Treatment of atopic dermatitis

Abstract

This invention relates to a method for treating atopic dermatitis in human individuals, the method comprising administering a therapeutically effective amount of an anti-OX40L antibody or an antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered by injection. Also provided are anti-OX40L antibodies or an antigen-binding fragment thereof; glass vials containing anti-OX40L antibodies or an antigen-binding fragment thereof; drug delivery devices; pre-filled syringes; microinfusion sets; pen-type delivery devices; auto-injectors; and kits for use in such methods.

Description

Technical field

[0001] The present invention relates to methods of treating atopic dermatitis 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. Also provided are anti-OX40L antibodies or antigen-binding fragments thereof; glass vials, drug delivery devices, prefilled syringes, microinfusion sets, pen delivery devices, auto-injectors and kits containing anti-OX40L antibodies or antigen-binding fragments thereof, It is used in such methods. prior art

[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 United States. It is a chronic condition that may come and go for years or a lifetime, and may overlap with other types of eczema.

[0003] The immune system of people with AD becomes disordered and overactive. This causes inflammation, which damages the skin barrier, making the skin dry and prone to itching and rashes, which may appear purple, brown or gray in darker skin tones and red in lighter skin tones.

[0004] Research shows that some people with eczema, especially atopic dermatitis, have mutations in the gene responsible for producing filaggrin. Filaggrin is a protein that helps our bodies maintain a healthy protective barrier in the top layer of skin. Without enough filaggrin to build a strong skin barrier, moisture may be lost and bacteria, viruses, etc. may enter. This is why many people with AD have very dry skin and are prone to infections.

[0005] Itching is a hallmark of AD, and some sources suggest that more than 85% of people with the condition experience this painful symptom on a daily basis. Skin soreness or pain caused by itching and poor sleep are also common.

[0006] People with AD may develop a rash anywhere on the body, which may ooze, leak fluid and bleed when scratched, leaving the skin susceptible to infection. The skin may become dry and discolored, and repeated scratching may cause thickening and hardening - a process called lichenification. Although AD can affect any part of the body, it most commonly affects children's hands, insides of elbows, backs of knees, and the face and scalp.

[0007] Atopic dermatitis typically begins in childhood, usually during the first six months of a baby's life. Although it is a common form of eczema, it can also be serious and long-lasting. When you or your child has atopic dermatitis, it may sometimes improve; but other times, it may get worse. In some children, symptoms may gradually disappear as they grow older, while in other children, flares of atopic dermatitis will continue into adulthood.

[0008] Atopic dermatitis is also associated with two other allergic conditions: asthma and hay fever (allergic rhinitis). People who have asthma and / or hay fever, or 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 AD, treatment includes lifestyle changes, over-the-counter (OTC) medication, or prescription medications.

[0010] The main treatments for AD are: · Emollients (moisturizers) - used daily to stop skin from drying out, 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 do not respond to simpler treatments · Antihistamines for severe itching · A bandage or special tights to 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 by topical prescription therapies or for whom those therapies are inappropriate. DUPIXENT can be used with or without topical corticosteroids. As described, for example, by Tubau et al., Immunotherapy 13:327-344, 2021, dupilumab, currently the only mAb approved for the treatment of AD, blocks the pathogenesis of AD by inhibiting the IL-4Rα1 subunit of its coreceptor. Cut off IL-13 but also IL-4. Although a significant proportion of patients develop dry eye and / or blepharoconjunctivitis, complicating their management, this is still highly effective and has an excellent safety profile. · Pipeline products include JAK inhibitors, IL-13 inhibitors and IL-31 inhibitors. However, JAK inhibitors are associated with safety concerns (e.g., black box warnings) and have poor efficacy against IL-31.

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

[0013] OX40L is not constitutively expressed but can be induced on 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 be induced to express OX40L. T cells can also express OX40L. The OX40L receptor OX40 is expressed on primed T cells (CD4+ and CD8+ T cells, Th2, Th1 and Th17 cells) and CD4+Foxp3+ cells, even in the absence of priming.

[0014] The interaction between OX40 and OX40L occurs during T cell-DC interactions 2 or 3 days after antigen recognition. After leaving DCs, OX40-expressing T cells may interact with OX40L-expressing cells other than DCs, and from there the cells receive OX40 signals, which may provide the necessary resources for the generation of memory T cells, enhancement of Th2 responses, and prolongation of the inflammatory response. Signal. OX40 signaling into reactive T cells renders them resistant to Treg-mediated suppression.

[0015] WO 2015 / 132580, WO 2016 / 139482 and WO 2018 / 083248 describe anti-human OX40L (hOX40L) antibodies and fragments and medical applications for the treatment or prevention of hOX40L-mediated diseases or conditions in humans. Contents of the invention

[0016] In some embodiments, treatments targeting upstream OX40L-dependent pathways are provided to effectively treat inflammatory diseases or disorders, immune-mediated diseases or disorders, inflammatory skin diseases or disorders. Some embodiments provide treatments targeting upstream OX40L-dependent pathways to effectively treat acute and chronic AD. The treatment is associated with attractive dosing frequency, low volume induction and maintenance regimens, and strong efficacy and safety profiles. Advantages of the formulation for subcutaneous administration include being more patient-friendly as it can be administered by the patient at home and therefore inconvenient doctor visits can be avoided. Additionally, administration time may be shortened, which is beneficial to patients and healthcare providers. Some embodiments also provide reduced needle burden, i.e., fewer injections per year, which will result in potentially improved compliance and therefore improved patient outcomes. Some embodiments also provide treatments with surprisingly consistent pharmacokinetic (PK) parameter estimates in IV and subcutaneous population PK models that are not significantly affected by anti-drug antibodies, which is particularly interesting for subcutaneous administration. surprise. To this end, some embodiments provide:

[0017] In a first configuration, a method of treating atopic dermatitis in a human subject is provided, 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 Administered by injection.

[0018] In an alternative to a first configuration, there is provided a method of treating atopic dermatitis in a human subject, said method comprising administering a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment thereof The fragment is administered by injection, and the method includes administering at least one injection at a dose of at least about 20 mg of the antibody or fragment thereof.

[0019] In an alternative to a first configuration, there is provided a method of treating atopic dermatitis in a human subject, said method comprising administering a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment thereof Fragments are disease-modifying drugs.

[0020] In an alternative to a first configuration, there is provided a method of treating atopic dermatitis in a human subject, said method comprising administering a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment thereof Fragments are administered at least twice at an interval of 2 to 6 months.

[0021] In an alternative to a first configuration, there is provided a method of treating atopic dermatitis in a human subject, said method comprising administering a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment thereof Fragments were administered at least twice with at least a 6-month interval.

[0022] In an alternative statement to a first configuration, there is provided a method of treating atopic dermatitis in a human subject, said method comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the post-administration EASI score A decrease in EASI score of at least 10% relative to baseline.

[0023] In an alternative statement of the first configuration, there is provided a method of treating atopic dermatitis in a human subject, the method comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein after administration vIGA- AD score decreased by at least 10% relative to baseline vIGA-AD score.

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

[0025] In an alternative statement to a first configuration, there is provided a method of treating atopic dermatitis in a human subject, the method comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the BSA score after administration A decrease in BSA score of at least 10% relative to baseline.

[0026] In an alternative statement of the first configuration, there is provided a method of treating atopic dermatitis in a human subject, said method comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the post-administration SCORAD index A decrease in SCORAD index of at least 10% relative to baseline.

[0027] In an alternative statement of the first configuration, there is provided a method of treating atopic dermatitis in a human subject, the method comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the administration is followed by PO- The SCORAD index decreases by at least 10% relative to the baseline PO-SCORAD index.

[0028] In an alternative statement to a first configuration, there is provided a method of treating atopic dermatitis in a human subject, the method comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the post-administration DQLI score A reduction of at least 10% in DQLI score relative to baseline.

[0029] In an alternative statement to a first configuration, there is provided a method of treating atopic dermatitis in a human subject, the method comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the subject is chronic Patients with atopic dermatitis.

[0030] In a second configuration, a glass vial containing an anti-OX40L antibody or antigen-binding fragment thereof is provided.

[0031] In a third configuration, a prefilled syringe containing an anti-OX40L antibody or antigen-binding fragment thereof is provided.

[0032] In a fourth configuration, a microinfusion set containing an anti-OX40L antibody or antigen-binding fragment thereof is provided.

[0033] In a fifth configuration, a pen delivery device containing an anti-OX40L antibody or antigen-binding fragment thereof is provided.

[0034] In a sixth configuration, an auto-injector delivery device containing an anti-OX40L antibody or antigen-binding fragment thereof is provided.

[0035] In a seventh configuration, a kit is provided, the kit comprising the glass vial according to any one of the third to sixth configurations, a drug delivery device, a prefilled syringe, a microinfusion set, a pen delivery device or an auto-injector; and labeling and / or instructions specifying administration according to the method of the first configuration.

[0036] In yet another configuration, an anti-OX40L antibody or antigen-binding fragment thereof is provided for use in the method of treating atopic dermatitis according to the first configuration.

[0037] In yet another configuration, there is provided a glass vial, drug delivery device, prefilled syringe, microinfusion set, pen delivery device, autoinjector or set according to any of the second to seventh configurations, Method for treating atopic dermatitis according to the method of a first configuration.

[0038] In yet another configuration, there is provided 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 configuration.

[0039] In yet another configuration, a glass vial, drug delivery device, prefilled syringe, microinfusion set, pen delivery device, autoinjector or kit according to any of the third to eighth configurations is provided. Use for manufacturing a medicament for treating atopic dermatitis according to the method of the first configuration.

[0040] In yet another 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, the method comprising administering a therapeutically effective an amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered by injection.

[0041] In yet another 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, the method comprising administering a therapeutically effective an amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered by subcutaneous injection.

[0042] In yet another configuration, an anti-OX40L antibody, or antigen-binding fragment thereof, is provided 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 A 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.

[0043] In yet another configuration, an anti-OX40L antibody, or antigen-binding fragment thereof, is provided 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 A 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.

[0044] In another configuration, a method of treating atopic dermatitis in an individual is provided, the method comprising selecting an individual having atopic dermatitis and administering to the individual a therapeutically effective amount of anti-OX40L Pharmaceutical compositions of antibodies or antigen-binding fragments thereof, wherein the anti-OX40L antibody or antigen-binding fragments thereof comprise the heavy chain complementary regions (HCDR) of SEQ ID Nos: 42, 44 and 46 and SEQ ID Nos: 56, 58 and 60 The light chain complementarity determining region (LCDR).

[0045] Reference to a first configuration as used herein includes "the first configuration" and any "alternative statement of the first configuration." Any stated features of the first configuration may be understood in combination with any second and subsequent configurations of the invention. Simple explanation of the diagram

[0046] [picture] [1] graphically depicts an overview of the research design for Example 1. Healthy volunteers in Cohorts 1 to 3 received a single intravenous infusion of KY1005 (0.006, 0.018, or 0.05 mg / kg) or placebo, from which blood samples were collected until day 113. Cohorts 4 to 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 %).

[0047] [picture] [2A-B] Graphically depicts the percent change (95% CI) in anti-tetanus toxoid (TT) IgG and IgM titers relative to placebo at Day 85 for Cohorts 4 to 8, against baseline variability. Adjustments were made. Immunization with the recall antigen tetanus toxoid (TT) results in a humoral (IgM and IgG) response in all persons immunized. No effect of KY1005 on mean anti-TT IgG levels was observed ( [picture] [2A]), although in all treatment groups anti-TT IgM ( [picture] [2B]) Suppression was numerically greater than placebo but not dose-dependent.

[0048] [picture] [3] graphically depicts an overview of the research design for Example 2. Patients underwent Day 1 / baseline assessments and were randomized in a 1:1:1 ratio to receive an intravenous (I.V.) injection of low-dose (200 mg) or high-dose (500 mg) KY1005, followed by Day 29, 57 and 85 days with three maintenance doses at 28 days apart at 50% of the loading dose, or matching placebo.

[0049] [picture] [4] graphically depicts the percentage change over time in EASI scores compared to baseline presented by LSM using 95% confidence intervals (CI). Decreases in EASI scores in the FAS from baseline to Day 113 were observed in all treatment groups, including placebo. A greater reduction was observed in the KY1005 group.

[0050] [picture] [5A-C] graphically depicts EASI 50( [picture] [5A]), EASI 75( [picture] [5B]) and EASI 90( [picture] [5C]) changes over time. Overall, progressive increases in the percentage of patients with a reduction in EASI of at least 50%, 75%, and 90% compared to baseline were observed across all treatment groups, including placebo. The percentage in the KY1005 group was greater than placebo at all time points (except for EASI 90 on days 15 and 29, where the percentage was zero for 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.

