Treatment of atopic dermatitis

Abstract

The present invention relates to a method for treating atopic dermatitis in a human subject, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered by injection. Also provided are anti-OX40L antibody or antigen-binding fragment thereof, glass vials containing anti-OX40L antibody or antigen-binding fragment thereof, drug delivery devices, pre-filled syringes, microinjectors, pen delivery devices, autoinjectors and kits for use in such methods.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of UK priority application numbers GB2111492.1 filed on August 10, 2021, GB2115152.7 filed on October 21, 2021, GB2204211.3 filed on March 24, 2022, and GB2204291.5 filed on March 25, 2022, the disclosures of which are incorporated herein by reference in their entirety for all purposes. [Background technology]

[0002] Atopic dermatitis (AD) is the most common type of eczema, affecting more than 9.6 million children and approximately 16.5 million adults in the U.S. It is a chronic condition that may come and go over years or a lifetime and may overlap with other types of eczema.

[0003] In people with AD, the immune system is malfunctioning and overactive, causing inflammation that damages the skin barrier, leaving the skin dry and prone to itching and rashes that can appear purple, brown, or grayish in darker skin tones and red in lighter skin tones.

[0004] Research has shown that some people with eczema, particularly atopic dermatitis, have mutations in the gene involved in making filaggrin. Filaggrin is a protein that helps our bodies maintain a healthy protective barrier on the top layer of our skin. Without enough filaggrin to build a strong skin barrier, moisture can escape, allowing bacteria, viruses, and more to enter. This is why many people with AD have extremely dry, infection-prone skin.

[0005] Itching is a hallmark of AD, and some data suggest that more than 85% of people with the condition experience this distressing symptom daily. Sore or painful skin and poor sleep caused by itching are also common.

[0006] People with AD can develop rashes anywhere on the body that can ooze, exude fluid, and bleed when scratched, making the skin vulnerable to infection. The skin can become dry and discolored, and repeated scratching can cause thickening and sclerosing—a process called lichenification. AD can affect any part of the body, but in children, it most commonly affects the hands, inner elbows, behind the knees, and the face and scalp.

[0007] Atopic dermatitis usually begins in childhood, usually around 6 months of age. It is a common form of eczema, but it can also be severe and long-lasting. If you or your child has atopic dermatitis, it may improve at times and worsen at other times. Some children may experience a gradual decrease in symptoms as they grow older, but some have atopic dermatitis flare-ups into adulthood.

[0008] Atopic dermatitis coexists with two other allergic conditions: asthma and seasonal nasal allergies (allergic rhinitis). People who have asthma and / or seasonal nasal allergies, or who have family members who do, are more likely to develop AD.

[0009] There is currently no cure for AD, but depending on the severity of the disease, treatments include lifestyle changes, over-the-counter (OTC) medications, or prescription medications.

[0010] The main treatments for AD include: Emollients (moisturizers) - used daily to stop the skin from becoming dry, and Topical corticosteroids - creams and ointments used to reduce swelling and redness during flare-ups

[0011] Other treatments include: Topical pimecrolimus or tacrolimus for eczema in sensitive areas that does not respond to simple treatment Antihistamines for severe itching Bandages or special body suits that allow the body to heal underneath Dupixent (dupilumab) is indicated for the treatment of adult patients with moderate to severe AD whose disease is not adequately controlled with topical prescription therapies or for whom such therapies are inadvisable. Dupixent may be used with or without topical corticosteroids. As described by [Publication ID No. 1], dupilumab, the only currently approved mAb for the treatment of AD, blocks IL-13 but also IL-4 by inhibiting their common receptor, the IL-4Rα1 subunit. It is highly effective and has an excellent safety profile, although a significant proportion of patients develop dry eye and / or blepharoconjunctivitis, which complicate its control. Pipeline products include JAK inhibitors, IL-13 inhibitors, and IL-31 inhibitors. However, JAK inhibitors have safety concerns (e.g., black box warnings), and anti-IL-31 inhibitors show insufficient efficacy.

[0012] OX40 ligand (OX40L) is a member of the TNF family; a 34 kDa type II transmembrane protein. The crystallized complex of human OX40 and OX40L consists of one OX40L (trimer) and three OX40 monomers. The human extracellular domain is 42% homologous to mouse OX40L.

[0013] OX40L is not constitutively expressed but is induced in professional 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 (CD4+ and CD8+ T cells, Th2, Th1, and Th17 cells) and on CD4+Foxp3+ cells even in the absence of activation.

[0014] Two or three days after antigen recognition, interaction between OX40 and OX40L occurs during T cell-DC interaction. After leaving DC, OX40-expressing T cells interact with OX40L-expressing cells other than DC and receive OX40 signals from these cells, which may provide essential signals for generating memory T cells, enhancing Th2 responses, and prolonging inflammatory reactions. OX40 signals to responder T cells render them resistant to Treg-mediated suppression.

[0015] US Patent Nos. 5,299,949, 5,399,963, 5,399,973, and 5,399,983 describe anti-human OX40L (hOX40L) antibodies and fragments and medical applications for treating or preventing hOX40L-mediated diseases or conditions in humans. [Prior art documents] [Patent documents]

[0016] [Patent Document 1] WO2015 / 132580 [Patent Document 2] WO2016 / 139482 [Patent Document 3] WO2018 / 083248 [Non-patent literature]

[0017] [Non-Patent Document 1] Tubau et al., Immunotherapy 13:327-344, 2021 Summary of the Invention [Means for solving the problem]

[0018] Some embodiments provide treatments that target upstream OX40L-dependent pathways that are effective in treating inflammatory diseases or disorders, immune-mediated diseases or disorders, and inflammatory skin diseases or disorders. Some embodiments provide treatments that target upstream OX40L-dependent pathways that are effective in treating both acute and chronic AD. The treatments have attractive dosing frequencies, low-dose induction and maintenance regimens, and strong efficacy and safety profiles. Advantages of subcutaneous formulations include greater patient convenience, as they can be administered by the patient at home, thus avoiding inconvenient doctor visits. Administration time can also be shortened, which is beneficial for patients and healthcare providers. Some embodiments also provide reduced needle burden, i.e., fewer injections per year, which potentially improves compliance and, therefore, patient outcomes. Some embodiments also provide treatments with surprisingly consistent pharmacokinetic (PK) parameter estimates in IV and subcutaneous population PK models, which are not significantly affected by drug antibodies, which is particularly surprising for subcutaneous administration. To this end, some embodiments provide:

[0019] In a first configuration, a method of treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered by injection.

[0020] In another description of the first configuration, a method of treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered by injection, and the method comprises administering at least one injection with a dose of at least about 20 mg of the antibody or fragment thereof.

[0021] In another description of the first configuration, a method of treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is a disease-modifying drug.

[0022] In another description of the first configuration, a method of treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered at least twice, with at least one interval of 2 to 6 months between each administration.

[0023] In another description of the first configuration, a method of treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered at least twice, with at least one interval of six months between each administration.

[0024] In another description of the first configuration, a method of treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the EASI score after administration is reduced by at least 10% relative to the baseline EASI score.

[0025] In another description of the first configuration, a method of treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein after administration, the vIGA-AD score is reduced by at least 10% relative to the baseline vIGA-AD score.

[0026] In another description of the first configuration, a method of treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein after administration, the IGA-AD score is reduced by at least 10% relative to the baseline IGA-AD score.

[0027] In another description of the first configuration, a method of treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the post-administration BSA score is reduced by at least 10% relative to the baseline BSA score.

[0028] In another description of the first configuration, a method of treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein after administration the SCORAD index is reduced by at least 10% relative to the baseline SCORAD index.

[0029] In another description of the first configuration, a method of treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the post-administration PO-SCORAD index is reduced by at least 10% relative to the baseline PO-SCORAD index.

[0030] In another description of the first configuration, a method of treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the DQLI score after administration is reduced by at least 10% relative to the baseline DQLI score.

[0031] In another description of the first configuration, a method of treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the subject is a patient with chronic atopic dermatitis.

[0032] In a second configuration, a glass vial containing an anti-OX40L antibody or antigen-binding fragment thereof is provided.

[0033] In a third configuration, a pre-filled syringe containing an anti-OX40L antibody or antigen-binding fragment thereof is provided.

[0034] In a fourth configuration, a microinjector containing an anti-OX40L antibody or antigen-binding fragment thereof is provided.

[0035] In a fifth configuration, a pen delivery device containing an anti-OX40L antibody or antigen-binding fragment thereof is provided.

[0036] In a sixth configuration, an autoinjector delivery device containing an anti-OX40L antibody or antigen-binding fragment thereof is provided.

[0037] In a seventh configuration, there is provided a kit comprising a glass vial, a drug delivery device, a pre-filled syringe, a microinjector, a pen delivery device or an autoinjector according to any of the third to sixth configurations and labeling and / or instructions for use specifying administration according to the method of the first configuration.

[0038] In a further aspect, there is provided an anti-OX40L antibody or antigen-binding fragment thereof for use in a method of treating atopic dermatitis according to the method of the first aspect.

[0039] In a further configuration, there is provided a glass vial, drug delivery device, pre-filled syringe, microinjector, pen delivery device, autoinjector or kit according to any one of configurations two to seven for use in a method of treating atopic dermatitis according to the method of the first configuration.

[0040] In a further aspect, there is provided the use of an anti-OX40L antibody or antigen-binding fragment thereof for the manufacture of a medicament for treating atopic dermatitis according to the method of the first aspect.

[0041] In a further aspect, there is provided the use of a glass vial, drug delivery device, pre-filled syringe, microinjector, pen delivery device, autoinjector or kit according to any one of the third to eighth aspects for the manufacture of a medicament for treating atopic dermatitis according to the method of the first aspect.

[0042] In a further aspect, a method of treating an inflammatory disease, inflammatory disorder, immune-mediated disease, immune-mediated disorder, inflammatory skin disease or inflammatory skin disorder in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered by injection.

[0043] In a further aspect, a method is provided for treating an inflammatory disease, inflammatory disorder, immune-mediated disease, immune-mediated disorder, inflammatory skin disease or inflammatory skin disorder in a human subject, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered by subcutaneous injection.

[0044] In a further aspect, an anti-OX40L antibody or antigen-binding fragment thereof is provided for use in a method of treating an inflammatory disease, inflammatory disorder, immune-mediated disease, immune-mediated disorder, inflammatory skin disease or inflammatory skin disorder in a human subject, the method comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered by injection.

[0045] In a further aspect, an anti-OX40L antibody or antigen-binding fragment thereof is provided for use in a method of treating an inflammatory disease, inflammatory disorder, immune-mediated disease, immune-mediated disorder, inflammatory skin disease or inflammatory skin disorder in a human subject, the method comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered by subcutaneous injection.

[0046] In another aspect, a method of treating atopic dermatitis in a subject is provided, comprising selecting a subject with atopic dermatitis and administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the anti-OX40L antibody or antigen-binding fragment thereof comprises heavy chain complementarity determining regions (HCDRs) of SEQ ID NOs: 42, 44, and 46 and light chain complementarity determining regions (LCDRs) of SEQ ID NOs: 56, 58, and 60.

[0047] Reference to a first configuration, as used herein, includes "the first configuration" and any "alternative description of the first configuration." Features of any description of the first configuration may be read in combination with any of the second and subsequent configurations of the present invention. [Brief explanation of the drawings]

[0048] [Figure 1] A graphical overview of the study design in Example 1 is shown. Healthy volunteers in Cohorts 1-3 received a single IV infusion of KY1005 (0.006, 0.018, or 0.05 mg / kg) or placebo, and blood was drawn through Day 113. Cohorts 4-8 received an initial loading dose (0.15, 0.45, 1.35, 4.0, or 12 mg / kg) on ​​Day 1 and two maintenance doses (50% of the loading dose) on Days 29 and 57. [Figure 2] Figures 2A-B graphically show the percent change in anti-tetanus toxoid (TT) IgG and IgM titers relative to placebo at day 85 for cohorts 4-8, adjusting for baseline variability. Vaccination with the recall antigen tetanus toxoid (TT) elicited humoral (IgM and IgG) responses in all recipients. No observable effect of KY1005 on mean anti-TT IgG levels (Figure 2A) was observed, whereas anti-TT IgM (Figure 2B) suppression was numerically greater than placebo in all treatment arms, but was not dose-dependent. [Figure 3]A graphical overview of the study design for Example 2 is provided. Patients underwent a Day 1 / baseline assessment and were randomized in a 1:1:1 ratio to receive an intravenous (IV) injection of either a low-dose (200 mg) or a high-dose (500 mg) of KY1005, followed by three maintenance doses of 50% of the loading dose at 28-day intervals on days 29, 57, and 85, or a matching placebo. [Figure 4] Figure 1 shows a graph of the percent change in EASI score from baseline over time, illustrated with 95% confidence intervals (CI) using LSM. Reductions in EASI score from baseline to day 113 in the FAS were observed in all treatment groups, including placebo. A greater reduction was observed in the KY1005 group. [Figure 5-1] Figures 5A-C graphically show EASI 50 (Figure 5A), EASI 75 (Figure 5B), and EASI 90 (Figure 5C) responders over time. A gradual increase in the percentage of patients with at least a 50%, 75%, and 90% reduction from baseline in EASI was generally observed across all treatment groups, including placebo. Percentages were higher in the KY1005 group compared to placebo at all time points (except for EASI on days 15 and 29, where percentages were zero in both the KY1005 low-dose and placebo groups). Black represents the 200 mg / 100 mg KY1005 dose; gray represents the 500 mg / 250 mg KY1005 dose; and white represents placebo. [Figure 5-2] Continued from Figure 5-1. [Figure 6A] The graph shows vIGA 0 (no problems) and vIGA 1 (very few problems) responders over time. A gradual increase in the percentage of vIGA 0 / 1 responders was generally observed in the KY1005-treated groups but not in the placebo group. By day 113, the percentage of vIGA 0 / 1 responders was 44.4% (12 / 27) and 37.0% (10 / 27) in the low- and high-dose KY1005 groups, respectively, compared with 8.3% (2 / 24) in the placebo group. Gray represents 200 mg / 100 mg KY1005 doses; black represents 500 mg / 250 mg KY1005 doses; and white represents placebo. [Figure 6B] The graph shows the proportion of responders who maintained a vIGA of 0 / 1 over the extended study period. vIGA is a validated Investigator Global Assessment. [Figure 6C] The percentage change in EASI over time is shown graphically. *Final dose was administered at week 12. EASI is the Eczema Area and Severity Index; SD is the standard deviation. [Figure 7-1] The table shows EASI scores for patients who received high or low doses of KY1005 or placebo throughout the study and safety follow-up period. This figure represents all patients who achieved vIGA 0 / 1 at Week 16 and were evaluated for efficacy during the safety follow-up period. This figure shows that those subjects who achieved vIGA 0 / 1 at Day 113 demonstrated long-lasting response up to 5.5 months after the last dose (approximately 70% of subjects receiving KY1005). [Figure 7-2] Continued from Figure 7-1. [Figure 8] The graph shows the percentage change from baseline in the SCORAD index between treatment regimens (MMRM analysis). A gradual decrease in SCORAD scores from baseline was observed in all treatment groups, including placebo, by days 29, 57, 85, and 113. However, a greater reduction was observed in the KY1005 group compared with placebo at all time points: the percentage change (95% CI) by LSM in the SCORAD index at day 113 was -60.30 (-72.57, -48.04) and -58.96 (-71.04, -46.87) for the low-dose and high-dose KY1005 groups, respectively, compared with placebo (-36.79 [-49.94, -23.65]). [Figure 9]The percent change in diseased BSA from baseline over time is shown graphically with 95% CI using LSM. A gradual decrease in diseased BSA from baseline by days 29, 57, 85, and 113 was observed in all treatment groups, including placebo. However, greater reductions were observed in the KY1005 group compared with placebo at all time points: the least-squares mean percentage change (95% CI) in diseased BSA at day 113 was -78.07 (-92.35, -63.79) and -71.97 (-86.10, -57.84) for the low- and high-dose KY1005 groups, respectively, compared with placebo (-41.58 [-57.35, -25.80]). [Figure 10] Figure 1 shows a graphical representation of the percent change in the PO-SCORAD index from baseline over time, illustrated with 95% CI using LSM. A gradual decrease in the PO-SCORAD index from baseline by days 15, 29, 57, 64, 85, and 113 was observed in all treatment groups, including placebo. Greater reductions were observed in the KY1005 group compared with placebo at nearly all time points: by day 113, the percentage change (95% CI) by LSM in the PO-SCORAD index was -55.16 (-69.11, -41.21) and -43.04 (-56.41, -29.67) for the low- and high-dose KY1005 groups, respectively, compared with -23.96 (-38.36, -9.46) for the placebo group. [Figure 11]Figure 1 shows a graphical representation of the percent change in DLQI total score from baseline over time, illustrated with 95% CI using LSM. A gradual decrease in DLQI total score from baseline by days 15, 29, 57, 64, 85, and 113 was observed in all treatment groups, including placebo. Overall, there was no clear difference in the magnitude of reduction between treatment groups, but greater reductions were observed in the KY1005 treatment group compared with placebo on days 85 and 113: by day 113, the percentage change (95% CI) by LSM in DLQI total score was -52.99 (-75.31, -30.67) and -59.15 (-80.32, -37.99) for the low- and high-dose KY1005 groups, respectively, compared with -20.51 (-44.95, 3.93) for the placebo group. [Figure 12] The percent change in mean weekly NRS for pruritus from baseline over time is graphed with 95% CI using LSM. A gradual decrease in mean weekly NRS for pruritus from baseline to days 15, 29, 57, 64, 85, and 113 was generally observed in all treatment groups, including placebo. Although there were no clear differences between treatment groups in the magnitude of reduction at any time point, comparison of the percentage change in NRS for pruritus between the KY1005 group and placebo did not reveal a nominally statistically significant difference. [Figure 13] A graph of serum KY1005 concentrations versus time data from the primary study is presented, expressed using geometric means. The serum concentration profiles of KY1005 were similar between the KY1005 groups, with higher concentrations recorded in the high-dose group compared to the low-dose group. With repeated IV administration, serum concentrations rapidly peaked and then declined after each dose. [Figure 14] A graph of serum KY1005 concentrations versus time data is presented using geometric means from the extension study. The serum concentration profiles of patients who entered the extension study were similar between the KY1005 groups, with higher concentrations recorded in the high-dose KY1005 group compared to the low-dose KY1005 group. After the fourth infusion on day 85, serum concentrations gradually declined until day 253. [Figure 15] A graphical overview of the study design for Example 3 is provided. The study included three groups: comparative group 1: a single 250 mg dose of KY1005 given by IV infusion over 30 minutes, followed by a 15-minute saline wash; group 2: a single 125 mg (1 mL) dose of KY1005 given by SC injection into the abdomen; and group 3: a single 250 mg (2 mL) dose of KY1005 given by successive 2 x 1 mL SC injections into the abdomen. [Figure 16] Figures 16A-B graphically show the mean serum concentration-time plots of KY1005 up to 92 days after single intravenous and subcutaneous administration, which are linear (Figure 16A) and semi-logarithmic (Figure 16B). Absorption via the SC route is slower than that seen with IV-administered drug: mean serum concentrations peaked at 168 hours post-dose (Day 8) for KY1005 administered SC at 250 mg (25,803 ng / mL) and 125 mg (14,222 ng / mL). Mean serum concentrations after 250 mg IV and SC administration converged to approximately 20,000 ng / mL by Day 36. Thereafter, the mean serum concentration-time curves for both regimens were very similar throughout the remainder of the sampling period, both declining to approximately 7,000 ng / mL at follow-up (Day 92). [Figure 17] Figures 17A-B graphically show the mean serum concentration-time plots of KY1005 up to 24 hours after single intravenous and subcutaneous administration, which are linear (Figure 17A) and semi-logarithmic (Figure 17B). Absorption via the SC route was slower than that seen with IV-administered drug. A single IV dose of 250 mg of KY1005 rapidly reached peak serum concentrations at the end of the infusion (30 minutes): the mean serum concentration was 88,931 ng / mL; individual subject concentrations at the end of the infusion ranged from 72,391 to 120,333 ng / mL (the ratio between subjects at each extreme was 1.66-fold). [Figure 18]Figures 18A-D graphically show the dose-normalized PK profiles of KY1005 versus IV treatment in different studies, including KY1005 FIH HV CT-01 (Figure 18A), KY1005 CT-02 (Figure 18B), and KY1005 CT-04 (Figure 18C). The three studies are overlaid in Figure 18D with different colors (CT-01 = purple, CT-02 = red, CT-04 = orange). The dose-normalized IV profiles showed biphasic behavior consistent with the assumed two-compartment distribution model. [Figure 19] The dose-normalized KY1005 PK profiles for SC treatment in the KY1005 CT-04 study are shown in the figure. The dose-normalized SC profiles were consistent with each other. The profiles were closely sampled on the first day and in the first week. The maximum concentration (Cmax) was reached between days 4 and 14. The SC profile after 14 days was much flatter than the IV profile. [Figure 20] Graphical representations of predicted Cmin at week 24 for induction scenarios I-III (various doses) and IV-XII (various regimens) are shown. Figure 20A shows induction scenario I (200 mg SC every 4 weeks (Q4W), 100 mg SC Q4W, 50 mg SC Q4W, and 25 mg SC Q4W). Figure 20B shows induction scenario II (300 mg SC Q4W, 250 mg SC Q4W, 200 mg SC Q4W, and 150 mg SC Q4W). Figure 20C shows induction scenario III (500 mg SC Q4W, 450 mg SC Q4W, 400 mg SC Q4W, and 350 mg SC Q4W). Figure 20D shows Induction Scenario IV (125 mg SC every 2 weeks (Q2W), 125 mg SC every 4 weeks, 125 mg SC every 6 weeks (Q6W), and 125 mg SC every 8 weeks (Q8W)). Figure 20E shows Induction Scenario V (150 mg SC every 2 weeks, 150 mg SC every 4 weeks, 150 mg SC every 6 weeks, and 150 mg SC every 8 weeks). Figure 20F shows Induction Scenario VI (200 mg SC every 2 weeks, 200 mg SC every 4 weeks, 200 mg SC every 6 weeks, and 200 mg SC every 8 weeks). [Figure 21] Figures 21A-F graphically show predicted Cmin at week 24 for induction scenarios I-III (various doses) and IV-XII (various regimens). Figure 21A shows induction scenario VII (250 mg SC Q2W, 250 mg SC Q4W, 250 mg SC Q6W, and 250 mg SC Q8W). Figure 21B shows induction scenario VIII (300 mg SC Q2W, 300 mg SC Q4W, 300 mg SC Q6W, and 300 mg SC Q8W). Figure 21C shows induction scenario IX (350 mg SC Q2W, 350 mg SC Q4W, 350 mg SC Q6W, and 350 mg SC Q8W). Figure 21D shows Induction Scenario X (400 mg SC Q2W, 400 mg SC Q4W, 400 mg SC Q6W, and 400 mg SC Q8W). Figure 21E shows Induction Scenario XI (450 mg SC Q2W, 450 mg SC Q4W, 450 mg SC Q6W, and 450 mg SC Q8W). Figure 21F shows Induction Scenario XII (500 mg SC Q2W, 500 mg SC Q4W, 500 mg SC Q6W, and 500 mg SC Q8W). [Figure 22] Figures 22A-C graphically show predicted Cmin at the end of the maintenance period: Figure 22A shows maintenance Q8W from week 52 onwards, Figure 22B shows maintenance Q12W from week 52 onwards, and Figure 22C shows maintenance Q16W from week 52 onwards. [Figure 23-1] Figures 23A-D graphically illustrate simulated PK profiles of KY1005 in patients with atopic dermatitis (AD) stratified by body weight. Simulations are shown for body weights of 50, 75, 100, 120, and 150 kg. Figure 23A shows four doses of 62.5 mg of KY1005 administered every four weeks (Q4W). Figure 23B shows four doses of 125 mg of KY1005 administered Q4W. Figure 23C shows four doses of 250 mg of KY1005 administered Q4W. Figure 23D shows one dose of 500 mg of KY1005 followed by three doses of 250 mg administered Q4W. [Figure 23-2]Continuation of Figure 23-1. [Figure 24] Figure 24A- graphically shows predicted Cmin after a 24-week run-in period. Different regimens (Q2W (Figure 24A), Q4W (Figure 24B), Q6W (Figure 24C), Q8W (Figure 24D)) were distributed across different panels. [Figure 25] Figures 25A-C graphically show the predicted time above Cmin during the maintenance period. Different regimens (Q8W (Figure 25A), Q12W (Figure 25B), Q16W (Figure 25C)) were distributed across different panels. [Figure 26] A graphical overview of the study design for Example 5 is shown. Four different SC dosing regimens of KY1005 are tested against placebo. From baseline to Day 169 (Week 24), KY1005 is administered at the following doses and intervals: a 500 mg loading dose (given as 2 x 2 mL SC doses) followed by 250 mg every 4 weeks (Q4W) from Day 28 onwards, or the following regimens from baseline: 250 mg Q4W, or 125 mg Q4W, or 62.5 mg Q4W, or placebo Q4W. [Figure 27] The correlation between baseline EASI and IL-13 serum levels is shown graphically. The figure demonstrates a significant correlation of IL-13 levels with disease severity at BL, as measured by EASI and SCORAD (data not shown). *Linear regression and correlation analysis (n=77) with r coefficient and p-value based on Spearman correlation. [Figure 28]Circulating IL-13 is graphically depicted over time. At day 113, IL-13 serum levels were significantly reduced in patients treated with amritelimab (KY1005 or 2D10), but not placebo. The reduction was maintained through day 253 in amritelimab responders‡, but not in placebo. The sustained reduction in IL-13 serum levels in amritelimab-treated patients was treatment-dependent, highlighting that amritelimab effectively targets immune dysregulation in AD. †Repeated measures two-way ANOVA + Tukey's multiple comparison test for fold change in IL-13 compared to BL (day 1) for patients with a complete dataset at day 113 (placebo, n=15; low-dose amritelimab, n=20; high-dose amritelimab, n=20). ns p>0.05; **p<0.01; ***p<0.001, ****p<0.0001. ‡Reductions were maintained in all patients except for one patient treated with low-dose amritelimab, who had increased IL-13 levels at day 169 compared with BL. AD, atopic dermatitis; BL, baseline; CI, confidence interval; EASI, Eczema Area and Severity Index; IL, interleukin; ns, not significant; SCORAD, scoring for atopic dermatitis. [Figure 29-1]Figures 29A-F graphically show the log fold changes of the biomarkers IL-13 (Figures 29A-B), IL-22 (Figures 29C-D), and IL-17A (Figures 29E-F) at baseline (day 0), day 29, and day 113 in patients receiving either KY1005 or placebo, while Figures 29B, 29D, and 29F further show data for patients receiving low-dose and high-dose KY1005. IL-13 and IL-22 data are from the KY1005 CT02 serum analysis. IL-17A data are from the KY1005 CT02 OLINK analysis. ns, not significant; *P≦0.05; **P≦0.01; ***P≦0.001; ****P≦0.0001. Two-way repeated measures ANOVA; Dunnett's multiple comparison test. Figures 29A-B illustrate that KY1005 is associated with a reduction in serum cytokines associated with Th2. Figures 29C-F illustrate that KY1005 is associated with a reduction in cytokines typically associated with Th22 and Th17 responses. [Figure 29-2] Continuation of Figure 29-1. [Figure 30] The graph shows the proportion of patients who achieved a score of 0 or 1 on the validated Investigator's Global Assessment-Atopic Dermatitis (vIGA-AD) scale during 16 weeks of treatment in groups receiving either high-dose KY1005, low-dose KY1005, or placebo once every 4 weeks. ***p<0.001 vs. placebo (Cochran-Mantel-Haenszel test), **p<0.001 vs. placebo, *p<0.05. [Figure 31] Figures 31A-B graphically show the relative protein levels of two proteins associated with disease severity (IL-22 in Figure 31A, and IL-13 in Figure 31B). Protein levels of IL-22 and IL-13 were found to be significantly associated (FDR p-value <0.05) with EASI score at baseline (column 1). This association persisted at days 29 and 113 for both patients. The coefficient of determination R2 and p-value were calculated using a linear model. Each dot represents a patient sample, the blue line represents the linear regression line, and the 95% confidence interval is shown in gray. [Figure 32] Figures 32A-C graphically show the levels of IL-13 (Figure 32A), IL-22 (Figure 32B), and IL-17A (Figure 32C), which were significantly reduced (FDR p-value < 0.05) at day 113 upon treatment with KY1005. The X-axis shows time in days (data points are at days 0, 29, and 113). The Y-axis shows the Log2 change from baseline levels. [Figure 33] Figures 33A-C graphically demonstrate that baseline IL-13 serum levels correlate with disease severity. IL-13 is significantly positively correlated with disease severity as measured by both baseline EASI (Figure 33A) and SCORAD (Figure 33B). IL-13 baseline levels are significantly different between treatment groups (Figure 33C). Spearman correlation of baseline IL-13 with EASI / SCORAD (n=78). One-way ANOVA with Tukey's multiple comparison test. [Figure 34] Circulating IL-13 in different treatment groups between baseline and D113 is shown graphically. IL-13 levels normalized to baseline. n = number of patients with the full set of samples up to D113. Two-way ANOVA + Tukey's multiple comparison test. IL-13 is significantly reduced in patients treated with KY1005 (KY1005-low and high) but not in placebo patients at D113. [Figure 35A] 35A-35B show graphs of the change in IL-13 levels at D113 relative to baseline, illustrating that IL-13 levels correlate with disease improvement. Only patients with a full set of samples up to D113 are included (n=58). Spearman correlation of fold change in IL-13 and EASI (FIG. 35A) / SCORAD (FIG. 35B) at D113. There is a weak correlation between the change in IL-13 at D113 and disease improvement by EASI (FIG. 35A) and SCORAD (FIG. 35A). [Figure 35B]35A-35B show graphs of the change in IL-13 levels at D113 relative to baseline, illustrating that IL-13 levels correlate with disease improvement. Only patients with a full set of samples up to D113 are included (n=58). Spearman correlation of fold change in IL-13 and EASI (FIG. 35A) / SCORAD (FIG. 35B) at D113. There is a weak correlation between the change in IL-13 at D113 and disease improvement by EASI (FIG. 35A) and SCORAD (FIG. 35A). [Figure 36] This graph shows that changes in IL-13 serum levels are maintained past D113 in vIGA 0 / 1 responders. 24 D169 samples and 15 evaluable D253 samples were obtained from 24 patients (vIGA 0-1) classified as responders at D113. In patients (vIGA 0-1) classified as responders at D113, the reduction in serum IL-13 was prolonged to D169 and D253 for responders treated with KY1005. [Figure 37] Figures 37A-C graphically show that baseline IL-22 serum levels correlate with disease severity. One-way ANOVA with Tukey's multiple comparison test. Spearman correlation of baseline IL-22 with EASI / SCORAD (n=78). IL-22 significantly correlates with disease severity as measured by both baseline EASI (Figure 37A) and SCORAD (Figure 37B). IL-22 baseline levels differ significantly between treatment groups (Figure 37C). [Figure 38] Graphical representation of circulating IL-22 in different treatment groups between baseline and D113. n = number of patients with full set of samples up to D113. Two-way ANOVA + Tukey's multiple comparison test. IL-22 levels change significantly from baseline in patients treated with KY1005 at D113 (and at D29 in patients treated with KY1005-high), but not in placebo patients. [Figure 39A]39A-39B show graphs of the change in IL-22 levels at D113 relative to baseline, illustrating that IL-22 levels correlate with disease improvement. Only patients with a full set of samples up to D113 are included (n=58). Spearman correlation of fold change in IL-22 and EASI (FIG. 39A) / SCORAD (FIG. 39B) at D113. There is a weak correlation between the change in IL-22 at D113 and disease improvement by EASI (FIG. 39A) and SCORAD (FIG. 39A). [Figure 39B] 39A-39B show graphs of the change in IL-22 levels at D113 relative to baseline, illustrating that IL-22 levels correlate with disease improvement. Only patients with a full set of samples up to D113 are included (n=58). Spearman correlation of fold change in IL-22 and EASI (FIG. 39A) / SCORAD (FIG. 39B) at D113. There is a weak correlation between the change in IL-22 at D113 and disease improvement by EASI (FIG. 39A) and SCORAD (FIG. 39A). [Figure 40] This graph shows that changes in IL-22 serum levels are maintained past D113 in vIGA 0 / 1 responders. 24 D169 samples and 16 evaluable D253 samples were obtained from 24 patients (vIGA 0-1) classified as responders at D113. In patients (vIGA 0-1) classified as responders at D113, the reduction in serum IL-22 was extended to D169 and D253 in responders treated with KY1005. [Figure 41-1]Graphical representation of the effect of amritelimab on serum biomarkers (total IgE, IL-13, IL-22, and IL-31). Fold change from baseline in serum (A) IgE, (B) IL-13, (C) IL-22, and (D) IL-31 over time by treatment regimen. All patients with biomarker data at baseline and week 16 or at least two alternative treatments through week 16 were included. To extend the study, only patients who achieved vIGA 0 / 1 at week 16 (w16 responders) were included. Post-hoc linear mixed-effects models with Dunnett's multiple comparison test on log10-transformed fold changes from baseline by treatment regimen (ns not significant, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). Median + 95% confidence interval; sample size indicated on the upper x-axis. [Figure 41-2] Continuation of Figure 41-1. [Figure 42] IL-13 serum levels during treatment over time are shown graphically. DETAILED DESCRIPTION OF THE INVENTION

