up to 100 mg, or up to 50 mg. The dosage can be up to 500 mg, up to 250 mg, or up to 150 mg. The dosage can be at least 50 mg, at least 100 mg, at least 120 mg, at least 150 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, at least 400 mg, at least 450 mg, at least 500 mg, or at least 550 mg. The dosage can be at least 50 mg, at least 120 mg, or at least 150 mg. Dosage can be selected from the following groups: 25 mg to 500 mg; 50 mg to 450 mg; 100 mg to 350 mg; 120 mg to 300 mg; 150 mg to 250 mg; and 200 mg to 250 mg. Dosage can also be selected from the following groups: 60 mg to 500 mg; 100 mg to 300 mg; or 125 mg to 150 mg.

[0456] The dosage can be 62.5 mg, 125 mg, 150 mg, 250 mg, or 500 mg. The dosage can be 125 mg or 150 mg. The dosage can be 125 mg. The dosage can be 150 mg. The dosage can be 62.5 mg. The dosage can be 250 mg. The dosage can be 500 mg.

[0457] Doses can be as high as 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2 mg / kg, 2.1 mg / kg, 2.2 mg / kg, 2.3 mg / kg, 2.4 mg / kg, 2.5 mg / kg, 2.6 mg / kg, 2.7 mg / kg, 2.8 mg / kg, 2.9 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, and up to 11 mg / kg. mg / kg or up to 12 mg / kg. Dosage can be up to 6 mg / kg or up to 3 mg / kg.

[0458] The dosage may be at least 0.45 mg / kg, at least 0.5 mg / kg, at least 0.6 mg / kg, at least 0.7 mg / kg, at least 0.8 mg / kg, at least 0.9 mg / kg, at least 1 mg / kg, at least 1.1 mg / kg, at least 1.2 mg / kg, at least 1.3 mg / kg, at least 1.4 mg / kg, at least 1.5 mg / kg, at least 1.6 mg / kg, at least 1.7 mg / kg, at least 1.8 mg / kg, at least 1.9 mg / kg, at least 2 mg / kg, at least 2.1 mg / kg, at least 2.2 mg / kg, at least 2.3 mg / kg, at least 2.4 mg / kg, at least 2.5 mg / kg, at least 2.6 mg / kg, at least 2.7 mg / kg, at least 2.8 mg / kg, at least 2.9 mg / kg, at least 3 mg / kg, at least 4 mg / kg, at least 5 mg / kg, at least 6 mg / kg, at least 7 mg / kg, at least 8 mg / kg, at least 9 mg / kg. The dosage may be at least 0.45 mg / kg, at least 0.7 mg / kg, or at least 1.4 mg / kg.

[0459] The dosage can be selected from the following groups: 0.1 mg / kg to 12 mg / kg; 0.4 mg / kg to 11 mg / kg; 0.7 mg / kg to 10 mg / kg; 1 mg / kg to 9 mg / kg; 1.3 mg / kg to 8 mg / kg; 1.6 mg / kg to 7 mg / kg; 1.9 mg / kg to 6 mg / kg; 2.2 mg / kg to 5 mg / kg; 2.5 mg / kg to 4 mg / kg; 2.6 mg / kg to 3.8 mg / kg; 2.7 mg / kg to 3.6 mg / kg; 2.6 mg / kg to 3.4 mg / kg; 2.7 mg / kg to 3.3 mg / kg; 2.8 mg / kg to 3.2 mg / kg; and 2.9 mg / kg to 3.1 mg / kg. The dosage can be selected from the following groups: 0.6 mg / kg to 11 mg / kg; 0.7 mg / kg to 10 mg / kg; 0.8 mg / kg to 9 mg / kg; 0.9 mg / kg to 8 mg / kg; 1 mg / kg to 7 mg / kg; 1.1 mg / kg to 6 mg / kg; 1.2 mg / kg to 5 mg / kg; 1.3 mg / kg to 4 mg / kg; 1.4 mg / kg to 3 mg / kg; 1.5 mg / kg to 2.9 mg / kg; 1.6 mg / kg to 2.8 mg / kg; 1.7 mg / kg to 2.7 mg / kg; 1.8 mg / kg to 2.6 mg / kg; 1.9 mg / kg to 2.5 mg / kg; 2 mg / kg to 2.4 mg / kg; and 2.1 mg / kg to 2.3 mg / kg.

[0460] The dosage can be from 0.7 mg / kg to 6 mg / kg. The dosage can be from 1.4 mg / kg to 3 mg / kg.

[0461] In some embodiments, 62.5 mg of anti-OX40L antibody or its antigen-binding fragment is administered. In some embodiments, 125 mg of anti-OX40L antibody or its antigen-binding fragment is administered. In some embodiments, 250 mg of anti-OX40L antibody or its antigen-binding fragment is administered. In some embodiments, 500 mg of anti-OX40L antibody or its antigen-binding fragment is administered.

[0462] In some embodiments, the subject weighs 25 kg or more and less than 40 kg, and is administered a formulation comprising a 62.5 mg / mL amotelimab solution provided in a prefilled syringe that delivers 125 mg of amotelimab in 2 mL injections.

[0463] In some exemplary embodiments, the subject weighs 25 kg or more and less than 40 kg, and the subject is administered a formulation comprising a 125 mg / mL amotelimab solution provided in a pre-filled syringe that delivers 125 mg of amotelimab in 1 mL injection.

[0464] Application plan

[0465] According to certain embodiments, multiple doses of anti-OX40L antibody or its antigen-binding fragment can be administered to a subject over a defined time period. Such methods include sequentially administering multiple doses of anti-OX40L antibody or its antigen-binding fragment to a subject. As used herein, “sequential administration” means administering each dose of anti-OX40L antibody or its antigen-binding fragment to a subject at different time points (e.g., on different dates separated by predetermined intervals, such as hours, days, weeks, or months). Methods are provided that include sequentially administering a single initial dose of anti-OX40L antibody or its antigen-binding fragment to a patient, followed by one or more second doses of anti-OX40L antibody or its antigen-binding fragment, and optionally subsequently administering one or more third doses of anti-OX40L antibody or its antigen-binding fragment.

[0466] Methods are provided that include administering a pharmaceutical composition comprising an anti-OX40L antibody or an antigen-binding fragment thereof to a subject at a frequency of approximately four times a week, twice a week, once a week (q1w), once every two weeks (q2w is interchangeable with every other week, once every two weeks, or every q2w), once every three weeks (q3w), once every four weeks (q4w), once a month (q4w), once every five weeks (q5w), once every six weeks (q6w), once every seven weeks (q7w), once every eight weeks (q8w), once every nine weeks (q9w), once every ten weeks (q10w), once every eleven weeks (q11w), once every twelve weeks (q12w), or fewer (provided a therapeutic response is achieved).

[0467] In some embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or an antigen-binding fragment thereof, the drug may be administered once weekly in amounts of about 62.5 mg, about 125 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or an antigen-binding fragment thereof, the drug may be administered once every two weeks in amounts of about 62.5 mg, about 125 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg (every two weeks is interchangeable with every other week, every two weeks, or q2w). In other embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or an antigen-binding fragment thereof, the drug may be administered once every three weeks in amounts of about 62.5 mg, about 125 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or an antigen-binding fragment thereof, the drug may be administered once every four weeks (monthly) in amounts of about 62.5 mg, about 125 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or an antigen-binding fragment thereof, the drug may be administered once every five weeks in amounts of about 62.5 mg, about 125 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or an antigen-binding fragment thereof, the drug may be administered once every six weeks in amounts of about 62.5 mg, about 125 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or an antigen-binding fragment thereof, the drug may be administered once every eight weeks in amounts of about 62.5 mg, about 125 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-OX40L antibody or an antigen-binding fragment thereof, the drug may be administered once every twelve weeks in amounts of about 62.5 mg, about 125 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg. In some exemplary embodiments, the route of administration is subcutaneous.

[0468] The term “week” or “weeks” refers to a period of time of (n x 7 days) ± 3 days, such as (n x 7 days) ± 2 days, (n x 7 days) ± 1 day, or (n x 7 days), where “n” represents the number of weeks, such as 1, 2, 3, 4, 5, 6, 8, 12, or more.

[0469] The terms “initial dose,” “second dose,” and “third dose” refer to the temporal sequence of administration of the anti-OX40L antibody or its antigen-binding fragment. Therefore, the “initial dose” is the dose administered at the start of the treatment regimen (also known as the “baseline dose” or “loading dose”); the “second dose” is the dose administered after the initial dose; and the “third dose” is the dose administered after the second dose. The initial, second, and third doses may all contain the same amount of the anti-OX40L antibody or its antigen-binding fragment, or they may differ in frequency of administration. However, in some embodiments, the amounts of the anti-OX40L antibody or its antigen-binding fragment contained in the initial, second, and / or third doses during treatment may differ from each other (e.g., appropriately increased or decreased). In some embodiments, two or more doses (e.g., 2, 3, 4, or 5) are administered at the start of the treatment regimen as a “loading dose,” followed by subsequent doses. For example, one or more initial doses or loading doses of an anti-OX40L antibody or its antigen-binding fragment of 62.5 mg, 125 mg, 250 mg, or 500 mg may be administered, followed by a second dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg. In one embodiment, the second dose may be equal to the initial dose / loading dose. For example, one or more initial doses / loading doses of an anti-OX40L antibody or its antigen-binding fragment of 62.5 mg, 125 mg, 250 mg, or 500 mg may be administered, followed by a second dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, respectively.

[0470] In some embodiments, the initial dose is about 50 mg to about 600 mg of anti-OX40L antibody or its antigen-binding fragment. In some embodiments, the initial dose is about 62.5 mg of anti-OX40L antibody or its antigen-binding fragment. In some embodiments, the initial dose is about 125 mg of anti-OX40L antibody or its antigen-binding fragment. In some embodiments, the initial dose is about 250 mg of anti-OX40L antibody or its antigen-binding fragment. In another embodiment, the initial dose is 500 mg of anti-OX40L antibody or its antigen-binding fragment.

[0471] In some embodiments, the second dose is about 50 mg to about 600 mg of anti-OX40L antibody or its antigen-binding fragment. In one embodiment, the second dose is about 62.5 mg of anti-OX40L antibody or its antigen-binding fragment. In one embodiment, the second dose is about 125 mg of anti-OX40L antibody or its antigen-binding fragment. In another embodiment, the second dose is about 125 mg of anti-OX40L antibody or its antigen-binding fragment. In yet another embodiment, the second dose is about 250 mg of anti-OX40L antibody or its antigen-binding fragment.

[0472] In some embodiments, the initial loading dose is about 500 mg (two injections of 250 mg), followed by a dose of about 250 mg (one injection of 250 mg) administered via Q12W.

[0473] In some embodiments, the initial loading dose is about 500 mg (two injections of 250 mg), followed by a dose of about 250 mg (one injection of 250 mg) administered Q4W, and for patients with clear or nearly clear skin at 24 weeks of treatment, a dose of about 250 mg is subsequently administered Q12W.

[0474] Specific elements of any of the foregoing embodiments may be combined or substituted for elements in other embodiments. Furthermore, while advantages associated with certain embodiments of this disclosure have been described in the context of these embodiments, other embodiments may also exhibit such advantages, and not all embodiments are required to exhibit such advantages to fall within the scope of this disclosure. Unless otherwise apparent from the context, any part of this disclosure may be read in conjunction with any other part of this disclosure.