[0051] [picture] [6A] graphically depicts vIGA 0 (clear) and 1 (almost clear) responders over time. A gradual increase in the percentage of vIGA 0 / 1 responders over time was observed overall in the KY1005 treatment group but not in the placebo group. By Day 113, the percentages of vIGA 0 / 1 responders in the KY1005 low-dose and high-dose groups were 44.4% (12 / 27) and 37.0% ( 10 / 27). Gray represents the 200 mg / 100 mg KY1005 dose; black represents the 500 mg / 250 mg KY1005 dose; and white represents placebo.

[0052] [picture] [6B] Graphically depicts the proportion of responders maintaining vIGA 0 / 1 over the study extension. vIGA, the validated researcher domain assessment.

[0053] [picture] [6C] graphically depicts the percentage change in EASI over time. *Final dose administered at Week 12. EASI, Eczema Area and Severity Index; SD, standard deviation.

[0054] [picture] [7] EASI scores for patients who received high or low doses of KY1005 or placebo during the study and throughout safety follow-up are depicted in the table. This graph represents all patients who achieved vIGA0 / 1 at Week 16 and were evaluated for efficacy during safety follow-up. This graph shows that among those individuals who achieved vIGA0 / 1 at Day 113, there was evidence of a long and sustained response up to 5.5 months after the last dose (approximately 70% of individuals who received KY1005).

[0055] [picture] [8] graphically depicts the percentage change from baseline in SCORAD index between different treatment regimens (MMRM analysis). Progressive reductions in SCORAD index from baseline to days 29, 57, 85, and 113 were observed in all treatment groups, including placebo. However, greater reductions were observed in the KY1005 group compared with placebo at all time points: compared with placebo (-36.79 [-49.94, -23.65]) for both the KY1005 low-dose and high-dose groups , the LSM percentage changes (95% CI) of the SCORAD index on day 113 were -60.30 (-72.57, -48.04) and -58.96 (-71.04, -46.87) respectively.

[0056] [picture] [9] graphically depicts the percentage change in affected BSA over time relative to baseline for LSM using 95% CI. Progressive reductions in affected BSA from baseline to days 29, 57, 85, and 113 were observed in all treatment groups, including placebo. However, greater reductions were observed in the KY1005 group compared with placebo at all time points: compared with placebo (-41.58 [-57.35, -25.80]) for both the KY1005 low-dose and high-dose groups , the least squares mean percent change (95% CI) of affected BSA on day 113 was -78.07 (-92.35, -63.79) and -71.97 (-86.10, -57.84), respectively.

[0057] [picture]

[10] graphically depicts the percentage change in PO-SCORAD index over time relative to baseline demonstrated by LSM using 95% CI. An overall progressive decrease in PO-SCORAD index from baseline to days 15, 29, 57, 64, 85 and 113 was observed across all treatment groups, including placebo. Greater reductions were observed in the KY1005 group compared with placebo at nearly all time points: by day 113, at the KY1005 low dose compared with -23.96 in the placebo group (-38.36, -9.46) In the low-dose and high-dose groups, the LSM percentage changes (95% CI) of PO-SCORAD index were -55.16 (-69.11, -41.21) and -43.04 (-56.41, -29.67) respectively.

[0058] [picture]

[11] graphically depicts the percentage change over time in the DLQI total score compared to baseline demonstrated by LSM using 95% CI. A progressive decrease in DLQI from baseline to days 15, 29, 57, 64, 85, and 113 was observed overall in all treatment groups, including placebo. There was no overall significant difference in the magnitude of reduction between treatment groups, although there was a trend toward greater reduction in the KY1005 treatment group compared with placebo at Days 85 and 113: by Day 113, in the KY1005 low-dose group In the and high-dose groups, the LSM percentage change (95% CI) of the DLQI total score was -52.99 (-75.31, -30.67) and -59.15 (-80.32, -37.99) respectively, while in the placebo group it was -20.51 ( -44.95,3.93).

[0059] [picture]

[12] graphically depicted the percentage change in mean weekly pruritus NRS over time relative to baseline using LSM with 95% CI. An overall progressive decrease in the weekly mean NRS for pruritus from baseline to Days 15, 29, 57, 85, and 113 was observed across all treatment groups, including placebo. There were no significant differences in the magnitude of reductions between treatment groups at any time point, and comparisons of the percent change in pruritus NRS between the KY1005 group and placebo revealed no nominally statistically significant differences.

[0060] [picture]

[13] graphically depicts serum KY1005 concentration versus time data presented using geometric mean values ​​from the main study. The serum concentration curves of KY1005 were similar between the KY1005 groups, with higher concentrations recorded in the KY1005 high-dose group than in the low-dose group. With repeated intravenous administration, serum concentrations rapidly reach peak values ​​and subsequently decrease after each dose.

[0061] [picture]

[14] graphically depicts serum KY1005 concentration versus time data presented using geometric means in an extension study. The serum concentration profiles of patients entering the study extension were similar between the KY1005 groups, with higher KY1005 concentrations recorded in the KY1005 high-dose group than in the low-dose group. After the fourth infusion on day 85, serum concentrations decreased steadily until day 253.

[0062] [picture]

[15] graphically depicts an overview of the research design for Example 3. The study included the following 3 groups: Comparative group 1: a single dose of 250 mg KY1005, administered by intravenous infusion over 30 minutes, followed by 15 minutes of saline flush; Group 2: a single dose of 125 mg (1 mL) KY1005, administered by intravenous infusion over 30 minutes given as a subcutaneous injection into the abdomen; and Group 3: single dose of 250 mg (2 mL) KY1005, given as a sequential 2 × 1 mL subcutaneous injection into the abdomen.

[0063] [picture] [16A-B] Graphically depicts the mean serum concentration-time profile of KY1005 over 92 days following single intravenous and subcutaneous doses, which is linear ( [picture] [16A]) and semilogarithm ( [picture] [16B] [). ] Absorption by the subcutaneous route is slower than that seen with intravenous administration of the drug: After both 250 mg (25,803 ng / mL) and 125 mg (14,222 ng / mL) subcutaneous doses, mean serum concentrations were The peak value was reached 168 hours after administration (day 8). Mean serum concentrations following the 250 mg intravenous and subcutaneous doses converged to approximately 20,000 ng / mL by day 36. After this point, the mean serum concentration-time curves for both regimens were very similar throughout the remainder of the sampling period, falling to approximately 7,000 ng / mL at follow-up (day 92).

[0064] [picture] [17A-B] Graphically depicts the mean serum concentration time curve of KY1005 after single intravenous and subcutaneous doses to 24 hours, which is linear ( [picture] [17A]) and semi-logarithmic ( [picture] [17B]). Absorption by the subcutaneous route is slower than that seen with drugs administered intravenously. A single 250 mg intravenous dose of KY1005 rapidly reached peak serum concentrations at the end of infusion (30 min): the mean serum concentration was 88,931 ng / mL; individual concentrations at end of infusion ranged from 72,391 to 120,333 ng / mL (each The ratio between extreme individuals is 1.66 times).

[0065] [picture] [18A-D] graphically depicts different studies including KY1005 FIH HV CT-01( [picture] [18A]), KY1005 CT-02( [picture] [18B]) and KY1005 CT-04( [picture] [18C]), dose-normalized KY1005 PK curve for intravenous treatment. These three studies were [picture] [18D] Different colors overlap in the middle image (CT-01 = purple, CT-02 = red, CT-04 = orange). The dose-normalized intravenous curves showed a biphasic behavior consistent with the assumed two-compartment distribution model.

[0066] [picture]

[19] graphically depicts the dose-normalized KY1005 PK curve for subcutaneous treatment in the KY1005 CT-04 study. The dose-normalized subcutaneous curves were consistent with each other. The curves are densely sampled within the first day and within the first week. Maximum concentration (C max) is reached between 4 and 14 days. The subcutaneous curve after 14 days was much flatter than the intravenous curve.

[0067] [picture]

[20] graphically depict the predicted C min at week 24 for induction scenarios I-III (different doses) and IV-XII (different regimens). [picture] [20A] depicts induction scenario I (200 mg Q4W subcutaneous, 100 mg Q4W subcutaneous, 50 mg Q4W subcutaneous, and 25 mg Q4W subcutaneous). [picture] [20B] depicts induction scenario II (300 mg Q4W subcutaneous, 250 mg Q4W subcutaneous, 200 mg Q4W subcutaneous and 150 mg Q4W subcutaneous). [picture] [20C] depicts induction scenario III (500 mg Q4W subcutaneous, 450 mg Q4W subcutaneous, 400 mg Q4W subcutaneous and 350 mg Q4W subcutaneous). [picture] [20D] depicts induction scenarios IV (125 mg subcutaneously every 2 weeks (Q2W), 125 mg Q4W subcutaneously, 125 mg every six weeks (Q6W) subcutaneously, and 125 mg every eight weeks (Q8W) subcutaneously). [picture] [20E] depicts induction scenario V (150 mg Q2W subcutaneous, 150 mg Q4W subcutaneous, 150 mg Q6W subcutaneous and 150 mg Q8W subcutaneous). [picture] [20F] depicts induction scenario VI (200 mg Q2W subcutaneous, 200 mg Q4W subcutaneous, 200 mg Q6W subcutaneous and 200 mg Q8W subcutaneous).

[0068] [picture] [21A-F] graphically depict the predicted Cmin at week 24 for induction scenarios I-III (different doses) and IV-XII (different regimens). [picture] [21A] depicts induction scenario VII (250 mg Q2W subcutaneous, 250 mg Q4W subcutaneous, 250 mg Q6W subcutaneous, and 250 mg Q8W subcutaneous). [picture] [21B] depicts induction scenario VIII (300 mg Q2W subcutaneous, 300 mg Q4W subcutaneous, 300 mg Q6W subcutaneous, and 300 mg Q8W subcutaneous). [picture] [21C] depicts induction scenario IX (350 mg Q2W subcutaneous, 350 mg Q4W subcutaneous, 350 mg Q6W subcutaneous, and 350 mg Q8W subcutaneous). [picture] [21D] depicts induction scenario X (400 mg Q2W subcutaneous, 400 mg Q4W subcutaneous, 400 mg Q6W subcutaneous, and 400 mg Q8W subcutaneous). [picture] [21E] depicts induction scenario XI (450 mg Q2W subcutaneous, 450 mg Q4W subcutaneous, 450 mg Q6W subcutaneous and 450 mg Q8W subcutaneous). [picture] [21F] depicts induction scenario XII (500 mg Q2W subcutaneous, 500 mg Q4W subcutaneous, 500 mg Q6W subcutaneous and 500 mg Q8W subcutaneous).

[0069] [picture] [22A-C] graphically depict the predicted C min at the end of the maintenance period. [picture] [22A] depicts the maintenance of Q8W after week 52, [picture] [22B] depicts maintenance Q12W after week 52, and [picture] [22C] depicts maintenance Q16W after week 52.

[0070] [picture] [23A-D] Graphically depict analog KY1005 PK profiles in atopic dermatitis (AD) patients stratified by body weight. Simulations are shown for 50, 75, 100, 120 and 150 kg body weight. [picture] [23A] depicts four doses of 62.5 mg KY1005 administered every 4 weeks (Q4W). [picture] [23B] depicts Q4W administration of four doses of 125 mg KY1005. [picture] [23C] depicts Q4W administration of four doses of 250 mg KY1005. [picture] [23D] depicts one dose of 500 mg of KY1005, followed by three doses of 250 mg, administered Q4W.

[0071] [picture] [24A-D] graphically depict predicted Cmin after a 24-week induction period. Different options (Q2W( [picture] [24A]), Q4W( [picture] [24B]), Q6W( [picture] [24C]), Q8W( [picture] [24D])) are distributed on different graphs.

[0072] [picture] [25A-C] graphically depict the predicted time above Cmin during the maintenance period. Different solutions (Q8W( [picture] [25A]), Q12W( [picture] [25B]), Q16W( [picture] [25C])) are distributed on different graphs.

[0073] [picture]

[26] graphically depicts an overview of the research design for Example 5. Four different dosing regimens of SC KY1005 will be tested compared to placebo. From baseline to day 169 (week 24), KY1005 will be administered at the following doses and intervals: 500 mg loading dose (given as 2 x 2 mL subcutaneously), after day 28 and 250 mg every 4 weeks thereafter (Q4W), or the following regimens from baseline: 250 mg Q4W or 125 mg Q4W or 62.5 mg Q4V or placebo Q4W.

[0074] [picture]

[27] graphically depicted the correlation between EASI and IL-13 serum levels at baseline. The graph depicts the 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) based on r coefficient and p value of Spearman correlation.

[0075] [picture]

[28] graphically depicted changes in circulating IL-13 over time. On day 113, patients treated with amlitelimab (KY1005 or 2D10) but not placebo had significantly lower serum IL-13 levels. Responders to amlitelimab but not placebo maintained reductions in ‡ until day 253. The sustained reduction in IL-13 serum levels in amlitelimab-treated patients was treatment-dependent and strongly suggests that amlitelimab is effective in targeting immune dysregulation in AD, † for patients with a complete data set at day 113, compared with BL (day 1) Repeated measures two-way ANOVA + Tukey's multiple comparison test for fold change compared to IL-13 (placebo, n=15; amlitelimab low dose, n=20; and amlitelimab high dose, n=20). ns p>0.05;** p<0.01;*** p<0.001,****p<0.0001. ‡The reduction was maintained in all patients except one patient treated with amlitelimab low dose, who had an increase in IL-13 levels compared with BL on day 169. AD, atopic dermatitis; BL, baseline; CI, confidence interval; EASI, eczema area and severity index; IL, interleukin; ns, not significant; SCORAD, atopic dermatitis score.