[0049] In a first configuration, a method for treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered by injection. The antibody or fragment thereof is administered by subcutaneous injection. The antibody or fragment thereof is a disease-modifying drug. Optionally, the method comprises administering at least one injection with a dose of at least about 20 mg of the antibody or fragment thereof. The antibody or fragment thereof is administered at least twice, with at least one interval of 2 to 6 months between doses. The antibody or fragment thereof is administered at least twice, with at least one interval of 6 months between doses. The subject is a patient with chronic atopic dermatitis.

[0050] In an alternative description of the first configuration, a method for treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is a disease-modifying drug. After administration of the disease-modifying drug, the subject achieves an IGA-AD score of 0 or 1 for at least 6 months. Any other suitable disease severity scale described herein, such as EASI75 or EASI90, is used instead of an IGA-AD score of 0 or 1. At least 6 months may be at least 7 months, at least 8 months, or at least 9 months. After discontinuing the disease-modifying drug, the subject may maintain an IGA-AD score of 0 or 1 for at least 6 months. At least 6 months may be at least 7 months, at least 8 months, or at least 9 months. The therapeutic effect may persist for at least approximately 6 half-lives of the antibody or fragment thereof after the last administration of the antibody or fragment thereof. At least 6 half-lives may be at least approximately 7 half-lives, at least approximately 8 half-lives, or at least approximately 9 half-lives. The antibody or fragment thereof is administered by injection, optionally subcutaneous injection. Optionally, the method includes administering at least one injection with a dose of at least about 20 mg of the antibody or fragment thereof. The antibody or fragment thereof is administered at least twice, with at least one interval of 2 to 6 months between doses. The antibody or fragment thereof is administered at least twice, with at least one interval of 6 months between doses. The subject is a patient with chronic atopic dermatitis. After administration, the EASI score, vIGA-AD score, IGA-AD score, BSA score, SCORAD index, PO-SCORAD index, and / or DQLI score may be reduced by at least 10% compared to the corresponding baseline EASI score, vIGA-AD score, IGA-AD score, BSA score, SCORAD index, PO-SCORAD index, and / or DQLI score.

[0051] In an alternative description of the first configuration, a method for treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered by injection, and the method comprises administering at least one injection at a dose of at least about 20 mg of the antibody or fragment thereof. The antibody or fragment thereof is administered by subcutaneous injection. The antibody or fragment thereof may be administered at least twice, with at least one interval of 2 to 6 months. The antibody or fragment thereof is administered at least twice, with at least one interval of 6 months. The subject is a patient with chronic atopic dermatitis. After administration, the EASI score, vIGA-AD score, IGA-AD score, BSA score, SCORAD index, PO-SCORAD index, and / or DQLI score may be reduced by at least 10% compared to the corresponding baseline EASI score, vIGA-AD score, IGA-AD score, BSA score, SCORAD index, PO-SCORAD index, and / or DQLI score.

[0052] In an alternative description of the first configuration, a method for treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is a disease-modifying drug. The antibody or fragment thereof is administered by injection, optionally subcutaneous injection. Optionally, the method comprises administering at least one injection with a dose of at least about 20 mg of the antibody or fragment thereof. The antibody or fragment thereof may be administered at least twice, with at least one interval between two and six months. The antibody or fragment thereof is administered at least twice, with at least one interval between six months. The subject is a patient with chronic atopic dermatitis. The post-administration EASI score, vIGA-AD score, IGA-AD score, BSA score, SCORAD index, PO-SCORAD index and / or DQLI score may be reduced by at least 10% relative to the corresponding baseline EASI score, vIGA-AD score, IGA-AD score, BSA score, SCORAD index, PO-SCORAD index and / or DQLI score.

[0053] In an alternative description of the first configuration, a method for treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered at least twice, with at least one interval of 2 to 6 months between doses. The antibody or fragment thereof is administered at least twice, with at least one interval of 2 to 5.5 months between doses, at least one interval of 2 to 5 months between doses, at least one interval of 2 to 4.5 months between doses, or at least one interval of 2 to 4 months between doses. The antibody or fragment thereof is administered at least twice, with at least one interval of approximately 3 months between doses. The antibody or fragment thereof is administered by injection, optionally subcutaneous injection. The antibody or fragment thereof is a disease-modifying drug. Optionally, the method comprises administering at least one injection with a dose of at least about 20 mg of the antibody or fragment thereof. The subject may be a patient with chronic atopic dermatitis. The post-administration EASI score, vIGA-AD score, IGA-AD score, BSA score, SCORAD index, PO-SCORAD index and / or DQLI score may be reduced by at least 10% relative to the corresponding baseline EASI score, vIGA-AD score, IGA-AD score, BSA score, SCORAD index, PO-SCORAD index and / or DQLI score.

[0054] In an alternative description of the first configuration, a method for treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered at least twice, with at least one interval of 6 months between doses. The antibody or fragment thereof is administered at least twice, with at least one interval of 5.5 months, at least one interval of 5 months, at least one interval of 4.5 months, or at least one interval of 4 months between doses. The antibody or fragment thereof is administered at least twice, with at least one interval of approximately 3 months between doses. Any period expressed in months may alternatively be expressed in weeks; for example, in one embodiment, one month is equal to four weeks. The antibody or fragment thereof is administered by injection, optionally subcutaneous injection. The antibody or fragment thereof is a disease-modifying drug. Optionally, the method includes administering at least one injection with a dose of at least about 20 mg of the antibody or fragment thereof. The subject may be a patient with chronic atopic dermatitis. The post-administration EASI score, vIGA-AD score, IGA-AD score, BSA score, SCORAD index, PO-SCORAD index and / or DQLI score may be reduced by at least 10% relative to the corresponding baseline EASI score, vIGA-AD score, IGA-AD score, BSA score, SCORAD index, PO-SCORAD index and / or DQLI score.

[0055] In an alternative description of the first configuration, a method of treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the subject has chronic atopic dermatitis. The antibody or fragment thereof is administered by injection, optionally subcutaneous injection. The antibody or fragment thereof is a disease-modifying drug. Optionally, the method comprises administering at least one injection with a dose of at least about 20 mg of the antibody or fragment thereof. The antibody or fragment thereof may be administered at least twice, at least once every two to six months. The antibody or fragment thereof is administered at least twice, at least once every six months. The post-administration EASI score, vIGA-AD score, IGA-AD score, BSA score, SCORAD index, PO-SCORAD index and / or DQLI score may be reduced by at least 10% relative to the corresponding baseline EASI score, vIGA-AD score, IGA-AD score, BSA score, SCORAD index, PO-SCORAD index and / or DQLI score.

[0056] In an alternative description of the first configuration, a method of treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein after administration, the EASI score is reduced by at least 10% relative to the baseline EASI score. The post-administration EASI score may be reduced by at least 10% relative to the baseline EASI score at least 113 days to 15 days (optionally at least 113 days to 7 days or at least 113 days to 29 days) after administration of the anti-OX40L antibody or antigen-binding fragment thereof. The post-administration EASI score may be reduced by at least 10% relative to the baseline EASI score at least 169 days or at least 253 days to 15 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof. The post-administration EASI score may be reduced by at least 20% relative to the baseline EASI score at approximately 113 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof. The post-administration EASI score may be reduced by at least 15%, at least 20%, at least 30%, at least 40%, or at least 45% relative to the baseline EASI score approximately 113 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof. The antibody or fragment thereof is administered by injection, optionally by subcutaneous injection. The antibody or fragment thereof is a disease-modifying drug. Optionally, the method includes administering at least one injection with a dose of at least about 20 mg of the antibody or fragment thereof. The antibody or fragment thereof may be administered at least twice, with at least one interval of 2 to 6 months between doses. The antibody or fragment thereof is administered at least twice, with at least one interval of 6 months between doses. The subject is a patient with chronic atopic dermatitis. The post-administration vIGA-AD score, IGA-AD score, BSA score, SCORAD index, PO-SCORAD index and / or DQLI score may be reduced by at least 10% relative to the corresponding baseline vIGA-AD score, IGA-AD score, BSA score, SCORAD index, PO-SCORAD index and / or DQLI score.

[0057] In an alternative description of the first configuration, a method of treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein a post-administration vIGA-AD score is reduced by at least 10% relative to the baseline vIGA-AD score. The post-administration vIGA-AD score may be reduced by at least 10% relative to the baseline vIGA-AD score from at least 113 days to 15 days (optionally from at least 113 days to 7 days or from at least 113 days to 29 days) after administration of the anti-OX40L antibody or antigen-binding fragment thereof. The post-administration vIGA-AD score may be reduced by at least 10% relative to the baseline vIGA-AD score from at least 169 days or from at least 253 days to 15 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof. The post-administration vIGA-AD score may be reduced by at least 20% relative to the baseline vIGA-AD score approximately 113 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof. The post-administration vIGA-AD score may be reduced by at least 15%, at least 20%, at least 30%, at least 40%, or at least 45% relative to the baseline vIGA-AD score approximately 113 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof. The antibody or fragment thereof is administered by injection, optionally subcutaneous injection. The antibody or fragment thereof is a disease-modifying drug. Optionally, the method includes administering at least one injection with a dose of at least about 20 mg of the antibody or fragment thereof. The antibody or fragment thereof may be administered at least twice, with at least one interval of 2 to 6 months between doses. The antibody or fragment thereof is administered at least twice, with at least one interval of 6 months between doses. The subject is a patient with chronic atopic dermatitis. The post-administration EASI score, IGA-AD score, BSA score, SCORAD index, PO-SCORAD index and / or DQLI score may be reduced by at least 10% relative to the corresponding baseline EASI score, IGA-AD score, BSA score, SCORAD index, PO-SCORAD index and / or DQLI score.

[0058] In an alternative description of the first configuration, a method of treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein a post-administration IGA-AD score is reduced by at least 10% relative to the baseline IGA-AD score. The post-administration IGA-AD score may be reduced by at least 10% relative to the baseline IGA-AD score from at least 113 days to 15 days (optionally from at least 113 days to 7 days or from at least 113 days to 29 days) after administration of the anti-OX40L antibody or antigen-binding fragment thereof. The post-administration IGA-AD score may be reduced by at least 10% relative to the baseline IGA-AD score from at least 169 days or from at least 253 days to 15 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof. The post-administration IGA-AD score may be reduced by at least 20% relative to the baseline IGA-AD score at approximately 113 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof. The post-administration IGA-AD score may be reduced by at least 15%, at least 20%, at least 30%, at least 40%, or at least 45% relative to the baseline IGA-AD score approximately 113 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof. The antibody or fragment thereof is administered by injection, optionally subcutaneous injection. The antibody or fragment thereof is a disease-modifying drug. Optionally, the method includes administering at least one injection with a dose of at least about 20 mg of the antibody or fragment thereof. The antibody or fragment thereof is administered at least twice, with at least one interval of 2 to 6 months between doses. The antibody or fragment thereof is administered at least twice, with at least one interval of 6 months between doses. The subject is a patient with chronic atopic dermatitis. The post-administration EASI score, vIGA-AD score, BSA score, SCORAD index, PO-SCORAD index and / or DQLI score may be reduced by at least 10% relative to the corresponding baseline EASI score, vIGA-AD score, BSA score, SCORAD index, PO-SCORAD index and / or DQLI score.

[0059] In an alternative description of the first configuration, a method of treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein after administration, the BSA score is reduced by at least 10% relative to the baseline BSA score. The post-administration BSA score may be reduced by at least 10% relative to the baseline BSA score at least 113 days to 29 days (optionally at least 113 days to 7 days or at least 113 days to 15 days) after administration of the anti-OX40L antibody or antigen-binding fragment thereof. The post-administration BSA score may be reduced by at least 20% relative to the baseline BSA score at approximately 113 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof. The post-administration BSA score may be reduced by at least 30% or at least 35% relative to the baseline BSA score at approximately 113 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof. The antibody or fragment thereof is administered by injection, optionally subcutaneous injection. The antibody or fragment thereof is a disease-modifying drug. Optionally, the method includes administering at least one injection of at least about 20 mg of the antibody or fragment thereof. The antibody or fragment thereof may be administered at least twice, with at least one interval of 2 to 6 months between doses. The antibody or fragment thereof is administered at least twice, with at least one interval of 6 months between doses. The subject is a patient with chronic atopic dermatitis. After administration, the EASI score, vIGA-AD score, IGA-AD score, SCORAD index, PO-SCORAD index, and / or DQLI score may be reduced by at least 10% compared to the corresponding baseline EASI score, vIGA-AD score, IGA-AD score, SCORAD index, PO-SCORAD index, and / or DQLI score.

[0060] In an alternative description of the first configuration, a method of treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein after administration, the SCORAD index is reduced by at least 10% relative to the baseline SCORAD score. The post-administration SCORAD index may be reduced by at least 10% relative to the baseline SCORAD index at least 113 days to 29 days (optionally at least 113 days to 7 days or at least 113 days to 15 days) after administration of the anti-OX40L antibody or antigen-binding fragment thereof. The post-administration SCORAD index may be reduced by at least 20% relative to the baseline SCORAD index at approximately 113 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof. The post-administration SCORAD index may be reduced by at least 30% or at least 35% relative to the baseline SCORAD index at approximately 113 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof. The post-administration SCORAD index may be reduced by at least 45% or at least 60% relative to the baseline SCORAD index approximately 113 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof. The antibody or fragment thereof is administered by injection, optionally subcutaneous injection. The antibody or fragment thereof is a disease-modifying drug. Optionally, the method includes administering at least one injection with a dose of at least about 20 mg of the antibody or fragment thereof. The antibody or fragment thereof is administered at least twice, with at least one interval of 2 to 6 months between doses. The antibody or fragment thereof is administered at least twice, with at least one interval of 6 months between doses. The subject is a patient with chronic atopic dermatitis. The post-administration EASI score, vIGA-AD score, IGA-AD score, BSA score, PO-SCORAD index and / or DQLI score may be reduced by at least 10% relative to the corresponding baseline EASI score, vIGA-AD score, IGA-AD score, BSA score, PO-SCORAD index and / or DQLI score.

[0061] In an alternative description of the first configuration, a method of treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein after administration, the PO-SCORAD index is reduced by at least 10% relative to the baseline PO-SCORAD index. The post-administration PO-SCORAD index may be reduced by at least 10% relative to the baseline PO-SCORAD index from at least 113 days to 29 days (optionally from at least 113 days to 7 days or at least 113 days to 15 days) after administration of the anti-OX40L antibody or antigen-binding fragment thereof. The post-administration PO-SCORAD index may be reduced by at least 15% relative to the baseline PO-SCORAD index at approximately 113 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof. The post-administration PO-SCORAD index may be reduced by at least 20% or at least 30% relative to the baseline PO-SCORAD index approximately 113 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof. The post-administration PO-SCORAD index may be reduced by at least 40% or at least 50% relative to the baseline PO-SCORAD index approximately 113 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof. The antibody or fragment thereof is administered by injection, optionally subcutaneous injection. The antibody or fragment thereof is a disease-modifying drug. Optionally, the method includes administering at least one injection with a dose of at least about 20 mg of the antibody or fragment thereof. The antibody or fragment thereof may be administered at least twice, with at least one interval of 2 to 6 months between doses. The antibody or fragment thereof is administered at least twice, with at least one interval of 6 months between doses. The subject is a patient with chronic atopic dermatitis. The post-administration EASI score, vIGA-AD score, IGA-AD score, BSA score, SCORAD index and / or DQLI score may be reduced by at least 10% relative to the corresponding baseline EASI score, vIGA-AD score, IGA-AD score, BSA score, SCORAD index and / or DQLI score.

[0062] In an alternative description of the first configuration, a method of treating atopic dermatitis in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein after administration, the DQLI score is reduced by at least 10% relative to the baseline DQLI score. The post-administration DQLI score may be reduced by at least 10% relative to the baseline DQLI score at least 113 days to 85 days (optionally at least 113 days to 7 days or at least 113 days to 15 days) after administration of the anti-OX40L antibody or antigen-binding fragment thereof. The post-administration DQLI score may be reduced by at least 20% relative to the baseline DQLI score at approximately 113 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof. The post-administration DQLI score may be reduced by at least 30% or at least 35% relative to the baseline DQLI score at approximately 113 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof. The antibody or fragment thereof is administered by injection, optionally subcutaneous injection. The antibody or fragment thereof is a disease-modifying drug. Optionally, the method includes administering at least one injection with a dose of at least about 20 mg of the antibody or fragment thereof. The antibody or fragment thereof may be administered at least twice, with at least one interval of 2 to 6 months. The antibody or fragment thereof is administered at least twice, with at least one interval of 6 months. The subject is a patient with chronic atopic dermatitis. The EASI score, vIGA-AD score, IGA-AD score, BSA score, SCORAD index, and / or PO-SCORAD index after administration may be reduced by at least 10% compared to the corresponding baseline EASI score, vIGA-AD score, IGA-AD score, BSA score, SCORAD index, and / or PO-SCORAD index.

[0063] Any feature described in connection with one description of the first configuration is expressly contemplated in combination with the feature of any other description of the first configuration. Any one description of the first configuration may be read in combination with any other part of this disclosure unless otherwise clear from the context. Any optional feature described in any part of this disclosure in connection with any one description of the first configuration or any alternative description of the first configuration may be read in combination with any other part of this disclosure unless otherwise clear from the context.

[0064] In a further aspect, a method of treating an inflammatory disease or disorder in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered by injection.

[0065] In a further aspect, a method of treating an immune-mediated disease or disorder in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered by injection.

[0066] In a further aspect, a method of treating an inflammatory skin disease or disorder in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered by injection.

[0067] In a further aspect, an anti-OX40L antibody or antigen-binding fragment thereof is provided for use in a method for treating an inflammatory disease or disorder in a human subject, the method comprising administering a therapeutically effective amount of the anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered by injection.

[0068] In a further aspect, an anti-OX40L antibody or antigen-binding fragment thereof is provided for use in a method of treating an immune-mediated disease or disorder in a human subject, the method comprising administering a therapeutically effective amount of the anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered by injection.

[0069] In a further aspect, an anti-OX40L antibody or antigen-binding fragment thereof is provided for use in a method for treating an inflammatory skin disease or disorder in a human subject, the method comprising administering a therapeutically effective amount of the anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered by injection.

[0070] In a further aspect, a method is provided for treating an inflammatory disease, inflammatory disorder, immune-mediated disease, immune-mediated disorder, inflammatory skin disease or inflammatory skin disorder in a human subject, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered once every four weeks during an induction phase and once every twelve weeks during a maintenance phase.

[0071] In a further aspect, a method of treating an inflammatory disease, inflammatory disorder, immune-mediated disease, immune-mediated disorder, inflammatory skin disease or inflammatory skin disorder in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof by subcutaneous injection.

[0072] In a further configuration, a method of treating an inflammatory disease, inflammatory disorder, immune-mediated disease, immune-mediated disorder, inflammatory skin disease or inflammatory skin disorder in a human subject is provided, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered by subcutaneous injection once every four weeks during an induction phase and once every twelve weeks during a maintenance phase.

[0073] In a further aspect, an anti-OX40L antibody or antigen-binding fragment thereof is provided for use in a method of treating an inflammatory disease, inflammatory disorder, immune-mediated disease, immune-mediated disorder, inflammatory skin disease or inflammatory skin disorder in a human subject, the method comprising administering a therapeutically effective amount of the anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered by subcutaneous injection.

[0074] In a further aspect, an anti-OX40L antibody or antigen-binding fragment thereof is provided for use in a method of treating an inflammatory disease, inflammatory disorder, immune-mediated disease, immune-mediated disorder, inflammatory skin disease or inflammatory skin disorder in a human subject, the method comprising administering a therapeutically effective amount of the anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered by subcutaneous injection once every four weeks during an induction phase and once every twelve weeks during a maintenance phase.

[0075] In a further configuration, there is provided an embodiment as described above that comprises administering a therapeutically effective amount of an OX40L antagonist antibody or antigen-binding fragment thereof.

[0076] Dosage and blood serum concentration The dose is 20 mg to 1000 mg. The dose is 20 mg to 600 mg. The dose is 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 dose is up to 500 mg, up to 250 mg, or up to 150 mg. The dose is 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 dose is at least 50 mg, at least 120 mg, or at least 150 mg. The dose is selected from the group consisting of 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. The dose is selected from the group consisting of 60 mg to 500 mg, 100 mg to 300 mg, or 125 mg to 150 mg.

[0077] The doses are 62.5 mg, 125 mg, 150 mg, 250 mg, or 500 mg. The doses are 125 mg or 150 mg. The dose is 125 mg. The dose is 150 mg. The dose is 62.5 mg. The dose is 250 mg. The dose is 500 mg.

[0078] Doses are up to 0.6mg / kg, up to 0.7mg / kg, up to 0.8mg / kg, up to 0.9mg / kg, up to 1mg / kg, up to 1.1mg / kg, up to 1.2mg / kg, up to 1.3mg / kg, up to 1.4mg / kg, up to 1.5mg / kg, up to 1.6mg / kg, up to 1.7mg / kg, up to 1.8mg / kg, up to 1.9mg / kg, up to 2mg / kg, up to 2.1mg / kg, and up to 2.2mg. g / kg, up to 2.3 mg / kg, up to 2.4 mg / kg, up to 2.5 mg / kg, up to 2.6 mg / kg, up to 2.7 mg / kg, up to 2.8 mg / kg, up to 2.9 mg / kg, up to 3 mg / kg, up to 4 mg / kg, up to 5 mg / kg, up to 6 mg / kg, up to 7 mg / kg, up to 8 mg / kg, up to 9 mg / kg, up to 10 mg / kg, up to 11 mg / kg or up to 12 mg / kg. Doses are up to 6 mg / kg or up to 3 mg / kg.

[0079] Doses may be at least 0.45mg / kg, at least 0.5mg / kg, at least 0.6mg / kg, at least 0.7mg / kg, at least 0.8mg / kg, at least 0.9mg / kg, at least 1mg / kg, at least 1.1mg / kg, at least 1.2mg / kg, at least 1.3mg / kg, at least 1.4mg / kg, at least 1.5mg / kg, at least 1.6mg / kg, at least 1.7mg / kg, at least 1.8mg / kg, at least 1.9mg / kg, at least 2mg / kg, at least 2.1mg / kg g / 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, at least 10 mg / kg, at least 11 mg / kg, or at least 12 mg / kg. Doses are at least 0.45 mg / kg. Doses are at least 0.7 mg / kg or at least 1.4 mg / kg.

[0080] The dose is selected from the group consisting of 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.

[0081] The dose is selected from the group consisting of 0.6mg / kg to 11mg / kg; 0.7mg / kg to 10mg / kg; 0.8mg / kg to 9mg / kg; 0.9mg / kg to 8mg / kg; 1mg / kg to 7mg / kg; 1.1mg / kg to 6mg / kg; 1.2mg / kg to 5mg / kg; 1.3mg / kg to 4mg / kg; 1.4mg / kg to 3mg / kg; 1.5mg / kg to 2.9mg / kg; 1.6mg / kg to 2.8mg / kg; 1.7mg / kg to 2.7mg / kg; 1.8mg / kg to 2.6mg / kg; 1.9mg / kg to 2.5mg / kg; 2mg / kg to 2.4mg / kg; and 2.1mg / kg to 2.3mg / kg.

[0082] The dosage is 0.7mg / kg to 6mg / kg. The dosage is 1.4mg / kg to 3mg / kg.

[0083] Preclinical data demonstrated that an IC90 of 0.405 μg / mL was required for inhibition of OX40L-OX40 interaction, an IC90 of 1.09 μg / mL was required for inhibition of soluble OX40L-induced IL-2 release from primary human T cells, and an IC90 of 1.5 μg / mL was required for evaluation of IL-2 reduction in a T cell allogeneic mixed lymphocyte reaction assay. Therefore, preclinical data suggest that the minimum concentration required at the site of action (skin) is in the range of 0.405-1.5 μg / mL. The dose can be any appropriate dose to deliver at least approximately 0.4-1.5 μg / mL to the skin.

[0084] The method can include administering at least two injections of the antibody or fragment thereof. The minimum blood serum concentration (C) reached by the antibody or fragment thereof after administration of the first injection and before administration of the second injection can be determined. min ) can be at least about 2.5 μg / ml.

[0085] The method can include administering at least three injections of the antibody or fragment thereof. The minimum blood serum concentration (C) reached by the antibody or fragment thereof after administration of the second injection and before administration of the third injection is determined. min The minimum blood serum concentration (C) achieved by the antibody or fragment thereof after administration of the first injection and before administration of the third injection may be at least about 2.5 μg / ml. min ) can be at least about 2.5 μg / ml.

[0086] The method can include administering at least four injections of the antibody or fragment thereof. The minimum blood serum concentration (C) achieved by the antibody or fragment thereof after administration of the third injection and before administration of the fourth injection can be determined. min ) can be at least about 2.5 μg / ml. The minimum blood serum concentration (C) achieved by the antibody or fragment thereof after administration of the first injection and before administration of the fourth injection can be at least about 2.5 μg / ml. minThe minimum blood serum concentration (C) achieved by the antibody or fragment thereof after administration of the second injection and before administration of the fourth injection may be at least about 2.5 μg / ml. min ) can be at least about 2.5 μg / ml.