[0475] In the following examples, animetimab (also known as SAR 445229 and KY1005) is exemplarily used as an antibody that specifically binds to hOX40L. Ametimab is a fully human IgG4κ monoclonal antibody with a “IgG4-PE” constant region containing Leu235Glu and Ser228Pro Fc mutations. Ametimab comprises: a VH domain containing the amino acid sequence shown in SEQ ID NO: 34 and a VL domain containing the amino acid sequence shown in SEQ ID NO: 48. Ametimab comprises: a heavy chain (HC) containing the amino acid sequence shown in SEQ ID NO: 62 and a light chain (LC) containing the amino acid sequence shown in SEQ ID NO: 64.

[0476] Example

[0477] The following examples further illustrate aspects of this disclosure. However, this is by no means a limitation on the teachings of this disclosure set forth. It should be understood that these examples are given by way of illustration only. Based on the foregoing discussion and these examples, those skilled in the art can determine the essential features of embodiments of this disclosure. Various changes and modifications can be made to this disclosure by those skilled in the art to adapt it to various uses and conditions without departing from its spirit and scope. All publications (including patent and non-patent documents) referenced in this specification are expressly incorporated herein by reference.

[0478] Example I

[0479] Positive phase 2b data from the novel experimental anti-OX40 ligand elemotriumab showed statistically significant improvement in the signs and symptoms of moderate to severe atopic dermatitis.

[0480] Research design overview Figure 14 In this study, after discontinuing previous AD treatment and undergoing a 28-day screening period, participants were randomized in a 1:1:1:1:1 ratio to receive a loading dose of 500 mg amotilimab via SC (administered in 2 x 2 mL SCs), followed by 250 mg SC Q4W; amotilimab 250 mg SC Q4W; amotilimab 125 mg SC Q4W; amotilimab 62.5 mg SC Q4W; or placebo Q4W, from baseline until week 24 (day 169).

[0481] The key inclusion criteria were: adults (218 years but <75 years old) with AD for 1 year or longer at baseline; an eczema area severity index (EASI) of 12 or higher at the screening visit and 16 or higher at baseline; an IGA of 3 or 4 at baseline; AD affecting 10% or more of the body surface area (BSA) at baseline; a weekly mean of 24 for the daily most severe / maximum pruritus NRS at baseline; and a history of inadequate response to topical treatment or inadvisable topical treatment within 6 months prior to baseline.

[0482] At week 16 (day 113), the percentage change in EASI score relative to baseline was assessed as the primary endpoint. The primary analysis (Part 1) was performed once all participants had completed or had the opportunity to complete week 24 (day 169). The final dose in Part 1 was administered at week 20 (day 141). Safety was assessed in all randomly assigned subjects exposed to the study drug.

[0483] The key secondary efficacy endpoints were: the percentage change in EASI relative to baseline at Week 24 (Day 169); the percentage of participants with at least a 75% reduction in EASI relative to baseline (EASI-75) at Week 16 (Day 113) and Week 24 (Day 169); the percentage of participants with an IGA of 0 (clear) or 1 (almost clear) response and a reduction of ≥2 points relative to baseline at Week 16 (Day 113) and Week 24 (Day 169); the proportion of participants with a weekly mean improvement (reduction) of ≥4 in the Itch NRS from baseline to Week 16 (Day 113) and Week 24 (Day 169) and a baseline Itch NRS ≥4.

[0484] Regarding Part 2 of the ongoing post-Week 24 study period (i.e., the withdrawal / maintenance part), participants who achieved EASI-75 or an IGA of 0 (clear) or 1 (almost clear) were re-randomized in a 3:1 ratio to enter the maintenance withdrawal period or continue their pre-Week twenty-fourth (Day 169) dose / interval. Those participants who were re-randomized at Week 24 (Day 169) and subsequently lost clinical response (defined in this study as the first instance of <EASI-50 and no rescue therapy was allowed on or after the Day of the Week 28 (Day 197) study visit) had the opportunity to receive emotricumab treatment in the long-term extension KY1005-CT06 / LTS17367 (RIVER-AD) study. At Week 52 (Day 365), participants who completed the second study period without losing clinical response had an additional 112 days of safety follow-up until Week 68 (Day 477), and then withdrew from the study. The last dose was no later than Week 48 (Day 337). If, during the safety follow-up period or after the study ended, participants in this cohort experienced a worsening of their AD and the investigator considered re-treatment with emotricumab to be appropriate, they could be considered for inclusion in the long-term extension KY1005-CT06 / LTS17367 (RIVER-AD) study (participants met the inclusion / exclusion criteria).

[0485] The study enrolled 390 participants. These 390 participants were randomized to the SC study intervention group as follows: 250 mg Q4W (500 mg loading dose) amotilimab group, 250 mg Q4W, 125 mg Q4W, 62.5 mg Q4W, or placebo Q4W groups (n=77, n=78, n=77, n=79, and n=79, respectively). Of these randomized participants, 388 (99.5%) received at least one dose of the study intervention (one participant each in the amotilimab 62.5 mg Q4W group and the placebo Q4W group was randomized and did not receive treatment). There were no participants exposed to the study intervention but not randomized. A total of 323 (83.2%) participants completed the 24-week double-blind treatment period, 65 (16.8%) discontinued treatment, and 51 (13.1%) discontinued the study before the week 24 visit.

[0486] The treatment discontinuation rates in the amotilimab group (250 mg Q4W, 500 mg loading dose), 250 mg Q4W, 125 mg Q4W, or 62.5 mg Q4W) were lower than in the placebo group (9 [11.7%], 16 [20.5%], 8 [10.4%], and 11 [14.1%] participants, respectively) than in the placebo group (21 [26.9%] participants). Before week 24, the most frequently reported reason for treatment discontinuation was participant withdrawal (amotelimab group 250 mg Q4W, 500 mg loading dose, 250 mg Q4W; 125 mg Q4W and 62.5 mg Q4W). In the mgQ4W group, there were 2 [2.6%], 9 [11.5%], 6 [7.8%], and 2 [2.6%] participants, respectively, and 8 [10.3%] participants in the placebo group; adverse events (AEs) (3 [3.9%], 5 [6.4%], 1 [1.3%], and 6 [6.7%] participants, respectively, and 4 [5.1%] participants in the placebo group; lack of efficacy (0 [0.0%], 1 [1.3%], 1 [1.3%], and 2 [2.6%] participants, respectively, and 5 [6.4%] participants in the placebo group).

[0487] Prior to the week 24 visit, the discontinuation rate in the amotilimab group (250 mg Q4W, 500 mg loading dose, 250 mg SCQ4W, 125 mg Q4W, 62.5 mg Q4W) was lower than that in the placebo group (16 participants [10.4%], 12 participants [15.4%], 8 participants [10.4%], and 7 participants [8.9%]). Prior to week 24, the most frequently reported discontinuation reason was participant withdrawal (5 participants [6.5%] in the amotilimab group and 500 mg loading dose, 250 mg Q4W, 125 mg Q4W, and 62.5 mg Q4W, respectively; 11 participants [14.1%] in the amotilimab group; 8 participants [10.4%] in the SCQ4W group; and 6 participants [7.6%] in the placebo group). (Table 1.)

[0488] Table 1. Subject treatment (during week 24)

[0489]

[0490] In the amotilemab groups (250 mg Q4W (500 mg loading dose), 250 mg Q4W, 125 mg Q4W, and 62.5 mg Q4W), the number (%) of participants experiencing at least one serious or major protocol deviation was similar in 15 [19.5%], 16 [20.5%], 11 [14.3%], and 20 [25.3%] participants, respectively, and in the placebo group (16 [20.3%] participants) (Table 2). The most frequently reported serious or major protocol deviations (at least 3 participants in any treatment group) were associated with the following: prohibited drugs, including amotilemab in the 250 mg Q4W (500 mg loading dose), 250 mg Q4W, 125 mg Q4W, and 62.5 mg Q4W groups. Unlicensed emergency treatment in Q4W (2 [2.6%], 9 [11.5%], 6 [7.8%], and 4 [5.1%] participants, respectively) and placebo group (8 [10.1%] participants); administration / allocation of study treatment in the amotilimab group at 250 mg Q4W (500 mg loading dose), 250 mg Q4W, 125 mg Q4W, and 62.5 mg Q4W (1 [1.3%], 3 [3.8%], 3 [3.9%], and 3 [3.8%] participants, respectively) and placebo group (2 [2.5%] participants); visit arrangements in the amotilimab group at 250 mg Q4W (500 mg loading dose), 250 mg Q4W, 125 mg Q4W, and 62.5 mg Q4W. In the Q4W group (3 [3.9%], none, 1 [1.3%], and 4 [5.1%] participants, respectively) and in the placebo group (1 [1.3%] participant), the exclusion criteria were due to visits at week 16 and / or week 24 exceeding the window of visits by 2 weeks; exclusion criteria were primarily due to use of prohibited drugs prior to the baseline visit in the amotelimab group at 250 mg Q4W (500 mg loading dose), 250 mg Q4W, 125 mg Q4W, and 62.5 mg Q4W (4 [5.2%], none, none, and 4 [5.1%] participants, respectively) and in the placebo group (1 [1.3%] participant).

[0491] Table 2. Serious or Major Program Deviations (During Week 24)

[0492]

[0493] Deviations from inclusion criteria were primarily related to a lack of prior record of topical therapy in the 250 mg Q4W (500 mg loading dose), 250 mg Q4W, 125 mg Q4W, and 62.5 mg Q4W groups (2 [2.6%], 2 [2.6%], 1 [1.3%], and 2 [2.5%] participants, respectively) and in the placebo group (2 [2.5%] participants).

[0494] Two participants reported an “ICH / GCP deviation” in the eCRF due to a 24-hour delay in reporting SAE. Two participants who changed from an additive-free lubricant to an additive-containing lubricant during the study reported two “Other Deviations.” A participant who underwent a skin biopsy before signing the substudy ICF reported an “Informed Consent (ICF)” deviation.

[0495] It is believed that deviations from these established main schemes will not compromise the integrity of the research results or conclusions.

[0496] The number of participants included in each analysis population is shown in Table 3.

[0497] Table 3. Analytical population up to week 24

[0498]

[0499] All included sets

[0500] All participants included in the analysis set were those who had signed up for the ICF and had not failed screening. The analysis was based on the study intervention assigned at the time of randomization.

[0501] Part 1: The Complete Analysis Set

[0502] The full analysis set (FAS1) in Part 1 includes all randomized participants up to week 24. Efficacy analyses were based on the study intervention assigned at randomization. Randomization was stratified according to disease severity at baseline (moderate / severe) and region (Asia Pacific, EMEA, North America). Disease severity at baseline was defined as moderate (baseline EASI ≤ 21) and severe (baseline EASI > 21).

[0503] Part 1 Security Analysis Set

[0504] The safety set (SAF1) in Part 1 comprised all participants who had received at least one dose of the study intervention (including placebo) by week 24. Any analysis based on SAF1 is based on the actual study intervention received, without regard to study interventions assigned according to the plan of randomization.

[0505] Part 1 Pharmacokinetics

[0506] The PK set includes all randomized participants who had at least one post-baseline PK sample in SAF1 up to week 24 (with fully documented dosing and sampling dates and times). Any analysis based on PK1 is based on the actual study intervention received, regardless of the study intervention assigned according to the plan of randomization. Participants who received placebo alone are excluded.

[0507] Part 1 Antidrug Antibody Collection

[0508] The ADA set comprises all randomized participants who received emotelimab in SAF1 up to week 24 and had at least one baseline ADA outcome (positive, negative, or indeterminate). Any analysis based on ADA1 is based on the actual study intervention received, regardless of the study intervention assigned according to the plan of randomization. Participants who received placebo alone were excluded.