[0076] [picture] [29A-F] Graphically depict the biomarker IL-13 ( [picture] [29A-B]), IL22( [picture] [29C-D]) and IL-17A( [picture] [29E-F]) log 10-fold change ( [picture] [29B], [picture] [29D] and [picture] [29F] further shows data from patients administered KY1005 low dose and KY1005 high dose). IL-13 and IL-22 data are from KY1005 CT02 serum analysis. IL-17A information comes from 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 comparisons test. [picture] [29A-B] demonstrated that KY1005 is associated with a decrease in Th2-related serum interleukins. [picture] [29C-F] demonstrate that KY1005 is associated with reductions in cytokines typically associated with Th22 and Th17 responses.

[0077] [picture]

[30] graphically depicts the results of the validated investigator-wide assessment of atopic dermatitis ( The proportion of patients achieving a score of 0 or 1 on the vIGA-AD) scale. ***p<0.001 vs. placebo (Cochran-Mantel-Haenszel test), **p<0.001 vs. placebo, *p<0.05 vs. placebo.

[0078] [picture] [31A-B] graphically depict two proteins associated with disease severity ( [picture] IL-22 and [picture] Relative protein levels of IL-13) in [31B]. IL-22 and IL-13 protein levels were found to be significantly associated with EASI score at baseline (FDR p-value <0.05) (first column). This correlation was also maintained on days 29 and 113 for both proteins. Calculate the coefficient of determination R2 and p-value using a linear model. Each point represents a patient sample, the blue line represents the linear regression line, and the 95% confidence interval is shown in gray.

[0079] [picture] [32A-C] graphically depict IL-13 ( [picture] [32A]), IL-22( [picture] [32B]) and IL-17A( [picture] [32C]) levels, which were significantly reduced on day 113 after KY1005 treatment (FDR p-value <0.05). The x-axis shows time in days (data points are at days 0, 29, and 113). The Y-axis shows the Log 2 change from baseline levels.

[0080] [picture] [33A-C] Graphically depict IL-13 serum levels at baseline in relation to disease severity. IL-13 is significantly positively correlated with disease severity, as measured by EASI at baseline ( [picture] [33A]) and SCORAD( [picture] [33B]) measured. There were no significant differences in baseline IL-13 levels between treatment groups ( [picture] [33C]). Spearman correlation between IL-13 and EASI / SCORAD at baseline (n=78). One-way ANOVA with Tukey's multiple comparison test.

[0081] [picture]

[34] graphically depicted circulating IL-13 between baseline and D113 in different treatment groups. IL-13 levels were normalized to baseline. n = number of patients with complete set of samples up to D113. Two-way analysis of variance + Tukey's multiple comparison test. On day 113, IL-13 was significantly reduced in KY1005-treated patients (KY1005-low and high), but not in placebo patients.

[0082] [picture] [35A-B] graphically depict changes in IL-13 levels at D113 compared to baseline, indicating that IL-13 levels are associated with disease improvement. Only patients with a complete set of samples up to D113 were included (n=58). In D113, IL-13 fold change correlated with EASI ( [picture] [35A]) / SCORAD( [picture] [35B]) Spearman correlation. In D113, IL-13 changes were correlated with EASI ( [picture] [35A]) and SCORAD( [picture] [35A]) weak correlation between disease improvement.

[0083] [picture]

[36] graphically depicted changes in IL-13 serum levels maintained beyond D113 in vIGA 0 / 1 responders. Twenty-four D169 samples and 15 evaluable D253 samples were obtained from 24 patients classified as responders (vIGA 0-1) at D113. Among patients classified as responders (vIGA 0-1) at D113, the decrease in IL-13 serum in patients treated with KY1005 was extended to D169 and D253.

[0084] [picture] [37A-C] Graphically depict IL-22 serum levels at baseline in relation to disease severity. One-way ANOVA with Tukey's multiple comparison test Spearman's correlation for IL-22 and EASI / SCORAD at baseline (n=78). IL-22 was significantly associated with disease severity, as measured by EASI at baseline ( [picture] [37A]) and SCORAD( [picture] [37B]) measured. There were no significant differences in baseline IL-22 levels between treatment groups ( [picture] [37C]).

[0085] [picture]

[38] graphically depicted circulating IL-22 between baseline and D113 in different treatment groups. n = number of patients with complete set of samples up to D113. Two-way analysis of variance + Tukey's multiple comparison test. IL-22 levels changed significantly from baseline on D113 in KY1005-treated patients (and on D29 in KY1005 high-dose-treated patients), but not in placebo patients.

[0086] [picture] [39A-B] graphically depict changes in IL-22 levels at D113 compared to baseline, indicating that IL-22 levels are associated with disease improvement. Only patients with a complete set of samples up to D113 were included (n=58). In D113, IL-22 fold change correlated with EASI ( [picture] [39A]) / SCORAD( [picture] [39B]) Spearman correlation. In D113, IL-22 changes were associated with EASI ( [picture] [39A]) and SCORAD( [picture] [39A]) weak correlation between disease improvement.

[0087] [picture]

[40] graphically depicted changes in IL-22 serum levels maintained beyond D113 in vIGA 0 / 1 responders. Twenty-four D169 samples and 16 evaluable D253 samples were obtained from 24 patients classified as responders (vIGA 0-1) at D113. Among patients classified as responders (vIGA 0-1) at D113, the decrease in IL-22 serum in patients treated with KY1005 was extended to D169 and D253.

[0088] [picture]

[41] graphically depicted the effect of Amlitelimab on serum biomarkers (total IgE, IL-13, IL-22 and IL-31). According to the treatment regimen, the fold change of serum (A) IgE, (B) IL-13, (C) IL-22 and (D) IL-31 over time compared with baseline. Until week 16, all patients with biomarker data at baseline and week 16 or at least two alternative treatment time points were included. For study extension, only patients who achieved vIGA0 / 1 at week 16 (w16 responders) were included. Post hoc linear mixed-effects model with Dunnett's multiple comparison test, log10-transformed fold change from baseline by treatment (ns not significant, * p < 0.05, ** p, 0.01, *** p < 0.001, ** **p<0.0001). Median + 95% confidence interval; sample size is shown above the x-axis.

[0089] [picture]

[42] graphically depicted changes in IL-31 serum levels over time during treatment. Implementation

[0090] [Related Applications]

[0091] This application claims UK priority application numbers GB 2111492.1 filed on 10 August 2021, GB 2115152.7 filed on 21 October 2021, GB 2204211.3 filed on 24 March 2022 and GB 2204211.3 filed on 25 March 2022. GB 2204291.5, the contents of which are incorporated by reference in their entirety for all purposes.

[0092] In a first configuration, a method of treating atopic dermatitis in a human subject is provided, 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 Administered by injection. The antibody or fragment thereof can be administered by subcutaneous injection. The antibody or fragment thereof may be a disease modifying drug. Optionally, the method includes 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 may be administered at least twice at at least an interval of 2 to 6 months. The antibody or fragment thereof may be administered at least twice at at least a 6-month interval. The individual may be a patient with chronic atopic dermatitis.

[0093] In an alternative to a first configuration, there is provided a method of treating atopic dermatitis in a human subject, said method comprising administering a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment thereof Fragments are disease-modifying drugs. After administration of the disease-modifying drug, the individual can achieve an IGA-AD score of 0 or 1 for at least six months. Any other suitable disease severity measure described herein, such as EASI75 or EASI90, which may indicate disease modification, may be substituted for an IGA-AD score of 0 or 1. The at least six months may be at least seven months, at least eight months or at least nine months. The individual may maintain an IGA-AD score of 0 or 1 for at least six months after cessation of treatment with the disease-modifying drug. The at least six months may be at least seven months, at least eight months or at least nine months. The therapeutic effect may persist for at least about six half-lives of the antibody or fragment thereof following final administration of the antibody or fragment thereof. The at least six half-lives can be at least about seven half-lives, at least about eight half-lives, or at least about nine half-lives of the antibody or fragment thereof. The antibody or fragment thereof may be administered by injection, optionally subcutaneous injection. Optionally, the method includes 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 may be administered at least twice at at least an interval of 2 to 6 months. The antibody or fragment thereof may be administered at least twice at at least a 6-month interval. The individual may be a patient with chronic atopic dermatitis. Post-administration EASI score, vIGA-AD score, IGA-ID score compared to the corresponding baseline EASI score, vIGA-AD score, IGA-AD score, BSA score, SCORAD index, PO-SCORAD index and / or DQLI score , BSA score, SCORAD index, PO-SCORAD index and / or DQLI score can be reduced by at least 10%.

[0094] In an alternative to a first configuration, there is provided a method of treating atopic dermatitis in a human subject, said method comprising administering a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment thereof The fragment is administered by injection, and the method includes 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 can be administered by subcutaneous injection. The antibody or fragment thereof may be administered at least twice at at least an interval of 2 to 6 months. The antibody or fragment thereof may be administered at least twice at at least a 6-month interval. The individual may be a patient with chronic atopic dermatitis. Post-administration EASI score, vIGA-AD score, IGA-ID score compared to the corresponding baseline EASI score, vIGA-AD score, IGA-AD score, BSA score, SCORAD index, PO-SCORAD index and / or DQLI score , BSA score, SCORAD index, PO-SCORAD index and / or DQLI score can be reduced by at least 10%.

[0095] In an alternative to a first configuration, there is provided a method of treating atopic dermatitis in a human subject, said method comprising administering a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment thereof Fragments are disease-modifying drugs. The antibody or fragment thereof may be administered by injection, optionally subcutaneous injection. Optionally, the method includes 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 may be administered at least twice at at least an interval of 2 to 6 months. The antibody or fragment thereof may be administered at least twice at at least a 6-month interval. The individual may be a patient with chronic atopic dermatitis. Post-administration EASI score, vIGA-AD score, IGA-ID score compared to the corresponding baseline EASI score, vIGA-AD score, IGA-AD score, BSA score, SCORAD index, PO-SCORAD index and / or DQLI score , BSA score, SCORAD index, PO-SCORAD index and / or DQLI score can be reduced by at least 10%.

[0096] In an alternative to a first configuration, there is provided a method of treating atopic dermatitis in a human subject, said method comprising administering a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment thereof Fragments are administered at least twice at an interval of 2 to 6 months. The antibody or fragment thereof may be administered at least one interval of 2 to 5.5 months, at least one interval of 2 to 5 months, at least one interval of 2 to 4.5 months, or at least one interval of 2 to 4 months. twice. The antibody or fragment thereof can be administered at least twice at least at an interval of approximately 3 months. The antibody or fragment thereof may be administered by injection, optionally subcutaneous injection. The antibody or fragment thereof may be a disease-modifying drug. Optionally, the method includes administering at least one injection at a dose of at least about 20 mg of the antibody or fragment thereof. The individual may be a patient with chronic atopic dermatitis. Post-administration EASI score, vIGA-AD score, IGA-ID score compared to the corresponding baseline EASI score, vIGA-AD score, IGA-AD score, BSA score, SCORAD index, PO-SCORAD index and / or DQLI score , BSA score, SCORAD index, PO-SCORAD index and / or DQLI score can be reduced by at least 10%.

[0097] In an alternative to a first configuration, there is provided a method of treating atopic dermatitis in a human subject, said method comprising administering a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment thereof Fragments were administered at least twice with at least a 6-month interval. The antibody or fragment thereof may be administered at least twice at at least a 5.5 month interval, at least a 5 month interval, at least a 4.5 month interval, or at least a 4 month interval. The antibody or fragment thereof can be administered at least twice at least at an interval of approximately 3 months. Any period of time expressed in months may also be expressed in weeks, for example, in one embodiment, one month equals four weeks. The antibody or fragment thereof may be administered by injection, optionally subcutaneous injection. The antibody or fragment thereof may be a disease-modifying drug. Optionally, the method includes administering at least one injection at a dose of at least about 20 mg of the antibody or fragment thereof. The individual may be a patient with chronic atopic dermatitis. Post-administration EASI score, vIGA-AD score, IGA-ID score compared to the corresponding baseline EASI score, vIGA-AD score, IGA-AD score, BSA score, SCORAD index, PO-SCORAD index and / or DQLI score , BSA score, SCORAD index, PO-SCORAD index and / or DQLI score can be reduced by at least 10%.