[0087] C in serum between any two injections min The serum C between any two injections is 2.5 μg / ml to 600 μg / ml. min The serum C between any two injections is 2.5 μg / ml to 375 μg / ml. min The serum C between any two injections is 4 μg / ml to 600 μg / ml. minis at least 2.5 μg / ml, 2.6 μg / ml, at least 2.7 μg / ml, at least 2.8 μg / ml, at least 2.9 μg / ml, at least 3 μg / ml, at least 3.1 μg / ml, at least 3.2 μg / ml, at least 3.3 μg / ml, at least 3.4 μg / ml, at least 3.5 μg / ml, at least 3.6 μg / ml, at least 3.7 μg / ml, at least 3.8 μg / ml, at least 3.9 μg / ml, at least 4 μg / ml , at least 4.1μg / ml, at least 4.2μg / ml, at least 4.3μg / ml, at least 4.4μg / ml, at least 4.5μg / ml, at least 4.6μg / ml, at least 4.7μg / ml, at least 4.8μg / ml, at least 4.9μg / ml, at least 5μg / ml, at least 5.1μg / ml, at least 5.2μg / ml, at least 5.3μg / ml, at least 5.4μg / ml, at least 5.5μg / ml, at least 5. 6μg / ml, at least 5.7μg / ml, at least 5.8μg / ml, at least 5.9μg / ml, at least 6μg / ml, at least 6.5μg / ml, at least 7μg / ml, at least 7.5μg / ml, at least 8μg / ml, at least 8.5μg / ml, at least 9μg / ml, at least 9.5μg / ml, at least 10μg / ml, at least 11μg / ml, at least 12μg / ml, at least 13μg / ml, at least 14μg / ml 1, at least 15 μg / ml, at least 16 μg / ml, at least 17 μg / ml, at least 18 μg / ml, at least 19 μg / ml, at least 20 μg / ml, at least 25 μg / ml, at least 30 μg / ml, at least 35 μg / ml, at least 40 μg / ml, at least 50 μg / ml, at least 60 μg / ml, at least 70 μg / ml, at least 80 μg / ml, at least 90 μg / ml, or at least 100 μg / ml. min is at least about 4 μg / ml, at least about 5 μg / ml, or at least about 20 μg / ml. minis at least about 4 μg / ml. The C in serum between any two injections min is at least about 5 μg / ml. The C in serum between any two injections min is at least about 20 μg / ml. The C in serum between any two injections min is up to 600μg / ml, up to 500μg / ml, up to 450μg / ml, up to 400μg / ml, up to 350μg / ml, up to 300μg / ml, up to 275μg / ml, up to 250μg / ml, up to 225μg / ml, up to 200μg / ml, up to 175μg / ml, up to 150μg / ml, up to 125μg / ml, up to 100μg / ml, up to 90μg / ml, up to 80μg / ml, up to 70μg / ml, up 60 μg / ml, max 50 μg / ml, max 45 μg / ml, max 40 μg / ml, max 35 μg / ml, max 30 μg / ml, max 25 μg / ml, max 23 μg / ml, max 20 μg / ml, max 15 μg / ml, max 10 μg / ml, max 9 μg / ml, max 8 μg / ml, max 7 μg / ml, max 6 μg / ml, max 5 μg / ml, max 4 μg / ml, max 3 μg / ml, or max 2.5 μg / ml. Serum C min is at most about 50 μg / ml, at most about 25 μg / ml, at most about 15 μg / ml, or at most about 7 μg / ml. min The maximum concentration of C in serum is approximately 50 μg / ml. min The maximum C in serum is approximately 25 μg / ml. min The maximum C in serum is approximately 15 μg / ml. min The serum C between any two injections is approximately 7 μg / ml. minis selected from the group consisting of at least 3 μg / ml to a maximum of 350 μg / ml; at least 10 μg / ml to a maximum of 300 μg / ml; at least 12.5 μg / ml to a maximum of 250 μg / ml; at least 15 μg / ml to a maximum of 250 μg / ml; at least 18 μg / ml to a maximum of 240 μg / ml; at least 20 μg / ml to a maximum of 220 μg / ml; at least 25 μg / ml to a maximum of 190 μg / ml; at least 30 μg / ml to a maximum of 150 μg / ml; at least 35 μg / ml to a maximum of 125 μg / ml; at least 40 μg / ml to a maximum of 90 μg / ml; and at least 50 μg / ml to a maximum of 65 μg / ml.

[0088] C min The above values ​​of C are obtained when measured in blood serum. min The value is Organization C min Shah & Betts (2013) mAbs 5:2, pp. 297-305 calculated that for mAbs, the distribution in the skin is approximately 16% of the systemic concentration. Therefore, serum C min A value of 2.5 μg / ml indicates skin C min A serum C value of 0.4 μg / ml was obtained. min The value of 375 μg / ml is skin C min This yields a value of 60 μg / mL. Alternative conversions based on other distribution values ​​assumed in the field are possible, where a range of approximately 10% to 15% of the total body concentration is often distributed to the skin. Thus, as a further example, assuming that distribution to the skin is 10% of the total body concentration, a serum concentration level of 4 μg / mL would yield a skin C min The value was 0.4 μg / ml, and serum C min If the value is 600 μg / ml, skin C min The value is 60 μg / ml.

[0089] The maximum blood serum concentration (C) achieved by the antibody or fragment thereof after administration of an injection and before administration of subsequent injections max) is at least about 1.5 μg / ml, at least about 2 μg / ml, at least about 5 μg / ml, at least about 10 μg / ml, at least about 15 μg / ml, at least about 20 μg / ml, at least about 23 μg / ml, at least about 30 μg / ml, at least about 40 μg / ml, at least about 45 μg / ml, at least about 50 μg / ml, at least about 60 μg / ml, at least about 70 μg / ml, at least about 80 μg / ml, at least about 90 μg / ml, at least about 100 μg / ml, at least about 150 μg / ml, at least about 200 μg / ml, at least about 300 μg / ml, or at least about 550 μg / ml. The maximum blood serum concentration (C) achieved by the antibody or fragment thereof after administration of an injection and before administration of a subsequent injection is max ) is up to about 550 μg / ml, up to about 400 μg / ml, up to about 300 μg / ml, up to about 200 μg / ml, up to about 150 μg / ml, up to about 100 μg / ml, up to about 90 μg / ml, up to about 80 μg / ml, up to about 70 μg / ml, up to about 60 μg / ml, up to about 50 μg / ml, up to about 45 μg / ml, up to about 40 μg / ml, up to about 35 μg / ml, up to about 30 μg / ml, up to about 25 μg / ml, up to about 23 μg / ml, up to about 20 μg / ml, up to about 15 μg / ml, or up to about 10 μg / ml.

[0090] In some embodiments, the injection is intravenous or subcutaneous. In some embodiments, the injection is subcutaneous and the dose is 62.5 mg, 125 mg, 150 mg, 250 mg, or 500 mg. In some embodiments, the dose is 125 mg or 150 mg. In other embodiments, the dose is 125 mg. In yet other embodiments, the dose is 150 mg. In some embodiments, the dose is 62.5 mg. In some embodiments, the dose is 250 mg. The dose is 500 mg.

[0091] In some embodiments, the injection is subcutaneous and the maximum blood serum concentration (C) reached by the antibody or fragment thereof after administration of the injection and before administration of any subsequent injections is measured. max) is 1.5μg / ml~275μg / ml;2μg / ml~200μg / ml;5μg / ml~150μg / ml;5μg / ml~100μg / ml; 10 μg / ml to 80 μg / ml; 10 μg / ml to 25 μg / ml; 25 μg / ml to 50 μg / ml; or 35 μg / ml to 75 μg / ml. C max is 10μg / ml to 80μg / ml. max is 10μg / ml to 25μg / ml. max is 25μg / ml to 50μg / ml. max is 35μg / ml to 75μg / ml.

[0092] In some embodiments, the injection is intravenous and the maximum blood serum concentration (C) reached by the antibody or fragment thereof after administration of the injection and before administration of any subsequent injections is measured. max ) is 6μg / ml~550μg / ml;15μg / ml~400μg / ml;20μg / ml~300μg / ml;30μg / ml~200μg / ml;3 0 μg / ml to 90 μg / ml; 40 μg / ml to 105 μg / ml; 95 μg / ml to 150 μg / ml; or 95 μg / ml to 200 μg / ml. C max is 30μg / ml to 200μg / ml. max is 30μg / ml to 90μg / ml. max is 40μg / ml to 105μg / ml. max is 95μg / ml to 150μg / ml. max is 95μg / ml to 200μg / ml.

[0093] The method can be carried out using any of the C min values ​​and any C disclosed herein max maintains a blood serum concentration of the antibody or its fragment below the C value min The value is C max For example, the method may: Maintain blood serum concentrations in the range of approximately 4 to approximately 15 μg / mL (tissue concentrations of 0.4 to 1.5 μg / mL or greater, assuming tissue / skin penetration of 10 to 15%). Maintain blood serum concentrations in the range of approximately 20 to approximately 45 μg / mL (tissue concentrations of 2 to 6.7 μg / mL or greater, assuming tissue / skin penetration of 10 to 15%). Maintain blood serum concentrations in the range of approximately 5 to approximately 23 μg / mL (tissue concentrations of 0.5 to 3.5 μg / mL or greater, assuming tissue / skin penetration of 10 to 15%). Maintain blood serum concentrations at or below 10 μg / mL.

[0094] The method can maintain a therapeutically effective concentration of the antibody or fragment thereof after the last administration. For example, the therapeutically effective concentration is maintained for at least 1 month, at least 2 months, or at least 3 months after the last administration. The therapeutically effective concentration can be maintained for any of the Cs disclosed herein. min and / or any C value disclosed herein. max is equal to or less than the value C min The value is C max The method can maintain a serum concentration of, for example, about 3 to about 12 μg / mL; about 5 to about 12 μg / mL; or about 3 to about 5 μg / mL, optionally for at least 3 months after the last administration.

[0095] Area under the serum concentration-time curve (AUC) after the first injection (AUC extrapolated to infinity [AUC 0-inf ]) is at least approximately 100,000 ng / ml * day, 500,000ng / ml * daily, at least approximately 600,000ng / ml * daily, at least approximately 700,000ng / ml * daily, at least approximately 800,000ng / ml * daily, at least approximately 900,000ng / ml * daily, at least approximately 1,000,000 ng / ml * daily, at least approximately 1,100,000 ng / ml * daily, at least approximately 1,300,000 ng / ml *daily, at least approximately 1,500,000 ng / ml * daily, at least approximately 1,700,000 ng / ml * daily, at least approximately 2,000,000 ng / ml * daily, at least approximately 2,500,000 ng / ml * daily, at least approximately 3,000,000 ng / ml * daily, at least approximately 3,300,000 ng / ml * day or at least approximately 3,500,000 ng / ml * day, e.g., at least about 1,000,000 ng / ml * day or at least approximately 3,000,000ng / ml * It is the day.

[0096] Area under the serum concentration-time curve (AUC) after the first injection (AUC extrapolated to infinity [AUC 0-inf ]) up to approximately 4,500,000ng / ml * daily, up to approximately 4,200,000ng / ml * daily, up to approximately 4,000,000ng / ml * daily, up to approximately 3,800,000ng / ml * daily, up to approximately 3,600,000ng / ml * daily, up to approximately 3,400,000ng / ml * daily, up to approximately 3,200,000ng / ml * daily, up to approximately 3,000,000ng / ml * daily, up to approximately 2,800,000ng / ml * daily, up to approximately 2,500,000ng / ml * daily, up to approximately 2,000,000ng / ml * daily, up to approximately 1,800,000ng / ml * daily, up to approximately 1,500,000ng / ml * daily, up to approximately 1,200,000ng / ml * day or up to approximately 1,000,000ng / ml * day, for example, up to approximately 1,500,000 ng / ml *day or up to approximately 3,800,000ng / ml * It is the day.

[0097] Area under the serum concentration-time curve (AUC) after the first injection (AUC extrapolated to infinity [AUC 0-inf ]) is approximately 100,000ng / ml * ~approximately 4,500,000ng / ml * day or approximately 1,000,000ng / ml * ~approximately 3,800,000ng / ml * The area under the serum concentration-time curve (AUC) after the first injection (AUC extrapolated to infinity [AUC 0-inf ]) is approximately 900,000ng / ml * ~approximately 1,400,000ng / ml * day or approximately 2,900,000ng / ml * ~approximately 3,800,000ng / ml * It is the day.

[0098] Implementation and Maintenance The method may include an induction phase and a maintenance phase.

[0099] The induction phase can include administering one or more induction phase injections of an antibody or fragment thereof at an induction dose of between 20 and 500 mg, 20 mg and 300 mg, 50 mg and 300 mg, 100 mg and 300 mg, or 150 mg and 300 mg. The induction dose can be between 200 mg and 300 mg or between 225 mg and 275 mg. The induction dose can be about 500 mg, 250 mg, about 125 mg, or about 62.5 mg. The induction dose can be about 250 mg.

[0100] The induction phase can be at least 2 weeks, at least 4 weeks, at least 8 weeks, at least 16 weeks, or at least 24 weeks in duration. The induction phase can include administering two or more induction phase injections of the antibody or fragment thereof.

[0101] Each induction phase injection can be administered at least 2 weeks, at least 4 weeks, at least 8 weeks, at least 16 weeks, or at least 24 weeks apart. Each induction phase injection can be administered 4 weeks apart.

[0102] Each induction phase injection can contain the same mass of antibody or fragment thereof as each other induction phase injection. The dose of each induction phase injection can be the same.

[0103] Alternatively, one or more induction phase injections may have a different mass of antibody or fragment thereof than one or more or all of the other induction phase injections. The dose of each induction phase injection may not be the same. The first induction phase injection may be a loading dose.

[0104] The loading dose may contain up to three times the mass of the antibody or fragment thereof for each subsequent induction phase injection. The loading dose may contain more than two times and up to three times the mass of the antibody or fragment thereof for each subsequent induction phase injection. The loading dose may contain up to two times the mass of the antibody or fragment thereof for each subsequent induction dose. The loading dose may contain up to 1.5 times the mass of the antibody or fragment thereof for each subsequent induction dose.

[0105] The loading dose can be between 100 and 600 mg, between 150 and 550 mg, or between 200 and 500 mg. The loading dose can be about 500 mg, about 250 mg, or about 125 mg. The loading dose can be about 500 mg.

[0106] The induction phase can include administering two or more induction phase injections of the antibody or fragment thereof. The second induction phase injection can be administered 2 to 16 weeks after the first induction phase injection, 3 to 14 weeks after the first induction phase injection, or 4 to 12 weeks after the first induction phase injection. The second induction phase injection can be administered 2 to 14 weeks after the first induction phase injection, 2 to 12 weeks after the first induction phase injection, 2 to 10 weeks after the first induction phase injection, 2 to 8 weeks after the first induction phase injection, 2 to 7 weeks after the first induction phase injection, or 2 to 6 weeks after the first induction phase injection. The second induction phase injection can be administered 3 to 13 weeks after the first induction phase injection, 5 to 11 weeks after the first induction phase injection, 6 to 10 weeks after the first induction phase injection, or 7 to 9 weeks after the first induction phase injection. The second induction phase injection can be administered 4 to 8 weeks after the first induction phase injection. The second induction phase injection can be administered about 4 weeks or about 8 weeks after the first induction phase injection. The second induction phase injection can be administered about 4 weeks after the first induction phase injection.

[0107] The induction phase can include administering three or more induction phase injections of the antibody or fragment thereof. The third induction phase injection can be administered 2 to 16 weeks after the second induction phase injection, 3 to 14 weeks after the second induction phase injection, or 4 to 12 weeks after the second induction phase injection. The third induction phase injection can be administered 2 to 14 weeks after the second induction phase injection, 2 to 12 weeks after the second induction phase injection, 2 to 10 weeks after the second induction phase injection, 2 to 8 weeks after the second induction phase injection, 2 to 7 weeks after the second induction phase injection, or 2 to 6 weeks after the second induction phase injection. The third induction phase injection can be administered 3 to 13 weeks after the second induction phase injection, 5 to 11 weeks after the second induction phase injection, 6 to 10 weeks after the second induction phase injection, or 7 to 9 weeks after the second induction phase injection. The third induction phase injection can be administered 4 to 8 weeks after the second induction phase injection. The third induction phase injection can be administered about 4 weeks or about 8 weeks after the second induction phase injection. The third induction phase injection can be administered about 4 weeks after the second induction phase injection. The interval between the first and second induction phase injections can be the same as the interval between the second and third induction phase injections.

[0108] Each induction phase injection may contain the same mass of antibody or fragment thereof as each of the other induction phase injections, and / or each interval between induction phase injections may have the same duration as each of the other intervals between induction phase injections. Each induction phase injection may therefore have the same dose. For example, a 250 mg dose may be administered per induction phase injection. The entire induction phase may have a dosing interval of, for example, 4 weeks. The induction phase may therefore include administering a 250 mg dose every 4 weeks. Alternatively, the induction phase may include administering a 125 mg dose every 4 weeks. Alternatively, the induction phase may include administering a 62.5 mg dose every 4 weeks. For example, a loading dose may be administered, so that a fixed dosing interval is used rather than a fixed dose for all induction phase injections. The induction phase may therefore include administering a 500 mg loading dose, followed by a 250 mg dose 4 weeks later, with an additional 250 mg dose administered every 4 weeks throughout the induction phase. Any and all combinations of doses and dose intervals and types of injection (eg, subcutaneous) described herein are expressly contemplated.

[0109] The maintenance phase may involve administering one or more maintenance injections of the antibody or fragment thereof at a maintenance dose of between 20 mg and 300 mg, between 50 mg and 300 mg, between 100 mg and 300 mg, or between 150 mg and 300 mg. The maintenance dose may be between 200 mg and 300 mg or between 225 mg and 275 mg. The maintenance dose may be about 500 mg, 250 mg, about 125 mg, or about 62.5 mg. The maintenance dose may be about 250 mg.

[0110] The maintenance phase can be at least 2 weeks, at least 4 weeks, at least 8 weeks, at least 16 weeks, at least 24 weeks, at least 32 weeks, at least 40 weeks, at least 52 weeks or at least 100 weeks.The duration of the maintenance phase can be any suitable length to achieve clinical purpose, and therefore can include any suitable number of maintenance phase injections.The duration of the maintenance phase can therefore be determined by a clinician.The maintenance period can last as long as the patient and clinician agree, as long as the patient benefits from this maintenance treatment or does not experience adverse events that require treatment to be discontinued.For some subjects, the maintenance phase can be indefinite.

[0111] The maintenance phase can include administering two or more maintenance injections of the antibody or fragment thereof, each of which can be administered at least 2 weeks, at least 4 weeks, at least 8 weeks, at least 16 weeks, at least 24 weeks, at least 32 weeks, at least 40 weeks, or at least 52 weeks apart.

[0112] Each maintenance phase injection may contain the same mass of antibody or fragment thereof as each other maintenance phase injection. The dose of antibody or fragment thereof used in the induction phase may be maintained throughout the maintenance phase, i.e., the induction phase dose (excluding any loading dose) may be the same as the maintenance phase dose. However, the dosing interval during the maintenance phase may be longer than the dosing interval during the induction phase. This may be because, once the therapeutic effect is initiated, maintenance of the therapeutic effect may be possible with a lower tissue concentration of the antibody or fragment thereof. Although a similar goal can be achieved by reducing the induction phase dose during the maintenance phase while maintaining the induction phase dosing interval, it may be clinically preferable to reduce the number of injections during the maintenance phase rather than the dose per injection.

[0113] The second maintenance injection can be administered 2 to 16 weeks after the first maintenance injection, 3 to 14 weeks after the first maintenance injection, or 4 to 12 weeks after the first maintenance injection. The second maintenance injection can be administered 2 to 14 weeks after the first maintenance injection, 2 to 12 weeks after the first maintenance injection, 2 to 10 weeks after the first maintenance injection, 2 to 8 weeks after the first maintenance injection, 2 to 7 weeks after the first maintenance injection, or 2 to 6 weeks after the first maintenance injection. The second maintenance injection can be administered 3 to 13 weeks after the first maintenance injection, 5 to 11 weeks after the first maintenance injection, 6 to 10 weeks after the first maintenance injection, or 7 to 9 weeks after the first maintenance injection. The second maintenance injection can be administered 4 to 8 weeks after the first maintenance injection. The second maintenance injection can be administered about 4 weeks or about 8 weeks after the first maintenance injection. The second maintenance injection can be administered about 4 weeks after the first maintenance injection.

[0114] The maintenance phase can include administering three or more maintenance injections of the antibody or fragment thereof. The third maintenance injection can be administered 2 to 16 weeks after the second maintenance injection, 3 to 14 weeks after the second maintenance injection, or 4 to 12 weeks after the second maintenance injection. The third maintenance injection can be administered 2 to 14 weeks after the second maintenance injection, 2 to 12 weeks after the second maintenance injection, 2 to 10 weeks after the second maintenance injection, 2 to 8 weeks after the second maintenance injection, 2 to 7 weeks after the second maintenance injection, or 2 to 6 weeks after the second maintenance injection. The third maintenance injection can be administered 3 to 13 weeks after the second maintenance injection, 5 to 11 weeks after the second maintenance injection, 6 to 10 weeks after the second maintenance injection, or 7 to 9 weeks after the second maintenance injection. The third maintenance injection can be administered 4 to 8 weeks after the second maintenance injection. The third maintenance injection can be administered about 4 weeks or about 8 weeks after the second maintenance injection.

[0115] The interval between the first and second maintenance injections may have the same duration as the interval between the second and third maintenance injections.

[0116] Each maintenance phase injection may contain the same mass of antibody or fragment thereof as each of the other maintenance phase injections, and / or each interval between maintenance phase injections may have the same duration as each of the other intervals between maintenance phase injections. Each maintenance phase injection may therefore have the same dose. For example, a 250 mg dose may be administered per maintenance phase injection. The entire maintenance phase may have, for example, a 16-week dosing interval. The maintenance phase may therefore include administering a 250 mg dose every 16 weeks. Alternatively, the induction phase may include administering a 125 mg dose every 16 weeks. Alternatively, the induction phase may include administering a 62.5 mg dose every 16 weeks. For further example, a 250 mg dose may be administered per maintenance phase injection. The entire maintenance phase may have, for example, a one-week dosing interval. The maintenance phase may therefore include administering a 250 mg dose every 12 weeks. Alternatively, the induction phase may include administering a 125 mg dose every 12 weeks. Alternatively, the induction phase may include administering a 62.5 mg dose every 12 weeks. Any and all combinations of doses and dose intervals and types of injection (eg, subcutaneous) described herein are expressly contemplated.

[0117] The interval between two or more maintenance phase injections may be equal to or longer than the interval between two or more induction phase injections. However, as mentioned above, the dosing interval during the maintenance phase may be longer than the dosing interval during the induction phase. If a fixed dosing interval is used during the induction phase and a fixed dosing interval is used during the maintenance phase, this may be a direct comparison of the intervals. For example, if the induction phase dosing interval is 4 weeks (Q4W) and the maintenance phase dosing interval is 4 weeks (Q4W), the interval between the induction phase injections will be equal to the interval between the maintenance phase injections. If the induction phase dosing interval is 4 weeks (Q4W) and the maintenance phase dosing interval is 12 weeks (Q12W), the interval between the maintenance phase injections will be longer than the interval between the maintenance phase injections. The comparison between the dosing interval during the maintenance phase and the dosing interval during the induction phase can instead be calculated as the average (mean, median, or mode) of all intervals within the induction and maintenance phases, respectively. Alternatively, the comparison between the dosing interval during the maintenance phase and the dosing interval during the induction phase can be calculated by comparing specific examples of dosing intervals as described further below.

[0118] The interval between the first and second maintenance phase injections can be equal to or longer than the interval between the two or more induction phase injections. The interval between the two or more induction phase injections can be about 2 weeks, about 4 weeks, or about 8 weeks, and the interval between the two or more maintenance phase injections can be about 12 weeks or about 16 weeks. The interval between the two or more induction phase injections can be about 4 weeks or about 8 weeks, and the interval between the two or more maintenance phase injections can be about 12 weeks. The interval between the two or more induction phase injections can be about 4 weeks or about 8 weeks, and the interval between the two or more maintenance phase injections can be about 16 weeks. The interval between the two or more induction phase injections can be about 4 weeks, and the interval between the two or more maintenance phase injections can be about 16 weeks. The interval between the two or more induction phase injections can be about 4 weeks, and the interval between the two or more maintenance phase injections can be about 12 weeks. The interval between two or more induction phase injections may be about 4 weeks, and the interval between two or more maintenance phase injections may be about 4 weeks. The interval between two or more induction phase injections may be about 8 weeks, and the interval between two or more maintenance phase injections may be about 8 weeks. The interval between two or more induction phase injections may be about 2 weeks, and the interval between two or more maintenance phase injections may be about 8 weeks.

[0119] The intervals between the three or more induction injections can be constant, or the intervals between the three or more maintenance injections can vary.

[0120] The combined duration of the induction and maintenance phases can be at least 52 weeks. The combined duration of the induction and maintenance phases can be any duration achieved by adding any duration of the induction phase described herein with any duration of the maintenance phase described herein. Since the maintenance phase can be indefinite, the combined duration of the induction and maintenance phases can be indefinite.

[0121] The target, (a) clinical response, and / or (b) Time from administration of the first induction injection Based on this, the patient can transition from the induction phase to the maintenance phase.

[0122] Clinical response can be defined by any post-administration score or index described herein. Clinical response may be achieved by achieving EASI50, EASI75, EASI90 or EASI100. Clinical response may be achieved by achieving a reduction in IGA-AD0 / 1 and / or at least 2 IGA-AD points. Clinical response may be achieved by achieving a reduction in NRS points of at least 3 or at least 4. Clinical response can be determined at any clinically appropriate time point, for example, 16 weeks, 20 weeks or 24 weeks after the administration of the first loading phase injection.

[0123] The transition from the induction phase to the maintenance phase can occur 16 weeks or more after administration of the first induction phase injection. The transition from the induction phase to the maintenance phase can occur 24 weeks or more after administration of the first induction phase injection. The transition from the induction phase to the maintenance phase can occur up to one year after administration of the first induction phase injection. The transition from the induction phase to the maintenance phase can occur 16 to 24 weeks after administration of the first induction phase injection.

[0124] In some cases, the transition from induction phase to maintenance phase can be based on the clinical response determined during induction phase.This may occur, for example, when it takes some time to analyze data on disease severity.Therefore, there may be a delay between collecting data that can determine clinical response and transferring subjects from induction phase to maintenance phase.Clinical response may be evaluated, for example, by collecting data on disease severity at 16 weeks, and lead to a later transition from induction phase to maintenance phase if clinical response is positive, for example, at 24 weeks after the administration of the first induction phase injection.The decision to transition from induction phase to maintenance phase can also take into account additional information that is available after the data that determines clinical response is collected, for example, subsequent clinical evaluation at the time of transition from induction phase to maintenance phase.

[0125] Transition from the induction phase to the maintenance phase may occur at week 24 if the subject has achieved a clinical response of at least EASI 75 at week 16.

[0126] The induction phase may be a variable induction phase. "Variable" means that the duration of the induction phase will vary between subjects and that the transition from the induction phase to the maintenance phase will vary based on patient-specific factors. Patient-specific factors may include clinical response. For example, transition may occur when a patient achieves IGA 0 / 1, has clear / almost clear skin, achieves EASI 50, achieves EASI 75, or achieves EASI 90.

[0127] Administration can be subcutaneous.Subcutaneous injection can be any suitable side of injection, such as the abdomen or the outside of the thigh.In some embodiments, subcutaneous administration is used for the treatment of atopic dermatitis, because it is more convenient for patients and less resource-intensive than intravenous injection.Any of the methods described herein can include subcutaneous administration.The method includes induction and maintenance periods, and is mainly intended for use when administration is subcutaneous.

[0128] The method may include any one of the following four configurations of the induction and / or maintenance phase, for each of which administration may be subcutaneous: 1. The induction phase may comprise administering at least five induction phase injections, the first of which is a loading dose of 500 mg of the antibody or fragment thereof, followed by at least four subsequent induction phase injections, each of which is a dose of 250 mg of the antibody or fragment thereof, with each subsequent induction phase injection administered four weeks after the preceding induction phase injection. The maintenance phase may comprise administering at least three maintenance phase injections, each of which is a dose of 250 mg of the antibody or fragment thereof, with the first maintenance phase injection administered at least four weeks after the final induction phase injection, and the second maintenance phase injection and each subsequent maintenance phase injection administered at least four weeks after the preceding maintenance phase injection. 2. The induction phase may comprise administering at least five induction phase injections, each induction phase injection being a dose of 250 mg of the antibody or fragment thereof, with the second induction phase injection and each subsequent induction phase injection being administered four weeks after the preceding induction phase injection. The maintenance phase may comprise administering at least three maintenance phase injections, each maintenance phase injection being a dose of 250 mg of the antibody or fragment thereof, with the first maintenance phase injection being administered at least four weeks after the final induction phase injection, and the second maintenance phase injection and each subsequent maintenance phase injection being administered at least four weeks after the preceding maintenance phase injection. 3. The induction phase may include administering at least five induction phase injections, each induction phase injection being a dose of 125 mg of the antibody or fragment thereof, with the second induction phase injection and each subsequent induction phase injection being administered four weeks after the preceding induction phase injection. The maintenance phase may include administering at least three maintenance phase injections, each maintenance phase injection being a dose of 125 mg of the antibody or fragment thereof, with the first maintenance phase injection being administered at least four weeks after the final induction phase injection, and the second maintenance phase injection and each subsequent maintenance phase injection being administered at least four weeks after the preceding maintenance phase injection. 4. The induction phase may include administering at least five induction phase injections, each induction phase injection being a dose of 62.5 mg of the antibody or fragment thereof, with the second induction phase injection and each subsequent induction phase injection being administered four weeks after the preceding induction phase injection. The maintenance phase may include administering at least three maintenance phase injections, each maintenance phase injection being a dose of 62.5 mg of the antibody or fragment thereof, with the first maintenance phase injection being administered at least four weeks after the final induction phase injection, and the second maintenance phase injection and each subsequent maintenance phase injection being administered at least four weeks after the preceding maintenance phase injection.