[0509] Statistical methods

[0510] Power analyses were performed using the full analysis set (FAS), which included all randomized participants assigned to treatment based on randomization. For all power variables, the analysis was a comparison between each emotelimab treatment group and the placebo group.

[0511] The primary efficacy endpoint was the percentage change in EASI from baseline to week 16 (day 113). Analysis of covariance (ANCOVA) was used to estimate the mean difference and 95% confidence interval between each active group and the placebo group, with treatment, randomization stratification (region, disease severity) as fixed effects and baseline values ​​as covariates.

[0512] Main analytical methods

[0513] Different types of concurrence events were defined, and the data processing methods for post-concurrence assessments were defined as follows: For treatment discontinuation before week 16 for reasons other than lack of efficacy, a treatment policy strategy was applied, i.e., all efficacy assessments collected after treatment discontinuation were used in the analysis. For treatment discontinuation and / or use of emergency medications or contraindicated medications or procedures affecting efficacy before week 16 due to lack of efficacy, a composite variable strategy was applied, i.e., the primary endpoint (WOCF) was assessed based on the worst baseline post-assessment at or before the time of discontinuation of study treatment or use of emergency medications / contraindicated medications / procedures affecting efficacy (whichever was earlier). Missing endpoint values ​​were imputed using multiple imputation (MI) methods, using all participants except those who took contraindicated medications / procedures and / or emergency medications affecting efficacy before week 16, and those who discontinued medication before week 16 due to lack of efficacy.

[0514] Treatment policies and methods

[0515] For treatment discontinuation and / or use of emergency medications or contraindicated concomitant medications or procedures affecting efficacy prior to week 16, the treatment policy strategy was applied, meaning all efficacy assessments collected after treatment discontinuation or use of emergency medications / contraindicated concomitant medications or procedures affecting efficacy were used in the analysis. Missing endpoint values ​​were estimated using the MI of all participants.

[0516] Analyze successive secondary efficacy endpoints using methods similar to those used for the primary efficacy endpoint.

[0517] For categorical secondary endpoints, the Cochran-Mantel-Haenszel method was used, stratified by randomization (region, disease severity). For the primary analysis approach handling concomitant events, participants who discontinued treatment and / or used emergency medications or contraindicated medications affecting efficacy at or before week 16 were considered non-responders. For the treatment policy approach, all data were analyzed before week 16 regardless of treatment discontinuation, use of emergency medications, or use of contraindicated medications or surgery affecting efficacy.

[0518] For the primary endpoint, a stratified testing procedure with four dosing regimens against placebo was used to control for the overall Type I error rate. A stratified testing procedure is a sequential test with a pre-specified order (i.e., from the highest dose to the lowest dose).

[0519] Summary statement of safety data / measurement results analyzed during the 24-week treatment period

[0520] For TEAEs, the TEAE summary table in Part 1 includes all AEs starting from or after the first IMP date up to the 24th week visit (re-randomized IMP date).

[0521] For laboratory data by visit: all assessments, including those from early termination or safety follow-up visits, are mapped to analytical visits and included in the safety summary table in Part 1, excluding unplanned assessments. Some assessments from week 24 are mapped to and presented from the analytical visit from week 28.

[0522] For vital signs, physical examination, and ECG data at each visit: all assessments (including unplanned, early termination, or safety follow-up visits) are mapped to the analytical visit and included in the safety summary table in Part 1. Some assessments at week 24 are mapped to and presented at the analytical visit at week 28.

[0523] For the PCSA table: The PCSA summary table in Part 1 takes into account unplanned, early termination, or security follow-up visits (PCSAs) including those mapped from week 24 to week 28 for analysis.

[0524] Demographic characteristics

[0525] Baseline demographics were generally balanced across treatment groups. Overall, the mean (SD) age was 37.8 (14.36) years (range: 18 to 72 years), and 20 [5.1%] participants were 65 years or older. The median BMI was 25.4 kg / m², and 84 (21.5%) participants had a BMI >30 kg / m². 2 .

[0526] Disease and other characteristics at baseline

[0527] Overall, the baseline disease characteristics of the intervention groups were generally balanced in terms of disease severity, sign intensity, symptom severity, duration of AD, and other baseline characteristics, and were representative of the global population with moderate to severe AD.

[0528] The mean (SD) duration of AD after initial diagnosis in FAS was 22.27 (16.5) years.

[0529] Baseline disease characteristics were: mean (SD) EASI 28.9 (10.65), 279 [71.5%] participants had EASI >21 and 111 [28.5%] participants had EASI ≤21; 280 [71.8%] participants had IGA 3 (moderate) and 110 [28.2%] participants had IGA 4 (severe); mean (SD) baseline weekly mean pruritus NRS 7.32 (1.3); mean (SD) impact BSA involvement 46.21 (19%) and mean (SD) SCORAD 67.17 (12.1).

[0530] Other baseline characteristics related to participants' QoL and AD-related symptoms were similar across intervention groups. Participants had a mean (SD) overall POEM score of 20.22 (5.5), a mean (SD) DLQI of 15.43 (6.8), a mean (SD) HADS of 13.22 (8.4), and a mean (SD) Atopic Dermatitis Control Tool (ADCT) score of 15.98 (4.5) at baseline.

[0531] Alzheimer's disease comorbid medication

[0532] All participants used a stable dose of topical lubricant / moisturizer at baseline and continued to use it throughout the study.

[0533] Exposure

[0534] The median duration of IMP exposure was similar across intervention groups in the safety population (23.9 weeks in each emotelimab group and 23.9 weeks in the placebo group) (Table 4). A total of 325 / 388 [83.8%] participants were exposed to IMP for ≥20 weeks to <24 weeks, and 145 / 388 [37.4%] participants were exposed to IMP for ≥24 weeks.

[0535] Table 4. Study treatment exposure-safety analysis set up to week 24

[0536]

[0537] Compared with the placebo group (53 [67.9%] participants), more participants in the amotelimab group received a total of 7 injections during the 24-week period in the 250 mg Q4W (500 mg loading dose), 250 mg Q4W, 125 mg Q4W and 62.5 mg Q4W groups (67 [87.0%], 61 [78.2%], 68 [88.3%] and 65 [83.3%] participants, respectively) (Table 5).

[0538] Table 5. Summary of Injections - Safety Analysis Set up to Week 24

[0539]

[0540] Research intervention compliance

[0541] Compared with the placebo group (86.4 (22.78)), participants in the amotelimab group who received 250 mg Q4W (500 mg loading dose), 250 mg Q4W, 125 mg Q4W, and 62.5 mg Q4W (93.5 (18.18), 89.6 (22.04), 94.4 (16.74), and 94.0 (16.04)) showed higher mean (SD) adherence to IMP administration.

[0542] Adherence to the study intervention was high across all treatment groups. Overall adherence was higher in the amotelimab group compared to the placebo group. Higher adherence rates (≥100%) to IMP administration were observed in the amotelimab group at 250 mg Q4W (500 mg loading dose), 250 mg Q4W, 125 mg Q4W, and 62.5 mg Q4W compared to the placebo group (53 (67.9%)). (Table 6)

[0543] Table 6. Summary of treatment adherence up to week 24 - safety analysis set

[0544]

[0545] Summary of Efficacy

[0546] This study evaluated the effects of emotelimab on AD lesions, pruritus, health-related QoL, anxiety, and depression in participants with AD whose disease was not adequately controlled or whose treatments were not advisable with topical medications. The primary endpoint was the change in EASI from baseline at week 16.

[0547] Statistically significant improvements in the primary endpoint (change in EASI from baseline to week 16) were observed, with all dose groups showing a statistically significant mean reduction in EASI score compared to the placebo group at week 16 (Table 7) and a nominally significant reduction at week 24 (Table 9). The 250 mg Q4W group (500 mg loading dose) showed the largest numerical differences at both weeks 16 and 24 compared to the placebo group and to all other groups (Tables 7 and 9). The 250 mg Q4W group (500 mg loading dose group) showed a larger early dissociation from the placebo group (as early as week 2, similar to the 62.5 mg Q4W dose), and this dissociation gradually increased throughout the 24-week intervention period, with the largest increase observed in the 250 mg Q4W (loading dose) group compared to other active groups (Table 7). Figure 5 No dose-response ratio was observed.

[0548] Table 7. Primary endpoint, primary analysis: percentage change in EASI relative to baseline at week 16 (estimate 1) - full analysis set in Part 1.

[0549]

[0550] Key secondary endpoints have also been improved.

[0551] At weeks 16 (Table 11) and 24 (Table 13), all dosage groups showed a greater proportion of participants achieving EASI-75 (at least 75% reduction in EASI from baseline) compared to the placebo group, both clinically and nominally statistically significant. The 250 mg Q4W (500 mg loading dose) group showed the greatest numerical difference at week 24 compared to the placebo group and other anilidemab groups (Table 13). The 250 mg Q4W group (500 mg loading dose group) showed a greater early dissociation from the placebo group at week 2. Starting at week 4, this dissociation from placebo gradually increased across all anilidemab dosing groups for the remainder of the 24-week intervention period, with the largest increase observed at week 24 in the 250 mg Q4W group (500 mg loading dose). Figure 4 No dose-response ratio was observed.

[0552] In all animotolimumab dose groups (except the 250 mg Q4W group at week 16), IGA 0 / 1 (the percentage of participants with an IGA 0 [clearance] or 1 [near-clearance] response and a reduction of ≥2 points relative to baseline) met nominal statistical significance at both weeks 16 and 24 (Tables 15 and 17). By week 24, sustained improvement was observed in all animotolimumab dose groups (except the 62.5 mg Q4W group, which showed a comparable proportion between weeks 16 and 24). The 250 mg Q4W (500 mg loading dose) group showed the largest numerical difference at week 24 compared to the placebo group and other animotolimumab groups (Table 17). Compared to other active groups, the 250 mg Q4W (500 mg loading dose) group showed a larger early dissociation from the placebo group at week 4. This dissociation from placebo among all anitolimab dosing groups gradually increased over the remainder of the 24-week intervention period, with the largest increase observed in the 250 mg Q4W group (500 mg loading dose). Figure 5 No dose-response ratio was observed.

[0553] At weeks 16 and 24, the endpoint of a ≥4-point reduction in the baseline pruritus NRS score was statistically significant in all amotelimab dose groups (Tables 19 and 21). Improvements were observed in all amotelimab dose groups at week 24 compared to week 16. The 250 mg amotelimab Q4W (500 mg loading dose) group showed the largest numerical differences at weeks 16 and 24 compared to the placebo group and other amotelimab groups (Tables 19 and 21). Compared to other active groups, the 250 mg amotelimab Q4W (500 mg loading dose) group showed the largest early dissociation from placebo at week 3. Dissociation from placebo generally increased gradually over the remainder of the 24-week treatment period, with the largest dissociation observed at week 24, which was similar across all amotelimab dose groups. Figure 8 No dose-response ratio was observed.

[0554] The primary endpoint analysis using the treatment policy strategy was consistent with the primary analysis at week 16 (Table 8). At week 24, for the primary endpoints (change in EASI relative to baseline %) (Table 10), EASI-75 (Table 36), IGA 0 / 1, and a 4-point reduction in the NRS score for pruritus, the overall treatment effect using the treatment policy was greater than that in the placebo group compared to the primary analysis method. In the analysis of the treatment policy using the IGA 0 / 1 endpoint, there were indications of dose-response dependence observed.

[0555] Table 8. Primary endpoint: Treatment policy approach: Percentage change in EASI from baseline to week 16 (estimate 2) - Full analysis set of Part 1.