[0098] In an alternative statement to a first configuration, there is provided a method of treating atopic dermatitis in a human subject, the method comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the subject is chronic Patients with atopic dermatitis. The antibody or fragment thereof may be administered by injection, optionally subcutaneous injection. The antibody or fragment thereof may be a disease-modifying drug. Optionally, the method includes 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 may be administered at least twice at at least an interval of 2 to 6 months. The antibody or fragment thereof may be administered at least twice at at least a 6-month interval. Post-administration EASI score, vIGA-AD score, IGA-ID score compared to the corresponding baseline EASI score, vIGA-AD score, IGA-AD score, BSA score, SCORAD index, PO-SCORAD index and / or DQLI score , BSA score, SCORAD index, PO-SCORAD index and / or DQLI score can be reduced by at least 10%.

[0099] In an alternative statement to a first configuration, there is provided a method of treating atopic dermatitis in a human subject, said method comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the post-administration EASI score A decrease in EASI score of at least 10% relative to baseline. On day 15 to day 113 (optionally on day 7 to at least day 113, or on day 29 to at least day 113) after administration of the anti-OX40L antibody or antigen-binding fragment thereof, post-administration EASI The score can be reduced by at least 10% relative to the baseline EASI score. From day 15 to at least day 169 or at least day 253 after administration of the anti-OX40L antibody or antigen-binding fragment thereof, the post-administration EASI score can be reduced by at least 10% relative to the baseline EASI score. At approximately day 113 after administration of the anti-OX40L antibody or antigen-binding fragment thereof, the post-administration EASI score can be reduced by at least 20% relative to the baseline EASI score. At approximately day 113 after administration of the anti-OX40L antibody or antigen-binding fragment thereof, the post-administration EASI score can 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. The antibody or fragment thereof may be administered by injection, optionally subcutaneous injection. The antibody or fragment thereof may be a disease-modifying drug. Optionally, the method includes 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 may be administered at least twice at at least an interval of 2 to 6 months. The antibody or fragment thereof may be administered at least twice at at least a 6-month interval. The individual may be a patient with chronic atopic dermatitis. Compared with the corresponding baseline vIGA-AD score, IGA-AD score, BSA score, SCORAD index, PO-SCORAD index and / or DQLI score, post-administration vIGA-AD score, IGA-ID score, BSA score, SCORAD index , PO-SCORAD index and / or DQLI score can be reduced by at least 10%.

[0100] In an alternative statement of the first configuration, there is provided a method of treating atopic dermatitis in a human subject, the method comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein after administration vIGA- AD score decreased by at least 10% relative to baseline vIGA-AD score. On day 15 to day 113 (optionally on day 7 to at least day 113, or on day 29 to at least day 113) after administration of the anti-OX40L antibody or antigen-binding fragment thereof, post-administration vIGA - AD score can be reduced by at least 10% relative to baseline vIGA-AD score. From day 15 to at least day 169 or at least day 253 after administration of the anti-OX40L antibody or antigen-binding fragment thereof, the post-administration vIGA-AD score can be reduced by at least 10% relative to the baseline vIGA-AD score. At approximately day 113 after administration of the anti-OX40L antibody or antigen-binding fragment thereof, the post-administration vIGA-AD score can be reduced by at least 20% relative to the baseline vIGA-AD score. At approximately day 113 after administration of the anti-OX40L antibody or antigen-binding fragment thereof, the post-administration vIGA-AD score can be reduced by at least 15%, at least 20%, at least 30%, at least 40%, or at least 40% relative to the baseline vIGA-AD score. At least 45%. The antibody or fragment thereof may be administered by injection, optionally subcutaneous injection. The antibody or fragment thereof may be a disease-modifying drug. Optionally, the method includes 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 may be administered at least twice at at least an interval of 2 to 6 months. The antibody or fragment thereof may be administered at least twice at at least a 6-month interval. The individual may be a patient with chronic atopic dermatitis. Compared with the corresponding baseline EASI score, IGA-AD score, BSA score, SCORAD index, PO-SCORAD index and / or DQLI score, post-administration EASI score, IGA-ID score, BSA score, SCORAD index, PO-SCORAD Index and / or DQLI scores can be reduced by at least 10%.

[0101] In an alternative to a first configuration, there is provided a method of treating atopic dermatitis in a human subject, the method comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein after administration IGA- AD score decreased by at least 10% relative to baseline IGA-AD score. On day 15 to day 113 (optionally on day 7 to at least day 113, or on day 29 to at least day 113) after administration of the anti-OX40L antibody or antigen-binding fragment thereof, post-administration IGA - AD score can be reduced by at least 10% relative to baseline IGA-AD score. From day 15 to day 169 or day 253 after administration of an anti-OX40L antibody or antigen-binding fragment thereof, the post-administration IGA-AD score may be at least 10% lower than the baseline IGA-AD score. At approximately day 113 after administration of the anti-OX40L antibody or antigen-binding fragment thereof, the post-administration IGA-AD score can be reduced by at least 20% relative to the baseline IGA-AD score. At approximately day 113 after administration of the anti-OX40L antibody or antigen-binding fragment thereof, the post-administration IGA-AD score can be reduced by at least 15%, at least 20%, at least 30%, at least 40%, or at least 40% relative to the baseline IGA-AD score. At least 45%. The antibody or fragment thereof may be administered by injection, optionally subcutaneous injection. The antibody or fragment thereof may be a disease-modifying drug. Optionally, the method includes 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 may be administered at least twice at at least an interval of 2 to 6 months. The antibody or fragment thereof may be administered at least twice at at least a 6-month interval. The individual may be a patient with chronic atopic dermatitis. Compared with the corresponding baseline EASI score, vIGA-AD score, BSA score, SCORAD index, PO-SCORAD index and / or DQLI score, post-administration EASI score, vIGA-ID score, BSA score, SCORAD index, PO-SCORAD Index and / or DQLI scores can be reduced by at least 10%.

[0102] In an alternative statement to a first configuration, there is provided a method of treating atopic dermatitis in a human subject, the method comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the BSA score after administration A decrease in BSA score of at least 10% relative to baseline. Post-administration BSA on day 29 to day 113 (optionally on day 7 to at least day 113, or on day 15 to at least day 113) after administration of the anti-OX40L antibody or antigen-binding fragment thereof The score can be reduced by at least 10% relative to the baseline BSA score. At approximately day 113 after administration of the anti-OX40L antibody or antigen-binding fragment thereof, the post-administration BSA score can be reduced by at least 20% relative to the baseline BSA score. At approximately day 113 after administration of the anti-OX40L antibody or antigen-binding fragment thereof, the post-administration BSA score can be reduced by at least 30% or at least 35% relative to the baseline BSA score. The antibody or fragment thereof may be administered by injection, optionally subcutaneous injection. The antibody or fragment thereof may be a disease-modifying drug. Optionally, the method includes 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 may be administered at least twice at at least an interval of 2 to 6 months. The antibody or fragment thereof may be administered at least twice at at least a 6-month interval. The individual may be a patient with chronic atopic dermatitis. Compared with the corresponding baseline EASI score, vIGA-AD score, IGA-AD score, SCORAD index, PO-SCORAD index and / or DQLI score, post-administration EASI score, vIGA-ID score, IGA-AD score, SCORAD index , PO-SCORAD index and / or DQLI score can be reduced by at least 10%.

[0103] In an alternative statement of the first configuration, there is provided a method of treating atopic dermatitis in a human subject, said method comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the post-administration SCORAD index A decrease in SCORAD index of at least 10% relative to baseline. On day 29 to day 113 (optionally on day 7 to at least day 113, or on day 15 to at least day 113) after administration of the anti-OX40L antibody or antigen-binding fragment thereof, post-SCORAD administration The index can be reduced by at least 10% relative to the baseline SCORAD index. At approximately day 113 after administration of an anti-OX40L antibody or antigen-binding fragment thereof, the post-administration SCORAD index can be reduced by at least 20% relative to the baseline SCORAD index. At approximately day 113 after administration of the anti-OX40L antibody or antigen-binding fragment thereof, the post-administration SCORAD index can be reduced by at least 30% or at least 35% relative to the baseline SCORAD index. At approximately day 113 after administration of the anti-OX40L antibody or antigen-binding fragment thereof, the post-administration SCORAD index can be reduced by at least 45% or at least 60% relative to the baseline SCORAD index. The antibody or fragment thereof may be administered by injection, optionally subcutaneous injection. The antibody or fragment thereof may be a disease-modifying drug. Optionally, the method includes 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 may be administered at least twice at at least an interval of 2 to 6 months. The antibody or fragment thereof may be administered at least twice at at least a 6-month interval. The individual may be a patient with chronic atopic dermatitis. Post-administration EASI score, vIGA-ID score, IGA-AD score, BSA score compared to the corresponding baseline EASI score, vIGA-AD score, IGA-AD score, BSA score, PO-SCORAD index and / or DQLI score , PO-SCORAD index and / or DQLI score can be reduced by at least 10%.

[0104] In an alternative statement of the first configuration, there is provided a method of treating atopic dermatitis in a human subject, the method comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the administration is followed by PO- The SCORAD index decreases by at least 10% relative to the baseline PO-SCORAD index. On day 29 to day 113 (optionally on day 7 to at least day 113, or on day 15 to at least day 113) after administration of the anti-OX40L antibody or antigen-binding fragment thereof, post-administration PO - The SCORAD index can be reduced by at least 10% relative to the baseline PO-SCORAD index. At approximately day 113 after administration of an anti-OX40L antibody or antigen-binding fragment thereof, the post-administration PO-SCORAD index can be reduced by at least 15% relative to the baseline PO-SCORAD index. At approximately day 113 after administration of the anti-OX40L antibody or antigen-binding fragment thereof, the post-administration PO-SCORAD index can be reduced by at least 20% or at least 30% relative to the baseline PO-SCORAD index. At approximately day 113 after administration of an anti-OX40L antibody or antigen-binding fragment thereof, the post-administration PO-SCORAD index can be reduced by at least 40% or at least 50% relative to the baseline PO-SCORAD index. The antibody or fragment thereof may be administered by injection, optionally subcutaneous injection. The antibody or fragment thereof may be a disease-modifying drug. Optionally, the method includes 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 may be administered at least twice at at least an interval of 2 to 6 months. The antibody or fragment thereof may be administered at least twice at at least a 6-month interval. The individual may be a patient with chronic atopic dermatitis. Compared with the corresponding baseline EASI score, vIGA-AD score, IGA-AD score, BSA score, SCORAD index and / or DQLI score, post-administration EASI score, vIGA-ID score, IGA-AD score, BSA score, SCORAD Index and / or DQLI scores can be reduced by at least 10%.

[0105] In an alternative statement to a first configuration, there is provided a method of treating atopic dermatitis in a human subject, the method comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the post-administration DQLI score A reduction of at least 10% in DQLI score relative to baseline. On day 85 to day 113 (optionally on day 7 to at least day 113, or on day 15 to at least day 113, or on day 29) after administration of the anti-OX40L antibody or antigen-binding fragment thereof By at least Day 113), the post-administration DQLI score can be reduced by at least 10% relative to the baseline DQLI score. At approximately day 113 after administration of the anti-OX40L antibody or antigen-binding fragment thereof, the post-administration DQLI score can be reduced by at least 20% relative to the baseline DQLI score. At approximately day 113 after administration of the anti-OX40L antibody or antigen-binding fragment thereof, the post-administration DQLI score can be reduced by at least 30% or at least 35% relative to the baseline DQLI score. The antibody or fragment thereof may be administered by injection, optionally subcutaneous injection. The antibody or fragment thereof may be a disease-modifying drug. Optionally, the method includes 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 may be administered at least twice at at least an interval of 2 to 6 months. The antibody or fragment thereof may be administered at least twice at at least a 6-month interval. The individual may be a patient with chronic atopic dermatitis. Post-administration EASI score, vIGA-ID score, IGA-AD score, BSA score compared to the corresponding baseline EASI score, vIGA-AD score, IGA-AD score, BSA score, SCORAD index and / or PO-SCORAD index , SCORAD index and / or PO-SCORAD index can be reduced by at least 10%.

[0106] Any feature described in connection with one statement of a first configuration is expressly considered in combination with features of any other statement of the first configuration. Any statement of the first configuration may be read in combination with any other part of this disclosure unless obvious from the context. Any optional feature described in any part of this disclosure in relation to any one statement of the first configuration or any alternative statement of the first configuration may be read in combination with any other part of this disclosure unless obvious from the context. out.

[0107] In yet another configuration, a method of treating an inflammatory disease or inflammatory disorder in a human subject is provided, 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 Administered by injection.

[0108] In yet another configuration, a method of treating an immune-mediated disease or immune-mediated disorder in a human subject is provided, the method comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein said Antibodies or fragments thereof are administered by injection.

[0109] In yet another configuration, a method of treating an inflammatory skin disease or inflammatory skin disorder in a human subject is provided, the method comprising administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof Administered by injection.

[0110] In yet another configuration, an anti-OX40L antibody, or an antigen-binding fragment thereof, is provided for a method of treating an inflammatory disease or inflammatory disorder in a human subject, the method comprising administering a therapeutically effective amount of an anti-OX40L antibody, or an antigen-binding fragment thereof Fragments, wherein the antibody or fragment thereof is administered by injection.