[0129] As used in the configurations presented herein, "at least 4 weeks" can be, for example, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 weeks. As used in the four configurations above, "at least 4 weeks" can be, for example, 4, 12, or 16 weeks. This applies to the period between induction injections, between the final induction injection and the first maintenance injection, and between maintenance injections.

[0130] The method may include administering at least six induction phase injections or at least seven induction phase injections. The first maintenance phase injection may be administered 4 weeks to 24 weeks or 4 weeks to 16 weeks after the final induction phase injection. The first maintenance phase injection may be administered 12 weeks after the final induction phase injection. The first maintenance phase injection may be administered 16 weeks after the final induction phase injection. The first maintenance phase injection may be administered 24 weeks after the final induction phase injection. The second maintenance phase injection and each subsequent maintenance phase injection may be administered 4 weeks to 24 weeks or 4 weeks to 16 weeks after the preceding maintenance phase injection. The second maintenance phase injection and each subsequent maintenance phase injection may be administered 12 weeks after the preceding maintenance phase injection. The second maintenance phase injection and each subsequent maintenance phase injection may be administered 16 weeks after the preceding maintenance phase injection. The second maintenance phase injection and each subsequent maintenance phase injection may be administered 24 weeks after the preceding maintenance phase injection.

[0131] The method is: (a) may include administering at least seven induction phase injections; (b) the first maintenance injection is administered at least 12 weeks after the final induction injection; (c) The second maintenance injection and each subsequent maintenance injection is administered at least 4 weeks after the preceding maintenance injection.

[0132] The method may include any one of the following four additional components of the induction and / or maintenance phase, administration of each of which may be subcutaneous:

[0133] 1'. The induction phase may include administering at least five induction phase injections, the first of which is a loading dose of 500 mg of the antibody or fragment thereof, followed by at least four subsequent induction phase injections, each of which is a dose of 250 mg of the antibody or fragment thereof, with each subsequent induction phase injection administered four weeks after the preceding induction phase injection. The maintenance phase may include administering at least three maintenance phase injections, each of which is a dose of 250 mg of the antibody or fragment thereof, with the first maintenance phase injection administered at least 16 weeks after the final induction phase injection, and the second maintenance phase injection and each subsequent maintenance phase injection administered at least 16 weeks after the preceding maintenance phase injection.

[0134] 2'. The induction phase may include administering at least five induction phase injections, each induction phase injection being a dose of 250 mg of the antibody or fragment thereof, with the second induction phase injection and each subsequent induction phase injection being administered four weeks after the preceding induction phase injection. The maintenance phase may include administering at least three maintenance phase injections, each maintenance phase injection being a dose of 250 mg of the antibody or fragment thereof, with the first maintenance phase injection being administered at least 16 weeks after the final induction phase injection, and the second maintenance phase injection and each subsequent maintenance phase injection being administered at least 16 weeks after the preceding maintenance phase injection.

[0135] 3'. The induction phase may include administering at least five induction phase injections, each induction phase injection being a dose of 125 mg of the antibody or fragment thereof, with the second induction phase injection and each subsequent induction phase injection being administered 4 weeks after the preceding induction phase injection. The maintenance phase may include administering at least three maintenance phase injections, each maintenance phase injection being a dose of 125 mg of the antibody or fragment thereof, with the first maintenance phase injection being administered at least 16 weeks after the final induction phase injection, and the second maintenance phase injection and each subsequent maintenance phase injection being administered at least 16 weeks after the preceding maintenance phase injection.

[0136] 4'. The induction phase may include administering at least five induction phase injections, each induction phase injection at a dose of 62.5 mg of the antibody or fragment thereof, with the second induction phase injection and each subsequent induction phase injection being administered 4 weeks after the preceding induction phase injection. The maintenance phase may include administering at least three maintenance phase injections, each maintenance phase injection at a dose of 62.5 mg of the antibody or fragment thereof, with the first maintenance phase injection being administered at least 16 weeks after the final induction phase injection, and the second maintenance phase injection and each subsequent maintenance phase injection being administered at least 16 weeks after the preceding maintenance phase injection.

[0137] The method may include any one of the following four additional components of the induction and / or maintenance phase, administration of each of which may be subcutaneous:

[0138] 1''. The induction phase may include administering at least five induction phase injections, the first induction phase injection being a loading dose of 500 mg of the antibody or fragment thereof, followed by at least four subsequent induction phase injections, each subsequent induction phase injection being a dose of 250 mg of the antibody or fragment thereof, with each subsequent induction phase injection administered four weeks after the preceding induction phase injection. The maintenance phase may include administering at least three maintenance phase injections, each maintenance phase injection being a dose of 250 mg of the antibody or fragment thereof, with the first maintenance phase injection administered at least 16 weeks after the final induction phase injection, and the second maintenance phase injection and each subsequent maintenance phase injection administered at least 16 weeks after the preceding maintenance phase injection, with the subject achieving a clinical response of at least EASI 75 16 weeks after the first induction phase injection.

[0139] 2''. The induction phase may include administering at least five induction phase injections, each induction phase injection being a dose of 250 mg of the antibody or fragment thereof, and the second induction phase injection and each subsequent induction phase injection being administered 4 weeks after the preceding induction phase injection. The maintenance phase may include administering at least three maintenance phase injections, each maintenance phase injection being a dose of 250 mg of the antibody or fragment thereof, the first maintenance phase injection being administered at least 16 weeks after the final induction phase injection, and the second maintenance phase injection and each subsequent maintenance phase injection being administered at least 16 weeks after the preceding maintenance phase injection, and the subject achieving a clinical response of at least EASI 75 16 weeks after the first induction phase injection.

[0140] 3''. The induction phase may include administering at least five induction phase injections, each induction phase injection being a dose of 125 mg of the antibody or fragment thereof, and the second induction phase injection and each subsequent induction phase injection being administered 4 weeks after the preceding induction phase injection. The maintenance phase may include administering at least three maintenance phase injections, each maintenance phase injection being a dose of 125 mg of the antibody or fragment thereof, the first maintenance phase injection being administered at least 16 weeks after the final induction phase injection, and the second maintenance phase injection and each subsequent maintenance phase injection being administered at least 16 weeks after the preceding maintenance phase injection, and the subject achieving a clinical response of at least EASI 75 16 weeks after the first induction phase injection.

[0141] 4''. The induction phase may include administering at least five induction phase injections, each induction phase injection at a dose of 62.5 mg of the antibody or fragment thereof, and wherein the second induction phase injection and each subsequent induction phase injection are administered 4 weeks after the preceding induction phase injection. The maintenance phase may include administering at least three maintenance phase injections, each maintenance phase injection at a dose of 62.5 mg of the antibody or fragment thereof, and wherein the first maintenance phase injection is administered at least 16 weeks after the final induction phase injection, and wherein the second maintenance phase injection and each subsequent maintenance phase injection are administered at least 16 weeks after the preceding maintenance phase injection, and wherein the subject achieves a clinical response of at least EASI 75 16 weeks after the first induction phase injection.

[0142] The method may include any one of the following four additional components of the induction and / or maintenance phase, administration of each of which may be subcutaneous:

[0143] 1'''. The induction phase may include administering at least five induction phase injections, the first of which is a loading dose of 500 mg of the antibody or fragment thereof, followed by at least four subsequent induction phase injections, each of which is a dose of 250 mg of the antibody or fragment thereof, with each subsequent induction phase injection administered four weeks after the preceding induction phase injection. The maintenance phase may include: (a) If the subject achieves a clinical response of at least EASI75 and / or IGA-AD 0 / 1 16 weeks after the first loading injection: (i) administering at least three maintenance injections, each maintenance injection being a dose of 250 mg of the antibody or fragment thereof, the first maintenance injection being administered at least four weeks after the final induction injection, and the second maintenance injection and each subsequent maintenance injection being administered at least four weeks after the preceding maintenance injection; or (ii) the subject discontinues the antibody or fragment thereof; (b) If the subject has not achieved an EASI75 clinical response and / or IGA-AD 0 / 1 16 weeks after the first loading injection: (i) administering at least three maintenance injections, each maintenance injection being a dose of 250 mg of the antibody or fragment thereof, the first maintenance injection being administered at least four weeks after the final induction injection, and the second maintenance injection and each subsequent maintenance injection being administered at least four weeks after the preceding maintenance injection.

[0144] 2'''. The induction phase may include administering at least five induction phase injections, each induction phase injection being a dose of 250 mg of the antibody or fragment thereof, with the second induction phase injection and each subsequent induction phase injection being administered four weeks after the preceding induction phase injection. The maintenance phase may include: (a) If the subject achieves a clinical response of at least EASI75 and / or IGA-AD 0 / 1 16 weeks after the first loading injection: (i) administering at least three maintenance injections, each maintenance injection being a dose of 250 mg of the antibody or fragment thereof, the first maintenance injection being administered at least four weeks after the final induction injection, and the second maintenance injection and each subsequent maintenance injection being administered at least four weeks after the preceding maintenance injection; or (ii) the subject discontinues the antibody or fragment thereof; (b) If the subject has not achieved an EASI75 and / or IGA-AD 0 / 1 clinical response 16 weeks after the first loading injection: (i) administering at least three maintenance injections, each maintenance injection being a dose of 250 mg of the antibody or fragment thereof, the first maintenance injection being administered at least four weeks after the final induction injection, and the second maintenance injection and each subsequent maintenance injection being administered at least four weeks after the preceding maintenance injection.

[0145] 3'''. The induction phase may include administering at least five induction phase injections, each induction phase injection being a dose of 125 mg of the antibody or fragment thereof, with the second induction phase injection and each subsequent induction phase injection being administered four weeks after the preceding induction phase injection. The maintenance phase may include: (a) If the subject achieves a clinical response of at least EASI75 and / or IGA-AD 0 / 1 16 weeks after the first loading injection: (i) administering at least three maintenance injections, each maintenance injection being a dose of 250 mg of the antibody or fragment thereof, the first maintenance injection being administered at least four weeks after the final induction injection, and the second maintenance injection and each subsequent maintenance injection being administered at least four weeks after the preceding maintenance injection; or (ii) the subject discontinues the antibody or fragment thereof; (b) If the subject has not achieved an EASI75 and / or IGA-AD 0 / 1 clinical response 16 weeks after the first loading injection: (i) administering at least three maintenance injections, each maintenance injection being a dose of 250 mg of the antibody or fragment thereof, the first maintenance injection being administered at least four weeks after the final induction injection, and the second maintenance injection and each subsequent maintenance injection being administered at least four weeks after the preceding maintenance injection.

[0146] 4'''. The induction phase may include administering at least five induction phase injections, each induction phase injection being a dose of 62.5 mg of the antibody or fragment thereof, with the second induction phase injection and each subsequent induction phase injection being administered four weeks after the preceding induction phase injection. The maintenance phase may include: (a) If the subject achieves a clinical response of at least EASI75 and / or IGA-AD 0 / 1 16 weeks after the first loading injection: (i) administering at least three maintenance injections, each maintenance injection being a dose of 250 mg of the antibody or fragment thereof, the first maintenance injection being administered at least four weeks after the final induction injection, and the second maintenance injection and each subsequent maintenance injection being administered at least four weeks after the preceding maintenance injection; or (ii) the subject discontinues the antibody or fragment thereof; (b) If the subject has not achieved an EASI75 and / or IGA-AD 0 / 1 clinical response 16 weeks after the first loading injection: (i) administering at least three maintenance injections, each maintenance injection being a dose of 250 mg of the antibody or fragment thereof, the first maintenance injection being administered at least four weeks after the final induction injection, and the second maintenance injection and each subsequent maintenance injection being administered at least four weeks after the preceding maintenance injection.

[0147] The method may include any one of the following four additional components of the induction and / or maintenance phase, administration of each of which may be subcutaneous:

[0148] 1''''. The induction phase may include administering at least five induction phase injections, a first induction phase injection of a loading dose of 500 mg of the antibody or fragment thereof, followed by at least four subsequent induction phase injections, each subsequent induction phase injection of a dose of 250 mg of the antibody or fragment thereof, each subsequent induction phase injection being administered four weeks after the preceding induction phase injection. The maintenance phase may include: (a) If the subject achieves a clinical response of at least EASI75 and / or IGA-AD 0 / 1 16 weeks after the first loading injection: (i) administering at least three maintenance injections, each maintenance injection being a dose of 250 mg of the antibody or fragment thereof, the first maintenance injection being administered at least 12 weeks after the final induction injection, and the second maintenance injection and each subsequent maintenance injection being administered at least 12 weeks after the preceding maintenance injection; or (ii) the subject discontinues the antibody or fragment thereof; (b) If the subject has not achieved an EASI75 and / or IGA-AD 0 / 1 clinical response 16 weeks after the first loading injection: (i) administering at least three maintenance injections, each maintenance injection being a dose of 250 mg of the antibody or fragment thereof, the first maintenance injection being administered at least 12 weeks after the final induction injection, and the second maintenance injection and each subsequent maintenance injection being administered at least 12 weeks after the preceding maintenance injection.

[0149] 2'''. The induction phase may include administering at least five induction phase injections, where an induction phase injection is at a dose of 250 mg of the antibody or fragment thereof, and where the second induction phase injection and each subsequent induction phase injection is administered four weeks after the preceding induction phase injection. The maintenance phase may include: (a) If the subject achieves a clinical response of at least EASI75 and / or IGA-AD 0 / 1 16 weeks after the first loading injection: (i) administering at least three maintenance injections, each maintenance injection being a dose of 250 mg of the antibody or fragment thereof, the first maintenance injection being administered at least 12 weeks after the final induction injection, and the second maintenance injection and each subsequent maintenance injection being administered at least 12 weeks after the preceding maintenance injection; or (ii) the subject discontinues the antibody or fragment thereof; (b) If the subject has not achieved an EASI75 and / or IGA-AD 0 / 1 clinical response 16 weeks after the first loading injection: (i) administering at least three maintenance injections, each maintenance injection being a dose of 250 mg of the antibody or fragment thereof, the first maintenance injection being administered at least 12 weeks after the final induction injection, and the second maintenance injection and each subsequent maintenance injection being administered at least 12 weeks after the preceding maintenance injection.

[0150] 3'''. The induction phase may include administering at least five induction phase injections, each induction phase injection being a dose of 125 mg of the antibody or fragment thereof, with the second induction phase injection and each subsequent induction phase injection being administered four weeks after the preceding induction phase injection. The maintenance phase may include: (a) If the subject achieves a clinical response of at least EASI75 and / or IGA-AD 0 / 1 16 weeks after the first loading injection: (i) administering at least three maintenance injections, each maintenance injection being a dose of 250 mg of the antibody or fragment thereof, the first maintenance injection being administered at least 12 weeks after the final induction injection, and the second maintenance injection and each subsequent maintenance injection being administered at least 12 weeks after the preceding maintenance injection; or (ii) the subject discontinues the antibody or fragment thereof; (b) If the subject has not achieved an EASI75 and / or IGA-AD 0 / 1 clinical response 16 weeks after the first loading injection: (i) administering at least three maintenance injections, each maintenance injection being a dose of 250 mg of the antibody or fragment thereof, the first maintenance injection being administered at least 12 weeks after the final induction injection, and the second maintenance injection and each subsequent maintenance injection being administered at least 12 weeks after the preceding maintenance injection.

[0151] 4'''. The induction phase may include administering at least five induction phase injections, each induction phase injection being at a dose of 62.5 mg of the antibody or fragment thereof, with the second induction phase injection and each subsequent induction phase injection being administered four weeks after the preceding induction phase injection. The maintenance phase may include: (a) If the subject achieves a clinical response of at least EASI75 and / or IGA-AD 0 / 1 16 weeks after the first loading injection: (i) administering at least three maintenance injections, each maintenance injection being a dose of 250 mg of the antibody or fragment thereof, the first maintenance injection being administered at least 12 weeks after the final induction injection, and the second maintenance injection and each subsequent maintenance injection being administered at least 12 weeks after the preceding maintenance injection; or (ii) the subject discontinues the antibody or fragment thereof; (b) If the subject has not achieved an EASI75 and / or IGA-AD 0 / 1 clinical response 16 weeks after the first loading injection: (i) administering at least three maintenance injections, each maintenance injection being a dose of 250 mg of the antibody or fragment thereof, the first maintenance injection being administered at least 12 weeks after the final induction injection, and the second maintenance injection and each subsequent maintenance injection being administered at least 12 weeks after the preceding maintenance injection.

[0152] The method is: (a) may include administering at least seven induction phase injections; (b) the first maintenance injection is administered 4 weeks after the final induction injection; (c) The second maintenance injection and each subsequent maintenance injection is administered 4 weeks after the preceding maintenance injection.

[0153] The method is: (a) may include administering at least seven induction phase injections; (b) the first maintenance injection is administered 12 weeks after the last induction injection; (c) The second maintenance injection and each subsequent maintenance injection is administered 12 weeks after the preceding maintenance injection.

[0154] The method is: (a) may include administering at least seven induction phase injections; (b) the first maintenance injection is administered 16 weeks after the final induction injection; (c) The second maintenance injection and each subsequent maintenance injection is administered 16 weeks after the preceding maintenance injection.

[0155] The method is: (a) may include administering at least seven induction phase injections; (b) the first maintenance injection is administered 24 weeks after the final induction injection; (c) The second maintenance injection and each subsequent maintenance injection is administered 24 weeks after the preceding maintenance injection.

[0156] According to one embodiment, a method is for treating an inflammatory disease, inflammatory disorder, immune-mediated disease, immune-mediated disorder, or inflammatory skin disorder in a human subject, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered once every four weeks, once every twelve weeks, or once every six months.

[0157] According to another embodiment, a method is for treating an inflammatory disease, inflammatory disorder, immune-mediated disease, immune-mediated disorder, or inflammatory skin disorder in a human subject, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered by subcutaneous injection once every four weeks, once every twelve weeks, or once every six months.

[0158] According to another embodiment, a method is for treating an inflammatory disease, inflammatory disorder, immune-mediated disease, immune-mediated disorder, or inflammatory skin disorder in a human subject, comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered once every four weeks, once every twelve weeks, or once every six months.

[0159] In a further configuration, there is provided an embodiment as described above that comprises administering a therapeutically effective amount of an OX40L antagonist antibody or antigen-binding fragment thereof.

[0160] Loading and treatment doses The method is: (a) administering a first injection as a loading dose of an antibody or fragment thereof, followed by (b) administering at least a second injection as a first treatment dose of the antibody or fragment thereof. may include:

[0161] The second injection can be administered 3 to 5 weeks after the first injection.

[0162] The method can further include administering at least a third injection of a therapeutic dose of the antibody or fragment thereof, which can be administered 3 to 5 weeks after the second injection.

[0163] The method can further include administering at least a fourth injection of a treatment dose of the antibody or fragment thereof, which can be administered 3 to 5 weeks after the third injection.

[0164] The method can further include administering at least a fifth injection of a treatment dose of the antibody or fragment thereof, which can be administered 3 to 5 weeks after the fourth injection.

[0165] The method can further include administering at least a sixth injection of a treatment dose of the antibody or fragment thereof, which can be administered 3 to 5 weeks after the fifth injection.

[0166] Each injection of the treatment dose can be administered 4 weeks after the preceding treatment dose.

[0167] The number of injections as a treatment dose can be any suitable number to achieve clinical purpose, and therefore can comprise any suitable number of injections as a treatment dose.The number of injections as a treatment dose can therefore be determined by a clinician.For example, the number of treatment doses can be at least 6, at least 7, at least 8, at least 9 or at least 10.For some embodiments, an unlimited number of injections can be administered as a treatment dose.

[0168] The loading dose may contain up to three times the mass of the antibody or fragment thereof for each subsequent injection as a treatment dose. The loading dose may contain more than two times and up to three times the mass of the antibody or fragment thereof for each subsequent injection as a treatment dose. The loading dose may contain up to two times the mass of the antibody or fragment thereof for each subsequent injection as a treatment dose. The loading dose may contain up to 1.5 times the mass of the antibody or fragment thereof for each subsequent injection as a treatment dose.

[0169] Each treatment dose may contain the same mass of antibody or fragment thereof as each other treatment dose.

[0170] The loading dose can be between 100 and 600 mg, between 150 and 550 mg, or between 200 and 500 mg. The loading dose can be 200 mg or 500 mg.

[0171] Each treatment dose can be between 50 and 300 mg or between 100 and 250 mg. Each treatment dose can be 100 mg or 250 mg.

[0172] An advantage of some embodiments derives from the favorable safety profile of the antibody or fragment thereof. This allows a wide range of treatment doses to be used in conjunction with the loading dose, which may not be advisable for other antibodies, where higher doses may lead to, for example, toxicity or unacceptable side effects. Any dose described herein can be used as the loading dose. Any dose described herein can be used as the treatment dose. Any dose described herein can be used as the treatment dose, with twice the treatment dose being used as the loading dose. For example, a 500 mg loading dose can be combined with a 250 mg treatment dose, a 250 mg loading dose can be combined with a 125 mg treatment dose, or a 125 mg loading dose can be combined with a 62.5 mg treatment dose. KY1005 has a particularly favorable safety profile and can be used in conjunction with a loading dose when the treatment dose is any of the doses described herein.

[0173] The first maintenance injection as a maintenance dose can be administered between 4 and 8 months after the last injection as a treatment dose, and one or more further maintenance injections as a maintenance dose are administered at intervals of between 4 and 8 months.

[0174] Administration can be intravenous. Injection can be subcutaneous, particularly for embodiments including a loading dose and a treatment dose. Data from a randomized, double-blind, placebo-controlled Phase 2a clinical trial in moderate to severe AD, in which administration was by intravenous injection, is disclosed herein.

[0175] Pharmacokinetic properties In some embodiments, the administered antibody or fragment thereof was found to exhibit surprisingly consistent pharmacokinetic (PK) parameter estimates in IV and subcutaneous population PK models. One observed advantage is linear PK (except for some nonlinearity observed at low doses, e.g., approximately 0.45 mg / kg in healthy subjects), which allows the PK model to be described as a "linear two-compartment distribution model" for both IV and subcutaneous administration. Here, the term "linear" refers to clearance, including the rate of clearance (CL) and the rate of clearance from the central compartment to the second compartment (Q1), both of which have been shown to be linear in the data disclosed herein. The same observation applies to both AD and healthy patients. Without being bound by theory, this may be related to low expression of OX40L, resulting in the rate of clearance not varying based on drug concentration (or therefore time).

[0176] In some embodiments, the administered antibody or fragment thereof has been found to surprisingly exhibit low immunogenicity. One component of a harmful immune response to a therapeutic protein is the formation of anti-drug antibodies (ADA). The consequences of an immune reaction to a therapeutic protein range from the transient appearance of ADA without any clinical significance to severe, life-threatening conditions. Potential clinical consequences of an unwanted immune response include loss of efficacy of the therapeutic protein and severe acute immune effects, such as anaphylaxis. ADA can affect the efficacy of a therapeutic protein either by interfering with the pharmacodynamic interaction between the therapeutic protein and its target or by altering its pharmacokinetic profile.

[0177] As stated in the European Medicines Agency (EMA) guideline on the immunogenicity assessment of therapeutic proteins (May 18, 2017, EMEA / CHMP / BMWP / 42832 / 2005 Rev1, Committee for Medicinal Products for Human Use (CHMP)), products given intravenously may be less immunogenic than drugs given subcutaneously. Therefore, it is surprising that the population PK profiles of treatments of some embodiments are very similar between IV and subcutaneous administration scenarios (based on a single subcutaneous dose). No meaningful effect of ADA is evident from the data disclosed herein.

[0178] Important factors influencing the immunogenicity of therapeutic proteins generally include the origin (e.g., foreign or human) and nature of the active substance (endogenous protein, post-translational modifications), significant modifications of the therapeutic protein (e.g., pegylated and fusion proteins), product-related (e.g., degradation products, impurities, aggregates) and process-related impurities (host cell proteins, lipids or DNA, microbial contaminants), formulation (excipients) and interactions between the drug and / or formulation and primary product packaging (e.g., container, closure).

[0179] Without being bound by theory, antibodies or fragments thereof administered according to some embodiments may advantageously maintain the native conformation of the antibody or fragment thereof. Denaturation and aggregation of therapeutic proteins can potentially trigger an immune response. Protein aggregation and adduct formation may reveal new epitopes and lead to the formation of multivalent epitopes that can stimulate the immune system. Furthermore, aggregation can enhance protein-specific immune responses and lead to the formation of ADAs. Higher molecular weight (MW) aggregates are more likely to induce an immune response than lower MW aggregates. When administered according to some embodiments, antibodies or fragments thereof may advantageously exhibit reduced aggregation and adduct formation, especially of higher MW aggregates.

[0180] Additional factors affecting the immunogenicity of therapeutic proteins include the characteristics of the active ingredient. Therapeutic protein analogs of human endogenous proteins may provoke an immune response due to variations in amino acid sequence or protein structure compared to the endogenous protein as a result of post-translational modifications, or other changes during all steps of the drug substance and / or drug product manufacturing process, storage, and administration. T cell epitopes are small linear peptides and are therefore modified by differences in amino acid sequence between the endogenous protein and the therapeutic protein. Therefore, analysis to identify potential T cell epitopes can be useful for selecting novel proteins or peptides for development. Glycosylation can affect both the physico-chemical and biological properties of proteins. The presence and structure of carbohydrate moieties can have both direct and indirect effects on the immunogenicity of therapeutic proteins. Glycans can induce an immune response themselves (e.g., glycans of non-human origin), or their presence can affect the conformation of the protein in such a way that it becomes immunogenic. In some embodiments, the administered antibody or fragment thereof may advantageously minimize such properties, thus minimizing immunogenicity.

[0181] The antibody or fragment thereof may be (a) clearance rate (CL) of about 0.05 to about 0.18 L / day; (b) an absorption constant (ka) of about 0.11 to about 0.33 L / day; (c) a central compartment volume (Vc) of about 1.6 to about 5.0 L; (d) a second (peripheral compartment) volume (Vp1) of about 1.2 to about 3.6 L; (e) the rate of clearance from the central compartment to the secondary compartment (Q) of about 0.31 to about 0.93 L / day, and (f) Bioavailability of about 0.6 to about 1.0 (Fabs1) It may be possible for the compound to exhibit one or more pharmacokinetic properties selected from the group consisting of:

[0182] The antibody or fragment thereof may have one, two, three, four, five or six of the pharmacokinetic properties (a) to (f).

[0183] The antibody or fragment thereof may exhibit a clearance rate (CL) of about 0.05 to about 0.18 L / day, about 0.06 to about 0.17 L / day, about 0.07 to about 0.16 L / day, about 0.08 to about 0.15 L / day, about 0.09 to about 0.14 L / day, or about 0.10 to about 0.13 L / day. The antibody or fragment thereof may exhibit a clearance rate (CL) of about 0.115 L / day.

[0184] The antibody or fragment thereof may exhibit an absorption constant (ka) of about 0.11 to about 0.33 L / day, about 0.12 to about 0.32 L / day, about 0.13 to about 0.31 L / day, about 0.14 to about 0.30 L / day, about 0.15 to about 0.29 L / day, about 0.16 to about 0.28 L / day, about 0.17 to about 0.27 L / day, about 0.18 to about 0.26 L / day, about 0.19 to about 0.25 L / day, about 0.20 to about 0.24 L / day, or about 0.21 to about 0.23 L / day. The antibody or fragment thereof may exhibit an absorption constant (ka) of about 0.22 L / day.

[0185] The antibody or fragment thereof may exhibit a central compartment volume (Vc) of about 1.6 to about 5.0 L, about 1.8 to about 4.8 L, about 2.0 to about 4.6 L, about 2.2 to about 4.4 L, about 2.4 to about 4.2 L, about 2.6 to about 4.0 L, about 2.8 to about 3.8 L, about 3.0 to about 3.6 L, or about 3.2 to about 3.4 L. The antibody or fragment thereof may exhibit a central compartment volume (Vc) of about 3.3 L.

[0186] The antibody or fragment thereof may exhibit a second (peripheral compartment) volume (Vp1) of about 1.2 to about 3.6 L, about 1.4 to about 3.4 L, about 1.6 to about 3.2 L, about 1.8 to about 3.0 L, about 2.0 to about 2.8 L, about 2.2 to about 2.6 L, or about 2.3 to about 2.5 L. The antibody or fragment thereof may exhibit a second (peripheral compartment) volume (Vp1) of about 2.4 L.

[0187] The antibody or fragment thereof may exhibit a clearance rate (Q1) from the central compartment to the second compartment of about 0.31 to about 0.93 L / day, about 0.36 to about 0.88 L / day, about 0.41 to about 0.83 L / day, about 0.46 to about 0.78 L / day, about 0.51 to about 0.73 L / day, about 0.56 to about 0.68 L / day, about 0.60 to about 0.64 L / day, or about 0.61 to about 0.63 L / day. The antibody or fragment thereof may exhibit a clearance rate (Q1) from the central compartment to the second compartment of about 0.62 L / day.