[0556]

[0557] Other secondary efficacy endpoints (EASI-90, EASI-100, BSA, SCORAD, see Tables 23, 24, 25, and 26) and other secondary endpoints including patient-reported outcomes (such as POEM, ADCT, and DLQI as shown in Tables 27, 29, and 30) showed that at weeks 16 and 24, participants receiving anilidelimumab had nominally statistically significant improvements in all dose groups compared to those receiving placebo. For the HADS endpoint, no nominal statistical significance was reached in any dose group, but there was a trend toward statistical significance in the 250 mg anilidelimumab Q4W (500 mg loading dose) group at week 16 (p = 0.0997), but this was inconsistent at week 24 (p = 0.7080) (Table 28).

[0558] Primary endpoint: Percentage change in EASI from baseline to week 16

[0559] The mean (SD) EASI scores at baseline were similar in the treatment and placebo groups, with scores of 30.35 [11.66] for the 250 mg Q4W (500 mg loading dose), 28.67 [10.53] for the 250 mg Q4W, 30.26 [12.43] for the 125 mg Q4W and 28.70 [10.09] for the placebo group, and 26.44 (7.85) for the placebo group (Table 7).

[0560] Main Analysis

[0561] Compared with the placebo group, a statistically significant reduction in the percentage change in EASI score relative to baseline was observed at week 16 across all animotolimumab dosing regimens. The 250 mg Q4W group (500 mg loading dose) showed the largest numerical difference at week 16 compared with the placebo group and with other animotolimumab groups (Table 7).

[0562] Analysis using treatment policy data processing methods

[0563] Analysis of data following all concomitant events using treatment policy strategy data processing methods provided efficacy results consistent with the primary analysis at week 16 (Table 8). At week 16, a nominally statistically significant reduction in the percentage change in EASI score relative to baseline was observed across all dosing regimens studied in the anilotrimumab groups compared to the placebo group. The 62.5 mg Q4W and 250 mg Q4W (500 mg loading dose) groups showed the largest numerical differences at week 16 compared to the placebo group and other anilotrimumab groups.

[0564] Key secondary efficacy endpoints

[0565] The percentage change of EASI relative to baseline during the primary analysis in week 24.

[0566] Compared with the placebo group, at week 24, a nominally statistically significant reduction in the percentage change in EASI score relative to baseline was observed in all dosing regimens studied in the animotolimab groups. The 250 mg Q4W group (500 mg loading dose) showed the largest numerical difference at week 24 compared with the placebo group and other animotolimab groups (Table 9).

[0567] Table 9. Key secondary endpoints, primary analysis: percentage change in EASI from baseline to week 24 (estimated 4a) - Full analysis set in Part 1

[0568]

[0569] Analysis using treatment policy data processing methods

[0570] Analysis of data following all concomitant events using the treatment policy strategy data processing method showed a greater overall treatment effect on the percentage change in EASI from baseline to week 24 compared to the placebo group (Table 10). At week 24, a nominally statistically significant reduction in the percentage change in EASI score relative to baseline was observed in all dosing regimens studied in the anilotrimumab group compared to the placebo group. The 250 mg Q4W group (500 mg loading dose) showed the largest numerical difference at week 24 compared to the placebo group and other anilotrimumab groups.

[0571] Table 10. Key secondary endpoints, treatment policy approach: Percentage change in EASI from baseline to week 24 (estimated 4b) – Full analysis in Part 1

[0572]

[0573] Average change of EASI over time relative to baseline (%)

[0574] During the 24-week treatment period, using observed data, both the 250 mg Q4W (500 mg loading dose) and 62.5 mg Q4W dose groups showed the greatest early discontinuity from placebo, as early as week 2, compared to other active groups. Figure 3 This separation from placebo among all anitolimab dosing groups gradually increased over the remainder of the 24-week intervention period, with the largest increase observed in the 250 mg Q4W (500 mg loading dose) group.

[0575] Main Analysis (Week 16)

[0576] At week 16, all dose groups showed a greater proportion of participants achieving EASI-75 with clinical significance and nominal statistical significance compared to the placebo group. The 125 mg Q4W group showed the largest numerical difference at week 16 compared to the placebo group and other emotelimab groups (Table 11).

[0577] Table 11. Key secondary endpoints, primary analysis: Percentage of EASI-75 participants in week 16 (estimated 5a) - Full analysis of Part 1

[0578]

[0579] Analysis using treatment policy data processing methods (Week 16)

[0580] Analysis of data following all concomitant events using the treatment policy strategy data processing method provided efficacy results consistent with the primary analysis method at week 16. At week 16, all dose groups showed a larger proportion of participants achieving EASI-75 with clinical significance and nominal statistical significance compared to the placebo group. The 62.5 mg Q4W group showed the largest numerical difference at week 16 compared to the placebo group and other emotelimab groups (Table 12).

[0581] Table 12. Key secondary endpoints, treatment policy approach: Proportion of EASI-75 participants at week 16 (estimated 5b) - Full analysis set of Part 1.

[0582]

[0583] Main Analysis (Week 24)

[0584] At week 24, all dose groups showed a greater proportion of participants achieving EASI-75 with clinical significance and nominal statistical significance compared to the placebo group. The 250 mg Q4W (500 mg loading dose) group showed the largest numerical difference at week 24 compared to the placebo group and other emotelimab groups (Table 13).

[0585] Table 13. Key secondary endpoints, primary analysis: Percentage of EASI-75 participants at week 24 (estimated at 5c) - full analysis set of Part 1.

[0586]

[0587] Analysis using treatment policy data processing methods (Week 24)

[0588] Analysis of data following all comorbidities at week 24, using the treatment policy strategy data processing method compared to the primary analysis method, showed a greater overall treatment effect compared to the placebo group. At week 24, all dose groups showed a larger proportion of participants achieving EASI-75 with clinical significance and nominal statistical significance compared to the placebo group. The 250 mg Q4W (loading dose) group showed the largest numerical difference at week 24 compared to the placebo group and other emotelimab groups (Table 14).

[0589] Table 14. Key secondary endpoints, treatment policies, and methods: Proportion of EASI-75 participants at week 24 (estimated 5 days) - Full analysis set of Part 1

[0590]

[0591] Percentage of participants reaching EASI-75 over time

[0592] During the 24-week treatment period, using observed data, the 250 mg Q4W group (500 mg loading dose) showed the greatest early dissociation from placebo at week 2. Starting at week 4, this dissociation from placebo gradually increased across all anilide-treated groups for the remainder of the 24-week intervention period, with the greatest increase observed at week 24 in the 250 mg Q4W group (500 mg loading dose). Figure 4 ).

[0593] Main Analysis (Week 16)

[0594] At week 16, compared with the placebo group, all dose groups except the 250 mg Q4W group (p=0.0562) showed a greater proportion of participants achieving IGA 0 (clearance) or 1 (near clearance) with clinical significance and nominal statistical significance. The 62.5 mg Q4W group showed the largest numerical difference at week 16 compared with the placebo group and other emotelimab groups (Table 15).

[0595] Table 15. Key secondary endpoints, primary analysis: Proportion of IGA 0 / 1 participants in week 16 (estimated 6a) - Full analysis set of Part 1

[0596]

[0597] Analysis using treatment policy data processing methods (Week 16)

[0598] Analysis of data following all concomitant events using the treatment policy strategy data processing method provided efficacy results consistent with the primary analysis method at week 16. At week 16, all dose groups showed a greater proportion of participants achieving IGA 0 (clearance) or 1 (near-clearance) with clinical significance and nominal statistical significance compared to the placebo group. The 62.5 mg Q4W group showed the largest numerical difference at week 16 compared to the placebo group and other emotelimab groups (Table 16).

[0599] Table 16. Key secondary endpoints, treatment policy and approach: Proportion of participants with IGA 0 / 1 at week 16 (estimate 6b) - Full analysis set of Part 1

[0600]

[0601] Main Analysis (Week 24)

[0602] At week 24, compared with the placebo group, all dose groups showed a greater proportion of participants achieving IGA 0 (clearance) or 1 (near clearance) with clinical significance and nominal statistical significance. Improvements were observed in all anilidemab groups at week 24 compared with week 16 (except for the 62.5 mg Q4W group, which had a comparable proportion between week 16 and week 24). The 250 mg Q4W (500 mg loading dose) group showed the largest numerical difference at week 24 compared with the placebo group and other anilidemab groups (Table 17).

[0603] Table 17. Key secondary endpoints, primary analysis: Percentage of IGA 0 / 1 participants in week 16 (estimated 6c) - Full analysis set of Part 1

[0604]

[0605] Analysis using treatment policy data processing methods (Week 24)

[0606] Analysis of data following all comorbidities at week 24, using the treatment policy strategy data processing method compared to the primary analysis method, showed a greater overall treatment effect compared to the placebo group. At week 24, all dose groups showed a greater proportion of participants achieving IGA 0 / 1 with clinical significance and nominal statistical significance compared to the placebo group. The 250 mg Q4W (500 mg loading dose) group showed the largest numerical difference at week 24 compared to the placebo group; and was compared with other groups (Table 18).

[0607] Table 18. Key secondary endpoints, treatment policy and approach: Proportion of IGA 0 / 1 participants at week 24 (estimated 6 days) - Full analysis set of Part 1

[0608]

[0609] The proportion of participants with an IGA response of 0 (cleared) or 1 (almost cleared) over time and a decrease of ≥2 points relative to baseline.

[0610] During the 24-week treatment period, using observed data, the 250 mg Q4W (500 mg loading dose) group showed the greatest early dissociation from placebo at week 4 compared to other active groups. This dissociation from placebo gradually increased across all anilidemab dosing groups for the remainder of the 24-week intervention period, with the largest increase observed in the 250 mg Q4W (500 mg loading dose) group. Figure 5 ).

[0611] The proportion of participants with a weekly mean improvement (reduction) of ≥4 in pruritus NRS from baseline to week 16 and week 24.

[0612] Main Analysis (Week 16)

[0613] At week 16, compared with the placebo group, all dose groups showed a greater proportion of participants achieving a clinically meaningful and nominally statistically significant weekly mean reduction of ≥4 points in the pruritus NRS. The 250 mg Q4W group (500 mg loading dose) showed the greatest numerical difference at week 16 compared with the placebo group and other emotelimab groups (Table 19).

[0614] Table 19. Key secondary endpoints, primary analysis: Proportion of participants with mean weekly pruritus improvement ≥ NRS 4 at week 16 (estimated 7a) - full analysis set in Part 1.

[0615]

[0616] Analysis using treatment policy data processing methods (Week 16)

[0617] Analysis of data following all comorbidities at week 16, using the treatment policy strategy data processing method compared to the primary analysis method, showed a slightly greater overall treatment effect compared to the placebo group. At week 16, all dose groups showed a greater proportion of participants achieving a clinically meaningful and nominally statistically significant weekly mean reduction of ≥4 points in the pruritus NRS compared to the placebo group. The 250 mg Q4W (500 mg loading dose) and 125 mg Q4W dose groups showed the largest numerical differences at week 16 compared to the placebo group and other emotelimab groups (Table 20).

[0618] Table 20. Key secondary endpoints, treatment policy approach: Proportion of participants with mean weekly improvement in pruritus ≥ NRS 4 at week 16 (estimated 7b) - Full analysis set in Part 1.

[0619]

[0620] Main Analysis (Week 24)

[0621] At week 24, compared with the placebo group, all dose groups showed a greater proportion of participants with a clinically meaningful and nominally statistically significant weekly mean reduction of ≥4 points in the peak pruritus NRS. Improvement was observed in all anilidelimab dose groups at week 24 compared with week 16. The 250 mg Q4W (500 mg loading dose) group showed the largest numerical difference at week 24 compared with the placebo group and other anilidelimab dose groups (Table 21).