[0111] In yet another configuration, an anti-OX40L antibody, or an antigen-binding fragment thereof, is provided for a method of treating an immune-mediated disease or immune-mediated disorder in a human subject, the method comprising administering a therapeutically effective amount of the anti-OX40L antibody or antigen-binding fragment thereof. An OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered by injection.

[0112] In yet another configuration, an anti-OX40L antibody, or an antigen-binding fragment thereof, is provided for a method of treating an 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 an antigen-binding fragment thereof. Antigen-binding fragments, wherein the antibody or fragment thereof is administered by injection.

[0113] In yet another 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, the method comprising: Administer every 4 weeks during the maintenance phase and every 12 weeks during the induction phase and every 12 weeks during the maintenance phase.

[0114] In yet another 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, the method comprising administering by subcutaneous injection A therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof is administered.

[0115] In yet another 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, the method comprising: Administered by subcutaneous injection once every 4 weeks during the maintenance phase and every 12 weeks during the induction phase and once every 12 weeks during the maintenance phase.

[0116] In yet another configuration, an anti-OX40L antibody, or antigen-binding fragment thereof, is provided 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 A 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.

[0117] In yet another configuration, an anti-OX40L antibody, or antigen-binding fragment thereof, is provided 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 A method comprising administering by subcutaneous injection once every 4 weeks during the induction period and once every 12 weeks during the maintenance period.

[0118] In yet other configurations, the above-described embodiments are provided, comprising administering a therapeutically effective amount of an OX40L antagonist antibody or antigen-binding fragment thereof.

[0119] Dosage and serum concentration

[0120] Dosage can be from 20 mg to 1000 mg. Dosage can be from 20 mg to 600 mg. Doses may be up to 550 mg, up to 500 mg, up to 450 mg, up to 400 mg, up to 350 mg, up to 300 mg, up to 250 mg, up to 200 mg, up to 150 mg, up to 120 mg, up to 100 mg, or up to 50 mg . Doses can be up to 500 mg, up to 250 mg, or up to 150 mg. The dosage may be at least 50 mg, at least 100 mg, at least 120 mg, at least 150 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, at least 400 mg, at least 450 mg, at least 500 mg, or at least 550 mg . The dose may be at least 50 mg, at least 120 mg, or at least 150 mg. The dosage may be selected from 25 mg to 500 mg; from 50 mg to 450 mg; from 100 mg to 350 mg; from 120 mg to 300 mg; from 150 mg to 250 mg; and from 200 mg to 250 mg. The dosage can be selected from 60 mg to 500 mg; from 100 mg to 300 mg or from 125 mg to 150 mg.

[0121] Doses can be 62.5 mg, 125 mg, 150 mg, 250 mg or 500 mg. The dosage can be 125 mg or 150 mg. The dose can be 125 mg. The dosage can be 150 mg. The dose can be 62.5 mg. The dosage can be 250 mg. The dosage can be 500 mg.

[0122] Doses can be up to 0.6 mg / kg, up to 0.7 mg / kg, up to 0.8 mg / kg, up to 0.9 mg / kg, up to 1 mg / kg, up to 1.1 mg / kg, up to 1.2 mg / kg, up to 1.3 mg / kg, Up to 1.4 mg / kg, up to 1.5 mg / kg, up to 1.6 mg / kg, up to 1.7 mg / kg, up to 1.8 mg / kg, up to 1.9 mg / kg, up to 2 mg / kg, up to 2.1 mg / kg, up to 2.2 mg / 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 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 can be as high as 6 mg / kg or as high as 3 mg / kg.

[0123] The dosage may be at least 0.45 mg / kg, at least 0.5 mg / kg, at least 0.6 mg / kg, at least 0.7 mg / kg, at least 0.8 mg / kg, at least 0.9 mg / kg, at least 1 mg / kg, at least 1.1 mg / kg , at least 1.2 mg / kg, at least 1.3 mg / kg, at least 1.4 mg / kg, at least 1.5 mg / kg, at least 1.6 mg / kg, at least 1.7 mg / kg, at least 1.8 mg / kg, at least 1.9 mg / kg, at least 2 mg / kg, at least 2.1 mg / kg, at least 2.2 mg / kg, at least 2.3 mg / kg, at least 2.4 mg / kg, at least 2.5 mg / kg, at least 2.6 mg / kg, at least 2.7 mg / kg, at least 2.8 mg / kg, at least 2.9 mg / kg, at least 3 mg / kg, at least 4 mg / kg, at least 5 mg / kg, at least 6 mg / kg, at least 7 mg / kg, at least 8 mg / kg, at least 9 mg / kg , at least 10 mg / kg, at least 11 mg / kg or at least 12 mg / kg. The dose may be at least 0.45 mg / kg. The dose may be at least 0.7 mg / kg or at least 1.4 mg / kg.

[0124] The dosage can be selected from 0.1 mg / kg to 12 mg / kg; from 0.4 mg / kg to 11 mg / kg; from 0.7 mg / kg to 10 mg / kg; from 1 mg / kg to 9 mg / kg; from 1.3 mg / kg to 8 mg / kg; from 1.6 mg / kg to 7 mg / kg; from 1.9 mg / kg to 6 mg / kg; from 2.2 mg / kg to 5 mg / kg; from 2.5 mg / kg to 4 mg / kg kg; from 2.6 mg / kg to 3.8 mg / kg; from 2.7 mg / kg to 3.6 mg / kg; from 2.6 mg / kg to 3.4 mg / kg; from 2.7 mg / mg to 3.3 mg / kg; from 2.8 mg / kg to 3.2 mg / kg; and from 2.9 mg / kg to 3.1 mg / kg.

[0125] The dosage can be selected from 0.6 mg / kg to 11 mg / kg; from 0.7 mg / kg to 10 mg / kg; from 0.8 mg / kg to 9 mg / kg; from 0.9 mg / kg to 8 mg / kg; from 1 mg / kg to 7 mg / kg; from 1.1 mg / kg to 6 mg / kg; from 1.2 mg / kg to 5 mg / kg; from 1.3 mg / kg to 4 mg / kg; from 1.4 mg / kg to 3 mg / kg kg; from 1.5 mg / kg to 2.9 mg / kg; from 1.6 mg / kg to 2.8 mg / kg; from 1.7 mg / mg to 2.7 mg / kg; from 1.8 mg / kg to 2.6 mg / kg; from 1.9mg / kg to 2.5 mg / kg; from 2 mg / kg to 2.4 mg / kg; and from 2.1 mg / kg to 2.3 mg / kg.

[0126] Doses can be from 0.7 mg / kg to 6 mg / kg. Doses can be from 1.4 mg / kg to 3 mg / kg.

[0127] Preclinical data indicate that an IC90 of 0.405 μg / mL is required to inhibit the OX40L-OX40 interaction and an IC90 concentration of 1.09 μg / mL is required to inhibit soluble OX40L-induced IL-2 release from primary human T cells, and to evaluate T cell allogeneic Reduction of IL-2 in the mixed lymphocyte reaction assay requires an IC90 concentration of 1.5 ug / mL. Therefore, preclinical data indicate that the minimum concentration required at the site of action (skin) can range from 0.405 to 1.5 μg / mL. The dosage can be any suitable dosage to deliver at least about 0.4 to 1.5 μg / mL to the skin.

[0128] The method may include administering at least two injections of the antibody or fragment thereof. The lowest serum concentration (Cmin) of the antibody or fragment thereof achieved after administration of the first injection and before administration of the second injection can be at least about 2.5 μg / ml.

[0129] The method may include administering at least three injections of the antibody or fragment thereof. The lowest serum concentration (Cmin) of the antibody or fragment thereof achieved after administration of the second injection and before administration of the third injection can be at least about 2.5 μg / ml. The lowest serum concentration (Cmin) of the antibody or fragment thereof achieved after administration of the first injection and before administration of the third injection can be at least about 2.5 μg / ml.

[0130] The method may include administering at least four injections of the antibody or fragment thereof. The lowest serum concentration (Cmin) of the antibody or fragment thereof achieved after administration of the third injection and before administration of the fourth injection can be at least about 2.5 μg / ml. The lowest serum concentration (Cmin) of the antibody or fragment thereof achieved after administration of the first injection and before administration of the fourth injection can be at least about 2.5 μg / ml. The lowest serum concentration (Cmin) of the antibody or fragment thereof achieved after administration of the second injection and before administration of the fourth injection can be at least about 2.5 μg / ml.

[0131] The C min in serum between any two injections can be between 2.5 μg / ml and 600 μg / ml. The C min in serum between any two injections can be between 2.5 μg / ml and 375 μg / ml. The C min in serum between any two injections can be between 4 μg / ml and 600 μg / ml. C min in serum between any two injections can be 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 ml, at least 4 μg / ml, at least 4.1 μg / ml, at least 4.2 μg / ml, at least 4.3 μg / ml, at least 4.4 μg / ml, at least 4.5 μg / ml, at least 4.6 μg / ml, at least 4.7 μg / ml, At least 4.8 μg / ml, at least 4.9 μg / ml, at least 5 μg / ml, at least 5.1 μg / ml, at least 5.2 μg / ml, at least 5.3 μg / ml, at least 5.4 μg / ml, at least 5.5 μg / ml, at least 5.6 μg / ml, at least 5.7 μg / ml, at least 5.8 μg / ml, at least 5.9 μg / ml, at least 6 μg / ml, at least 6.5 μg / ml, at least 7 μg / ml, at least 7.5 μg / ml, at least 8 μg / ml ml, at least 8.5 μg / ml, at least 9 μg / ml, at least 9.5 μg / ml, at least 10 μg / ml, at least 11 μg / ml, at least 12 μg / ml, at least 13 μg / ml, at least 14 μg / ml, 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. The Cmin in serum between any two injections can be at least about 4 μg / ml, at least about 5 μg / ml, or at least about 20 μg / ml. The C min in serum between any two injections can be at least about 4 μg / ml. The C min in serum between any two injections can be at least about 5 μg / ml. The C min in serum between any two injections can be at least about 20 μg / ml. C min in serum between any two injections can be up to 600 μg / ml, up to 500 μg / ml, up to 450 μg / ml, up to 400 μg / ml, up to 350 μg / ml, up to 300 μg / ml, up to 275 μg / ml, up to 250 μg / ml, up to 225 μg / ml, up to 200 μg / ml, up to 175 μg / ml, up to 150 μg / ml, up to 125 μg / ml, up to 100 μg / ml, up to 90 μg / ml, up to 80 μg / ml, up to 70 μg / ml, up to 60 μg / ml, up to 50 μg / ml, up to 45 μg / ml, up to 40 μg / ml, up to 35 μg / ml, up to 30 μg / ml , up to 25 μg / ml, up to 23 μg / ml, up to 20 μg / ml, up to 15 μg / ml, up to 10 μg / ml, up to 9 μg / ml, up to 8 μg / ml, up to 7 μg / ml, up to 6 μg / ml, up to 5 μg / ml, up to 4 μg / ml, up to 3 μg / ml or up to 2.5 μg / ml. The Cmin in serum can be up to about 50 μg / ml, up to about 25 μg / ml, up to about 15 μg / ml, or up to about 7 μg / ml. Cmin in serum can be as high as about 50 μg / ml. C min in serum can be as high as about 25 μg / ml. C min in serum can be as high as about 15 μg / ml. Cmin in serum can be as high as about 7 μg / ml. The C min in serum between any two injections can be selected from at least 3 μg / ml and up to 350 μg / ml; at least 10 μg / ml and up to 300 μg / ml; at least 12.5 μg / ml and up to 250 μg / ml; At least 15 μg / ml and up to 250 μg / ml; At least 18 μg / ml and up to 240 μg / ml; At least 20 μg / ml and up to 220 μg / ml; At least 25 μg / ml and up to 190 μg / ml; At least 30 μg / ml and up to 150 μg / ml; at least 35 μg / ml and up to 125 μg / ml; at least 40 μg / ml and up to 90 μg / ml; and at least 50 μg / ml and up to 65 μg / ml.

[0132] The C min values ​​given above are as measured in serum. Serum C min values ​​can be converted to tissue C min values. Shah & Betts (2013) mAbs 5:2, 297-305 Calculated for mAb, distribution in skin is approximately 16% of systemic concentration. Therefore, a serum Cmin value of 2.5 μg / ml will result in a skin Cmin value of 0.4 μg / ml, and a serum Cmin value of 375 μg / ml will result in a skin Cmin value of 60 μg / ml. Alternative conversions can be made based on other distribution values ​​assumed in the field, which can typically range from approximately 10% to 15% of the systemic concentration distributed to the skin. Therefore, as yet another example, assuming distribution in the skin is 10% of the systemic concentration, a serum concentration level of 4 μg / ml would result in a skin Cmin value of 0.4 μg / ml, and a serum Cmin value of 600 μg / ml Will result in a skin C min value of 60 μg / ml.

[0133] The method of any preceding embodiment, wherein the highest serum concentration (C max ) of the antibody or fragment thereof achieved after administering an injection and before administering a subsequent injection may be 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 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 serum concentration (C max ) of the antibody or fragment thereof achieved after administration of an injection and before administration of subsequent injections 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.