[0188] The antibody or fragment thereof may exhibit a bioavailability (Fabs1) of about 0.6 to about 1.0, about 0.65 to about 0.95, about 0.70 to about 0.90, or about 0.75 to about 0.85. The antibody or fragment thereof may exhibit a bioavailability (Fabs1) of about 0.8.

[0189] The pharmacokinetic properties can result from administration of a single dose of the antibody or fragment thereof. Alternatively, the pharmacokinetic properties can result from administration of more than one dose (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) of the antibody or fragment thereof. The subject is medicated with the antibody or fragment thereof such that the antibody or fragment thereof is present at a steady-state level in the subject.

[0190] The pharmacokinetic properties can be determined based on samples from a single subject. Alternatively, the pharmacokinetic properties can be determined based on samples from a population, for example, a mixed population (e.g., healthy and non-healthy), a population with AD, or a population with moderate to severe AD.

[0191] The pharmacokinetic properties can be determined using a two-compartment model. The two-compartment model can be a linear two-compartment model. In the linear two-compartment model, CL and Q1 can be linear with respect to the concentration of the antibody or fragment thereof.

[0192] The antibody or fragment thereof may have at least any two of the above pharmacokinetic properties as determined using a two-compartment model. The antibody or fragment thereof may have at least any three of the above pharmacokinetic properties as determined using a two-compartment model. The antibody or fragment thereof may have at least any four of the above pharmacokinetic properties as determined using a two-compartment model. The antibody or fragment thereof may have at least any five of the above pharmacokinetic properties as determined using a two-compartment model. The antibody or fragment thereof may have at least six of the above pharmacokinetic properties as determined using a two-compartment model.

[0193] The pharmacokinetic properties may result from administration of the antibody or fragment thereof by intravenous injection or by subcutaneous injection. The pharmacokinetic properties may result from administration of any dose or dose combination described herein.

[0194] The method may further comprise obtaining one or more blood samples from the subject and, optionally, measuring the blood serum concentration achieved by the antibody or fragment thereof.

[0195] Patient population The subject is a human subject. The subject can be a male subject. The subject can be a female subject. The subject can be between about 6 and about 100 years old, about 15 and about 100 years old, about 18 and about 93 years old, about 20 and about 80 years old, about 30 and about 70 years old, or about 40 and about 60 years old. The subject can be between about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58 , 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 years old. The subject may be 44 years old. The subject may weigh about 92 kg. The subject may weigh between about 40 and about 210 kg. The subject may weigh between about 50 and 200 kg, about 60 and about 150 kg, or about 75 and about 100 kg. The subject may weigh about 40, 43, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 92, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205 or 210 kg.

[0196] The subject may have an age selected from the group consisting of up to 6 years old, 6-12 years old, 12-18 years old, at least 18 years old, and under 75 years old. The subject may be at least 18 years old and / or under 75 years old. The subject may have an age between 6 months and 11 years old. The subject may have an age between 12 and 17 years old.

[0197] The subject may be a patient with an inflammatory disease or disorder. The subject may be a patient with an immune-mediated disease or disorder. The subject may be a patient with an inflammatory skin disease or disorder.

[0198] The subject can be a type 2 patient. The subject can be a high-grade type 2 patient. The subject can be a low-grade type 2 patient. The subject can be a non-type 2 patient. The subject can be a patient with a mixed inflammatory response.

[0199] The subject may have been diagnosed with atopic dermatitis at least one year prior to administration of the antibody or fragment thereof. The subject may be a patient with chronic atopic dermatitis. The antibody or fragment thereof may be a first-line treatment. The antibody or fragment thereof may be a second-line treatment. The atopic dermatitis may be moderate to severe atopic dermatitis. The atopic dermatitis may not be adequately controlled with topical and / or systemic therapy, or these therapies may not be advisable.

[0200] The subject may be a patient with moderate to severe atopic dermatitis who is a candidate for systemic therapy. The subject may be a patient with moderate to severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapy or for whom such therapy is not advisable.

[0201] Subjects can be defined by biomarker levels, which can be any suitable biomarker levels known in the art or described elsewhere herein.

[0202] Topical corticosteroids Topical corticosteroids are a type of steroid drug that is applied directly to the skin to reduce inflammation and irritation.Topical corticosteroids can be used to treat AD, for example, to reduce swelling, redness and itching during flare-ups.When used correctly, the serious side effects of topical corticosteroids tend to be rare, although they have been reported.However, they may not be sufficiently effective as the sole treatment for AD in many subjects, especially when AD is moderate to severe.The approach described herein benefits from the use of topical corticosteroids by treating with anti-OX40L antibody or its antigen-binding fragment according to the embodiment of the method.

[0203] Atopic dermatitis may be resistant, unresponsive, or inadequately responsive to treatment with either topical corticosteroids and / or systemic therapy, or these therapies are not recommended, or the subject has had an inadequate response, been intolerant, or is resistant to one or more topical corticosteroids.Atopic dermatitis may not be adequately controlled or be inadequately responsive to treatment with topical corticosteroids.The subject may have had an inadequate response, been intolerant, or is resistant to one or more topical corticosteroids.The subject may also have been treated with one or more topical corticosteroids.An antibody or fragment thereof can be used together with topical corticosteroids.The subject may have previously been treated with one or more topical corticosteroids.

[0204] The method may further comprise administering a therapeutically effective amount of one or more topical corticosteroids. The one or more topical corticosteroids may be administered before the anti-OX40L antibody or antigen-binding fragment thereof. The first injection of the anti-OX40L antibody or antigen-binding fragment thereof may be administered on the day the subject discontinues treatment with one or more topical corticosteroids. The first injection of the anti-OX40L antibody or antigen-binding fragment thereof may be administered on the day the clinical decision is made to discontinue treatment with one or more topical corticosteroids.

[0205] For several reasons, a clinical decision may be made to discontinue treatment with one or more topical corticosteroids, or a subject may discontinue treatment.For example, a subject may have an inadequate response to one or more topical corticosteroids, be intolerant to one or more topical corticosteroids, or be resistant to one or more topical corticosteroids.The possible time course for discontinuing treatment may vary depending on the reason for discontinuing treatment.For example, it may be quickly apparent to a clinician that a patient is intolerant to one or more topical corticosteroids, and thus the decision to discontinue treatment can be made relatively quickly.It may take longer to determine that a patient is resistant to or has an inadequate response to one or more topical corticosteroids, and therefore the decision to discontinue treatment for these reasons may be made correspondingly less quickly.The reason may be lack of primary efficacy, lack of secondary efficacy, or intolerance.Lack of primary efficacy may be when there is no response to the start of treatment.In this case, treatment can be discontinued promptly. Secondary lack of efficacy may occur when a patient loses responsiveness and does not respond to further treatment, which may occur any time after an initial response is observed, for example, 6 months, 1 year, 18 months, or 2 years. Intolerance may occur any time after the start of treatment and may be evident early or may occur after a period of time when adverse events begin to appear.

[0206] At least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or 4-6 months after administration of the first dose of one or more topical corticosteroids, a clinical decision can be made to discontinue treatment with the one or more topical corticosteroids, or the subject can discontinue treatment.

[0207] One or more topical corticosteroids may be administered after the anti-OX40L antibody or antigen-binding fragment thereof. The first administration of one or more topical corticosteroids can be administered on the day the subject discontinues treatment with the anti-OX40L antibody or antigen-binding fragment thereof. The first administration of one or more topical corticosteroids can be administered on the day the clinical decision is made to discontinue treatment with the anti-OX40L antibody or antigen-binding fragment thereof.

[0208] A clinical decision to discontinue treatment with the anti-OX40L antibody or antigen-binding fragment thereof may be made, or the subject may discontinue treatment, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or 4-6 months after administration of the first injection of the anti-OX40L antibody or antigen-binding fragment thereof.

[0209] In many cases, the subject may receive a combination treatment using both a topical corticosteroid and an anti-OX40L antibody or its antigen-binding fragment. However, in some cases, one or more topical corticosteroids and an anti-OX40L antibody or its antigen-binding fragment may be administered sequentially, and the period between administering one or more topical corticosteroids and injecting an anti-OX40L antibody or its antigen-binding fragment is at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, or at least 52 weeks.

[0210] One or more topical corticosteroids can be administered simultaneously with the anti-OX40L antibody or antigen-binding fragment thereof. Simultaneous administration can include overlapping dosing schedules and / or simultaneous administration.

[0211] The topical corticosteroid may be any suitable topical corticosteroid, and may be selected from the group consisting of betamethasone dipropionate, clobetasol propionate, dexamethasone, methylprednisolone, methylprednisolone aceponate, mometasone furoate, diflorasone acetate, halobetasol propionate, amcinonide, fortified betamethasone dipropionate, fluocinonide, halcinonide, triamcinolone acetonide, betamethasone valerate, clocortolone pivalate, desoximetasone, fluocinolone acetonide, flurandrenolide, fluticasone propionate, hydrocortisone butyrate, hydrocortisone probutate, hydrocortisone valerate, prednicarbate, alclometasone propionate, desonide, hydrocortisone, and hydrocortisone acetate. The topical corticosteroid may be selected from the group consisting of betamethasone dipropionate, betamethasone dipropionate, gentamicin sulfate, clobetasol propionate, dexamethasone, methylprednisolone, methylprednisolone aceponate, and mometasone furoate. The topical corticosteroid may be betamethasone dipropionate, and optionally, betamethasone dipropionate is combined with gentamicin sulfate.

[0212] Topical corticosteroids can be formulated as creams, ointments, gels, foams, liquids, lotions, or gels. Topical corticosteroids can be applied twice daily or once daily. Topical corticosteroids can be applied once weekly or twice weekly.

[0213] The duration of topical corticosteroid administration can be any suitable length to achieve clinical purpose, and therefore can include any suitable number of administrations.The duration of topical corticosteroid administration can therefore be determined by a clinician.For some subjects, topical corticosteroid administration can be indefinite.

[0214] In a further configuration, there is provided an embodiment as described above that comprises administering a therapeutically effective amount of an OX40L antagonist antibody or antigen-binding fragment thereof.

[0215] Calcineurin inhibitors Topical calcineurin inhibitors (TCIs) work by modifying the immune system and have been developed to treat atopic dermatitis. Two types are available: tacrolimus ointment (Protopic) for moderate to severe atopic dermatitis and pimecrolimus cream (Elidel) for mild to moderate atopic dermatitis. "Topical" means applied to the skin. "Calcineurin inhibitors" means they block calcineurin, which may contribute to atopic dermatitis flare-ups. TCIs are used to treat atopic dermatitis in adults and children over the age of 2 who do not adequately respond to or cannot tolerate conventional therapies, such as topical steroids. They can be used to treat and prevent flare-ups. The approaches described herein benefit from the use of topical calcineurin inhibitors, as well as by treatment with anti-OX40L antibodies or antigen-binding fragments thereof, according to method embodiments.

[0216] Atopic dermatitis may be resistant, unresponsive, or inadequately responsive to treatment with either a topical calcineurin inhibitor and / or systemic therapy, or these therapies are not recommended, or the subject has had an inadequate response to, been intolerant of, or is resistant to one or more topical calcineurin inhibitors. Atopic dermatitis may not be adequately controlled or may be inadequately responsive to treatment with a topical calcineurin inhibitor. The subject may have had an inadequate response to, been intolerant of, or is resistant to one or more topical calcineurin inhibitors. The subject may also have been treated with one or more topical calcineurin inhibitors. The antibody or fragment thereof can be used together with a topical calcineurin inhibitor. The subject may have previously been treated with one or more topical calcineurin inhibitors.

[0217] The method may further comprise administering a therapeutically effective amount of one or more local calcineurin inhibitors. The one or more local calcineurin inhibitors may be administered before the anti-OX40L antibody or antigen-binding fragment thereof. The first injection of the anti-OX40L antibody or antigen-binding fragment thereof can be administered on the day the subject discontinues treatment with one or more local calcineurin inhibitors. The first injection of the anti-OX40L antibody or antigen-binding fragment thereof can be administered on the day the clinical decision is made to discontinue treatment with one or more local calcineurin inhibitors.

[0218] For several reasons, a clinical decision may be made to discontinue treatment with one or more local calcineurin inhibitors, or a subject may discontinue treatment. For example, a subject may have an inadequate response to one or more local calcineurin inhibitors, be intolerant to one or more local calcineurin inhibitors, or be resistant to one or more local calcineurin inhibitors. The possible time course for discontinuing treatment may vary depending on the reason for discontinuing treatment. For example, it may be quickly apparent to a clinician that a patient is intolerant to one or more local calcineurin inhibitors, and thus the decision to discontinue treatment can be made relatively quickly. It may take longer to determine that a patient is resistant to or has an inadequate response to one or more local calcineurin inhibitors, and therefore the decision to discontinue treatment for these reasons may be made correspondingly less quickly. The reason may be lack of primary efficacy, lack of secondary efficacy, or intolerance. Lack of primary efficacy may be when no response is observed to the start of treatment. In this case, treatment can be discontinued promptly. Secondary lack of efficacy may occur when a patient loses responsiveness and does not respond to further treatment, which may occur any time after an initial response is observed, for example, 6 months, 1 year, 18 months, or 2 years. Intolerance may occur any time after the start of treatment and may be evident early or may occur after a period of time when adverse events begin to appear.

[0219] A clinical decision may be made to discontinue treatment with one or more topical calcineurin inhibitors at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or 4-6 months after administering the first dose of one or more topical calcineurin inhibitors.

[0220] One or more local calcineurin inhibitors may be administered after the anti-OX40L antibody or antigen-binding fragment thereof. The first administration of one or more local calcineurin inhibitors can be administered on the day the subject discontinues treatment with the anti-OX40L antibody or antigen-binding fragment thereof. The first administration of one or more local calcineurin inhibitors can be administered on the day the clinical decision is made to discontinue treatment with the anti-OX40L antibody or antigen-binding fragment thereof.

[0221] A clinical decision to discontinue treatment with the anti-OX40L antibody or antigen-binding fragment thereof may be made, or the subject may discontinue treatment, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or 4-6 months after administration of the first injection of the anti-OX40L antibody or antigen-binding fragment thereof.

[0222] In many cases, the subject may receive combined treatment with both a local calcineurin inhibitor and an anti-OX40L antibody or its antigen-binding fragment.However, in some cases, one or more local calcineurin inhibitors and an anti-OX40L antibody or its antigen-binding fragment may be administered sequentially, and the period between administering one or more local calcineurin inhibitors and injecting an anti-OX40L antibody or its antigen-binding fragment is at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, or at least 52 weeks.

[0223] One or more topical calcineurin inhibitors can be administered simultaneously with the anti-OX40L antibody or antigen-binding fragment thereof. Simultaneous administration can include overlapping dosing schedules and / or simultaneous administration.

[0224] The topical calcineurin inhibitor can be any suitable topical calcineurin inhibitor. The topical calcineurin inhibitor can be a tacrolimus ointment or pimecrolimus cream, e.g., a tacrolimus ointment.

[0225] Topical calcineurin inhibitors can be formulated as creams, ointments, gels, foams, liquids, lotions, or gels. Topical calcineurin inhibitors can be applied twice daily or once daily. Topical calcineurin inhibitors can be applied two to three times weekly.

[0226] The period of administration of the local calcineurin inhibitor can be any suitable length to achieve clinical purpose, and therefore can include any suitable number of administrations.The period of administration of the local calcineurin inhibitor can therefore be determined by a clinician.For some subjects, the local calcineurin inhibitor administration can be indefinite.

[0227] In a further configuration, there is provided an embodiment as described above that comprises administering a therapeutically effective amount of an OX40L antagonist antibody or antigen-binding fragment thereof.

[0228] Other concurrent treatments Any other suitable treatment for atopic dermatitis can be characterized in the subject to be treated and / or can be used in combination with the antibody or fragment thereof according to the methods described herein.

[0229] The subject may also be being treated with one or more topical antihistamines. The antibody or fragment thereof can be used in conjunction with one or more topical antihistamines.

[0230] The subject may also be being treated with one or more oral steroids. The antibody or fragment thereof may be used in conjunction with one or more oral steroids.

[0231] Disease severity There are several different methods that can be used to assign disease severity when evaluating patients with atopic dermatitis. Each method of assigning disease severity can therefore inform patient selection in method embodiments. Each method of assigning disease severity can be used to monitor the treatment of interest in method embodiments. Each method of assigning disease severity can be used to transition patients from induction to maintenance phases. Each method of assigning disease severity can be used to identify treatments as disease-modifying. Each method of assigning disease severity can be performed, where applicable, as described below and / or in the Examples. Methods of assigning disease severity include:

[0232] EASI (including EASI75 and EASI90) EASI is a continuous scale (0 (no disease)-72 (most severe disease)) used to evaluate the severity and extent of atopic dermatitis. For example, it is described in Schram ME, Spuls PI, Leeflang MM, Lindeboom R, Bos JD, Schmitt J. EASI, (objective) SCORAD and POEM for atopic eczema: responsiveness and minimal clinically important difference. Allergy. 2012 Jan;67(1):99-106 and Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. Exp Dermatol. 2001 Feb;10(1):11-8. The method of determining EASI score is known, and if applicable, can be as described below and / or in the Examples.

[0233] The EASI assesses four disease features of AD (erythema, infiltrate / papule formation, epidermal peeling, and lichenification) for severity by the investigator on a scale of 0 (absent) to 3 (severe). Scores are then summed for each of four body regions (head, arms, trunk, and legs). Each body section is assigned a percentage of body surface area (BSA): 10% for the head, 20% for the arms, 30% for the trunk, and 40% for the legs. Each subtotal score is multiplied by the BSA represented by that region. Additionally, each body region is assigned a regional score of 0–6 depending on the percentage of skin affected by AD in that region: 0 (none), 1 (1%–9%), 2 (10%–29%), 3 (30%–49%), 4 (50%–69%), 5 (70%–89%), or 6 (90%–100%). Each body domain score is multiplied by the area affected. The resulting EASI score ranges from 0 to 72 points, with the highest scores indicating greater severity of AD.

[0234] It has been suggested that the severity of AD based on the EASI score should be categorized as follows: 0 = no problem; 0.1-1.0 = little problem; 1.1-7.0 = mild; 7.1-21.0 = moderate; 21.1-50.0 = severe; 50.1-72.0 = very severe. EASI50 indicates a ≥ 50% improvement from baseline. EASI75 indicates a ≥ 75% improvement from baseline. EASI90 indicates a ≥ 90% improvement from baseline. EASI100 indicates a 100% improvement from baseline.

[0235] The overall minimal clinically important difference (MCID) is considered to be 6.6 points.

[0236] Baseline score - EASI Atopic dermatitis may be assessed by determining a baseline EASI score. Determining a baseline EASI score may include: (a) selecting a body region from the group consisting of the head and neck, the trunk including the genital area, the upper limbs, and the lower limbs including the buttocks; (b) assessing the extent of atopic dermatitis in selected body regions and assigning an area score based on the extent of atopic dermatitis in the selected body regions; (c) Rate the severity of each of the following symptoms in selected body areas: 1. Erythema, 2. Edema and / or papule formation, 3. Epidermal peeling, and 4. Lichenification and assigning a severity score to each symptom in selected body regions; (d) determining a total score for the selected body region based on the region score in the selected body region and the severity score for each symptom; (e) repeating steps (b) through (d) for each of the remaining body regions; and (f) Determining a baseline EASI score based on the total score for each body domain.

[0237] The baseline EASI score can be any score that indicates moderate to severe AD. The baseline EASI score can be at least 12.1, at least 16.1, or at least 21.1. The baseline EASI score can be at least 16.1.

[0238] The first injection of the anti-OX40L antibody or fragment thereof can be administered on the same day that the baseline EASI score is determined.

[0239] Some embodiments of the method may further include determining a baseline EASI score.

[0240] Clinical Outcome-EASI Some embodiments of the method may further include assessing atopic dermatitis by determining a post-administration EASI score at least 7 days or at least 15 days after administration of the first injection of the antibody or fragment thereof. Obtaining a post-administration EASI score at least 7 days or at least 15 days after administration of the first injection of the antibody or fragment thereof is expected to be the earliest reliably observable change in the EASI score due to the action of the antibody or fragment thereof, although any clinically appropriate delay between administration and assessment can be utilized. The post-administration EASI score can be determined at least approximately 7 days, at least approximately 15 days, at least approximately 29 days, at least approximately 57 days, at least approximately 85 days, at least approximately 113 days, at least approximately 169 days, and / or at least approximately 253 days after administration of the first injection of the antibody or fragment thereof. The post-administration EASI score can be determined at about 7 days, about 15 days, about 29 days, about 57 days, about 85 days, about 113 days, about 169 days, and / or about 253 days after administration of the first injection of the antibody or fragment thereof. The post-administration EASI score can be determined at the end of the induction phase.

[0241] The post-administration EASI score may be 21.0 or less. The post-administration EASI score may indicate that the AD is no longer severe AD. The post-administration EASI score may be 16.0 or less. The post-administration EASI score may be 16.0 or less, 15.0 or less, 14.0 or less, 13.0 or less, 12.0 or less, 11.0 or less, 10.0 or less, 9.0 or less, 8.0 or less, 7.0 or less, 6.0 or less, 5.0 or less, 4.0 or less, 3.0 or less, 2.0 or less, 1.0 or less, or approximately 0. The post-administration EASI score may indicate that the AD is no longer moderate AD. The post-administration EASI score may be 7.0 or less or 1.0 or less. The post-administration EASI score may indicate that the AD is mild AD. The post-administration EASI score may indicate that the AD is causing little problems. The post-administration EASI score is reduced by at least 10 percent, at least 25 percent, or at least 50 percent relative to the baseline EASI score. The post-administration EASI score is reduced by at least 6 points, at least 6.6 points, at least 7 points, at least 8 points, at least 9 points, or at least 10 points relative to the baseline EASI score.

[0242] Some embodiments of the method may further include assessing atopic dermatitis by determining one or more additional post-administration EASI scores. The one or more additional post-administration EASI scores may be determined at least about 15 days, at least about 29 days, at least about 57 days, at least about 85 days, at least about 113 days, at least about 169 days, and / or at least about 253 days after administration of the first injection of the antibody or fragment thereof. The one or more additional post-administration EASI scores may be determined at about 29 days, at about 57 days, at about 85 days, at about 113 days, at about 169 days, and / or at least about 253 days after administration of the first injection of the antibody or fragment thereof. The one or more additional post-administration EASI scores may be determined at the end of the induction phase.

[0243] The EASI score after one or more further administrations may be 21.0 or less. The EASI score after one or more further administrations may indicate that AD is no longer severe AD. The EASI score after one or more further administrations may be 16.0 or less, 15.0 or less, 14.0 or less, 13.0 or less, 12.0 or less, 11.0 or less, 10.0 or less, 9.0 or less, 8.0 or less, 7.0 or less, 6.0 or less, 5.0 or less, 4.0 or less, 3.0 or less, 2.0 or less, 1.0 or less, or approximately 0. The EASI score after one or more further administrations may indicate that AD is no longer moderate AD. The EASI score after one or more further administrations may be 7.0 or less or 1.0 or less. The EASI score after one or more further administrations may indicate that AD is mild AD. The EASI score after one or more further administrations may indicate that AD is mostly problem-free. The EASI score after one or more additional administrations is reduced by at least 10 percent, at least 25 percent, or at least 50 percent relative to the baseline EASI score. The EASI score after one or more additional administrations is reduced by at least 6 points, at least 6.6 points, at least 7 points, at least 8 points, at least 9 points, or at least 10 points relative to the baseline EASI score. The EASI score after one or more additional administrations is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% relative to the baseline EASI score. The post-administration EASI score may be reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% relative to the baseline EASI score without additional administration of an anti-OX40L antibody or antigen-binding fragment thereof. (a) at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after the administration of the last injection; or (b) at least about 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, or 253 days It can be maintained.

[0244] Determining the post-administration EASI score and / or one or more further post-administration EASI scores may include: (a) selecting a body region from the group consisting of the head and neck, the trunk including the genital area, the upper limbs, and the lower limbs including the buttocks; (b) assessing the extent of atopic dermatitis in selected body regions and assigning an area score based on the extent of atopic dermatitis in the selected body regions; (c) Rate the severity of each of the following symptoms in selected body areas: 1. Erythema, 2. Edema and / or papule formation, 3. Epidermal peeling, and 4. Lichenification and assigning a severity score to each symptom in selected body regions; (d) determining a total score for the selected body region based on the region score in the selected body region and the severity score for each symptom; (e) repeating steps (b) through (d) for each of the remaining body regions; and (f) Determining a baseline EASI score based on the total score for each body domain.

[0245] The post-administration EASI and / or further post-administration EASI may be determined at least about 113 days after administration of the first injection of the antibody or fragment thereof, and the post-administration EASI and / or further post-administration EASI may be EASI50, EASI75, EASI90, or EASI100. The post-administration EASI and / or further post-administration EASI may be determined at least about 169 days after administration of the first injection of the antibody or fragment thereof, and the post-administration EASI and / or further post-administration EASI may be EASI50, EASI75, EASI90, or EASI100. The post-administration EASI and / or further post-administration EASI may be determined at least about 253 days after administration of the first injection of the antibody or fragment thereof, and the post-administration EASI and / or further post-administration EASI may be EASI50, EASI75, EASI90, or EASI100. Atopic dermatitis may be treated as evidenced by a reduction in EASI score of at least 40% after the third injection as a treatment dose, wherein the reduction in EASI score persists for at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after administration of the last injection as a treatment dose.

[0246] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in a decrease in EASI score. Some embodiments include methods of treatment that result in at least about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more decrease in EASI score from baseline 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, 253 days or more after administration of the anti-OX40L antibody or antigen-binding fragment thereof (e.g., after a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by subcutaneous administration of 250 mg of the anti-OX40L antibody or antigen-binding fragment thereof). The post-administration EASI score is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% relative to the baseline EASI score. The reduction in the post-administration EASI score relative to the baseline EASI score can be derived from any baseline EASI score and any post-administration EASI score at any time point or between any time points disclosed herein. In certain exemplary embodiments, administration of an anti-OX40L antibody or antigen-binding fragment thereof to a subject optionally results in a reduction in the EASI score from baseline of at least 15%, at least 20%, or at least 30%, approximately 113 days after the first administration of the anti-OX40L antibody or antigen-binding fragment thereof. In certain exemplary embodiments, administration of an anti-OX40L antibody or antigen-binding fragment thereof to a subject optionally results in a decrease from baseline in EASI score of at least 40% or at least 45% approximately 113 days after the first administration of the anti-OX40L antibody or antigen-binding fragment thereof.

[0247] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in a reduction in EASI score of equal to or greater than the minimal clinically important difference (MCID) on or after 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, 253 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof (e.g., after a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by subcutaneous administration of 250 mg of the anti-OX40L antibody or antigen-binding fragment thereof).

[0248] Investigator's Global Assessment - Atopic Dermatitis (IGA-AD) The IGA-AD scale, which ranges from 0 to 4, is assigned by a physician and was developed by Eli Lilly in collaboration with several atopic dermatitis clinical experts, and has been reviewed and agreed upon by the FDA. Methods for determining IGA-AD scores are known and can be as described below and / or in the Examples, where applicable.

[0249] A summary of the various score assignments is given in Table 1a below.

[0250] [Table 1]

[0251] Thus, a decrease in IGA-AD score is associated with an improvement in signs and / or symptoms.

[0252] Baseline score - IGA-AD Atopic dermatitis may be assessed by determining a baseline IGA-AD score. Determining a baseline IGA-AD score involves: (a) The morphological description that best fits is: No inflammatory signs of atopic dermatitis (no erythema, no induration / papular formation, no lichenification, no weeping / crusting); post-inflammatory hyperpigmentation and / or hypopigmentation may be present assign a score of 0 - no problem - if (b) The morphological description that best fits is: Barely perceptible erythema and / or barely perceptible induration / papule formation, no weeping or crusting assign a score of 1 - almost no problems - if (c) The morphological description that best fits is: slight but definite erythema (light pink) and / or slight but definite induration / papule formation, no weeping or crusting assign a score of 2 (mild) if (d) The morphological description that best fits is: There may be clearly visible erythema (dull red color) and / or clearly visible induration / papular formation, oozing, and crusting assign a score of 3 (moderate) if (e) The morphological description that best fits is: Marked erythema (deep or pale red) and / or marked induration / papular formation; disease is widespread; weeping or crusting may be present If the condition is severe, assign a score of 4 (severe). This may involve describing the overall appearance of AD lesions at a given time point.

[0253] The baseline IGA-AD score can be any score that indicates moderate to severe AD. The baseline IGA-AD score can be 3 or 4.

[0254] The first injection of the anti-OX40L antibody or fragment thereof can be administered on the same day that the baseline IGA-AD score is determined.

[0255] Some embodiments of the method may further include determining a baseline IGA-AD score.

[0256] Clinical Outcome-IGA-AD Some embodiments of the method may further include assessing atopic dermatitis by determining a post-administration IGA-AD score at least 15 days after administration of the first injection of the antibody or fragment thereof. Obtaining a post-administration IGA-AD score at least 7 days or at least 15 days after administration of the first injection of the antibody or fragment thereof is expected to be the earliest reliably observable change in the IGA-AD score due to the action of the antibody or fragment thereof, although any clinically appropriate delay between administration and assessment can be utilized. The post-administration IGA-AD score can be determined at least approximately 7 days, at least approximately 15 days, at least approximately 29 days, at least approximately 57 days, at least approximately 85 days, at least approximately 113 days, at least approximately 169 days, and / or at least approximately 253 days after administration of the first injection of the antibody or fragment thereof. The post-administration IGA-AD score can be determined at about 7 days, about 15 days, about 29 days, about 57 days, about 85 days, about 113 days, about 169 days, and / or about 253 days after administration of the first injection of the antibody or fragment thereof. The post-administration IGA-AD score can be determined at the end of the induction phase.