[0622] Table 21. Key secondary endpoints, primary analysis: Proportion of participants with mean weekly pruritus improvement ≥ NRS 4 at week 24 (estimated 7c) - full analysis set in Part 1.

[0623]

[0624] Analysis using treatment policy data processing methods (Week 24)

[0625] Analysis of data following all comorbidities at week 24, using the treatment policy strategy data processing method compared to the primary analysis method, showed a greater overall treatment effect compared to the placebo group. At week 24, all dose groups showed a greater proportion of participants achieving a clinically meaningful and nominally statistically significant weekly mean reduction of ≥4 points in the pruritus NRS compared to the placebo group. At week 24, all emotelimab dose groups showed comparable differences to placebo. The 250 mg Q4W (500 mg loading dose) group, the 125 mg Q4W dose group, and the 62.5 mg Q4W dose group showed the largest numerical differences at week 24 compared to the placebo group, but the 250 mg Q4W group was comparable (Table 22).

[0626] Table 22. Key secondary endpoints, treatment policy and approach: Proportion of participants with mean weekly improvement in pruritus ≥ NRS 4 at week 24 (estimated 7 days) - full analysis set in Part 1.

[0627]

[0628] The proportion of participants with a weekly mean improvement of ≥4 in the NRS of pruritus relative to baseline over time.

[0629] During the 24-week treatment period, using observed data, the 250 mg Q4W group (500 mg loading dose group) showed the greatest early dissociation from placebo at week 3 compared to other active groups. Dissociation from placebo generally increased gradually throughout the remainder of the treatment period, with the greatest dissociation observed at week 24, which was similar across all elmodilimab dose groups. Figure 6 ).

[0630] Other secondary endpoints

[0631] The proportion of participants whose EASI decreased by at least 90% relative to baseline at weeks 16 and 24 (EASI-90)

[0632] Week 16

[0633] At week 16, all dose groups showed a greater proportion of participants achieving EASI-90 with clinical significance and nominal statistical significance compared to the placebo group. The 62.5 mg Q4W group showed the largest numerical difference at week 16 compared to the placebo group and other emotelimab groups (Table 23).

[0634] Week 24

[0635] At week 24, all dose groups showed a greater proportion of participants achieving EASI-90 with clinical significance and nominal statistical significance compared to the placebo group. The 250 mg Q4W (500 mg loading dose) group showed the largest numerical difference at week 24 compared to the placebo group and other emotelimab groups (Table 23).

[0636] Table 23. Other secondary endpoints, primary analysis: EASI-90 – proportion of participants with a reduction of at least 90% from baseline at weeks 16 and 24.

[0637]

[0638] The proportion of participants whose EASI decreased by at least 100% relative to baseline (EASI-100) at weeks 16 and 24.

[0639] Week 16

[0640] In the animotolimumab 250 mg Q4W (500 mg loading dose), 250 mg Q4W, 125 mg Q4W, and 62.5 mg Q4W groups, 3 [3.9%], 1 [1.3%], 2 [2.6%], and 1 [1.3%] participants, respectively, and in the placebo Q4W group, 1 [1.3%] participant achieved EASI-100 at week 16. The 250 mg Q4W and 500 mg loading dose groups showed the highest proportion of participants achieving EASI-100 at week 16 compared to the placebo group and other animotolimumab groups. No groups showed statistically significant differences from the placebo group (Table 24).

[0641] Week 24

[0642] More participants achieved EASI-100 at week 24 compared to week 16: 6 [7.8%] in the animotolimumab 250 mg Q4W (500 mg loading dose), 5 [6.4%] in the 250 mg Q4W, 125 mg Q4W, and 1 [1.3%] groups, and 3 [3.8%] in the placebo Q4W group. The 125 mg Q4W group showed the highest proportion of participants achieving EASI-100 at week 24 compared to the placebo group and other animotolimumab groups. No group showed a significant difference from the placebo group (Table 24).

[0643] Table 24. Other secondary endpoints, primary analysis: EASI-100 – proportion of participants with a reduction of at least 100% from baseline at weeks 16 and 24.

[0644]

[0645] Percentage change in affected BSA relative to baseline in weeks 16 and 24

[0646] The mean (SD) affected BSA scores at baseline were well balanced between the treatment and placebo groups: 48.43 (19.16) for the 250 mg Q4W (500 mg loading dose), 46.47 (19.66) for the 250 mg Q4W, 47.36 (20.26) for the 125 mg Q4W and 45.82 (20.03) for the placebo group, and 43.03 (15.71) for the placebo group.

[0647] Week 16

[0648] Compared with the placebo group, at week 16, a nominally statistically significant reduction in the percentage change in affected BSA scores relative to baseline was observed across all animotolimumab dosing regimens. The 62.5 mg Q4W group showed the largest numerical difference at week 16 compared with the placebo group and other animotolimumab groups (Table 25).

[0649] Week 24

[0650] Compared with the placebo group, at week 24, a nominally statistically significant reduction in the percentage change in affected BSA scores relative to baseline was observed across all animotolimumab dosing regimens. The 250 mg Q4W group (500 mg loading dose) showed the largest numerical difference at week 24 compared with the placebo group and other animotolimumab groups (Table 25).

[0651] Table 25. Other secondary endpoints, primary analysis: affected BSA (%), percentage change relative to baseline at weeks 16 and 24 using WOCF – Full analysis set in Part 1

[0652]

[0653] Percentage change in SCORAD relative to baseline at week 24

[0654] The mean (SD) SCORAD scores at baseline were well balanced between the treatment and placebo groups: 67.08 (13.49) for the 250 mg Q4W (500 mg loading dose), 67.78 (11.67) for the 250 mg Q4W, 68.83 (12.19) for the 125 mg Q4W, and 66.22 (12.21) for the placebo group, and 66.00 (10.96) for the placebo group.

[0655] Week 16

[0656] Compared with the placebo group, at week 16, a nominally statistically significant reduction in the percentage change in SCORAD score relative to baseline was observed across all animotolimumab dosing regimens. The 250 mg Q4W group (500 mg loading dose) showed the largest numerical difference at week 16 compared with the placebo group and other animotolimumab groups (Table 26).

[0657] Week 24

[0658] Compared with the placebo group, at week 24, a nominally statistically significant reduction in the percentage change in affected BSA scores relative to baseline was observed across all animotolimumab dosing regimens. The 250 mg Q4W group (500 mg loading dose) showed the largest numerical difference at week 24 compared with the placebo group and other animotolimumab groups (Table 26).

[0659] Table 26. Other secondary endpoints, primary analysis: SCORAD index, percentage change relative to baseline at weeks 16 and 24 using WOCF – Full analysis set in Part 1

[0660]

[0661] Participant self-assessment (POEM, HADS, ADCT, DLQI)

[0662] Percentage change in POEM relative to baseline at weeks 16 and 24

[0663] The mean (SD) POEM scores at baseline were well balanced between the treatment and placebo groups, with scores of 19.87 (5.12) for the 250 mg Q4W (500 mg loading dose), 19.88 (6.14) for the 250 mg Q4W, 125 mg Q4W, and 20.48 (5.44) for the placebo group, and 19.70 (5.73) for the placebo group.

[0664] Week 16

[0665] Compared with the placebo group, at week 16, a nominally statistically significant reduction in the percentage change in POEM score relative to baseline was observed in all animotolimumab dosing regimens. The 250 mg Q4W group (500 mg loading dose) showed the largest numerical difference at week 16 compared with the placebo group and other animotolimumab groups (Table 27).

[0666] Week 24

[0667] Compared with the placebo group, at week 24, a nominally statistically significant reduction in the percentage change in POEM score relative to baseline was observed across all animotolimumab dosing regimens. The 250 mg Q4W group (500 mg loading dose) showed the largest numerical difference at week 24 compared with the placebo group and other animotolimumab groups (Table 27).

[0668] Table 27. Other secondary endpoints, primary analysis: POEM index, percentage change relative to baseline at weeks 16 and 24 using WOCF – Full analysis set in Part 1

[0669]

[0670] Percentage change in HADS relative to baseline at weeks 16 and 24

[0671] The mean (SD) HADS scores at baseline were well balanced between the treatment and placebo groups, with scores of 12.18 (8.03) for the 250 mg Q4W (500 mg loading dose), 14.44 (9.47) for the 250 mg Q4W, 125 mg Q4W, and 14.23 (7.96) for the placebo group, and 12.52 (8.497) for the placebo group.

[0672] Week 16

[0673] Compared with placebo, there was no statistically significant percentage change in HADS score relative to baseline at week 16 in all anitolide dosing regimens, although there was a slight trend toward statistical significance in the 250 mg Q4W (500 mg loading dose) group [p=0.0997] (Table 28).

[0674] Week 24

[0675] Compared with placebo, there was no statistically significant percentage change in HADS score relative to baseline at week 24 across all emotelimab dosing regimens (Table 28).

[0676] Table 28. Other secondary endpoints, primary analysis: HADS, percentage change relative to baseline at weeks 16 and 24 using WOCF - Full analysis set in Part 1

[0677]

[0678] Percentage change in ADCT relative to baseline at weeks 16 and 24

[0679] The mean (SD) ADCT scores at baseline were well balanced between the treatment and placebo groups: 15.53 (4.37) for the 250 mg Q4W (500 mg loading dose), 16.06 (4.91) for the 250 mg Q4W, 16.52 (4.48) for the 125 mg Q4W, and 16.32 (4.51) for the 62.5 mg Q4W amotelimab group, and 15.47 (4.57) for the placebo group.

[0680] Week 16

[0681] Compared with the placebo group, at week 16, a nominally statistically significant decrease in the percentage change in ADCT score relative to baseline was observed across all animotolimumab dosing regimens. The 250 mg Q4W group (500 mg loading dose) showed the largest numerical difference at week 16 compared with the placebo group and other animotolimumab groups. (Table 29.)

[0682] Week 24

[0683] Compared with the placebo group, at week 24, a nominally statistically significant decrease in the percentage change in ADCT score relative to baseline was observed across all animotolimumab dosing regimens. The 250 mg Q4W group (500 mg loading dose) showed the largest numerical difference at week 24 compared with the placebo group and other animotolimumab groups. (Table 29.)

[0684] Table 29. Other secondary endpoints, primary analysis: ADCT, percentage change relative to baseline at weeks 16 and 24 using WOCF - Full analysis set in Part 1

[0685]

[0686] Percentage change in DLQI relative to baseline at weeks 16 and 24

[0687] The mean (SD) DLQI scores at baseline were well balanced between the treatment and placebo groups, with scores of 14.78 (6.17) for the 250 mg Q4W (500 mg loading dose), 15.41 (6.98) for the 250 mg Q4W, 15.60 (6.91) for the 125 mg Q4W, and 15.95 (7.19) for the placebo group, and 15.41 (7.23) for the placebo group.

[0688] Week 16

[0689] Compared with the placebo group, at week 16, a nominally statistically significant decrease in the percentage change in DLQI score relative to baseline was observed in all emotelimab dosing regimens. The 62.5 mg Q4W group showed the largest numerical difference at week 16 compared with the placebo group and other groups. (Table 30.)

[0690] Week 24

[0691] Compared with the placebo group, at week 24, a nominally statistically significant reduction in the percentage change in ADCT score relative to baseline was observed in all emotelimab dosing regimens. The 250 mg Q4W and 500 mg loading dose groups showed the largest numerical differences at week 24 compared with the placebo group and other groups. (Table 30.)