[0134] In some embodiments, injection may be intravenous or subcutaneous. In some embodiments, the injection is subcutaneous, and the dose can be 62.5 mg, 125 mg, 150 mg, 250 mg, or 500 mg. In some embodiments, the dose may be 125 mg or 150 mg. In other embodiments, the dose may be 125 mg. In yet other embodiments, the dose may be 150 mg. In some embodiments, the dose may be 62.5 mg. In some embodiments, the dose may be 250 mg. The dose can be 500 mg.

[0135] The injection is subcutaneous, and the highest serum concentration (Cmax) of the antibody or fragment thereof achieved after administration of the injection and before administration of subsequent injections may be from 1.5 μg / ml to 275 μg / ml; 2 μg / ml to 200 μg / ml; 5 μg / ml to 150 μg / ml; 5 μg / ml to 100 μg / 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. Cmax can be 10 μg / ml to 80 μg / ml. Cmax can be 10 μg / ml to 25 μg / ml. Cmax can be 25 μg / ml to 50 μg / ml. C max can be 35 μg / ml to 75 μg / ml.

[0136] In some embodiments, the injection is intravenous, and the highest serum concentration (Cmax) of the antibody or fragment thereof achieved after administering the injection and before administering a subsequent injection can be from 6 μg / ml to 550 μg / ml. ml;15 μg / ml to 400 μg / ml;20 μg / ml to 300 μg / ml;30 μg / ml to 200 μg / ml;30 μg / ml to 90 μg / ml;40 μg / ml to 105 μg / ml ml; 95 μg / ml to 150 μg / ml; or 95 μg / ml to 200 μg / ml. C max can be from 30 μg / ml to 200 μg / ml. Cmax can be from 30 μg / ml to 90 μg / ml. C max can be 40 μg / ml to 105 μg / ml. C max can be 95 μg / ml to 150 μg / ml. C max can be 95 μg / ml to 200 μg / ml.

[0137] The method can maintain the serum concentration of the antibody or fragment thereof above any Cmin value disclosed herein and below any Cmax value disclosed herein, wherein the Cmin value is lower than the Cmax value. For example, the method can: · Maintain serum concentrations between about 4 to about 15 μg / mL (tissue concentrations of 0.4 to 1.5 μg / mL and higher assuming 10% to 15% tissue / skin penetration), · Maintain serum concentrations between about 20 to about 45 μg / mL (tissue concentrations of 2 to 6.7 μg / mL and higher assuming 10% to 15% tissue / skin penetration), · Maintain serum concentrations between about 5 to about 23 μg / mL (tissue concentrations of 0.5 to 3.5 μg / mL and higher assuming 10% to 15% tissue / skin penetration), · Maintain serum concentrations around or below 10 μg / mL.

[0138] The method can maintain a therapeutically effective concentration of the antibody or fragment thereof after the final administration. For example, the therapeutically effective concentration may be maintained for at least one month, at least two months, or at least three months after the last administration. The therapeutically effective concentration may be at or above any Cmin value disclosed herein and / or at or below any Cmax value disclosed herein, where the Cmin value is below the Cmax value. For example, the method can optionally maintain serum concentrations at about 3 to about 12 μg / mL; about 5 to about 12 μg / mL; or about 3 to about 5 μg / mL for at least three months after the last administration. .

[0139] The area under the serum concentration-time curve (AUC) after the first injection (AUC extrapolated to infinity [AUC 0-inf]) can be at least about 100,000 ng / ml*day, 500,000 ng / ml*day, at least About 600,000 ng / ml* day, At least about 700,000 ng / ml* day, At least about 800,000 ng / ml* day, At least about 900,000 ng / ml* day, At least about 1,000,000 ng / ml* day, At least about 1,100,000 ng / ml * day, at least about 1,300,000 ng / ml* day, at least about 1,500,000 ng / ml* day, at least about 1,700,000 ng / ml* day, at least about 2,000,000 ng / ml* day, at least about 2,500,000 ng / ml* day, at least about 3,000,000 ng / ml* day, at least about 3,300,000 ng / ml* day, or at least about 3,500,000 ng / ml* day, such as at least about 1,000,000 ng / ml* day or at least about 3,000,000 ng / ml* day.

[0140] The area under the serum concentration-time curve (AUC) after the first injection (AUC extrapolated to infinity [AUC 0-inf]) can be as high as about 4,500,000 ng / ml*day, up to about 4,200,000 ng / ml*day , up to about 4,000,000 ng / ml* day, up to about 3,800,000 ng / ml* day, up to about 3,600,000 ng / ml* day, up to about 3,400,000 ng / ml* day, up to about 3,200,000 ng / ml* day, up to about 3,000,000 ng / ml* day, up to approximately 2,800,000 ng / ml* day, up to approximately 2,500,000 ng / ml* day, up to approximately 2,000,000 ng / ml* day, up to approximately 1,800,000 ng / ml* day, up to approximately 1,500,000 ng / ml* day, Up to about 1,200,000 ng / ml* day or up to about 1,000,000 ng / ml* day, such as up to about 1,500,000 ng / ml* day or up to about 3,800,000 ng / ml* day.

[0141] The area under the serum concentration-time curve (AUC) after the first injection (AUC extrapolated to infinity [AUC 0-inf]) can range from approximately 100,000 ng / ml* day to approximately 4,500,000 ng / ml* day or approximately 1,000,000 ng / ml* day to approximately 3,800,000 ng / ml* day. The area under the serum concentration-time curve (AUC) after the first injection (AUC extrapolated to infinity [AUC 0-inf]) can range from approximately 900,000 ng / ml* day to approximately 1,400,000 ng / ml* day or approximately 2,900,000 ng / ml* day to approximately 3,800,000 ng / ml* day. induction and maintenance

[0142] The method may include an induction phase and a maintenance phase.

[0143] The induction period may include between 20 and 500 mg; 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. induction dose. The induction dose may be one or more induction phase injections of the antibody or fragment thereof administered 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.

[0144] The duration of the induction period may be at least 2 weeks, at least 4 weeks, at least 8 weeks, at least 16 weeks, or at least 24 weeks. The induction phase may include the administration of two or more induction phase injections of antibody or fragments thereof.

[0145] The interval between administration of each induction injection can be at least 2 weeks, at least 4 weeks, at least 8 weeks, at least 16 weeks, or at least 24 weeks. Each induction injection can be administered 4 weeks apart.

[0146] Each induction phase injection may include the same quality antibody or fragment thereof as each other induction phase injection. The dose injected during each induction period can be the same.

[0147] Alternatively, one or more induction phase injections may have a different quality of antibody or fragment thereof than one or more or all other induction phase injections. The dose injected during each induction period can be different. The first induction injection can be the loading dose.

[0148] The loading dose can contain up to three times the quality of antibody or its fragments as each subsequent induction phase injection. The loading dose can contain greater than 2x and up to 3x the quality of antibody or fragments thereof as each subsequent induction phase injection. The loading dose can contain up to twice the quality of antibody or its fragments as each subsequent induction dose. The loading dose can contain up to 1.5x the quality of the antibody or its fragment as each subsequent induction dose.

[0149] Loading doses can be between 100 and 600 mg; between 150 and 550 mg; or between 200 and 500 mg. The loading dose may be about 500 mg, about 250 mg, or about 125 mg. The loading dose can be about 500 mg.

[0150] The induction phase may include the administration of two or more induction phase injections of antibody or fragments thereof. Can be administered 2 to 16 weeks after the first induction injection; 3 to 14 weeks after the first induction injection; or 4 to 12 weeks after the first induction injection for the second induction period injection. Can be administered 2 to 14 weeks after the first induction injection; administered 2 to 12 weeks after the first induction injection; administered 2 to 10 weeks after the first induction injection; Give 2 to 8 weeks after the induction injection; 2 to 7 weeks after the first induction injection; or 2 to 6 weeks after the first induction injection for the second induction injection. Can be administered 3 to 13 weeks after the first induction injection; 5 to 11 weeks after the first induction injection; or 6 to 10 weeks after the first induction injection; or 1 The second induction injection is administered 7 to 9 weeks after the first induction injection. The second induction injection can be given 4 to 8 weeks after the first induction injection. The second induction injection can be administered about 4 weeks or about 8 weeks after the first induction injection. The second induction injection can be given 4 weeks after the first induction injection.

[0151] The induction phase may include administration of three or more induction phase injections of antibody or fragments thereof. Can be administered 2 to 16 weeks after the second induction injection; 3 to 14 weeks after the second induction injection; or 4 to 12 weeks after the second induction injection for the third induction period injection. Can be administered 2 to 14 weeks after the second induction injection; administered 2 to 12 weeks after the second induction injection; administered 2 to 10 weeks after the second induction injection; Give 2 to 8 weeks after the induction injection; 2 to 7 weeks after the second induction injection; or 2 to 6 weeks after the second induction injection for the third induction injection. Can be administered 3 to 13 weeks after the second induction injection; 5 to 11 weeks after the second induction injection; or 6 to 10 weeks after the second induction injection; or 5 to 11 weeks after the second induction injection. The third induction injection was administered 7 to 9 weeks after the first induction injection. The third induction injection can be given 4 to 8 weeks after the second induction dose. The third induction injection can be administered about 4 weeks or about 8 weeks after the second induction injection. The third induction injection can be given 4 weeks after the second induction injection. The interval between the first induction injection and the second induction injection may be of the same duration as the interval between the second induction injection and the third induction injection.

[0152] Each induction phase injection may include the same quality of said antibody or fragment thereof as each other induction phase injection, and / or the duration of each interval between induction phase injections may be the same as the duration of each interval between induction phase injections. The other intervals are the same. Therefore, each induction phase injection can have the same dose. For example, in each injection during the induction phase, a 250 mg dose may be administered. The entire induction period may have a dosing interval of, for example, 4 weeks. Therefore, the induction phase can involve doses of 250 mg given every four weeks. Alternatively, the induction phase may involve administration of 125 mg doses every four weeks. Alternatively, the induction phase may involve administration of 62.5 mg doses every four weeks. A fixed dosing interval can be used without a fixed dose for each induction injection, for example, because a loading dose can be administered. Therefore, the induction period could involve the administration of a loading dose of 500 mg, followed four weeks later by 250 mg, and a further 250 mg every four weeks throughout the induction period. Any and all combinations of dosages and dosage intervals and injection types (e.g., subcutaneous) described herein are expressly contemplated herein.

[0153] The maintenance phase may include a maintenance dose 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 one or more maintenance injections of the antibody or fragment thereof administered 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 approximately 250 mg.

[0154] The duration of 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 of any suitable length to achieve clinical goals, and thus can involve any suitable number of maintenance injections. Therefore, the duration of the maintenance phase can be determined by the clinician. The maintenance period may continue as long as the patient and clinician feel that the patient benefits from such maintenance therapy or does not experience adverse events that would require discontinuation of therapy. For some individuals, the maintenance period can be indefinite.

[0155] The maintenance phase may include administration of two or more maintenance injections of the antibody or fragment thereof. Administration of each maintenance injection 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, or at least 52 weeks apart.

[0156] Each maintenance injection may include the same quality of antibody or fragment thereof as each other maintenance injection. The dose of antibody or fragment thereof used in the induction phase can be maintained during the maintenance phase, i.e., the induction phase dose (other than any loading dose) can be the same as the maintenance phase dose. However, the dosing interval during the maintenance phase can be longer than the dosing interval during the induction phase. This may be because once the therapeutic effect is initiated, it may be maintained at lower tissue concentrations of the antibody or its fragments. Although a similar goal can be achieved by maintaining the dosing interval during the induction phase while reducing the dose during the induction phase during the maintenance phase, it is clinically preferred to reduce the number of injections rather than reducing the dose per injection during the maintenance phase.

[0157] Can be given 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 for the second maintenance injection period injection. Can be administered 2 to 14 weeks after the first maintenance injection; Administered 2 to 12 weeks after the first maintenance injection; Administered 2 to 10 weeks after the first maintenance injection; Give 2 to 8 weeks after the maintenance injection; 2 to 7 weeks after the first maintenance injection; or 2 to 6 weeks after the first maintenance injection for 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; or 6 to 10 weeks after the first maintenance injection; or 5 to 11 weeks after the first maintenance injection. The second maintenance injection is given 7 to 9 weeks after the first maintenance injection. The second maintenance injection can be given 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.

[0158] The maintenance phase may include administration of three or more maintenance injections of the antibody or fragment thereof. Can be given 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 for the third maintenance injection period injection. Can be administered 2 to 14 weeks after the second maintenance injection; Administered 2 to 12 weeks after the second maintenance injection; Administered 2 to 10 weeks after the second maintenance injection; Give 2 to 8 weeks after the maintenance injection; 2 to 7 weeks after the second maintenance injection; or 2 to 6 weeks after the second maintenance injection for 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; or 6 to 10 weeks after the second maintenance injection; or 6 to 10 weeks after the second maintenance injection. The third maintenance injection is given 7 to 9 weeks after the first maintenance injection. The third maintenance injection can be given 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.