[0257] The post-administration IGA-AD score can be 0 or 1. The post-administration IGA-AD score may indicate that AD is no longer severe AD. The post-administration IGA-AD score may indicate that AD is no longer moderate AD. The post-administration IGA-AD score may indicate that AD is little to no problem. The post-administration IGA-AD score is reduced by at least 1 point, at least 2 points, at least 3 points, or up to 4 points relative to the baseline IGA-AD score. The post-administration IGA-AD score is reduced by at least 2 points relative to the baseline IGA-AD score. The post-administration IGA-AD score is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% relative to the baseline IGA-AD score. The post-administration IGA-AD score was calculated without additional administration of the anti-OX40L antibody or its antigen-binding fragment. (a) at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after the administration of the last injection; or (b) at least about 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, or 253 days It can be maintained.

[0258] Some embodiments of the method may further include assessing atopic dermatitis by determining one or more additional post-administration IGA-AD scores. The one or more additional post-administration IGA-AD scores may be determined at least about 15 days, at least about 29 days, at least about 57 days, at least about 85 days, at least about 113 days, at least about 169 days, and / or at least about 253 days after administration of the first injection of the antibody or fragment thereof. The one or more additional post-administration IGA-AD scores may be determined at about 29 days, at about 57 days, at about 85 days, at about 113 days, at about 169 days, and / or at least about 253 days after administration of the first injection of the antibody or fragment thereof. The one or more additional post-administration IGA-AD scores may be determined at the end of the induction phase.

[0259] The one or more additional post-administration IGA-AD scores can be 0 or 1. The one or more additional post-administration IGA-AD scores can indicate that AD is no longer severe AD. The one or more additional post-administration IGA-AD scores can indicate that AD is no longer moderate AD. The one or more additional post-administration IGA-AD scores can indicate that AD is little to no problem. The one or more additional post-administration IGA-AD scores can be reduced by at least 1 point, at least 2 points, at least 3 points, or up to 4 points relative to the baseline IGA-AD score. The one or more additional post-administration IGA-AD scores can be reduced by at least 2 points relative to the baseline IGA-AD score.

[0260] Determining the post-administration IGA-AD score and / or one or more additional post-administration IGA-AD scores includes: (a) The morphological description that best fits is: No inflammatory signs of atopic dermatitis (no erythema, no induration / papule formation, no weeping / crusting), although post-inflammatory hyperpigmentation and / or hypopigmentation may be present assign a score of 0 - no problem - if (b) The morphological description that best fits is: Barely perceptible erythema and / or barely perceptible induration / papule formation, no weeping or crusting assign a score of 1 - almost no problems - if (c) The morphological description that best fits is: slight but definite erythema (light pink) and / or slight but definite induration / papule formation, no weeping or crusting assign a score of 2 (mild) if (d) The morphological description that best fits is: There may be clearly visible erythema (dull red color) and / or clearly visible induration / papular formation, oozing, and crusting assign a score of 3 (moderate) if (e) The morphological description that best fits is: Marked erythema (deep or pale red) and / or marked induration / papular formation; disease is widespread; weeping or crusting may be present If the condition is severe, assign a score of 4 (severe). This may include describing the overall appearance of AD lesions at a given time point by:

[0261] The post-administration IGA-AD and / or further post-administration IGA-AD may be determined at least about 113 days after administration of the first injection of the antibody or fragment thereof, and the post-administration IGA-AD and / or further post-administration IGA-AD may be determined at least about 113 days after administration of the first injection of the antibody or fragment thereof. (a) may have an IGA-AD score of 0 or 1; and / or (b) at least a 2-point reduction relative to the baseline IGA-AD score;

[0262] The post-administration IGA-AD and / or further post-administration IGA-AD may be determined at least about 169 days after administration of the first injection of the antibody or fragment thereof, and the post-administration IGA-AD and / or further post-administration IGA-AD may be determined at least about 169 days after administration of the first injection of the antibody or fragment thereof. (a) may have an IGA-AD score of 0 or 1; and / or (b) at least a 2-point reduction relative to the baseline IGA-AD score;

[0263] The post-administration IGA-AD and / or further post-administration IGA-AD may be determined at least about 253 days after administration of the first injection of the antibody or fragment thereof, and the post-administration IGA-AD and / or further post-administration IGA-AD may be determined at least about 253 days after administration of the first injection of the antibody or fragment thereof. (a) may have an IGA-AD score of 0 or 1; and / or (b) at least a 2-point reduction relative to the baseline IGA-AD score;

[0264] Atopic dermatitis may be treated as evidenced by a reduction in IGA-AD score of at least 2 points after the third injection as a treatment dose, wherein the reduction in IGA-AD score persists for at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after administration of the last injection as a treatment dose.

[0265] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in a decrease in IGA-AD score. Some embodiments include methods of treatment that result in at least about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more decrease in IGA-AD score from baseline 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, 253 days or more after administration of the anti-OX40L antibody or antigen-binding fragment thereof (e.g., after a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by subcutaneous administration of 250 mg of the anti-OX40L antibody or antigen-binding fragment thereof). The post-administration IGA-AD score is reduced by at least at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% relative to the baseline EASI score. The reduction in the post-administration IGA-AD score relative to the baseline IGA-AD score can be derived from any baseline IGA-AD score and any post-administration IGA-AD score at any time point or between any time points disclosed herein. In certain exemplary embodiments, administration of an anti-OX40L antibody or antigen-binding fragment thereof to a subject optionally results in a reduction in the IGA-AD score from baseline of at least 15%, at least 20%, or at least 30%, approximately 113 days after the first administration of the anti-OX40L antibody or antigen-binding fragment thereof.

[0266] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in a reduction in IGA-AD score of equal to or greater than the minimal clinically important difference (MCID) on or after 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, 253 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof (e.g., after a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by subcutaneous administration of 250 mg of the anti-OX40L antibody or antigen-binding fragment thereof).

[0267] Validated Investigator Global Assessment-Atopic Dermatitis (vIGA-AD) The vIGA-AD scale, ranging from 0 to 4, is assigned by a physician, was developed by Eli Lilly in collaboration with several atopic dermatitis clinical experts, and was reviewed and agreed upon by the FDA. Further information can be found in Simpson et al., "The Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD): The development and reliability testing of a novel clinical outcome measurement instrument for the severity of atopic dermatitis," J. Am. Acad. Dermatol., 2020 Sep;83(3):839-846. doi: 10.1016·j.jaad.2020.04.104. Epub 2020 Apr 25. The vIGA-AD scale corresponds to the IGA-AD scale but also takes lichenification into account. Methods for determining the vIGA-AD score are known and, where applicable, can be as described below and / or in the Examples.

[0268] A summary of the various score assignments is provided in Table 1b below.

[0269] [Table 2]

[0270] Thus, a decrease in vIGA-AD score is associated with an improvement in signs and / or symptoms.

[0271] Baseline score - vIGA-AD Atopic dermatitis can be assessed by determining a baseline vIGA-AD score. Determining a baseline vIGA-AD score can be (a) The morphological description that best fits is: No inflammatory signs of atopic dermatitis (no erythema, no induration / papules, no lichenification, no weeping / crusting); post-inflammatory hyperpigmentation and / or pigmentation may be present assign a score of 0 - no problem - if (b) The morphological description that best fits is: Barely perceptible erythema, barely perceptible induration / papule, and / or minimal lichenification; no weeping or crusting assign a score of 1 - almost no problems - if (c) The morphological description that best fits is: Slight but distinct erythema (pink), slight but distinct induration / papule, and / or slight but distinct lichenification; no weeping or crusting assign a score of 2 - mild - if (d) The morphological description that best fits is: Visible erythema (dull red), visible induration / papule, and / or visible lichenification; weeping and crusting may be present assign a score of 3 (moderate) if (e) The morphological description that best fits is: Marked erythema (deep or bright red), marked induration / papules, and / or marked lichenification; disease is widespread; weeping or crusting may be present If the condition is severe, assign a score of 4 (severe). This may include describing the overall appearance of AD lesions at a given time point by:

[0272] The baseline vIGA-AD score is any score that indicates moderate to severe AD. The baseline vIGA-AD score is 3 or 4.

[0273] The first injection of the anti-OX40L antibody or fragment thereof can be administered on the same day that the baseline vIGA-AD score is determined.

[0274] Some embodiments of the method may further include determining a baseline vIGA-AD score.

[0275] Clinical Outcome-vIGA-AD Some embodiments of the method can further include assessing atopic dermatitis by determining a post-administration vIGA-AD score at least 15 days after the first injection of the antibody or fragment thereof. Obtaining a post-administration vIGA-AD score at least 7 days or at least 15 days after the first injection of the antibody or fragment thereof is expected to be the earliest time at which a change in the vIGA-AD score due to the action of the antibody or fragment thereof can be reliably observed, although any clinically appropriate delay between administration and assessment can be employed. The post-administration vIGA-AD score can be determined at least approximately 7 days, at least approximately 15 days, at least approximately 29 days, at least approximately 57 days, at least approximately 85 days, at least approximately 113 days, at least approximately 169 days, and / or at least approximately 253 days after the first injection of the antibody or fragment thereof. The post-administration vIGA-AD score can be determined at least about 7 days, about 15 days, about 29 days, about 57 days, about 85 days, about 113 days, about 169 days, and / or about 253 days after administration of the first injection of the antibody or fragment thereof. The post-administration vIGA-AD score can be determined at the end of the run-in phase.

[0276] The post-administration vIGA-AD score is 0 or 1. The post-administration vIGA-AD score can indicate that AD is no longer severe AD. The post-administration vIGA-AD score can indicate that AD is no longer moderate AD. The post-administration vIGA-AD score can indicate that AD is little to no problem. The post-administration vIGA-AD score is reduced by at least 1 point, at least 2 points, at least 3 points, or up to 4 points relative to the baseline vIGA-AD score. The post-administration vIGA-AD score is reduced by at least 2 points relative to the baseline vIGA-AD score. The post-administration vIGA-AD score is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% relative to the baseline vIGA-AD score. Post-administration vIGA-AD scores, without additional administration of anti-OX40L antibody or its antigen-binding fragment: (a) at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after the administration of the last injection; or (b) at least about 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, or 253 days be maintained.

[0277] Some embodiments of the method can further include assessing atopic dermatitis by determining one or more additional post-administration vIGA-AD scores. The one or more additional post-administration vIGA-AD scores can be determined at least about 15 days, at least about 29 days, at least about 57 days, at least about 85 days, at least about 113 days, at least about 169 days, and / or at least about 253 days after the administration of the first injection of the antibody or fragment thereof. The one or more additional post-administration vIGA-AD scores can be determined at least about 29 days, at least about 57 days, at least about 85 days, at least about 113 days, at least about 169 days, and / or at least about 253 days after the administration of the first injection of the antibody or fragment thereof. The one or more additional post-administration vIGA-AD scores can be determined at the end of the induction phase.

[0278] The vIGA-AD score after one or more additional administrations is 0 or 1. The vIGA-AD score after one or more additional administrations can indicate that AD is no longer severe AD. The vIGA-AD score after one or more additional administrations can indicate that AD is no longer moderate AD. The vIGA-AD score after one or more additional administrations can indicate that AD is little to no problem. The vIGA-AD score after one or more additional administrations is reduced by at least 1 point, at least 2 points, at least 3 points, or up to 4 points relative to the baseline vIGA-AD score. The vIGA-AD score after one or more additional administrations is reduced by at least 2 points relative to the baseline vIGA-AD score.

[0279] Determining the post-dose vIGA-AD score and / or one or more additional post-dose vIGA-AD scores includes: (a) The morphological description that best fits is: No inflammatory signs of atopic dermatitis (no erythema, no induration / papules, no lichenification, no weeping / crusting); post-inflammatory hyperpigmentation and / or pigmentation may be present assign a score of 0 - no problem - if (b) The morphological description that best fits is: Barely perceptible erythema, barely perceptible induration / papule, and / or minimal lichenification; no weeping or crusting assign a score of 1 - almost no problems - if (c) The morphological description that best fits is: Slight but distinct erythema (pink), slight but distinct induration / papule, and / or slight but distinct lichenification; no weeping or crusting assign a score of 2 - mild - if (d) The morphological description that best fits is: Visible erythema (dull red), visible induration / papule, and / or visible lichenification; weeping and crusting may be present assign a score of 3 (moderate) if (e) The morphological description that best fits is: Marked erythema (deep or bright red), marked induration / papules, and / or marked lichenification; disease is widespread; weeping or crusting may be present If the condition is severe, assign a score of 4 (severe). This may include describing the overall appearance of AD lesions at a given time point by:

[0280] The post-administration vIGA-AD and / or further post-administration vIGA-AD can be determined at least about 113 days after administration of the first injection of the antibody or fragment thereof, and the post-administration vIGA-AD and / or further post-administration vIGA-AD is: (a) a vIGA-AD score of 0 or 1; and / or (b) at least a 2-point reduction relative to the baseline vIGA-AD score;

[0281] The post-administration vIGA-AD and / or further post-administration vIGA-AD can be determined at least about 169 days after administration of the first injection of the antibody or fragment thereof, and the post-administration vIGA-AD and / or further post-administration vIGA-AD is: (a) a vIGA-AD score of 0 or 1; and / or (b) at least a 2-point reduction relative to the baseline vIGA-AD score;

[0282] The post-dose vIGA-AD and / or further post-dose vIGA-AD can be determined at least about 253 days after administration of the first injection of the antibody or fragment thereof, and the post-dose vIGA-AD and / or further post-dose vIGA-AD is: (a) a vIGA-AD score of 0 or 1; and / or (b) at least a 2-point reduction relative to the baseline vIGA-AD score;

[0283] Atopic dermatitis can be treated as evidenced by a reduction in the vIGA-AD score of at least 2 points after the third injection as a treatment dose, wherein the reduction in the vIGA-AD score persists for at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after administration of the last injection as a treatment dose.

[0284] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in a decrease in the vIGA-AD score. Some embodiments include methods of treatment that result in at least about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more decrease in the vIGA-AD score from baseline on or after 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, 253 days or more after administration of the anti-OX40L antibody or antigen-binding fragment thereof (e.g., after a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by subcutaneous administration of 250 mg of the anti-OX40L antibody or antigen-binding fragment thereof). The post-administration vIGA-AD score is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% relative to the baseline vIGA-AD score. The reduction in the post-administration vIGA-AD score relative to the baseline vIGA-AD score can be derived from any baseline vIGA-AD score and any post-administration vIGA-AD score at any time point or between any time points disclosed herein. In certain exemplary embodiments, administration of an anti-OX40L antibody or antigen-binding fragment thereof to a subject optionally results in a reduction in the vIGA-AD score from baseline of at least 15%, at least 20%, or at least 30%, approximately 113 days after the first administration of the anti-OX40L antibody or antigen-binding fragment thereof.

[0285] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in a reduction in vIGA-AD score that is equal to or exceeds the minimal clinically important difference (MCID) on days 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, 253 or more after administration of the anti-OX40L antibody or antigen-binding fragment thereof (e.g., after a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by subcutaneous administration of 250 mg of the anti-OX40L antibody or antigen-binding fragment thereof).

[0286] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in problem-free skin for at least 113 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof (e.g., after a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by subcutaneous administration of 250 mg of the anti-OX40L antibody or antigen-binding fragment thereof).

[0287] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in problem-free skin for at least 169 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof (e.g., after a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by subcutaneous administration of 250 mg of the anti-OX40L antibody or antigen-binding fragment thereof).

[0288] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in problem-free skin for at least 253 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof (e.g., after a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by subcutaneous administration of 250 mg of the anti-OX40L antibody or antigen-binding fragment thereof).

[0289] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in substantially problem-free skin for at least 113 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof (e.g., after a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by subcutaneous administration of 250 mg of the anti-OX40L antibody or antigen-binding fragment thereof).

[0290] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in substantially problem-free skin for at least 169 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof (e.g., after a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by subcutaneous administration of 250 mg of the anti-OX40L antibody or antigen-binding fragment thereof).

[0291] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in substantially problem-free skin for at least 253 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof (e.g., after a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by subcutaneous administration of 250 mg of the anti-OX40L antibody or antigen-binding fragment thereof).

[0292] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in problem-free or nearly problem-free skin for at least 113 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof (e.g., after a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by subcutaneous administration of 250 mg of the anti-OX40L antibody or antigen-binding fragment thereof).

[0293] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in problem-free or nearly problem-free skin for at least 169 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof (e.g., after a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by subcutaneous administration of 250 mg of the anti-OX40L antibody or antigen-binding fragment thereof).

[0294] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in problem-free or nearly problem-free skin for at least 253 days after administration of the anti-OX40L antibody or antigen-binding fragment thereof (e.g., after a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by subcutaneous administration of 250 mg of the anti-OX40L antibody or antigen-binding fragment thereof).

[0295] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in problem-free or nearly problem-free skin at least two months after administration of the last injection.

[0296] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in problem-free or nearly problem-free skin at least three months after administration of the last injection.

[0297] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in problem-free or nearly problem-free skin at least four months after administration of the last injection.

[0298] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in problem-free or nearly problem-free skin at least 5 months after administration of the last injection.

[0299] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in problem-free or nearly problem-free skin at least six months after administration of the last injection.

[0300] Pruritus Numerical Rating Scale (NRS) The Numerical Rating Scale (NRS) for pruritus is described in Reich et al., Acta Derm Venereol 2016 Nov. 2;96(7):978-980. As used herein, the terms "pruritus" and "itch" are interchangeable. Methods for determining an NRS score are known and are described below and / or in the Examples, as appropriate. Determining an NRS score involves a subject providing a numerical rating of their worst itch in the past 24 hours on a scale of "0" (no itch) to "10" (worst imaginable itch). In English, the subject is asked the following question: "On a scale of "0" (no itch) to "10" (worst imaginable itch), how was your worst itch in the past 24 hours?" Subjects are asked to mark only one number on a scale from 0 to 10.

[0301] The mean absolute NRS score was calculated for the week, i.e., the current day and the preceding 6 days, if at least four values ​​were available. Absolute change from baseline was calculated for these means. The baseline value was the value assessed on day 1. The value at early termination was the value on the actual day the early termination visit occurred.

[0302] The most appropriate definition of a responder on the Pruritus NRS is thought to be in the range of 2 to 4 points.

[0303] Baseline Score-NRS: Pruritus / itch Atopic dermatitis can be assessed by determining a baseline NRS score. Determining a baseline NRS score involves the subject providing a numerical rating of their worst itch in the past 24 hours on a scale of 0 to 10, with "0" being no itch and "10" being the worst imaginable itch. Determining a baseline NRS score involves the patient providing a numerical rating of their worst itch in the past 24 hours once daily for seven days, and assessing the average of the numerical values ​​as the baseline NRS score.

[0304] The baseline NRS score is any score associated with moderate to severe cases of AD. While AD is often accompanied by itching, the NRS itself does not measure the severity of AD. Severe AD may not be accompanied by itching. However, itching may contribute to the severity of AD; for example, epidermal peeling is a symptom assessed when determining the EASI score. Therefore, the NRS may be an appropriate descriptive factor for AD. The baseline NRS score can be selected from the group consisting of at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, 6 to 9, and 7 to 8.

[0305] The first injection of the anti-OX40L antibody or fragment thereof can be administered on the same day that the baseline NRS score is determined.

[0306] Some embodiments may further include determining a baseline NRS score.

[0307] Clinical Outcome-NRS: Pruritus / itch Some embodiments may further include assessing atopic dermatitis by determining a post-administration NRS (Numeric Rating Scale) score after administration of the first injection of the antibody or fragment thereof. Any clinically appropriate delay between administration and assessment may be employed. Changes in NRS score are observed rapidly, for example, with JAKi, and some topical creams may provide immediate improvement. The post-administration NRS score may be determined within 2 hours, 6 hours, 12 hours, 24 hours, or 7 days after administration of the first injection of the antibody or fragment thereof. While the onset of effect of the NRS may be more rapidly measurable than other severity measures, the post-administration NRS score may be determined on a time scale similar to one or more other disease severity measures, which is clinically advantageous. The post-administration NRS score may be determined at least approximately 15 days, at least approximately 29 days, at least approximately 57 days, at least approximately 85 days, at least approximately 113 days, at least approximately 169 days, and / or at least approximately 253 days after administration of the first injection of the antibody or fragment thereof. The post-administration NRS score can be determined at least about 15, about 29, about 57, about 85, about 113, about 169, and / or about 253 days after administration of the first injection of the antibody or fragment thereof. The post-administration NRS score is determined at the end of the induction phase.

[0308] The post-administration NRS score is 0 to 7. The post-administration NRS score is reduced by at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, or 10 points relative to the baseline NRS score. The post-administration NRS score is reduced by at least 3 points or at least 4 points relative to the baseline NRS score. The post-administration NRS score is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% ... without additional administration of an anti-OX40L antibody or antigen-binding fragment thereof: (a) at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after the administration of the last injection; or (b) at least about 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, or 253 days be maintained.

[0309] Some embodiments can further include assessing atopic dermatitis by determining one or more additional post-administration NRS scores. The one or more additional post-administration NRS scores can be determined at least about 15 days, at least about 29 days, at least about 57 days, at least about 85 days, at least about 113 days, at least about 169 days, and / or at least about 253 days after administration of the first injection of the antibody or fragment thereof. The one or more additional post-administration NRS scores can be determined at least about 29 days, at least about 57 days, at least about 85 days, at least about 113 days, at least about 169 days, and / or at least about 253 days after administration of the first injection of the antibody or fragment thereof. The one or more additional post-administration NRS scores can be determined at the end of the induction phase.

[0310] The one or more additional post-dose NRS scores are between 0 and 7. The one or more additional post-dose NRS scores are reduced by at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, or 10 points relative to the baseline NRS score. The one or more additional post-dose NRS scores are: (a) at least a 3-point reduction relative to the baseline NRS score, the baseline NRS score being selected from the group consisting of at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, 6 to 9, and 7 to 8; or (b) at least a 4-point reduction relative to the baseline NRS score, the baseline NRS score being selected from the group consisting of at least 4, at least 5, at least 6, at least 7, at least 8, 6-9, and 7-8.

[0311] Determining the post-administration NRS score and / or one or more additional post-administration NRS scores involves the subject providing a numerical rating of their worst itch in the past 24 hours on a scale of 0 to 10, with "0" being no itch and "10" being the worst imaginable itch.

[0312] The post-dose NRS and / or further post-dose NRS can be determined at least about 113 days after administration of the first injection of the antibody or fragment thereof, wherein the post-dose NRS and / or further post-dose NRS is: (a) at least a 3-point reduction relative to the baseline NRS score, the baseline NRS score being selected from the group consisting of at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, 6 to 9, and 7 to 8; or (b) at least a 4-point reduction relative to the baseline NRS score, the baseline NRS score being selected from the group consisting of at least 4, at least 5, at least 6, at least 7, at least 8, 6-9, and 7-8.

[0313] The post-dose NRS and / or further post-dose NRS can be determined at least about 169 days after administration of the first injection of the antibody or fragment thereof, wherein the post-dose NRS and / or further post-dose NRS is: (a) at least a 3-point reduction relative to the baseline NRS score, the baseline NRS score being selected from the group consisting of at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, 6 to 9, and 7 to 8; or (b) at least a 4-point reduction relative to the baseline NRS score, the baseline NRS score being selected from the group consisting of at least 4, at least 5, at least 6, at least 7, at least 8, 6-9, and 7-8.

[0314] The post-dose NRS and / or further post-dose NRS can be determined at least about 253 days after administration of the first injection of the antibody or fragment thereof, wherein the post-dose NRS and / or further post-dose NRS is: (a) at least a 3-point reduction relative to the baseline NRS score, the baseline NRS score being selected from the group consisting of at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, 6 to 9, and 7 to 8; or (b) at least a 4-point reduction relative to the baseline NRS score, the baseline NRS score being selected from the group consisting of at least 4, at least 5, at least 6, at least 7, at least 8, 6-9, and 7-8.

[0315] Atopic dermatitis can be treated as evidenced by a reduction in NRS score of at least 4 points after the third treatment injection, which reduction in NRS score persists for at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after the administration of the final treatment injection.

[0316] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in a decrease in NRS score. Some embodiments include methods of treatment that result in at least about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more decrease in NRS score from baseline on 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, 253 or more days after administration of the anti-OX40L antibody or antigen-binding fragment thereof (e.g., after a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by subcutaneous administration of 250 mg of the anti-OX40L antibody or antigen-binding fragment thereof). The post-administration NRS score is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% relative to the baseline NRS score. The reduction in the post-administration NRS score relative to the baseline NRS score can be derived from any baseline NRS score and any post-administration NRS score at any time point or between any time points disclosed herein. In certain exemplary embodiments, administration of an anti-OX40L antibody or antigen-binding fragment thereof to a subject optionally results in a reduction in the NRS score from baseline of at least 15%, at least 20%, or at least 30%, approximately 113 days after the first administration of the anti-OX40L antibody or antigen-binding fragment thereof.

[0317] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in a reduction in NRS score that is equal to or exceeds the minimal clinically important difference (MCID) on days 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, 253 or more after administration of the anti-OX40L antibody or antigen-binding fragment thereof (e.g., after a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by subcutaneous administration of 250 mg of the anti-OX40L antibody or antigen-binding fragment thereof).

[0318] Patient Oriented (PO) Eczema Evaluation (POEM) The POEM is a seven-item questionnaire used to assess disease symptoms in children and adults. It is described in Charman CR, Venn AJ, Williams HC. The patient-oriented eczema measure: development and initial validation of a new tool for measuring atopic eczema severity from the patients' perspective. Arch Dermatol. 2004 December;140(12):1513-9. Methods for determining the POEM score are known and are described below and / or in the Examples, as appropriate.

[0319] Seven symptoms (dryness, itching, peeling, cracking, insomnia, bleeding, and weeping) are rated on a 5-point scale based on frequency of occurrence over the past week. Each of the seven questions has equal weighting and is scored from 0 to 4. Possible scores for each question are: 0 (none), 1 (1-2 days), 2 (3-4 days), 3 (5-6 days), and 4 (every day). The maximum total score is 28. If any question is left unanswered, a score of 0 is recorded, and the total is added up to a maximum of 28 points, expressed as a standard score. If two or more questions are left unanswered, the questionnaire is not scored. If more than one answer option is selected, the answer option with the highest score is recorded.

[0320] Higher scores indicate poorer quality of life: 0-2 indicates fair or minimally fair skin, 3-7 indicates mild eczema, 8-16 indicates moderate eczema, 17-24 indicates severe eczema, and 25-28 indicates very severe eczema. The overall mean MCID for the POEM is considered to be 3.4 points.

[0321] Baseline Score - POEM Atopic dermatitis can be assessed by determining baseline POEM (Patient Oriented Eczema Scale) score.Determining baseline POEM score includes frequency assessment of subjects for the frequency of the following events caused by eczema over the last week: i. itchy skin, ii. sleep disorders, iii. Bleeding skin, iv. Skin that oozes or exudes a clear fluid; v. Cracked skin, vi. peeling skin, vii. Dry or rough-feeling skin.

[0322] The frequency rating is: i. "None", ii. "1-2 days"; iii. "3-4 days", iv. "5-6 days," and v. "Every day" It can be selected from the group consisting of:

[0323] The method comprises: Assigning a frequency rating score to each frequency rating, with "every day" assigned a score of 4, "5-6 days" assigned a score of 3, "3-4 days" assigned a score of 2, "1-2 days" assigned a score of 1, and "never" assigned a score of 0; and The method may further include summing the frequency rating scores to calculate a POEM score.

[0324] A baseline POEM score of 0-2 indicates no or little eczema; a baseline POEM score of 3-7 indicates mild eczema; a baseline POEM score of 8-16 indicates moderate eczema; a baseline POEM score of 17-24 indicates severe eczema, and a baseline POEM score of 25-28 indicates very severe eczema.

[0325] The baseline POEM score is any score that indicates moderate to severe or very severe AD. The baseline POEM score can be selected from the group consisting of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, 8-28, 8-24, 8-16, 17-24, and 25-28.

[0326] The first injection of the anti-OX40L antibody or fragment thereof can be administered on the same day that the baseline POEM score is determined.

[0327] Some embodiments may further include determining a baseline POEM score.

[0328] Clinical Outcome-POEM Some embodiments can further include assessing atopic dermatitis by determining a post-administration POEM score at least 15 days after administration of the first injection of the antibody or fragment thereof. Obtaining a post-administration POEM score at least 7 days or at least 15 days after administration of the first injection of the antibody or fragment thereof is expected to be the earliest time at which a change in the POEM score due to the action of the antibody or fragment thereof can be reliably observed, although any clinically appropriate delay between administration and assessment can be employed. The post-administration POEM score can be determined at least approximately 7 days, at least approximately 15 days, at least approximately 29 days, at least approximately 57 days, at least approximately 85 days, at least approximately 113 days, at least approximately 169 days, and / or at least approximately 253 days after administration of the first injection of the antibody or fragment thereof. The post-administration POEM score can be determined about 7 days, about 15 days, about 29 days, about 57 days, about 85 days, about 113 days, about 169 days, and / or about 253 days after administration of the first injection of the antibody or fragment thereof. The post-administration POEM score can be determined at the end of the induction phase.