[0692] Table 30. Other secondary endpoints, primary analysis: DLQI index, percentage change relative to baseline at weeks 16 and 24 using WOCF – Full analysis set in Part 1

[0693]

[0694] Security Summary

[0695] Based on laboratory data from visits: all assessments, including those from early termination or safety follow-up visits, are mapped to analytical visits and included in the safety summary table in Part 1, excluding unplanned assessments. Some assessments from week 24 are mapped to and presented from analytical visits from week 28.

[0696] Based on vital signs, physical examination results, and ECG data from each visit: All assessments (including unplanned, early termination, or safety follow-up visits) are mapped to analytical visits and included in the safety summary table in Part 1. Some assessments from week 24 are mapped to the analytical visit from week 28 and are presented in this table.

[0697] PCSA Form (for Laboratory, Urine Analysis and Vital Signs): The PCSA summary form in Part 1 takes into account unplanned, early termination or safety follow-up visits (PCSAs) (including those mapped from the week 24 analysis visit to week 28).

[0698] For AEs that occur after treatment, all AEs that occur on or after the date of the first IMP and are followed by the 24-week visit (the re-randomized IMP in Part 2 is included in the TEAE summary table in Part 1).

[0699] In this study of AD participants, emotelimab was well tolerated and had an acceptable safety profile.

[0700] Table 31 provides an overview of adverse events in the safety population.

[0701] Table 31. Summary of adverse events following treatment up to week 24 - Part 1 Safety Analysis Set

[0702]

[0703] Compared with placebo (47 / 78, 60.3%), the overall incidence of treatment-associated adverse events (TEAEs) from baseline to week 24 was slightly higher with total anilidemab (209 / 310, 67.4%) (256 / 388, 66%). The 7.1% difference was primarily due to TEAEs caused by nasopharyngitis, headache, and hypertension. The incidence of treatment-associated adverse events (SAEs) was slightly higher in the combined anilidemab group compared with placebo (2.6% vs. 1.3%), with the highest incidence in the 62.5 mg Q4W group (6.4%). The incidence of TEAEs leading to permanent intervention discontinuation was lower in the combined anilidemab group compared with placebo (4.5% vs. 6.4%). The incidence of adverse events of particular concern (AESIs) was similar in the combined anilidemab group compared with placebo (1.9% vs. 1.3%). There were no deaths during the study period. Although there is no clear relationship between anitolide dose and the incidence of adverse events (AEs), a trend suggests that the 250 mg Q4W (500 mg loading dose) group had a higher incidence of two specific AEs compared to other groups: nasopharyngitis (14 cases [18.2%] in the 250 mg (500 mg loading dose) group and elevated blood CPK (4 cases [5.2%] in the 250 mg Q4W (500 mg loading dose) group). These two AEs will be discussed in more detail below.

[0704] The most common TEAEs (>5% in any dose group) in descending order of total incidence were atopic dermatitis (17.1% with total amotelimab vs. 38.5% with placebo), nasopharyngitis (11.0% with total amotelimab vs. 9.0% with placebo), COVID-19 (7.7% with total amotelimab vs. 6.4% with placebo), headache (6.1% with total amotelimab vs. 2.6% with placebo), upper respiratory tract infection (4.5% with total amotelimab vs. 6.4% with placebo), elevated blood CPK (2.6% with total amotelimab vs. 2.6% with placebo), and hypertension (2.6% with total amotelimab vs. 0% with placebo).

[0705] When comparing any single anilidemab dose group with placebo, three imbalances were observed in TEAEs (differences of ≥5% between any single anilidemab group and placebo, see Table 38). The first imbalance was nasopharyngitis (11% with anilidemab versus 9.0% with placebo), with the highest incidence (18.2%) in the 250 mg Q4W (500 mg loading dose) group. The second imbalance was headache (6.1% with anilidemab versus 2.6% with placebo), with the highest incidence (9.0%) in the 62.5 mg Q4W group. The third imbalance observed was hypertension (2.6% with anilidemab versus 0% with placebo), with the highest incidence (5.1%) in the 62.5 mg Q4W group. None of these events showed any obvious dose dependence, although nasopharyngitis was most common in the highest dose group (250 mg Q4W (500 mg loading dose)).

[0706] Most TEAEs were mild or moderate (39.3% mild, 56.6% moderate, and 4.1% severe). Thirteen (4.2%) subjects in the anitolimumab group and three (3.8%) subjects in the placebo group reported TEAEs of severity grade 3 or higher (“severe”). There appeared to be no dose-dependent relationship between anitolimumab and the number of participants experiencing serious events; the 62.5 mg Q4W dose group had the highest number of participants experiencing serious events (6 [7.7%]) (Table 32).

[0707] Table 32. TEAEs by Severity as of Week 24

[0708]

[0709] Nine participants experienced serious treatment-associated adverse events (SAEs), totaling 11 events (n=2 in the 250 mg Q4W (500 mg loading dose) group [4 events], n=0 in the 250 mg Q4W group [0 events], n=1 in the 125 mg Q4W group [1 event], n=5 in the 62.5 mg Q4W group [5 events], and n=1 in the placebo group [1 event]). Most reported SAEs reflected underlying comorbidities in individual AD participants or had a clear explanation independent of emotelimab treatment (see Tables 32 and 33 below and patient brief descriptions).

[0710] Table 33. Set of Severe TEAEs - Safety Analysis Up to Week 24

[0711]

[0712] Nineteen participants experienced adverse events (AEs) leading to treatment discontinuation, totaling 21 events (n=3 [5 events] in the 250 mg Q4W (500 mg loading dose) group, n=5 [5 events] in the 250 mg Q4W group, n=1 [1 event] in the 125 mg Q4W group, n=5 [5 events] in the 62.5 mg Q4W group, and n=5 [5 events] in the placebo group). Of the 21 treatment-related AEs leading to permanent intervention discontinuation, nine were serious TEAEs, and the others were moderate events. The most common cause of treatment discontinuation was atopic dermatitis, with 4 events in all groups (1 in the 250 mg Q4W (500 mg loading dose) group [1.3%], 2 in the 250 mg Q4W group [2.6%], and 1 in the placebo group [1.3%]). No significantly more common causes of treatment discontinuation / PT were identified (Tables 31 and 34).

[0713] Table 34. Safety analysis set of TEAEs leading to permanent discontinuation of research interventions up to week 24

[0714]

[0715] Seven participants experienced AESI, totaling nine events (n=3 in the 250 mg Q4W (500 mg loading dose) group [5 events], n=0 in the 250 mg Q4W group [0 events], n=2 in the 125 mg Q4W group [2 events], n=1 in the 62.5 mg Q4W group [1 event], and n=1 in the placebo group [1 event]) (see Tables 31 and 35).

[0716] Table 35. AESI-Safety Analysis Set Up to Week 24

[0717]

[0718] Overall, no cases of symptomatic eosinophilic conditions, anaphylactic reactions, or serum sickness have been reported. There were three potential cases of hypersensitivity reactions (two of which were reported as AESIs). All cases involved participants who were ADA-negative. The third case involved a 43-year-old female participant (250 mg Q4W animotriumab group) who developed “lip swelling” one day after her first IMP administration. This event was reported as mild, unrelated, “mild lip swelling (anaphylactic) / unknown allergen.” The participant fully recovered within two days without any corrective treatment. Aimoteumab was continued, and the participant received four more doses without symptom recurrence. Treatment was ultimately discontinued on day 110 due to systemic steroid use in a case of sinusitis. This event was not reported as an AESI.

[0719] Of the five participants, six had elevated ALT >3 x ULN (4 in the animotolimab group [1.3%] vs. 1 in the placebo group [1.3%]). For participants receiving animotolimab, all events could be explained by a reported history of known hepatic steatosis or recent alcohol consumption. All events were reported as unrelated to animotolimab at the investigator's discretion; they were mild or moderate, and all cases resolved. Two of the five participants discontinued the study (withdrawing informed consent).

[0720] Three injection site problems (discoloration, erythema, and itching) were reported as TEAEs in the anitolimumab group. Specifically, there was one case in each anitolimumab dose group except the 250 mg (500 mg loading dose) group, compared to zero cases in the placebo group. Based on the analysis of all recorded injection site skin reactions, the anitolimumab combined group (53 patients [17.1%]) had a higher rate of injection site reactions compared to the placebo group (8 patients [10.3%]). Of these recorded reactions, all were mild or moderate except for one participant (62.5 mg Q4W group) who experienced severe injection site pain. The researchers did not report the occurrence of severe injection site pain as an AE, but it was associated with a pre-syncope AE reported during the first IMP injection. According to the researchers, the participant was very afraid of the injection and experienced pain during the injection, after which the participant's blood pressure "temporarily dropped" and then returned to normal when the participant lay down. The event subsided after one minute. The severity was reported to be moderate. Participants continued to complete the study, and no further injection-related adverse events were reported. Overall, there was no significant relationship between dose and injection site response. No serious, persistent, or premature discontinuation of the intervention occurred at the injection site. No cases of chills were observed in the emotelimab group, but one case of fever was observed (67 days after the last dose and unrelated to the injection). No cases of oral ulceration were reported.

[0721] No malignant tumors, including non-melanoma skin cancer, were reported.

[0722] No symptomatic drug overdoses were reported.

[0723] It is important to note that investigator-suspected IMP overdose was defined as reaching at least twice the expected dose within an interval of less than 21 days. In the safety population, 7 participants [2.3%] in the emotelimab group who received two consecutive doses within 14 and 20 days reported IMP overdose (1 participant in the 250 mg Q4W (500 mg loading dose) group, 3 participants in the 250 mg Q4W group, 1 participant in the 125 mg Q4W group, and 2 participants in the 62.5 mg Q4W group); and 1 participant [1.3%] in the placebo group who received two consecutive doses within 14 days. None of these participants experienced any symptoms. Therefore, no symptomatic overdose was reported in this study. These irregularities in dosing intervals were reported as protocol deviations, primarily due to visit scheduling logistics (i.e., participants had to delay or advance their visits for personal reasons).

[0724] No pregnancy was reported.

[0725] Pregnancy was reported as a parasitic infection or a serious opportunistic infection. Overall, safety data supported the conclusion that emotelimab use was not associated with an increased risk of serious and / or severe infections. In participants who developed bullous and pustular dermatitis (investigator-reported as severe and related to the study drug), biopsies showed a pustular reaction. In the context of Alzheimer's disease (AD), this could be an infection.

[0726] The overall incidence of herpes infection was reassuring compared to the placebo group. Seven participants (2.3%) in the combined emotelimab group developed herpes virus infection (combined PTs: oral herpes, herpes simplex reactivation, herpetic dermatitis, and herpetic eczema), compared to two participants (2.5%) in the placebo group.

[0727] The overall incidence of conjunctivitis was reassuring compared to the placebo group. For conjunctivitis (including PT "allergic conjunctivitis", "conjunctivitis", and "bacterial conjunctivitis"), there were 5 participants (1.6%) in the amotelimab-conjugated group and 3 participants (3.8%) in the placebo group. Specifically, for PT "allergic conjunctivitis", there were 3 participants (1.0%) in the amotelimab-conjugated group and 1 participant (1.3%) in the placebo group; for PT "conjunctivitis", there were 1 participant (0.3%) in the amotelimab-conjugated group and 1 participant (1.3%) in the placebo group; and for PT "bacterial conjunctivitis", there were 1 participant (0.3%) in the amotelimab-conjugated group and 1 participant (1.3%) in the placebo group.

[0728] No participants died during this study.

[0729] Pharmacokinetics

[0730] The pharmacokinetics of anitolide in participants with moderate to severe AD were recorded using sparse PK samples (primarily pre-dose samples) collected in study KY1005-CT05 / DRI17366 (STREAM-AD). Additionally, a population PK (PopPK) analysis was performed using pooled data from a Phase 1 study in healthy subjects and a Phase 2 study in AD participants.