[0159] The interval between the first maintenance injection and the second maintenance injection may be of the same duration as the interval between the second maintenance injection and the third maintenance injection.

[0160] Each maintenance injection may include the same quality of said antibody or fragment thereof as each other maintenance injection, and / or the duration of each interval between maintenance injections may be the same as the duration of each interval between maintenance injections. The other intervals are the same. Therefore, each maintenance injection can have the same dose. For example, in each injection during the maintenance phase, a 250 mg dose may be administered. The entire maintenance period may have dosing intervals of, for example, 16 weeks. Therefore, the maintenance phase could involve administration of 250 mg doses every 16 weeks. Alternatively, the induction phase may involve administration of 125 mg doses every 16 weeks. Alternatively, the induction phase may involve administration of 62.5 mg doses every 16 weeks. As another example, in each injection during the maintenance phase, a 250 mg dose may be administered. The entire maintenance period may have dosing intervals of, for example, 1 week. Therefore, the maintenance phase may involve administration of 250 mg doses every 12 weeks. Alternatively, the induction phase may involve administration of a 125 mg dose every 12 weeks. Alternatively, the induction phase may involve administration of a 62.5 mg dose every 12 weeks. Any and all combinations of dosages and dosage intervals and injection types (e.g., subcutaneous) described herein are expressly contemplated herein.

[0161] The duration of the interval between two or more maintenance phase injections may be equal to or longer than the duration of the interval between two or more induction phase injections. As mentioned above, the dosing interval during the maintenance phase can be longer than the dosing interval during the induction phase. In cases where a constant dosing interval is used for the induction phase and a constant dosing interval is used for the maintenance phase, then this can be a direct comparison of the intervals, for example, when the induction phase dosing interval is four weeks (Q4W) and the maintenance phase dosing interval At four weeks (Q4W), the interval between induction injections is of equal duration to the interval between maintenance injections. When the induction dosing interval is four weeks (Q4W) and the maintenance dosing interval is 12 weeks (Q12W), the interval between maintenance injections is longer than the interval between maintenance injections. The comparison between dosing intervals in the maintenance phase and dosing intervals in the induction phase may alternatively be calculated as the average (mean, median, or mode) of all intervals in the induction and maintenance phases, respectively. Alternatively, a comparison between the maintenance phase dosing interval and the induction phase dosing interval may be calculated by comparing specific dosing interval examples as described further below.

[0162] The duration of the interval between the first maintenance injection and the second maintenance injection may be equal to or longer than the duration of the interval between two or more induction injections. The interval between two or more induction injections can be about 2 weeks, about 4 weeks, or about 8 weeks, and the interval between two or more maintenance injections can be about 12 weeks or about 16 weeks . The interval between two or more induction injections can be about 4 or 8 weeks, and the interval between two or more maintenance injections can be about 12 weeks. The interval between two or more induction injections can be about 4 or 8 weeks, and the interval between two or more maintenance injections can be about 16 weeks. The interval between two or more induction injections can be about 4 weeks, and the interval between two or more maintenance injections can be about 16 weeks. The interval between two or more induction injections can be about 4 weeks, and the interval between two or more maintenance injections can be about 12 weeks. The interval between two or more induction injections can be about 4 weeks, and the interval between two or more maintenance injections can be about 4 weeks. The interval between two or more induction injections can be about 8 weeks, and the interval between two or more maintenance injections can be about 8 weeks. The interval between two or more induction injections can be about 2 weeks, and the interval between two or more maintenance injections can be about 8 weeks.

[0163] The intervals between three or more induction injections can be constant. Alternatively, the intervals between three or more maintenance injections may vary.

[0164] The combined duration of the induction and maintenance phases may be at least 52 weeks. The combined duration of the induction and maintenance periods may be any duration obtained by summing any duration of the induction phase described herein with any duration of the maintenance phase described herein. The combined duration of the induction and maintenance phases may be indefinite, as may the maintenance phase.

[0165] An individual can transition from the induction phase to the maintenance phase based on the following conditions: (a) clinical response; and / or (b) Time from administration of the first induction injection.

[0166] Clinical response may be defined by any post-administration score or index described herein. Clinical response can reach EASI50, EASI75, EASI90 or EASI100. Clinical response can reach IGA-AD0 / 1 and / or reduce IGA-AD by at least 2 points. Clinical response is a reduction in NRS of at least 3 points or NRS of at least 4 points. Clinical response can be determined at any clinically appropriate time point, such as 16 weeks, 20 weeks, or 24 weeks after administration of the first induction injection.

[0167] The transition from induction to maintenance can occur 16 weeks or more after the first induction injection is given. The transition from induction to maintenance can occur 24 weeks or more after the first induction injection is given. The transition from induction to maintenance can occur up to one year after the first induction injection is given. The transition from induction to maintenance can occur 16 to 24 weeks after the first induction injection is given.

[0168] In some cases, the transition from induction to maintenance can occur based on clinical response established during the induction period. This may occur, for example, when it takes some time to analyze disease severity data. Therefore, there may be a delay between collecting data that can determine clinical response and transitioning individuals from the induction phase to the maintenance phase. For example, clinical response can be assessed at week 16 by collecting data on disease severity, which, if positive, leads to a subsequent transition from induction to maintenance, such as after the administration of the first induction injection. Week 24. The decision to transition from induction to maintenance may further inform the availability of additional information as data to determine clinical response are collected, such as subsequent clinical assessments at the time of transition from induction to maintenance.

[0169] If the individual achieves a clinical response of at least EASI75 at Week 16, the transition from induction to maintenance can occur at Week 24.

[0170] The induction period can be a variable induction period. "Variable" means that the duration of the induction phase will vary from individual to individual and that the transition from induction to maintenance will depend on patient-specific factors. Patient-specific factors may include clinical response. For example, transition can occur when a patient reaches IGA0 / 1, has healed / almost healed skin, reaches EASI 50, reaches EASI75, or reaches EASI90.

[0171] Administration can be subcutaneous. Subcutaneous injections can be given on any suitable side of the injection, such as the abdomen or outer thigh. In some embodiments, subcutaneous administration is used to treat atopic dermatitis because it is more convenient for the patient and less resource intensive than intravenous injection. Any of the methods described herein may involve subcutaneous administration. The methods involve induction and maintenance periods and are primarily intended for use when administration is subcutaneous.

[0172] The method may include any of the following four configurations of induction and / or maintenance periods, administration of each configuration may be subcutaneous: 1. The induction phase may include the administration of at least five induction phase injections, where the first induction phase injection is a loading dose of 500 mg of the antibody or fragment thereof, followed by at least four subsequent induction phase injections, where each subsequent induction phase injection The induction injection is a dose of 250 mg of the antibody or fragment thereof, and wherein each subsequent induction injection is administered 4 weeks after the previous induction injection. The maintenance phase may include the administration of at least 3 maintenance phase injections, wherein each maintenance phase injection is a dose of 250 mg of the antibody or fragment thereof, and wherein the first maintenance phase injection is administered at least 4 weeks after the last induction phase injection, and wherein the second maintenance injection and each subsequent maintenance injection are administered at least 4 weeks after the previous maintenance injection. 2. The induction phase may include the administration of at least five induction phase injections, wherein each induction phase injection is a dose of 250 mg of the antibody or fragment thereof, and wherein the second induction phase injection and each subsequent induction phase injection precede An induction phase was administered 4 weeks after injection. The maintenance phase may include the administration of at least 3 maintenance phase injections, wherein each maintenance phase injection is a dose of 250 mg of the antibody or fragment thereof, and wherein the first maintenance phase injection is administered at least 4 weeks after the last induction phase injection, and wherein the second maintenance injection and each subsequent maintenance injection are administered at least 4 weeks after the previous maintenance injection. 3. The induction phase may include the administration of at least five induction phase injections, wherein each induction phase injection is a dose of 125 mg of the antibody or fragment thereof, and wherein the second induction phase injection and each subsequent induction phase injection precede An induction phase was administered 4 weeks after injection. The maintenance phase may include the administration of at least 3 maintenance phase injections, wherein each maintenance phase injection is a dose of 125 mg of the antibody or fragment thereof, and wherein the first maintenance phase injection is administered at least 4 weeks after the last induction phase injection, and wherein the second maintenance injection and each subsequent maintenance injection are administered at least 4 weeks after the previous maintenance injection. 4. The induction phase may include the administration of at least five induction phase injections, wherein each induction phase injection is 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 precede An induction phase was administered 4 weeks after injection. The maintenance phase may include the administration of at least 3 maintenance phase injections, wherein each maintenance phase injection is a dose of 62.5 mg of the antibody or fragment thereof, and wherein the first maintenance phase injection is administered at least 4 weeks after the last induction phase injection, and wherein the second maintenance injection and each subsequent maintenance injection are administered at least 4 weeks after the previous maintenance injection.

[0173] As used in the configurations listed herein, "at least 4 weeks" may, for example, be 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks , 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks or 24 weeks. As used in the above four configurations, "at least 4 weeks" can be, for example, 4 weeks, 12 weeks, 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.

[0174] The method may include administering at least six induction injections or at least seven induction injections. The first maintenance injection can be administered from 4 weeks to 24 weeks or from 4 weeks to 16 weeks after the last induction injection. The first maintenance injection can be given 12 weeks after the last induction injection. The first maintenance injection can be given 16 weeks after the last induction injection. The first maintenance injection can be given 24 weeks after the last induction injection. The second maintenance injection and each subsequent maintenance injection can be administered from 4 weeks to 24 weeks or from 4 weeks to 16 weeks after the previous maintenance injection. The second maintenance injection and each subsequent maintenance injection may be given 12 weeks after the previous maintenance injection. The second maintenance injection and each subsequent maintenance injection can be given 16 weeks after the previous maintenance injection. The second maintenance injection can be given 24 weeks after the previous maintenance injection.

[0175] The method described can: (a) Includes the administration of at least seven induction injections; (b) wherein the first maintenance injection is administered at least 12 weeks after the last induction injection; and (c) wherein the second maintenance injection and each subsequent maintenance injection are administered at least 4 weeks after the previous maintenance injection.

[0176] The method may include any of the following four additional configurations of induction and / or maintenance phases, administration of each of which may be subcutaneous: 1'. The induction phase may include the administration of at least five induction phase injections, wherein the first induction phase injection is a loading dose of 500 mg of the antibody or fragment thereof, followed by at least four subsequent induction phase injections, wherein each Subsequent induction injections are at a dose of 250 mg of the antibody or fragment thereof, and wherein each subsequent induction injection is administered 4 weeks after the previous induction injection. The maintenance phase may include the administration of at least 3 maintenance phase injections, wherein each maintenance phase injection is a dose of 250 mg of the antibody or fragment thereof, and wherein the first maintenance phase injection is administered at least 16 weeks after the last induction phase injection, and wherein the second maintenance injection and each subsequent maintenance injection are administered at least 16 weeks after the previous maintenance injection. 2'. The induction phase may comprise the administration of at least five induction phase injections, wherein each induction phase injection is a dose of 250 mg of the antibody or fragment thereof, and wherein the second induction phase injection and each subsequent induction phase injection are in Administer 4 weeks after the previous induction period injection. The maintenance phase may include the administration of at least 3 maintenance phase injections, wherein each maintenance phase injection is a dose of 250 mg of the antibody or fragment thereof, and wherein the first maintenance phase injection is administered at least 16 weeks after the last induction phase injection, and wherein the second maintenance injection and each subsequent maintenance injection are administered at least 16 weeks after the previous maintenance injection. 3'. The induction phase may comprise the administration of at least five induction phase injections, wherein each induction phase injection is a dose of 125 mg of the antibody or fragment thereof, and wherein the second induction phase injection and each subsequent induction phase injection are in Administer 4 weeks after the previous induction period injection. The maintenance phase may include the administration of at least 3 maintenance phase injections, wherein each maintenance phase injection is a dose of 125 mg of the antibody or fragment thereof, and wherein the first maintenance phase injection is administered at least 16 weeks after the last induction phase injection, and wherein the second maintenance injection and each subsequent maintenance injection are administered at least 16 weeks after the previous maintenance injection. 4'. The induction phase may comprise the administration of at least five induction phase injections, wherein each induction phase injection is 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 in Administer 4 weeks after the previous induction period injection. The maintenance phase may include the administration of at least 3 maintenance phase injections, wherein each maintenance phase injection is 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 last induction phase injection, and wherein the second maintenance injection and each subsequent maintenance injection are administered at least 16 weeks after the previous maintenance injection.