[0329] The post-administration POEM score can be selected from the group consisting of 0-2; 3-7; 8-16; 17-24, and 25-28. The post-administration POEM score can indicate that AD is no longer very severe. The post-administration POEM score can indicate that AD is no longer severe. The post-administration POEM score can indicate that AD is no longer moderate. The post-administration POEM score can indicate that AD is mild. The post-administration POEM score can indicate that AD is barely causing any problems. The post-administration POEM score is reduced by at least 2 points, at least 3 points, at least 3.4 points, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, or 10 points relative to the baseline POEM score. The post-administration POEM score is reduced by at least 2 points or at least 3 points relative to the baseline POEM score. The post-administration POEM score is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% relative to the baseline POEM score. The post-administration POEM score is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% relative to the baseline POEM score without further administration of the anti-OX40L antibody or antigen-binding fragment thereof. (a) at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after the administration of the last injection; or (b) at least about 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, or 253 days be maintained.

[0330] Some embodiments can further include assessing atopic dermatitis by determining one or more additional post-administration POEM scores. The one or more additional post-administration POEM scores can be determined at least about 15 days, at least about 29 days, at least about 57 days, at least about 85 days, at least about 113 days, at least about 169 days, and / or at least about 253 days after administration of the first injection of the antibody or fragment thereof. The one or more additional post-administration POEM scores can be determined at least about 29 days, at least about 57 days, at least about 85 days, at least about 113 days, at least about 169 days, and / or at least about 253 days after administration of the first injection of the antibody or fragment thereof. The one or more additional post-administration POEM scores can be determined at the end of the induction phase.

[0331] The one or more additional post-administration POEM scores can be selected from the group consisting of 0 to 2; 3 to 7; 8 to 16; 17 to 24, and 25 to 28. The one or more additional post-administration POEM scores can indicate that AD is no longer very severe AD. The one or more additional post-administration POEM scores can indicate that AD is no longer severe AD. The one or more additional post-administration POEM scores can indicate that AD is no longer moderate AD. The one or more additional post-administration POEM scores can indicate that AD is mild AD. The one or more additional post-administration POEM scores can indicate that AD is barely causing any problems. The one or more additional post-administration POEM scores are reduced by at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, or 10 points relative to the baseline POEM score. The one or more additional post-administration POEM scores are reduced by at least 2 points or at least 3 points relative to the baseline POEM score.

[0332] Determining the post-administration POEM score and / or one or more additional post-administration POEM scores includes frequency assessing the subject for how often the following events were caused by eczema over the last week: i. itchy skin, ii. sleep disorders, iii. Bleeding skin, iv. Skin that oozes or exudes a clear fluid; v. Cracked skin, vi. peeling skin, vii. Dry or rough-feeling skin.

[0333] The frequency rating is: i. "None", ii. "1-2 days"; iii. "3-4 days", iv. "5-6 days," and v. "Every day" It can be selected from the group consisting of:

[0334] The method comprises: assigning a frequency rating score to each frequency rating, where "every day" is assigned a score of 4, "5-6 days" is assigned a score of 3, "3-4 days" is assigned a score of 2, "1-2 days" is assigned a score of 1, and "never" is assigned a score of 0; and The method may further include summing the frequency rating scores to calculate a POEM score.

[0335] The post-dose POEM and / or further post-dose POEM can be determined at least about 113 days after administration of the first injection of the antibody or fragment thereof, and the post-dose POEM and / or further post-dose POEM is reduced by at least 2 points or at least 3 points relative to the baseline POEM score.

[0336] The post-dose POEM and / or further post-dose POEM can be determined at least about 169 days after administration of the first injection of the antibody or fragment thereof, and the post-dose POEM and / or further post-dose POEM is reduced by at least 2 points or at least 3 points relative to the baseline POEM score.

[0337] The post-dose POEM and / or further post-dose POEM can be determined at least about 253 days after administration of the first injection of the antibody or fragment thereof, and the post-dose POEM and / or further post-dose POEM is reduced by at least 2 points or at least 3 points relative to the baseline POEM score.

[0338] Atopic dermatitis can be treated as evidenced by a reduction in the POEM score of at least 2 points after the third treatment injection, which reduction in the POEM score persists for at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after the administration of the final treatment injection.

[0339] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in a decrease in POEM score. Some embodiments include methods of treatment that result in at least about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more decrease in POEM score from baseline on 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, 253 or more days after administration of the anti-OX40L antibody or antigen-binding fragment thereof (e.g., after a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by subcutaneous administration of 250 mg of the anti-OX40L antibody or antigen-binding fragment thereof). The post-administration POEM score is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% relative to the baseline POEM score. The reduction in the post-administration POEM score relative to the baseline POEM score can be derived from any baseline POEM score and any post-administration POEM score at any time point or between any time points disclosed herein. In certain exemplary embodiments, administration of an anti-OX40L antibody or antigen-binding fragment thereof to a subject optionally results in a reduction in the POEM score from baseline of at least 15%, at least 20%, or at least 30%, approximately 113 days after the first administration of the anti-OX40L antibody or antigen-binding fragment thereof.

[0340] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in a reduction in POEM score that is equal to or exceeds the minimal clinically important difference (MCID) on days 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, 253 or more after administration of the anti-OX40L antibody or antigen-binding fragment thereof (e.g., after a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by subcutaneous administration of 250 mg of the anti-OX40L antibody or antigen-binding fragment thereof).

[0341] Affected body surface area (BSA) The extent of AD can also be described using BSA. Methods for determining BSA scores are known and are described below and / or in the Examples, as appropriate. BSA typically uses the "rule of nines" to divide body area into 9% (or fractions thereof) - see Table 2 below. As shown in Table 2, different calculations can be performed because children and adults have different body proportions. The area of ​​each individual area is calculated and then summed.

[0342] [Table 3]

[0343] BSA or its variants are part of EASI, SCORAD and POSCORAD.Because patients may have a large coverage even with low-grade disease, or may have limited coverage even with high-grade disease, which is often more clinically problematic, BSA itself can not characterize disease severity.Nevertheless, after treatment, the reduction of BSA from baseline can indicate clinical improvement, if AD severity does not increase in areas that still show AD involvement (possibly measured by alternative methods described herein).

[0344] Baseline score - BSA Atopic dermatitis has been assessed by determining a baseline BSA (body surface area) score. Determining a baseline BSA score involves: (a) Assigning a BSA value to each of the following body parts: (a) The entire left arm, (b) the entire right arm, (c) Entire head; (d) Entire chest; (e) Entire abdomen; (f) Entire back; (g) Entire left leg; (h) the entire right leg, and (i) Inguinal area, (b) To assess the proportion of each body part affected by atopic dermatitis: (c) multiplying the proportion of each body part affected by dermatitis by the BSA value for that body part to obtain an affected BSA value for each body part; and (d) Sum the affected BSA values ​​of the body parts to obtain a BSA score. Includes.

[0345] The baseline BSA score is any score associated with moderate to severe AD cases. BSA itself is not a measure of AD severity. A low severity level may have a high degree of coverage, which means that the overall severity of AD is not very high. However, BSA may contribute to the severity of AD; for example, assigning a percentage of body surface area is part of the EASI score determination. Therefore, BSA may be an appropriate descriptive factor for AD. The baseline BSA score is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%.

[0346] The first injection of anti-OX40L antibody or fragment thereof can be administered on the same day that the baseline BSA score is determined.

[0347] Some embodiments may further include determining a baseline BSA score.

[0348] Clinical Outcome-BSA Some embodiments can further include assessing atopic dermatitis by determining a post-administration BSA score at least 15 days after administration of the first injection of the antibody or fragment thereof. Obtaining a post-administration BSA score at least 7 days or at least 15 days after administration of the first injection of the antibody or fragment thereof is expected to be the earliest time at which a change in the BSA score due to the action of the antibody or fragment thereof can be reliably observed, although any clinically appropriate delay between administration and assessment can be employed. The post-administration BSA score can be determined at least approximately 7 days, at least approximately 15 days, at least approximately 29 days, at least approximately 57 days, at least approximately 85 days, at least approximately 113 days, at least approximately 169 days, and / or at least approximately 253 days after administration of the first injection of the antibody or fragment thereof. The post-administration BSA score can be determined about 7 days, about 15 days, about 29 days, about 57 days, about 85 days, about 113 days, about 169 days, and / or about 253 days after administration of the first injection of antibody or fragment thereof. The post-administration BSA score can be determined at the end of the induction phase.

[0349] The post-administration BSA score can be selected from the group consisting of less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, less than 50%, less than 55%, less than 60%, less than 65%, less than 70%, less than 75%, less than 80%, less than 85%, less than 90%, and less than 95%. The post-administration BSA score can indicate that AD is no longer severe AD. The post-administration BSA score can indicate that AD is no longer moderate AD. The post-administration BSA score can indicate that AD is mild AD. The post-administration BSA score can indicate that AD is almost problem-free. The post-administration BSA score is reduced by at least 2 percentage points, at least 3 percentage points, at least 4 percentage points, at least 5 percentage points, at least 6 percentage points, at least 7 percentage points, at least 8 percentage points, at least 9 percentage points, 10 percentage points, at least 11 percentage points, at least 12 percentage points, at least 13 percentage points, at least 14 percentage points, at least 15 percentage points, at least 20 percentage points, at least 25 percentage points, at least 30 percentage points, at least 40 percentage points, at least 50 percentage points, at least 60 percentage points, at least 70 percentage points, at least 80 percentage points, or at least 90 percentage points relative to the baseline BSA score. The post-administration BSA score is reduced by at least 5 percentage points relative to the baseline BSA score. The post-administration BSA score is reduced by at least 10 percentage points relative to the baseline BSA score, and the baseline BSA score is at least 10%.The post-administration BSA score is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% relative to the baseline BSA score without further administration of the anti-OX40L antibody or antigen-binding fragment thereof. (a) at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after the administration of the last injection; or (b) at least about 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, or 253 days be maintained.

[0350] Some embodiments can further include assessing atopic dermatitis by determining one or more additional post-administration BSA scores. The one or more additional post-administration BSA scores can be determined at least about 15 days, at least about 29 days, at least about 57 days, at least about 85 days, at least about 113 days, at least about 169 days, and / or at least about 253 days after administration of the first injection of the antibody or fragment thereof. The one or more additional post-administration BSA scores can be determined at least about 29 days, at least about 57 days, at least about 85 days, at least about 113 days, at least about 169 days, and / or at least about 253 days after administration of the first injection of the antibody or fragment thereof. The one or more additional post-administration BSA scores can be determined at the end of the induction phase.

[0351] The post-administration BSA score can be selected from the group consisting of less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, less than 50%, less than 55%, less than 60%, less than 65%, less than 70%, less than 75%, less than 80%, less than 85%, less than 90%, and less than 95%. One or more additional post-administration BSA scores can indicate that AD is no longer severe AD. One or more additional post-administration BSA scores can indicate that AD is no longer moderate AD. One or more additional post-administration BSA scores can indicate that AD is mild AD. One or more additional post-administration BSA scores can indicate that AD is barely problematic. The BSA score after one or more further administrations is reduced by at least 2 percentage points, at least 3 percentage points, at least 4 percentage points, at least 5 percentage points, at least 6 percentage points, at least 7 percentage points, at least 8 percentage points, at least 9 percentage points, 10 percentage points, at least 11 percentage points, at least 12 percentage points, at least 13 percentage points, at least 14 percentage points, at least 15 percentage points, at least 20 percentage points, at least 25 percentage points, at least 30 percentage points, at least 40 percentage points, at least 50 percentage points, at least 60 percentage points, at least 70 percentage points, at least 80 percentage points, or at least 90 percentage points relative to the baseline BSA score. The BSA score after one or more additional doses is reduced by at least 10 percentage points relative to the baseline BSA score.

[0352] Determining the post-dose BSA score and / or one or more additional post-dose BSA scores includes: (a) Assigning a BSA value to each of the following body parts: (a) The entire left arm, (b) the entire right arm, (c) Entire head; (d) Entire chest; (e) Entire abdomen; (f) Entire back; (g) Entire left leg; (h) the entire right leg, and (i) Inguinal area, (b) To assess the proportion of each body part affected by atopic dermatitis: (c) multiplying the proportion of each body part affected by dermatitis by the BSA value for that body part to obtain an affected BSA value for each body part; and (d) Sum the affected BSA values ​​of the body parts to obtain a BSA score. Includes:

[0353] The post-administration BSA and / or further post-administration BSA can be determined at least approximately 113 days after administration of the first injection of the antibody or fragment thereof, wherein the post-administration BSA and / or further post-administration BSA is reduced by at least 10 percentage points relative to the baseline BSA score. The post-administration BSA and / or further post-administration BSA can be determined at least approximately 169 days after administration of the first injection of the antibody or fragment thereof, wherein the post-administration BSA and / or further post-administration BSA is reduced by at least 10 percentage points relative to the baseline BSA score. The post-administration BSA and / or further post-administration BSA can be determined at least approximately 253 days after administration of the first injection of the antibody or fragment thereof, wherein the post-administration BSA and / or further post-administration BSA is reduced by at least 10 percentage points relative to the baseline BSA score.

[0354] Atopic dermatitis can be treated as evidenced by a reduction in BSA score of at least 10 percentage points after the third treatment injection, which reduction in BSA score persists for at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after administration of the final treatment injection.

[0355] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in a decrease in BSA score. Some embodiments include methods of treatment that result in at least about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more decrease in BSA score from baseline on or after 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, 253 days or more after administration of the anti-OX40L antibody or antigen-binding fragment thereof (e.g., after a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by subcutaneous administration of 250 mg of the anti-OX40L antibody or antigen-binding fragment thereof). The post-administration BSA score is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% relative to the baseline BSA score. The reduction in the post-administration BSA score relative to the baseline BSA score can be derived from any baseline BSA score and any post-administration BSA score at any time point or between any time points disclosed herein. In certain exemplary embodiments, administration of an anti-OX40L antibody or antigen-binding fragment thereof to a subject optionally results in a reduction in the BSA score from baseline of at least 20%, at least 30%, or at least 35%, approximately 113 days after the first administration of the anti-OX40L antibody or antigen-binding fragment thereof.

[0356] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in a reduction in BSA score that equals or exceeds the minimal clinically important difference (MCID) on days 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, 253 or more after administration of the anti-OX40L antibody or antigen-binding fragment thereof (e.g., after a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by subcutaneous administration of 250 mg of the anti-OX40L antibody or antigen-binding fragment thereof).

[0357] Scoring of the Atopic Dermatitis Index (SCORAD) SCORAD was developed to standardize the assessment of the extent and severity of atopic dermatitis. See Severity scoring of atopic dermatitis: the SCORAD index. Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology. 1993;186(1):23-31. It assesses three components of AD: affected BSA, severity of clinical signs, and symptoms.

[0358] Methods for determining the SCORAD index are known and are as described below and / or in the Examples, as appropriate.

[0359] The extent of AD is assessed as a percentage of each defined body area and reported as a sum of all areas. The maximum score is 100%. The severity of six specific symptoms of AD (redness, swelling, oozing / crusting, peeling, thickened / lichenified skin, and dryness) is assessed using a 4-point scale (i.e., none = 0, mild = 1, moderate = 2, severe = 3) for a maximum total score of 18. Symptoms (itching and insomnia) are recorded by the patient or caregiver on a visual analog scale, with 0 being no symptoms, 10 being the worst imaginable symptoms, and 20 being the maximum score. The maximum SCORAD score is 103, with higher scores indicating worse or more severe conditions.

[0360] An 8.7-point difference in SCORAD has been estimated as the minimal clinically important difference (MCID) for patients with atopic dermatitis (Schram ME, Spuls PI, Leeflang MM, Lindeboom R, Bos JD, Schmitt J. EASI, (objective) SCORAD and POEM for atopic eczema: responsiveness and minimal clinically important difference. Allergy. 2012 Jan;67(1):99-106).

[0361] Baseline score - SCORAD index Atopic dermatitis has been assessed by determining a baseline SCORAD (Scoring Atopic Dermatitis) index. Determining a baseline SCORAD index involves: (a) Estimating the severity of atopic dermatitis as a percentage of body area involvement, resulting in a severity score of "A"; (b) Rate the intensity of the following clinical signs and assign an intensity score of "B": (i) Erythema; (ii) edema / papules; (iii) oozing / eschar; (iv) epidermal abrasion; (v) lichenification, and (vi) drying; (c) Rate the severity of the following symptoms and receive a severity score of "C": (i) pruritus, and (ii) insomnia; and (d) Calculating the baseline SCORAD index using the extent score "A," the intensity score "B," and the severity score "C." Includes.

[0362] Determining the baseline SCORAD index may further include assigning to each clinical sign a sign intensity level selected from the group consisting of: i. "None" ii. "Mild" iii. "moderate," and iv. “Severe”.

[0363] Determining the baseline SCORAD index involves: assigning a symptom intensity score to each symptom intensity level, with "severe" assigned a score of 3, "moderate" assigned a score of 2, "mild" assigned a score of 1, and "none" assigned a score of 0; and The method may further include summing the symptom intensity scores to calculate an intensity score "B."

[0364] Determining the baseline SCORAD index involves the subject or caregiver providing a numerical rating of the severity of pruritus and insomnia symptoms for the past three days and / or past three nights on a scale of 0 to 10, with "0" being no symptoms and "10" being the worst imaginable symptoms. Determining the baseline SCORAD index can further include summing the numerical ratings of the severity of pruritus and insomnia symptoms to calculate a severity score "C."

[0365] Determining the baseline SCORAD index can include calculating the baseline SCORAD index using the following formula: SCORAD index=A / 5+7B / 2+C.

[0366] The baseline SCORAD index is any index that indicates moderate to severe AD. A baseline SCORAD index of 0 to 24 indicates mild disease; a baseline SCORAD index of 25 to 50 indicates moderate disease; and a baseline SCORAD index of 51 to 103 indicates severe disease. The baseline SCORAD index may be at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, or at least 95.

[0367] The first injection of the anti-OX40L antibody or fragment thereof can be administered on the same day that the baseline SCORAD index is determined.

[0368] Some embodiments may further include determining a baseline SCORAD index.

[0369] Clinical Outcome Based - SCORAD Some embodiments can further include assessing atopic dermatitis by determining a post-administration SCORAD index at least 15 days after administration of the first injection of the antibody or fragment thereof. Obtaining a post-administration SCORAD index at least 7 days or at least 15 days after administration of the first injection of the antibody or fragment thereof is expected to be the earliest time at which a change in the SCORAD index due to the action of the antibody or fragment thereof can be reliably observed, although any clinically appropriate delay between administration and evaluation can be employed. The post-administration SCORAD index can be determined at least approximately 7 days, at least approximately 15 days, at least approximately 29 days, at least approximately 57 days, at least approximately 85 days, at least approximately 113 days, at least approximately 169 days, and / or at least approximately 253 days after administration of the first injection of the antibody or fragment thereof. The post-administration SCORAD index can be determined at about 7 days, about 15 days, about 29 days, about 57 days, about 85 days, about 113 days, about 169 days, and / or about 253 days after administration of the first injection of the antibody or fragment thereof. The post-administration SCORAD index can be determined at the end of the induction phase.

[0370] The post-administration SCORAD index can be selected from the group consisting of less than 10, less than 15, less than 20, less than 25, less than 30, less than 35, less than 40, less than 45, less than 50, less than 55, less than 60, less than 65, less than 70, less than 75, less than 80, less than 85, less than 90 and less than 95. The post-administration SCORAD index is reduced by at least 8 points, at least 8.7 points, at least 9 points, 10 points, at least 11 points, at least 12 points, at least 13 points, at least 14 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 40 points, at least 50 points, at least 55 points, at least 60 points, at least 65 points, at least 70 points, at least 80 points or at least 90 points compared to the baseline SCORAD index. The post-administration SCORAD index is reduced by at least 20 points compared to the baseline SCORAD index. The post-administration SCORAD index can indicate that AD is no longer very severe AD. The post-administration SCORAD index can indicate that AD is no longer severe AD. The post-administration SCORAD index can indicate that AD is no longer moderate AD. The post-administration SCORAD index can indicate that AD is mild AD. The post-administration SCORAD index can indicate that AD is barely causing any problems. The post-administration SCORAD index is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% relative to the baseline SCORAD index. The post-administration SCORAD index can be reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% relative to the baseline SCORAD index without additional administration of an anti-OX40L antibody or antigen-binding fragment thereof: (a) at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after the administration of the last injection; or (b) at least about 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, or 253 days be maintained.

[0371] Some embodiments can further include assessing atopic dermatitis by determining a SCORAD index after one or more additional administrations. The SCORAD index after one or more additional administrations can be determined at least about 15 days, at least about 29 days, at least about 57 days, at least about 85 days, at least about 113 days, at least about 169 days, and / or at least about 253 days after administration of the first injection of the antibody or fragment thereof. The SCORAD index after one or more additional administrations can be determined at least about 29 days, at least about 57 days, at least about 85 days, at least about 113 days, at least about 169 days, and / or at least about 253 days after administration of the first injection of the antibody or fragment thereof. The SCORAD index after one or more additional administrations can be determined at the end of the induction phase.

[0372] The SCORAD index after one or more further administrations can be selected from the group consisting of less than 10, less than 15, less than 20, less than 25, less than 30, less than 35, less than 40, less than 45, less than 50, less than 55, less than 60, less than 65, less than 70, less than 75, less than 80, less than 85, less than 90 and less than 95. The SCORAD index after one or more further administrations is reduced by at least 8 points, at least 8.7 points, at least 9 points, 10 points, at least 11 points, at least 12 points, at least 13 points, at least 14 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 40 points, at least 50 points, at least 55 points, at least 60 points, at least 65 points, at least 70 points, at least 80 points or at least 90 points relative to the baseline SCORAD index. The SCORAD index after one or more further administrations is reduced by at least 20 points relative to the baseline SCORAD index. A SCORAD index after one or more further administrations can indicate that AD is no longer very severe AD. A SCORAD index after one or more further administrations can indicate that AD is no longer severe AD. A SCORAD index after one or more further administrations can indicate that AD is no longer moderate AD. A SCORAD index after one or more further administrations can indicate that AD is mild AD. A SCORAD index after one or more further administrations can indicate that AD is barely a problem.

[0373] Determining the post-administration SCORAD index and / or one or more further post-administration SCORAD indices includes: (a) Estimating the severity of atopic dermatitis as a percentage of body area involvement, resulting in a severity score of "A"; (b) Rate the intensity of the following clinical signs and assign an intensity score of "B": (i) Erythema; (ii) edema / papules; (iii) oozing / eschar; (iv) epidermal abrasion; (v) lichenification, and (vi) drying; (c) Rate the severity of the following symptoms and receive a severity score of "C": (i) pruritus, and (ii) insomnia; and (d) Calculating the SCORAD index using the extent score "A," the intensity score "B," and the severity score "C." Includes:

[0374] Determining the post-administration SCORAD index and / or the one or more further post-administration SCORAD indexes can further comprise assigning a clinical intensity level to each clinical sign selected from the group consisting of: i. "None" ii. "Mild" iii. "moderate," and iv. “Severe”.

[0375] Determining the post-administration SCORAD index and / or one or more further post-administration SCORAD indices includes: assigning each symptom intensity level to a symptom intensity score, where a score of 3 is assigned "severe," a score of 2 is assigned "moderate," a score of 1 is assigned "mild," and a score of 0 is assigned "none," and The method may further include summing the symptom intensity scores to calculate an intensity score "B."

[0376] Determining the post-administration SCORAD index and / or one or more additional post-administration SCORAD indices involves the subject or a caregiver providing a numerical rating of the severity of the pruritus and insomnia symptoms for the past three days and / or the past three nights on a scale of 0 to 10, with "0" being no symptoms and "10" being the worst imaginable symptoms. The method can further include summing the numerical ratings of the severity of the pruritus and insomnia symptoms to calculate a severity score "C."

[0377] Determining the post-administration SCORAD index and / or one or more further post-administration SCORAD indexes includes calculating the SCORAD index using the following formula: SCORAD index=A / 5+7B / 2+C.

[0378] The post-administration SCORAD and / or further post-administration SCORAD can be determined at least approximately 113 days after administration of the first injection of the antibody or fragment thereof, wherein the post-administration SCORAD and / or further post-administration SCORAD is reduced by at least 20 points relative to the baseline SCORAD index. The post-administration SCORAD and / or further post-administration SCORAD can be determined at least approximately 169 days after administration of the first injection of the antibody or fragment thereof, wherein the post-administration SCORAD and / or further post-administration SCORAD is reduced by at least 20 points relative to the baseline SCORAD index. The post-administration SCORAD and / or further post-administration SCORAD can be determined at least approximately 253 days after administration of the first injection of the antibody or fragment thereof, wherein the post-administration SCORAD and / or further post-administration SCORAD is reduced by at least 20 points relative to the baseline SCORAD index. Atopic dermatitis can be treated as evidenced by a reduction in the SCORAD index of at least 20 points after the third injection of the treatment dose. The reduction in the SCORAD index persists for at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after administration of the last injection of the treatment dose.

[0379] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in a decrease in the SCORAD index. Some embodiments include methods of treatment that result in at least about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more decrease in the SCORAD index from baseline on or after 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, 253 days or more after administration of the anti-OX40L antibody or antigen-binding fragment thereof (e.g., after a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by subcutaneous administration of 250 mg of the anti-OX40L antibody or antigen-binding fragment thereof). The post-administration SCORAD index is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% relative to the baseline SCORAD index. The reduction in the post-administration SCORAD index relative to the baseline SCORAD index can be derived from any baseline SCORAD index and any post-administration SCORAD index at any time point or between any time points disclosed herein. In certain exemplary embodiments, administration of an anti-OX40L antibody or antigen-binding fragment thereof to a subject optionally results in a reduction in the SCORAD index from baseline of at least 20%, at least 30%, or at least 35%, approximately 113 days after the first administration of the anti-OX40L antibody or antigen-binding fragment thereof.

[0380] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in a reduction in the SCORAD index that is equal to or exceeds the minimal clinically important difference (MCID) on days 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, 253 or more after administration of the anti-OX40L antibody or antigen-binding fragment thereof (e.g., after a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by subcutaneous administration of 250 mg of the anti-OX40L antibody or antigen-binding fragment thereof).

[0381] Patient-oriented scoring of atopic dermatitis (POSCORAD) The POSCORAD is derived from the SCORAD and can be easily used by patients without specific experimentation. It is designed for patients to help patients or caregivers understand the course of their disease and the effects of treatment. The POSCORAD has been validated in several studies, including Vorc'h-Jourdain M, Barbarot S, Taieb A, et al. "Patient-oriented SCORAD: a self-assessment score in atopic dermatitis. A preliminary feasibility study." Dermatology. 2009;218:246-251 and "Stalder JF, Barbarot S, Wollenberg A, et al. Patient-Oriented SCORAD (PO-SCORAD): a new self-assessment scale in atopic dermatitis validated in Europe." Allergy. 2011;66:1114-1121.

[0382] POSCORAD is available as software for mobile devices and computers. By using the POSCORAD software on a regular basis (weekly), patients can create a curve that depicts the variability of their disease between visits.

[0383] Methods for determining the PO-SCORAD index are known and are described below and / or in the Examples, as appropriate.

[0384] Baseline Score - PO-SCORAD Atopic dermatitis has been assessed by determining a baseline PO-SCORAD (Patient-Oriented Scoring of Atopic Dermatitis) index. Determining a baseline PO-SCORAD index involves: (a) Estimating the severity of atopic dermatitis as a percentage of body area involvement, resulting in a severity score of "A"; (b) Rate the intensity of the following clinical signs and assign an intensity score of "B": (i) redness, (ii) swelling, (iii) oozing / crusting; (iv) scratches, (v) thickening of the skin, and (vi) drying; (c) Rate the severity of the following symptoms and receive a severity score of "C": (i) itching, and (ii) Sleep disorders and (d) Calculating the baseline PO-SCORAD index using the extent score "A," the intensity score "B," and the severity score "C." Includes:

[0385] The input of steps (a), (b) and (c) can be performed by the subject or a caregiver. The input of steps (a), (b) and (c) can be input into a computer program by the subject or a caregiver via a graphical user interface. The estimation of the severity of atopic dermatitis as a percentage of body area involvement and the severity score "A" can be performed by the computer program.

[0386] Determining the baseline PO-SCORAD index involves the subject or caregiver obtaining a symptom intensity score for each clinical sign selected from the group consisting of: i. "0" ii. "1" iii. "2", and iv. "3"; where "0" is the lowest intensity and "3" is the highest intensity; The symptom intensity scores are summed to calculate an intensity score "B." Summing the symptom intensity scores to calculate an intensity score "B" can be performed by a computer program.

[0387] Determining the baseline PO-SCORAD index involves the subject or caregiver providing a numerical rating of the severity of itch and sleep disturbance symptoms for the past two days and / or the past two nights on a scale of 0 to 10, with "0" being no symptoms and "10" being the worst imaginable symptoms. The method can further include summing the numerical ratings of the severity of itch and sleep disturbance symptoms to calculate a severity score "C." Summing the numerical ratings of the severity of itch and sleep disturbance symptoms to calculate a severity score "C" can be performed by a computer program.

[0388] Determining the baseline PO-SCORAD index can include calculating the baseline PO-SCORAD index using the following formula: PO-SCORAD index=A / 5+7B / 2+C.

[0389] The baseline PO-SCORAD score is any score that indicates moderate to severe AD, such as at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, or at least 95.

[0390] The first injection of the anti-OX40L antibody or fragment thereof can be administered on the same day that the baseline PO-SCORAD index is determined.