[0731] Serum valence of elemotriumab

[0732] Serum concentrations of anitolimab were measured at baseline and prior to administration at weeks 4, 8, 12, 16, 20, and 24. Additionally, samples were collected after administration at weeks 1, 2, and 17. Descriptive statistics of anitolimab concentrations are summarized in Table 36.

[0733] Table 36. Serum elemotriumab concentrations (μg / mL) up to week 24 (Part 1) - PK population

[0734]

[0735] The 250 mg Q4W group (500 mg loading dose) appeared to reach pharmacokinetic steady state at week 4, and the dose groups (without loading dose) appeared to reach pharmacokinetic steady state at week 12. At week 24, the mean trough concentrations (standard deviations) of anitolimab in the 250 mg Q4W (500 mg loading dose), 250 mg Q4W, 125 mg Q4W, and 62.5 mg Q4W groups were 42.0 (23.1) µg / mL, 43.8 (17.4) µg / mL, 20.3 (10.6) µg / mL, and 11.1 (3.92) µg / mL groups, respectively.

[0736] Immunogenicity

[0737] Table 38 provides a summary of the incidence of ADA in all randomized participants who had at least one ADA measurement from baseline up to the cutoff date of the primary analysis. Three participants with pre-existing ADA were reported: one in the 250 mg group (loading dose); one in the 250 mg Q4W group (without a 500 mg loading dose); and one in the 125 mg Q4W group. A dose-dependent effect on ADA response was observed, with a higher incidence of ADA following treatment at 62.5 mg Q4W (28.2%) and 125 mg Q4W (13.2%) compared to 250 mg Q4W (with or without a 500 mg loading dose, 3.8% and 2.6%, respectively). All cases were identified as drug-induced ADA.

[0738] Table 38. Summary of ADA Incidence - ADA Population

[0739]

[0740] Table 39 summarizes the ADA that occurred post-treatment in the participants. The median time to ADA response after treatment ranged from 16 to 20 weeks. The median peak ADA titer remained low (=5) across all dose groups, with higher titers (≥20) observed in the lower dose groups (125 mg Q4W and 62.5 mg Q4W). Only one participant in the 62.5 mg Q4W group had persistent ADA, while the response of the other participants with post-treatment ADA was indeterminate.

[0741] Table 39. Summary of ADA after treatment - ADA population

[0742]

[0743] Potential association analysis between ADA and pharmacokinetics

[0744] In population pharmacokinetic analyses including the KY1005-CT02 and KY1005-CT05 / DRI17366 (STREAM-AD) studies, no effect of ADA on anitolide pharmacokinetics was found.

[0745] Potential association analysis between ADA and adverse events following treatment

[0746] No relationship was observed between TEAE and ADA response status. Furthermore, a more focused analysis was conducted to assess any potential association between ADA response status and hypersensitivity by using the “Anaphylactic Reaction” and “Hypersensitivity” SMQs and comparing subjects’ ADA status with TEAEs within these categories (Table 40). No evidence was observed of a relationship between anaphylactic reactions and hypersensitivity and a positive ADA status.

[0747] Table 40. Allergic and Hypersensitivity Reactions in ADA Response Status - Part 1 of the ADA Population

[0748]

[0749] The results of this Phase 2b study (KY1005-CT05 / DRI17366 [STREAM-AD]) demonstrate that animotolimumab is effective in multiple domains of the disease and provides therapeutic benefit for signs and symptoms, as well as QoL, in moderate to severe AD. Amutemulimab was generally well tolerated and had a favorable safety profile with a positive benefit-risk profile in participants with moderate to severe AD who had a history of inadequate or undesirable local treatment within 6 months prior to baseline. The safety profile of animotolimumab observed in this Phase 2b study (KY1005-CT05 / DRI17366 [STREAM-AD]) is consistent with the findings of the Phase 2a study (KY1005-CT02), and no new safety issues were observed.

[0750] The study met its primary endpoint of percentage change in EASI score relative to baseline at week 16 and maintained improvement throughout 24 weeks. All key secondary endpoints also showed improvement at weeks 16 and 24.

[0751] Data support anitolide as a potential first-class anti-OX40 ligand monoclonal antibody for adults with moderate to severe atopic dermatitis, addressing both type 2 and non-type 2 inflammation.

[0752] In a phase 2b study (STREAM-AD), the primary endpoint and all key secondary endpoints were met. This study evaluated the efficacy and safety of emotelimab (a novel investigational human monoclonal antibody targeting the key immune system modulator OX40 ligand) compared with placebo in adults with moderate to severe atopic dermatitis whose disease is not adequately controlled by topical medications or for whom topical medications are not a recommended treatment.

[0753] In this study, for all four subcutaneous doses investigated, emotelimab treatment resulted in a statistically significant improvement in the mean EASI score at week 16 compared to placebo. Key secondary endpoints also improved, including a reduction of at least 75% in EASI score relative to baseline, an Investigator Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) with a reduction of at least 2 points relative to baseline, and a weekly mean improvement (reduction) of at least 4 points in the Numerical Rating Scale for Pruritus (NRS). Continued treatment improvements in these endpoints were observed at week 24. Biomarker results supported the impact on both type 2 and non-type 2 pathways.

[0754] Amotelimab was well tolerated in all dose groups, and no new safety signals were identified. The most frequently reported adverse events occurring in at least 5% of patients were atopic dermatitis, COVID-19 infection, elevated serum creatine phosphokinase, headache, hypertension, nasopharyngitis, and upper respiratory tract infection. Except for atopic dermatitis, none of these events led to treatment discontinuation.

[0755] STREAM-AD is a phase 2b, randomized, double-blind, placebo-controlled study evaluating the efficacy of emotelimab in adult patients with moderate to severe atopic dermatitis whose disease is not adequately controlled or is not desirable with topical therapy. In the trial, participants were randomized (1:1:1:1:1) to receive 250 mg every four weeks (500 mg loading dose), or 250 mg, 125 mg, 62.5 mg, or placebo every four weeks (without a loading dose).

[0756] The primary endpoint was the percentage change in EASI from baseline at 16 weeks. Key secondary endpoints included the change in EASI from baseline at 24 weeks, the percentage of patients with a reduction of at least 75% in EASI from baseline at 16 and 24 weeks, the percentage of patients with an IGA 0 (clear) or 1 (nearly clear) response at 16 and 24 weeks with a reduction of ≥ 2 points from baseline, and the proportion of patients with a weekly mean improvement (reduction) of ≥ 4 in the pruritus NRS at 16 and 24 weeks and a baseline pruritus ≥ 4.

[0757] The study enrolled 390 people.

[0758] Study Design and Key Analytical Details

[0759] A 24-week induction period (KRM focus) followed by a 28-week randomization period was conducted to examine 5 groups of patients with moderate to severe Alzheimer's disease (n=390) (250 mg Q4W (500 mg LD), 250 mg Q4W, 125 mg Q4W, 62.5 mg Q4W, pbo).

[0760] PA includes all randomized participants who completed week 24 / early discontinuation (efficacy analysis) and all participants who received treatment (safety analysis, n=388).

[0761] Primary endpoint results (week 16)

[0762] ∆EASI: The mean % reduction in EASI score at week 16 was statistically significant compared to the placebo group, and nominally significant at week 24. Among them, 250 mgLD showed the highest response (weeks 16 and 24) compared to the placebo group and compared to other groups.

[0763] No dose-response ratio was observed.

[0764] Key secondary endpoints in weeks 16 and 24:

[0765] EASI-75: All dose groups achieved nominal statistical significance, with the 250 mg LD showing the highest response in early separation (week 2) and compared to pbo and other groups (week 24);

[0766] IGA 0 / 1: Nominal statistical significance was achieved in all dose groups except for 250 mg at week 16, with the 250 mg LD showing the highest response at early separation (week 4) and compared to pbo and other groups (week 24);

[0767] Reduction of 4-pt in PP-NRS: Nominal statistical significance was achieved in all dose groups, with 250 mg LD and 62.5 mg showing early separation (week 3), and 250 mg LD showing the highest response compared to pbo and compared to other groups (weeks 16 and 24).

[0768] See Figures 1 to 13 .

[0769] Security Summary

[0770] In the Phase 1 healthy volunteer study (KY1005-CT01 [NCT03161288], KY1005-CT04 [NCT04449939]) and the Phase 2a study KY1005-CT02 [NCT03754309], animotolimab was well tolerated in all four dose groups and demonstrated an acceptable safety profile with no safety issues identified. Results from the Phase 2a study in AD participants also indicated that animotolimab is effective and provides therapeutic benefit for the signs and symptoms of moderate to severe AD.

[0771] Compared to placebo, the overall incidence of TEAEs was slightly increased in the emotelimab combination group (67.1% vs. 60.3%), while the incidence was comparable in the treatment group.

[0772] There were no significant differences in characteristics among the dose groups.

[0773] In this study, for all four subcutaneous doses investigated, emotelimab treatment resulted in statistically significant improvements in mean eczema area and severity index (EASI) scores at week 16 compared to placebo. Key secondary endpoints also improved, including a reduction of at least 75% in EASI from baseline, an Investigator Global Assessment (IGA) score of 0 (cleared) or 1 (almost cleared) with a reduction of at least 2 points from baseline, and a weekly mean improvement (reduction) of at least 4 points in the Numerical Rating Scale for Pruritus (NRS). Continued treatment improvements in these endpoints were observed at week 24.

[0774] A dose-response effect was observed in ADA response, with the incidence of ADA occurring after treatment with 62.5 mg Q4W (28.2%) and 125 mg Q4W (13.2%) being higher than that after treatment with 250 mg Q4W (with or without loading) (2.6% and 3.8%, respectively).

[0775] Changes in blood biomarkers, eosinophil count, and LDH

[0776] The effects of treatment on blood biomarkers were assessed by measuring serum total IgE, IL-13, IL-17A, IL-22, and TARC at baseline and weeks 4, 16, and 24, and serum IL-5, IL-31, and plasma eosinophil chemokine-3 at baseline and week 16. The effects of treatment on serum eosinophil count and lactate dehydrogenase (LDH) were also assessed at baseline and weeks 4, 16, and 24. The effects of treatment on blood biomarkers were analyzed in the non-emergency medication population because they were determined to be more relevant to the mechanism of action of emotelimab.

[0777] Blood levels of biomarkers assessed at baseline in the non-emergency medication population are presented in Table 41 as medians (Q1, Q3). All assessed biomarkers showed an asymmetric distribution, with means above the median and above baseline values. Overall, there appeared to be a potential slight imb...

Claims

1. A method of treating an immune-mediated disease in a subject in need thereof, the method comprising administering to the subject an anti-OX40 ligand (OX40L) antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises a heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO: 42, a HCDR2 of SEQ ID NO: 44, and a HCDR3 of SEQ ID NO: 46, and a light chain complementarity determining region (LCDR) 1 of SEQ ID NO: 56, a LCDR2 of SEQ ID NO: 58, and a LCDR3 of SEQ ID NO: 60, wherein the subject receives a dose directly every 12 weeks (Q12W) without requiring a prior dose administration every 4 weeks (Q4W).

2. A method of treating atopic dermatitis in a subject in need thereof, the method comprising administering to the subject an anti-OX40 ligand (OX40L) antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises a heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO: 42, a HCDR2 of SEQ ID NO: 44, and a HCDR3 of SEQ ID NO: 46, and a light chain complementarity determining region (LCDR) 1 of SEQ ID NO: 56, a LCDR2 of SEQ ID NO: 58, and a LCDR3 of SEQ ID NO: 60, wherein the subject receives a dose directly every 12 weeks (Q12W) without requiring a prior dose administration every 4 weeks (Q4W).

3. The method of claim 1 or 2, wherein the antibody or antigen binding fragment thereof is amotuzumab or a variant thereof.

4. The method of claim 1, 2, or 3, wherein the antibody is amotuzumab.

5. The method of any one of claims 1 to 4, wherein the antibody or antigen binding fragment thereof is administered by a pre-filled syringe, a pen delivery device, or an autoinjector.

6. The method of any one of claims 1 to 4, wherein the subject receives an initial dose of about 500 mg of the antibody or antigen binding fragment thereof, followed by one or more secondary doses of about 250 mg of the antibody or antigen binding fragment thereof.

7. The method of any one of the preceding claims, wherein the atopic dermatitis is moderate to severe atopic dermatitis.

8. The method of claim 7, wherein the moderate to severe atopic dermatitis is not adequately controlled with topical prescription therapies or with systemic therapies or these therapies are not an option.

9. The method of any one of the preceding claims, wherein the subject has a reduction in EASI score.

10. The method of claim 9, wherein the EASI score is selected from the group consisting of EASI-75, EASI-90, and EASI-100.

11. The method of any one of the preceding claims, wherein the subject has a reduction in Investigator’s Global Assessment (IGA) score.

12. A method of treating an immune-mediated disease in a juvenile subject in need thereof, the method comprising administering to the juvenile subject an anti-OX40 ligand (OX40L) antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO: 42, a HCDR2 of SEQ ID NO: 44, and a HCDR3 of SEQ ID NO: 46, and a light chain complementarity determining region (LCDR) 1 of SEQ ID NO: 56, a LCDR2 of SEQ ID NO: 58, and a LCDR3 of SEQ ID NO:

60.

13. A method of treating atopic dermatitis in a juvenile subject in need thereof, the method comprising administering to the juvenile subject an anti-OX40 ligand (OX40L) antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO: 42, a HCDR2 of SEQ ID NO: 44, and a HCDR3 of SEQ ID NO: 46, and a light chain complementarity determining region (LCDR) 1 of SEQ ID NO: 56, a LCDR2 of SEQ ID NO: 58, and a LCDR3 of SEQ ID NO:

60.

14. The method of claim 12 or 13, wherein the antibody is amotuzumab or a variant thereof.

15. The method of claim 12, 13, or 14, wherein the antibody is amotuzumab.

16. The method of any one of claims 12 to 15, wherein the antibody or antigen-binding fragment thereof is administered by a pre-filled syringe, a pen delivery device, or an autoinjector.

17. The method of any one of claims 12 to 16, wherein the juvenile subject has a body weight ranging from about 25 kg to about 40 kg.

18. The method of any one of claims 12 to 17, wherein the juvenile subject receives an initial dose of about 250 mg of the antibody or antigen-binding fragment thereof, followed by one or more second doses of about 125 mg of the antibody or antigen-binding fragment thereof.

19. The method of any one of claims 12 to 18, wherein each dose is administered Q12W.

20. The method of any one of claims 12 to 18, wherein the subject receives a dose Q12W from the start of treatment.

21. The method of any one of claims 12 to 18, wherein the subject receives a dose Q12W directly without a prior dose administration Q4W.

22. The method of any one of claims 12 to 21, wherein the subject is 12 years of age or older (e.g., the subject is 12-17 years of age).

23. The method of any one of claims 12 to 22, wherein the atopic dermatitis is moderate to severe atopic dermatitis.

24. The method of claim 23, wherein the moderate to severe atopic dermatitis is not adequately controlled with topical prescription therapies or with systemic therapies or these therapies are not indicated.

25. The method of any one of claims 12-24, wherein the subject has a reduction in EASI score.

26. The method of claim 25, wherein the EASI score is selected from the group consisting of EASI-75, EASI-90, and EASI-100.

27. The method of any one of claims 12-24, wherein the subject has a reduction in IGA score.

28. The method of any one of claims 12-24, wherein (a) the subject has a body weight of equal to or greater than 25 kg and less than 40 kg, and wherein the subject is administered a formulation comprising a 62.5 mg / mL emapalumab solution provided in a pre-filled syringe that delivers 125 mg of emapalumab in a 2 mL injection, or (b) the subject has a body weight of equal to or greater than 25 kg and less than 40 kg, and wherein the subject is administered a formulation comprising a 125 mg / mL emapalumab solution provided in a pre-filled syringe that delivers 125 mg of emapalumab in a 1 mL injection.

29. A method of treating an immune-mediated disease in a subject in need thereof, the method comprising administering to the subject an anti-OX40 ligand (OX40L) antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises a heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO: 42, a HCDR2 of SEQ ID NO: 44, and a HCDR3 of SEQ ID NO: 46, and a light chain complementarity determining region (LCDR) 1 of SEQ ID NO: 56, a LCDR2 of SEQ ID NO: 58, and a LCDR3 of SEQ ID NO: 60, wherein the subject has a body weight ranging from about 25 kg to about 40 kg.

30. A method of treating atopic dermatitis in a subject in need thereof, the method comprising administering to the subject an anti-OX40 ligand (OX40L) antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises a heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO: 42, a HCDR2 of SEQ ID NO: 44, and a HCDR3 of SEQ ID NO: 46, and a light chain complementarity determining region (LCDR) 1 of SEQ ID NO: 56, a LCDR2 of SEQ ID NO: 58, and a LCDR3 of SEQ ID NO: 60, wherein the subject has a body weight ranging from about 25 kg to about 40 kg.

31. The method of claim 29 or 30, wherein the antibody is emapalumab or a variant thereof.

32. The method of claim 29, 30, or 31, wherein the antibody is amdursulfur.

33. The method of any one of claims 29 to 32, wherein the antibody or antigen binding fragment thereof is administered by a pre-filled syringe, a pen delivery device, or an autoinjector.

34. The method of any one of claims 29 to 33, wherein the subject receives an initial dose of about 250 mg of the antibody or antigen binding fragment thereof, followed by one or more second doses of about 125 mg of the antibody or antigen binding fragment thereof.

35. The method of any one of claims 29 to 34, wherein each dose is administered Q12W.

36. The method of any one of claims 29 to 34, wherein the subject receives a dose Q12W from the start of treatment.

37. The method of any one of claims 29 to 34, wherein the subject receives a dose Q12W directly without a prior dose administration Q4W.

38. The method of claim 34, wherein each second dose is administered Q12W over a 24 week period, or each second dose is administered Q12W until the patient has achieved vIGA O / 1, or has cleared or substantially cleared the skin, or has achieved EASI 75 or has achieved EASI 90.

39. The method of any one of claims 29 to 38, wherein the subject is 12 years of age or older (e.g., the subject is 12-17 years of age).

40. The method of any one of claims 29 to 38, wherein the atopic dermatitis is moderate to severe atopic dermatitis.

41. The method of claim 40, wherein the moderate to severe atopic dermatitis is not adequately controlled with topical prescription therapy or with systemic therapy or these therapies are not indicated.

42. The method of any one of claims 29 to 38, wherein the subject has a reduction in EASI score.

43. The method of claim 42, wherein the EASI score is selected from the group consisting of EASI-75, EASI-90, and EASI-100.

44. The method of any one of claims 29 to 43, wherein the subject has a reduction in IGA score.

45. A method of treating atopic dermatitis in a subject in need thereof, the method comprising administering to the subject an anti-OX40 ligand (OX40L) antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises a heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO: 42, a HCDR2 of SEQ ID NO: 44, and a HCDR3 of SEQ ID NO: 46, and a light chain complementarity determining region (LCDR) 1 of SEQ ID NO: 56, a LCDR2 of SEQ ID NO: 58, and a LCDR3 of SEQ ID NO: 60, wherein efficacy is maintained at week 28 after treatment is stopped or at week 32 after a final dose of the antibody or antigen binding fragment thereof is administered to the subject.

46. The method of claim 45, wherein each dose is administered Q12W.

47. The method of claim 45 or 46, wherein the subject receives a dose Q12W from the start of treatment.

48. The method of any one of claims 45-47, wherein the subject receives a dose Q12W directly without a prior dose administration Q4W.

49. The method of any one of claims 45-48, wherein the subject is a vIGA 0 / 1 responder and vIGA O / 1 response efficacy is maintained in the subject, or wherein the subject is an EASI 75 responder and EASI 75 response efficacy is maintained in the subject.

50. The method of any one of claims 45-48, wherein the subject is a vIGA 0 / 1 responder and vIGA O / 1 response efficacy is maintained in the subject.

51. The method of any one of claims 45-48, wherein the subject is an EASI 75 responder and EASI 75 response efficacy is maintained in the subject.

52. A method of treating atopic dermatitis in a subject in need thereof, the method comprising administering to the subject emapalumab, wherein the subject receives a dose directly Q12W without a prior dose administration Q4W, and wherein the subject receives an initial dose of about 500 mg of emapalumab followed by one or more secondary doses of about 250 mg of emapalumab.

53. A method of treating atopic dermatitis in a juvenile subject in need thereof, the method comprising administering to the juvenile subject emapalumab, wherein the juvenile subject receives an initial dose of about 250 mg of emapalumab followed by one or more secondary doses of about 125 mg of emapalumab, and wherein the subject receives a dose Q12W from the start of treatment.

54. A method of treating atopic dermatitis in a subject in need thereof, the method comprising administering to the subject emlitzumab, wherein the subject has a body weight ranging from about 25 kg to about 40 kg, wherein the subject receives an initial dose of about 250 mg of emlitzumab followed by one or more secondary doses of about 125 mg of emlitzumab, and wherein the subject receives a dose every 12 weeks (Q12W) from the start of treatment.

55. A method of treating atopic dermatitis (AD) in a subject in need thereof, the method comprising administering to the subject emlitzumab, wherein the subject receives a dose directly every 12 weeks (Q12W) without a prior dose administration every 4 weeks (Q4W), wherein the subject receives an initial dose of about 500 mg of emlitzumab followed by one or more secondary doses of about 250 mg of emlitzumab, and wherein the method results in a reduction in the level of at least one biomarker in the subject relative to a control.

56. A method of treating atopic dermatitis (AD) in a subject in need thereof, the method comprising administering to the subject emlitzumab, wherein the subject receives a dose directly every 12 weeks (Q12W) without a prior dose administration every 4 weeks (Q4W), and wherein the subject receives an initial dose of about 500 mg of emlitzumab followed by one or more secondary doses of about 250 mg of emlitzumab.

57. A method of treating atopic dermatitis (AD) in a subject in need thereof, the method comprising administering to the subject emlitzumab, wherein the subject receives a dose directly every 12 weeks (Q12W) without a prior dose administration every 4 weeks (Q4W), and wherein the subject receives an initial dose of about 500 mg of emlitzumab followed by one or more secondary doses of about 250 mg of emlitzumab.

58. A method of treating atopic dermatitis in a subject in need thereof, the method comprising administering to the subject emlitzumab, wherein the subject receives a dose directly every 12 weeks (Q12W) without a prior dose administration every 4 weeks (Q4W), and wherein the subject receives an initial dose of about 500 mg of emlitzumab followed by one or more secondary doses of about 250 mg of emlitzumab, and wherein efficacy is maintained at week 28 from the stop of treatment or at week 32 after the final administration of emlitzumab.

59. The method of any one of claims 1, 2, 12, 13, 29, 30, and 45, wherein the antibody or antigen-binding fragment thereof is an OX40L antagonist.

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