[0391] Some embodiments may further include determining a baseline PO-SCORAD index.

[0392] Clinical Outcome Based - PO-SCORAD Some embodiments can further include assessing atopic dermatitis by determining a post-administration PO-SCORAD index at least 15 days after administration of the first injection of the antibody or fragment thereof. Obtaining a post-administration PO-SCORAD index at least 7 days or at least 15 days after administration of the first injection of the antibody or fragment thereof is expected to be the earliest time at which a change in the PO-SCORAD score due to the effect of the antibody or fragment thereof can be reliably observed, although any clinically appropriate delay between administration and assessment can be employed. The post-administration PO-SCORAD index can be determined at least approximately 7 days, at least approximately 15 days, at least approximately 29 days, at least approximately 57 days, at least approximately 85 days, at least approximately 113 days, at least approximately 169 days, and / or at least approximately 253 days after administration of the first injection of the antibody or fragment thereof. The post-administration PO-SCORAD index can be determined at about 7 days, about 15 days, about 29 days, about 57 days, about 85 days, about 113 days, about 169 days, and / or about 253 days after administration of the first injection of the antibody or fragment thereof. The post-administration PO-SCORAD index can be determined at the end of the induction phase.

[0393] The post-administration PO-SCORAD index can be selected from the group consisting of less than 10, less than 15, less than 20, less than 25, less than 30, less than 35, less than 40, less than 45, less than 50, less than 55, less than 60, less than 65, less than 70, less than 75, less than 80, less than 85, less than 90, and less than 95. The post-administration PO-SCORAD index is reduced by at least 8 points, at least 8.7 points, at least 9 points, 10 points, at least 11 points, at least 12 points, at least 13 points, at least 14 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 40 points, at least 50 points, at least 55 points, at least 60 points, at least 65 points, at least 70 points, at least 80 points, or at least 90 points relative to the baseline PO-SCORAD index. The post-administration PO-SCORAD index is reduced by at least 20 points relative to the baseline PO-SCORAD index. The post-administration PO-SCORAD index can indicate that AD is no longer very severe AD. The post-administration PO-SCORAD index can indicate that AD is no longer severe AD. The post-administration PO-SCORAD index can indicate that AD is no longer moderate AD. The post-administration PO-SCORAD index can indicate that AD is mild AD. The post-administration PO-SCORAD index can indicate that AD is barely causing any problems. The post-administration PO-SCORAD index is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% relative to the baseline PO-SCORAD index. The post-administration PO-SCORAD index can be reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% relative to the baseline PO-SCORAD index without additional administration of an anti-OX40L antibody or antigen-binding fragment thereof: (a) at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after the administration of the last injection; or (b) at least about 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, or 253 days be maintained.

[0394] Some embodiments can further include assessing atopic dermatitis by determining one or more additional post-administration PO-SCORAD indices. The one or more additional post-administration PO-SCORAD indices can be determined at least about 15 days, at least about 29 days, at least about 57 days, at least about 85 days, at least about 113 days, at least about 169 days, and / or at least about 253 days after administration of the first injection of the antibody or fragment thereof. The one or more additional post-administration PO-SCORAD indices can be determined at least about 29 days, at least about 57 days, at least about 85 days, at least about 113 days, at least about 169 days, and / or at least about 253 days after administration of the first injection of the antibody or fragment thereof. The one or more additional post-administration PO-SCORAD indices can be determined at the end of the run-in phase.

[0395] The one or more further post-administration PO-SCORAD index is selected from the group consisting of less than 10, less than 15, less than 20, less than 25, less than 30, less than 35, less than 40, less than 45, less than 50, less than 55, less than 60, less than 65, less than 70, less than 75, less than 80, less than 85, less than 90 and less than 95. The one or more further post-administration PO-SCORAD index is reduced by at least 8 points, at least 8.7 points, at least 9 points, 10 points, at least 11 points, at least 12 points, at least 13 points, at least 14 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 40 points, at least 50 points, at least 55 points, at least 60 points, at least 65 points, at least 70 points, at least 80 points or at least 90 points relative to the baseline PO-SCORAD index. The PO-SCORAD index after one or more additional doses is reduced by at least 20 points relative to the baseline PO-SCORAD index.

[0396] Determining the post-dose PO-SCORAD index and / or one or more additional post-dose PO-SCORAD indexes includes: (a) Estimating the severity of atopic dermatitis as a percentage of body area involvement, resulting in a severity score of "A"; (b) Rate the intensity of the following clinical signs and assign an intensity score of "B": (i) redness, (ii) swelling, (iii) oozing / crusting; (iv) scratches, (v) thickening of the skin, and (vi) drying; (c) Rate the severity of the following symptoms and receive a severity score of "C": (i) itching, and (ii) sleep disorders; and (d) Calculating the PO-SCORAD index using the extent score "A," the intensity score "B," and the severity score "C." Includes:

[0397] The input of steps (a), (b) and (c) can be performed by the subject or a caregiver. The input of steps (a), (b) and (c) can be input into a computer program by the subject or a caregiver via a graphical user interface. The estimation of the severity of atopic dermatitis as a percentage of body area involvement and the severity score "A" can be performed by the computer program.

[0398] Determining the post-administration PO-SCORAD index involves the subject or caregiver obtaining a symptom intensity score for each clinical sign selected from the group consisting of: i. "0" ii. "1" iii. "2", and iv. "3"; where "0" is the lowest intensity and "3" is the highest intensity; The symptom intensity scores are summed to calculate an intensity score "B." Summing the symptom intensity scores to calculate an intensity score "B" can be performed by a computer program.

[0399] Determining the post-administration PO-SCORAD index involves the subject or caregiver providing a numerical rating of the severity of itch and sleep disturbance symptoms for the past two days and / or past two nights on a scale of 0 to 10, with "0" being no symptoms and "10" being the worst imaginable symptoms. The method can further include summing the numerical ratings of the severity of itch and sleep disturbance symptoms to calculate a severity score "C." Summing the numerical ratings of the severity of itch and sleep disturbance symptoms to calculate a severity score "C" can be performed by a computer program.

[0400] Determining the post-administration PO-SCORAD index and / or one or more further post-administration PO-SCORAD indices may include calculating the PO-SCORAD index using the following formula: PO-SCORAD index=A / 5+7B / 2+C.

[0401] The post-administration PO-SCORAD and / or further post-administration PO-SCORAD can be determined at least approximately 113 days after administration of the first injection of the antibody or fragment thereof, wherein the post-administration PO-SCORAD and / or further post-administration PO-SCORAD is reduced by at least 20 points relative to the baseline PO-SCORAD index. The post-administration PO-SCORAD and / or further post-administration PO-SCORAD can be determined at least approximately 169 days after administration of the first injection of the antibody or fragment thereof, wherein the post-administration PO-SCORAD and / or further post-administration PO-SCORAD is reduced by at least 20 points relative to the baseline PO-SCORAD index. The post-administration PO-SCORAD and / or further post-administration PO-SCORAD can be determined at least approximately 253 days after administration of the first injection of the antibody or fragment thereof, wherein the post-administration PO-SCORAD and / or further post-administration PO-SCORAD is reduced by at least 20 points relative to the baseline PO-SCORAD index. Atopic dermatitis can be treated as evidenced by a reduction in the PO-SCORAD index of at least 20 points after the third injection as a treatment dose. The reduction in the PO-SCORAD index persists for at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after the administration of the last injection as a treatment dose. According to certain embodiments, administering a therapeutically effective amount of an anti-OX40L antibody or its antigen-binding fragment to a patient results in a reduction in the PO-SCORAD index. In some embodiments, the method of treatment results in at least about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more reduction from baseline in the PO-SCORAD index on day 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, 253 or more days after administration of the anti-OX40L antibody or antigen-binding fragment thereof (e.g., after a loading dose of about 62.5 mg, 125 mg, 250 mg or 500 mg followed by subcutaneous administration of 250 mg of the anti-OX40L antibody or antigen-binding fragment thereof).The post-administration PO-SCORAD index is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% relative to the baseline PO-SCORAD index. The reduction in the post-administration PO-SCORAD index relative to the baseline PO-SCORAD index can be derived from any baseline PO-SCORAD index and any post-administration PO-SCORAD index at any time point or between any time points disclosed herein. In certain exemplary embodiments, administration of an anti-OX40L antibody or antigen-binding fragment thereof to a subject optionally results in a decrease from baseline in the PO-SCORAD index of at least 15%, at least 20%, or at least 30%, approximately 113 days after the first administration of the anti-OX40L antibody or antigen-binding fragment thereof.

[0402] According to certain embodiments, administration of a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in a reduction in the PO-SCORAD index that is equal to or exceeds the minimal clinically important difference (MCID) on days 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, 253 or more after administration of the anti-OX40L antibody or antigen-binding fragment thereof (e.g., after a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by subcutaneous administration of 250 mg of the anti-OX40L antibody or antigen-binding fragment thereof).

[0403] Dermatology Life Quality Index (DLQI) The DLQI is designed to measure health-related quality of life in patients with skin diseases, including atopic dermatitis. It was published in 1994 and was the first dermatology-specific quality of life questionnaire. See Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)—a simple practical measure for routine clinical use. Clin Exp Dermatol. 1994 May;19(3):210-6. Methods for determining DLQI scores are known and are described below and / or in the Examples, as appropriate.

[0404] The DLQI consists of 10 questions regarding patients' perceptions of the impact of their skin disease on various aspects of their health-related quality of life over the last week. The DLQI is designed for use in adults, i.e., patients aged 16 years and older.

[0405] Each question is scored on a 4-point Likert scale: Very = 3 Quite = 2 Slightly = 1 Totally = 0 Irrelevant=0 No answer to question = 0 The DLQI is calculated by adding the scores for each question, resulting in a maximum value of 30 and a minimum value of 0. The higher the score, the more impaired the quality of life. A score higher than 10 indicates that the patient's life is severely affected by the skin disease.

[0406] Score meaning: 0-1 = No impact on patient's life 2-5 = Minimal impact on patient's life 6-10 = Moderate impact on patient's life 11-20 = Very significant impact on patient's life 21-30 = Extremely significant impact on patient's life

[0407] In common inflammatory skin conditions, a change in DLQI score of at least 4 points is considered clinically important. In an alternative embodiment, a change in DLQI score of 2.2 to 6.9 points is considered clinically important.

[0408] Baseline Score - DQLI Atopic dermatitis has been assessed by determining a baseline DQLI (Dermatology Quality of Life Index) score. Determining a baseline DQLI score involves subjects answering the following questions about how much their skin problems have affected their life over the past week: i. the degree of itching, burning, pain or throbbing of the skin; ii. The extent to which you felt embarrassed or self-conscious about your skin; iii. The extent to which the skin gets in the way when going shopping or tending to the house or garden; iv. The extent to which the skin affected the clothing worn; v. The extent to which the skin affected social or leisure activities; vi. The extent to which your skin makes it difficult to play sports vii. Whether or not your skin interfered with your work or studies, and if not, the extent to which your skin caused problems at work or studies; viii. The extent to which your skin has caused problems with either your partner or close friends or relatives; ix. The extent to which the skin caused sexual problems x. The extent to which skin treatment was a problem.

[0409] Each answer can be selected from the group consisting of: i. "Very" ii. "Quite" iii. "Slightly" iv. "Not at all" v. "irrelevant"

[0410] The method comprises: assigning each response a score of 3 for "very," 2 for "quite a bit," 1 for "slightly," and 0 for "not at all," "irrelevant," or not answering the question; and It may further include summing the answer scores to calculate a DQLI score.

[0411] The baseline DQLI index is any index that indicates that AD has a moderate, large, or extremely large effect on the subject's life. The baseline DQLI score can be selected from the group consisting of at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, 6 to 30, 6 to 10, 11 to 20, and 21 to 30.

[0412] The first injection of the anti-OX40L antibody or fragment thereof can be administered on the same day that the baseline DQLI score is determined.

[0413] Some embodiments may further include determining a baseline DQLI score.

[0414] Clinical Outcome Based - DQLI Some embodiments can further include assessing atopic dermatitis by determining a post-administration DQLI score at least 15 days after administration of the first injection of the antibody or fragment thereof. Obtaining a post-administration DQLI score at least 7 days or at least 15 days after administration of the first injection of the antibody or fragment thereof is expected to be the earliest time at which a change in the DQLI score due to the action of the antibody or fragment thereof can be reliably observed, although any clinically appropriate delay between administration and assessment can be employed. The post-administration DQLI score can be determined at least approximately 7 days, at least approximately 15 days, at least approximately 29 days, at least approximately 57 days, at least approximately 85 days, at least approximately 113 days, at least approximately 169 days, and / or at least approximately 253 days after administration of the first injection of the antibody or fragment thereof. The post-administration DQLI score can be determined about 7 days, about 15 days, about 29 days, about 57 days, about 85 days, about 113 days, about 169 days, and / or about 253 days after administration of the first injection of the antibody or fragment thereof. The post-administration DQLI score can be determined at the end of the induction phase.

[0415] The post-administration DQLI score can be selected from the group consisting of 0-1; 2-5; 6-10; 11-20, and 21-30. The post-administration DQLI score is reduced by at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, at least 10 points, at least 15 points, or at least 20 points relative to the baseline DQLI score. The post-administration DQLI score is reduced by at least 2.2 points or at least 6.9 points relative to the baseline DQLI score. The post-administration DQLI score is reduced by at least 4 points relative to the baseline DQLI score. The post-administration DQLI score is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% relative to the baseline DQLI score. The post-administration DQLI score is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% relative to the baseline DQLI score without further administration of the anti-OX40L antibody or antigen-binding fragment thereof: (a) at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after the administration of the last injection; or (b) at least about 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, or 253 days be maintained.

[0416] Some embodiments can further include assessing atopic dermatitis by determining one or more additional post-administration DQLI scores. The one or more additional post-administration DQLI scores can be determined at least about 15 days, at least about 29 days, at least about 57 days, at least about 85 days, at least about 113 days, at least about 169 days, and / or at least about 253 days after administration of the first injection of the antibody or fragment thereof. The one or more additional post-administration DQLI scores can be determined at least about 29 days, at least about 57 days, at least about 85 days, at least about 113 days, at least about 169 days, and / or at least about 253 days after administration of the first injection of the antibody or fragment thereof. The one or more additional post-administration DQLI scores can be determined at the end of the induction phase.

[0417] The one or more additional post-dose DQLI scores can be selected from the group consisting of 0-1; 2-5; 6-10; 11-20, and 21-30. The one or more additional post-dose DQLI scores are reduced by at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, at least 10 points, at least 15 points, or at least 20 points relative to the baseline DQLI score. The one or more additional post-dose DQLI scores are reduced by at least 2.2 points or at least 6.9 points relative to the baseline DQLI score. The one or more additional post-dose DQLI scores are reduced by at least 4 points relative to the baseline DQLI score.

[0418] Determining the post-administration DQLI score and / or one or more further post-administration DQLI scores involves the subject a...

Claims

1. 1. An anti-OX40L antibody or antigen-binding fragment thereof for use in treating atopic dermatitis in a human subject, comprising: The antibody or antigen-binding fragment thereof is selected from the group consisting of: (a) the HCDR1 amino acid sequence of SEQ ID NO: 36; HCDR2 amino acid sequence of SEQ ID NO: 38; HCDR3 amino acid sequence of SEQ ID NO: 40; LCDR1 amino acid sequence of SEQ ID NO: 50; AAS LCDR2 amino acid sequence; and The LCDR3 amino acid sequence of SEQ ID NO: 54; or (b) the HCDR1 amino acid sequence of SEQ ID NO: 42; HCDR2 amino acid sequence of SEQ ID NO: 44; HCDR3 amino acid sequence of SEQ ID NO: 46; LCDR1 amino acid sequence of SEQ ID NO: 56; AAS or the LCDR2 amino acid sequence of SEQ ID NO: 58; and LCDR3 amino acid sequence of SEQ ID NO: 60 Including, An anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered by subcutaneous injection.

2. 1. An anti-OX40L antibody or antigen-binding fragment thereof for use in treating an inflammatory disease, inflammatory disorder, immune-mediated disease, immune-mediated disorder, inflammatory skin disease or inflammatory skin disorder in a human subject, comprising: The antibody or antigen-binding fragment thereof is selected from the group consisting of: (a) the HCDR1 amino acid sequence of SEQ ID NO: 36; HCDR2 amino acid sequence of SEQ ID NO: 38; HCDR3 amino acid sequence of SEQ ID NO: 40; LCDR1 amino acid sequence of SEQ ID NO: 50; AAS LCDR2 amino acid sequence; and The LCDR3 amino acid sequence of SEQ ID NO: 54; or (b) the HCDR1 amino acid sequence of SEQ ID NO: 42; HCDR2 amino acid sequence of SEQ ID NO: 44; HCDR3 amino acid sequence of SEQ ID NO: 46; LCDR1 amino acid sequence of SEQ ID NO: 56; AAS or the amino acid sequence of LCDR2 of SEQ ID NO: 58; and LCDR3 amino acid sequence of SEQ ID NO: 60 Including, An anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered by subcutaneous injection.

3. 3. The anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 1 or 2, wherein the antibody or fragment thereof is a disease-modifying drug.

4. The anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 3, wherein the subject achieves an IGA-AD score of 0 or 1 for at least 6 months after administration of the disease-modifying drug.

5. The antibody or fragment thereof (i) at least twice with at least one interval of 2 to 6 months; (ii) at least twice with at least one interval of approximately 3 months; (iii) once every 4 weeks during the induction phase and once every 12 weeks during the maintenance phase; and / or (iv) once every 4 weeks, once every 12 weeks, or once every 6 months The anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 1 or 2, wherein the antibody or antigen-binding fragment is administered to a subject.

6. 3. The anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 1 or 2, wherein the antibody or fragment thereof is administered once every 12 weeks.

7. (i) each dose is between 20 mg and 1000 mg; (ii) each dose is 62.5 mg, 125 mg, 150 mg, 250 mg, or 500 mg; (iii) the dose is 125 mg; (iv) the dose is 150 mg; (v) the dose is 62.5 mg; (vi) the dose is 250 mg; (vii) the dose is in the range of 0.7 mg / kg to 6 mg / kg; and / or (viii) the dose is in the range of 1.4 mg / kg to 3 mg / kg; An anti-OX40L antibody or an antigen-binding fragment thereof for use according to claim 1 or 2.

8. The treatment is (a) administering a first injection as a loading dose of an antibody or fragment thereof, followed by (b) administering at least a second injection as a first treatment dose of the antibody or fragment thereof.

3. An anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 1 or 2, comprising:

9. (i) the loading dose is between 200 mg and 500 mg; (ii) each treatment dose is between 100 mg and 250 mg, optionally with each treatment dose being 100 mg or 250 mg; (iii) the loading dose is 500 mg and the treatment dose is 250 mg; and / or teeth (iv) each treatment dose contains the same mass of antibody or fragment thereof as each other treatment dose; The anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 8.

10. The anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 1 or 2, comprising an induction phase and a maintenance phase.

11. (i) the induction dose is about 500 mg, 250 mg, about 125 mg, or about 62.5 mg; (ii) the maintenance dose is about 500 mg, 250 mg, about 125 mg, or about 62.5 mg; (iii) the interval between two or more induction injections is about 4 weeks and the interval between two or more maintenance injections is about 12 weeks; and / or (iv) each maintenance injection contains the same mass of antibody or fragment thereof as each other maintenance injection; An anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 10.

12. The anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 10, wherein the induction phase comprises administering at least five induction phase injections, the first of which is a loading dose of 500 mg of the antibody or fragment thereof, followed by at least four subsequent induction phase injections, each of which is a dose of 250 mg of the antibody or fragment thereof, and each subsequent induction phase injection is administered four weeks after the preceding induction phase injection.

13. The anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 10, wherein the maintenance phase comprises administering at least three maintenance phase injections, each maintenance phase injection being at a dose of 250 mg of the antibody or fragment thereof, the first maintenance phase injection being administered at least four weeks after the final induction phase injection, and the second maintenance phase injection and each subsequent maintenance phase injection being administered at least four weeks after the preceding maintenance phase injection.

14. (i) the induction phase comprises administering at least five induction phase injections, each induction phase injection being a dose of 250 mg of antibody or fragment thereof, and the second induction phase injection and each subsequent induction phase injection being administered four weeks after the preceding induction phase injection; or (ii) the induction phase comprises administering at least five induction phase injections, each induction phase injection being a dose of 125 mg of antibody or fragment thereof, with the second induction phase injection and each subsequent induction phase injection being administered 4 weeks after the preceding induction phase injection; or (iii) the induction phase comprises administering at least five induction phase injections, each induction phase injection being a dose of 62.5 mg of the antibody or fragment thereof, and wherein the second induction phase injection and each subsequent induction phase injection is administered 4 weeks after the preceding induction phase injection; An anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 10.

15. The anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 10, wherein the maintenance phase comprises administering at least three maintenance phase injections, each maintenance phase injection being a dose of 125 mg of the antibody or fragment thereof, the first maintenance phase injection being administered at least four weeks after the final induction phase injection, and the second maintenance phase injection and each subsequent maintenance phase injection being administered at least four weeks after the preceding maintenance phase injection.

16. 11. The method of claim 10, wherein the maintenance phase comprises administering at least three maintenance phase injections, each maintenance phase injection being a dose of 62.5 mg of the antibody or fragment thereof, the first maintenance phase injection being administered at least four weeks after the final induction phase injection, and the second maintenance phase injection and each subsequent maintenance phase injection being administered at least four weeks after the preceding maintenance phase injection. OL antibody or an antigen-binding fragment thereof.

17. (i) the first maintenance injection is administered 12 weeks after the final induction injection; and / or (ii) the second maintenance injection and each subsequent maintenance injection is administered 12 weeks after the preceding maintenance injection; An anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 10.

18. The anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 1 or 2, wherein the subject is at least 18 years old and / or under 75 years old.

19. The anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 1, wherein the atopic dermatitis is moderate to severe atopic dermatitis.

20. (i) the subject is a patient candidate for systemic therapy; or (ii) the subject is a patient whose disease is not adequately controlled with topical prescription therapies or for whom such therapies are not advisable; 20. An anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 19.

21. An anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 1, wherein the atopic dermatitis is resistant, unresponsive, or inadequately responsive to treatment with either topical corticosteroids and / or systemic therapy, or these therapies are not recommended, or the subject has had an inadequate response to, is intolerant of, or is resistant to one or more topical corticosteroids.

22. The anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 1 or 2, further comprising administering a therapeutically effective amount of one or more topical corticosteroids.

23. (i) the topical corticosteroid is selected from the group consisting of betamethasone dipropionate, clobetasol propionate, dexamethasone, methylprednisolone, methylprednisolone aceponate, mometasone furoate, diflorasone acetate, halobetasol propionate, amcinonide, fortified betamethasone dipropionate, fluocinonide, halcinonide, triamcinolone acetonide, betamethasone valerate, clocortolone pivalate, desoximetasone, fluocinolone acetonide, flurandrenolide, fluticasone propionate, hydrocortisone butyrate, hydrocortisone probutate, hydrocortisone valerate, prednicarbate, alclometasone propionate, desonide, hydrocortisone, and hydrocortisone acetate; and / or (ii) the topical corticosteroid is selected from the group consisting of betamethasone dipropionate, betamethasone dipropionate, gentamicin sulfate, clobetasol propionate, dexamethasone, methylprednisolone, methylprednisolone aceponate, and mometasone furoate; An anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 21.

24. administration of an anti-OX40L antibody or antigen-binding fragment thereof, a. A decrease from baseline in the vIGA score of at least 2 points, or b. Achievement of clear or almost clear skin (vIGA 0 / 1) from baseline 2. The anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 1, which results in at least one improvement selected from the group consisting of:

25. administration of an anti-OX40L antibody or antigen-binding fragment thereof, a. A decrease from baseline in the EASI score of at least 50%, or b. A reduction from baseline in the EASI score of at least 75%, or c. Achievement of EASI-75, or d. Achievement of EASI-90, or e. Achieving at least a 3-point Pruritus NRS, or f. Achieve at least a 4-point Pruritus NRS, or g. A decrease from baseline in the SCORAD score of at least 50%, or h. A decrease from baseline in the SCORAD index of at least 55%, or i. A decrease from baseline in diseased BSA of at least 60%; j. A reduction from baseline in diseased BSA of at least 70% 2. The anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 1, which results in at least one improvement selected from the group consisting of:

26. The anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 1 or 2, wherein administration of the anti-OX40L antibody or antigen-binding fragment thereof results in a reduction in the serum level of at least one biomarker selected from the group consisting of IL-13, IL-22, IL-17A, IL-31 and IgE.

27. The anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 1 or 2, wherein at least one of the reductions in serum levels of at least one biomarker selected from the group consisting of IL-13, IL-22, IL-17A, IL-31 and IgE is maintained for at least 12 weeks or at least 24 weeks after the final dose, and / or at least one of the improvements is maintained for at least 12 weeks or at least 24 weeks after the final dose.

28. The anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 1 or 2, wherein the atopic dermatitis is assessed by determining a baseline EASI score.

29. (i) The EASI score after administration is: (a) at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after the administration of the last injection; or (b) at least about 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, or 253 days maintained; and / or (ii) the post-dose EASI and / or further post-dose EASI is determined at least about 113 days after administration of the first injection of the antibody or fragment thereof, and the post-dose EASI and / or further post-dose EASI is EASI 50, EASI 75, EASI 90, or EASI 100; and / or (iii) the post-dose EASI and / or further post-dose EASI is determined at least about 169 days after administration of the first injection of the antibody or fragment thereof, and the post-dose EASI and / or further post-dose EASI is EASI 50, EASI 75, EASI 90, or EASI 100; and / or (iv) the post-dose EASI and / or further post-dose EASI is determined at least about 253 days after administration of the first injection of the antibody or fragment thereof, and the post-dose EASI and / or further post-dose EASI is EASI 50, EASI 75, EASI 90, or EASI 100; An anti-OX40L antibody or an antigen-binding fragment thereof for use according to claim 1 or 2.

30. The anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 1, wherein the atopic dermatitis is treated as evidenced by a reduction in EASI score of at least 40% after the third injection as a treatment dose, and the reduction in EASI score persists for at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after administration of the last injection as a treatment dose.

31. The anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 1, wherein the atopic dermatitis is assessed by determining a baseline vIGA-AD score.

32. (i) post-administration vIGA-AD score of 0 or 1; (ii) the post-administration vIGA-AD score is greater than or equal to 100% without additional administration of an anti-OX40L antibody or antigen-binding fragment thereof; (a) at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after the administration of the last injection; or (b) at least about 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, or 253 days maintained; and / or (iii) the post-administration vIGA-AD and / or further post-administration vIGA-AD are determined at least about 113 days after administration of the first injection of the antibody or fragment thereof, and the post-administration vIGA-AD and / or further post-administration vIGA-AD are: (a) a vIGA-AD score of 0 or 1, and / or (b) at least a 2-point reduction relative to the baseline vIGA-AD score; and / or (iv) the post-administration vIGA-AD and / or further post-administration vIGA-AD are determined at least about 169 days after administration of the first injection of the antibody or fragment thereof, and the post-administration vIGA-AD and / or further post-administration vIGA-AD are: (a) a vIGA-AD score of 0 or 1, and / or (b) at least a 2-point reduction relative to the baseline vIGA-AD score; and / or (v) the post-administration vIGA-AD and / or further post-administration vIGA-AD are determined at least about 253 days after administration of the first injection of the antibody or fragment thereof, and the post-administration vIGA-AD and / or further post-administration vIGA-AD are: (a) a vIGA-AD score of 0 or 1, and / or (b) at least a 2-point reduction relative to baseline vIGA-AD score; An anti-OX40L antibody or an antigen-binding fragment thereof for use according to claim 1 or 2.

33. The anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 1, wherein the atopic dermatitis is treated as evidenced by a reduction in the vIGA-AD score of at least 2 points after the third injection as a treatment dose, and the reduction in the vIGA-AD score persists for at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after administration of the final injection as a treatment dose.

34. An anti-OX40L antibody or its antigen-binding fragment for use in the manufacture of a medicament for treating atopic dermatitis according to claim 1, comprising a glass vial, drug delivery device, pre-filled syringe, microinjector, pen delivery device, auto-injector or kit containing the anti-OX40L antibody or its antigen-binding fragment.

35. An anti-OX40L antagonist antibody or antigen-binding fragment thereof for use in treating atopic dermatitis, an inflammatory disease, an inflammatory disorder, an immune-mediated disease, an immune-mediated disorder, an inflammatory skin disease or an inflammatory skin disorder in a human patient, wherein the antibody or fragment thereof antagonizes the specific binding of hOX40L to OX40, and wherein the antibody or fragment thereof is administered by subcutaneous injection.

36. The antibody or antigen-binding fragment thereof, or the anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 35, wherein the use is according to any one of claims 1 to 34.

37. An anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 1 or 2, wherein the antibody or fragment thereof comprises a VH domain having the amino acid sequence set forth in SEQ ID NO: 34 and / or a VL domain having the amino acid sequence set forth in SEQ ID NO:

48.

38. An anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 1 or 2, wherein the antibody or fragment thereof comprises a heavy chain having the amino acid sequence set forth in SEQ ID NO: 62 and a light chain having the amino acid sequence set forth in SEQ ID NO:

64.

39. The anti-OX40L antibody or antigen-binding fragment thereof for use according to claim 1 or 2, wherein the subject is classified as a Th2 AD patient and / or a non-Th2 AD patient.

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