[0177] The method may include any of the following four additional configurations of induction and / or maintenance phases, administration of each of which may be subcutaneous: 1''. The induction period may include the administration of at least five induction injections, wherein the first induction injection is a loading dose of 500 mg of the antibody or fragment thereof, followed by at least four subsequent induction injections, each of which is a loading dose of 500 mg. Each subsequent induction injection is a dose of 250 mg of the antibody or fragment thereof, and wherein each subsequent induction injection is administered 4 weeks after the previous induction injection. The maintenance phase may include the administration of at least 3 maintenance phase injections, wherein each maintenance phase injection is a dose of 250 mg of the antibody or fragment thereof, and wherein the first maintenance phase injection is administered at least 16 weeks after the last induction phase injection, and wherein the second maintenance injection and each subsequent maintenance injection are administered at least 16 weeks after the previous maintenance injection, and wherein the individual achieves a clinical response of at least EASI75 16 weeks after the first induction injection. 2''. The induction phase may comprise the administration of at least five induction phase injections, wherein each induction phase injection is a dose of 250 mg of the antibody or fragment thereof, and wherein the second induction phase injection and each subsequent induction phase injection Administer 4 weeks after the previous induction period injection. The maintenance phase may include the administration of at least 3 maintenance phase injections, wherein each maintenance phase injection is a dose of 250 mg of the antibody or fragment thereof, and wherein the first maintenance phase injection is administered at least 16 weeks after the last induction phase injection, and wherein the second maintenance injection and each subsequent maintenance injection are administered at least 16 weeks after the previous maintenance injection, and wherein the individual achieves a clinical response of at least EASI75 16 weeks after the first induction injection. 3''. The induction phase may include the administration of at least five induction phase injections, wherein each induction phase injection is a dose of 125 mg of the antibody or fragment thereof, and wherein the second induction phase injection and each subsequent induction phase injection Administer 4 weeks after the previous induction period injection. The maintenance phase may include the administration of at least 3 maintenance phase injections, wherein each maintenance phase injection is a dose of 125 mg of the antibody or fragment thereof, and wherein the first maintenance phase injection is administered at least 16 weeks after the last induction phase injection, and wherein the second maintenance injection and each subsequent maintenance injection are administered at least 16 weeks after the previous maintenance injection, and wherein the individual achieves a clinical response of at least EASI75 16 weeks after the first induction injection. 4''. The induction phase may include the administration of at least five induction phase injections, wherein each induction phase injection is 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 Administer 4 weeks after the previous induction period injection. The maintenance phase may include the administration of at least 3 maintenance phase injections, wherein each maintenance phase injection is 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 last induction phase injection, and wherein the second maintenance injection and each subsequent maintenance injection are administered at least 16 weeks after the previous maintenance injection, and wherein the individual achieves a clinical response of at least EASI75 16 weeks after the first induction injection.

[0178] The method may include any of the following four additional configurations of induction and / or maintenance phases, administration of each of which may be subcutaneous: 1'''. The induction period may include the administration of at least five induction injections, wherein the first induction injection is a loading dose of 500 mg of the antibody or fragment thereof, followed by at least four subsequent induction injections, wherein Each subsequent induction phase injection is a dose of 250 mg of the antibody or fragment thereof, and wherein each subsequent induction phase injection is administered 4 weeks after the previous induction phase injection. The maintenance period can include: (a) wherein said individual achieves a clinical response of at least EASI75 and / or IGA-AD 0 / 1 16 weeks after the first induction phase injection: (i) administer at least 3 maintenance injections, wherein each maintenance injection is a dose of 250 mg of the antibody or fragment thereof, and wherein the first maintenance injection is administered at least 4 weeks after the last induction injection, and wherein the second maintenance injection and each subsequent maintenance injection are administered at least 4 weeks after the previous maintenance injection, or (ii) the individual withdraws from use of the antibody or fragment thereof; (b) wherein said individual does not achieve a clinical response to EASI75 and / or IGA-AD 0 / 1 16 weeks after the first induction phase injection: (i) The maintenance period includes the administration of at least 3 maintenance injections, wherein each maintenance injection is a dose of 250 mg of the antibody or fragment thereof, and the first maintenance injection is at least 4 after the last induction injection. weekly, and the second maintenance injection and each subsequent maintenance injection are administered at least 4 weeks after the previous maintenance injection. 2'''. The induction period may comprise the administration of at least five induction injections, wherein each induction injection is a dose of 250 mg of the antibody or fragment thereof, and wherein the second induction injection and each subsequent induction period Injections were administered 4 weeks after the previous induction phase injection. The maintenance period can include: (a) wherein said individual achieves a clinical response of at least EASI75 and / or IGA-AD 0 / 1 16 weeks after the first induction phase injection: (i) administer at least 3 maintenance injections, wherein each maintenance injection is a dose of 250 mg of the antibody or fragment thereof, and wherein the first maintenance injection is administered at least 4 weeks after the last induction injection, and wherein the second maintenance injection and each subsequent maintenance injection are administered at least 4 weeks after the previous maintenance injection, or (ii) the individual withdraws from use of the antibody or fragment thereof; (b) wherein said individual does not achieve a clinical response to EASI75 and / or IGA-AD 0 / 1 16 weeks after the first induction phase injection: (i) The maintenance period includes the administration of at least 3 maintenance injections, wherein each maintenance injection is a dose of 250 mg of the antibody or fragment thereof, and the first maintenance injection is at least 4 after the last induction injection. weekly, and the second maintenance injection and each subsequent maintenance injection are administered at least 4 weeks after the previous maintenance injection. 3'''. The induction period may include the administration of at least five induction injections, wherein each induction injection is a dose of 125 mg of the antibody or fragment thereof, and wherein the second induction injection and each subsequent induction period Injections were administered 4 weeks after the previous induction phase injection. The maintenance period can include: (a) wherein said individual achieves a clinical response of at least EASI75 and / or IGA-AD 0 / 1 16 weeks after the first induction phase injection: (i) administer at least 3 maintenance injections, wherein each maintenance injection is a dose of 250 mg of the antibody or fragment thereof, and wherein the first maintenance injection is administered at least 4 weeks after the last induction injection, and wherein the second maintenance injection and each subsequent maintenance injection are administered at least 4 weeks after the previous maintenance injection, or (ii) the individual withdraws from use of the antibody or fragment thereof; (b) wherein said individual does not achieve a clinical response to EASI75 and / or IGA-AD 0 / 1 16 weeks after the first induction phase injection: (i) The maintenance period includes the administration of at least 3 maintenance injections, wherein each maintenance injection is a dose of 250 mg of the antibody or fragment thereof, and the first maintenance injection is at least 4 after the last induction injection. weekly, and the second maintenance injection and each subsequent maintenance injection are administered at least 4 weeks after the previous maintenance injection. 4'''. The induction phase may include the administration of at least five induction phase injections, wherein each induction phase injection is a dose of 62.5 mg of the antibody or fragment thereof, and wherein the second induction phase injection and each subsequent induction phase Injections were administered 4 weeks after the previous induction phase injection. The maintenance period can include: (a) wherein said individual achieves a clinical response of at least EASI75 and / or IGA-AD 0 / 1 16 weeks after the first induction phase injection: (i) administer at least 3 maintenance injections, wherein each maintenance injection is a dose of 250 mg of the antibody or fragment thereof, and wherein the first maintenance injection is administered at least 4 weeks after the last induction injection, and wherein the second maintenance injection and each subsequent maintenance injection are administered at least 4 weeks after the previous maintenance injection, or (ii) the individual withdraws from use of the antibody or fragment thereof; (b) wherein said individual does not achieve a clinical response to EASI75 and / or IGA-AD 0 / 1 16 weeks after the first induction phase injection: (i) The maintenance period includes the administration of at least 3 maintenance injections, wherein each maintenance injection is a dose of 250 mg of the antibody or fragment thereof, and the first maintenance injection is at least 4 after the last induction injection. weekly, and the second maintenance injection and each subsequent maintenance injection are administered at least 4 weeks after the previous maintenance injection.

[0179] The method may include any of the following four additional configurations of induction and / or maintenance phases, administration of each of which may be subcutaneous: 1''''. The induction period may include the administration of at least five induction injections, with a first induction injection being a loading dose of 500 mg of the antibody or fragment thereof, followed by at least four subsequent induction injections, wherein each subsequent induction phase injection is a dose of 250 mg of the antibody or fragment thereof, and wherein each subsequent induction phase injection is administered 4 weeks after the previous induction phase injection. The maintenance period can include: (a) wherein said individual achieves a clinical response of at least EASI75 and / or IGA-AD 0 / 1 16 weeks after the first induction phase injection: (i) administer at least 3 maintenance injections, wherein each maintenance injection is a dose of 250 mg of the antibody or fragment thereof, wherein the first maintenance injection is administered at least 12 weeks after the last induction injection, and wherein the second maintenance injection and each subsequent maintenance injection are administered at least 12 weeks after the previous maintenance injection, or (ii) the individual withdraws from use of the antibody or fragment thereof; (b) wherein said individual does not achieve a clinical response to EASI75 and / or IGA-AD 0 / 1 16 weeks after the first induction phase injection: (i) The maintenance phase includes the administration of at least 3 maintenance phase injections, wherein each maintenance phase injection is a dose of 250 mg of the antibody or fragment thereof, and wherein the first maintenance phase injection is at least 12 after the last induction phase injection. weekly, and the second maintenance injection and each subsequent maintenance injection are administered at least 12 weeks after the previous maintenance injection. 2''''. The induction phase may include the administration of at least five induction phase injections, wherein each induction phase injection is a dose of 250 mg of the antibody or fragment thereof, and wherein the second induction phase injection and each subsequent induction phase The first phase injection was administered 4 weeks after the previous induction phase injection. The maintenance period can include: (a) wherein said individual achieves a clinical response of at least EASI75 and / or IGA-AD 0 / 1 16 weeks after the first induction phase injection: (i) administer at least 3 maintenance injections, wherein each maintenance injection is a dose of 250 mg of the antibody or fragment thereof, wherein the first maintenance injection is administered at least 12 weeks after the last induction injection, and wherein the second maintenance injection and each subsequent maintenance injection are administered at least 12 weeks after the previous maintenance injection, or (ii) the individual withdraws from use of the antibody or fragment thereof; (b) wherein said individual does not achieve a clinical response to EASI75 and / or IGA-AD 0 / 1 16 weeks after the first induction phase injection: (i) The maintenance phase includes the administration of at least 3 maintenance phase injections, wherein each maintenance phase injection is a dose of 250 mg of the antibody or fragment thereof, and wherein the first maintenance phase injection is at least 12 after the last induction phase injection. weekly, and the second maintenance injection and each subsequent maintenance injection are administered at least 12 weeks after the previous maintenance injection. 3''''. The induction phase may include the administration of at least five induction phase injections, wherein each induction phase injection is a dose of 125 mg of the antibody or fragment thereof, and wherein the second induction phase injection and each subsequent induction phase The first phase injection was administered 4 weeks after the previous induction phase injection. The maintenance period can include: (a) wherein said individual achieves a clinical response of at least EASI75 and / or IGA-AD 0 / 1 16 weeks after the first induction phase injection: (i) administer at least 3 maintenance injections, wherein each maintenance injection is a dose of 250 mg of the antibody or fragment thereof, wherein the first maintenance injection is administered at least 12 weeks after the last induction injection, and wherein the second maintenance injection and each subsequent maintenance injection are administered at least 12 weeks after the previous maintenance injection, or (ii) the individual withdraws from use of the antibody or fragment thereof; (b) wherein said individual does not achieve a clinical response to EASI75 and / or IGA-AD 0 / 1 16 weeks after the first induction phase injection: (i) The maintenance phase includes the administration of at least 3 maintenance phase injections, wherein each maintenance phase injection is a dose of 250 mg of the antibody or fragment thereof, and wherein the first maintenance phase injection is at least 12 after the last induction phase injection. weekly, and the second maintenance injection and each subsequent maintenance injection are administered at least 12 weeks after the previous maintenance injection. 4''''. The induction phase may include the administration of at least five induction phase injections, wherein each induction phase injection is a dose of 62.5 mg of the antibody or fragment thereof, and wherein the second induction phase injection and each subsequent induction phase The first phase injection was administered 4 weeks after the previous induction phase injection. The maintenance period can include: (a) wherein said individual achieves a clinical response of at least EASI75 and / or IGA-AD 0 / 1 16 weeks after the first induction phase injection: (i) administer at least 3 maintenance injections, wherein each maintenance injection is a dose of 250 mg of the antibody or fragment thereof, wherein the first maintenance injection is administered at least 12 weeks after the last induction injection, and wherein the second maintenance injection and each subsequent maintenance injection are administered at least 12 weeks after the previous maintenance injection, or (ii) the individual withdraws from use of the antibody or fragment thereof; (b) wherein said individual does not achieve a clinical response to EASI75 and / or IGA-AD 0 / 1 16 weeks after the first induction phase injection: (i) The maintenance phase includes the administration of at least 3 maintenance phase injections, wherein each maintenance phase injection is a dose of 250 mg of the antibody or fragment thereof, and wherein the first maintenance phase injection is at least 12 after the last induction phase injection. weekly, and the second maintenance injection and each subsequent maintenance injection are administered at least 12 weeks after the previous maintenance injection. The method described can: (a) Includes the administration of at least seven induction injections; (b) wherein the first maintenance injection is administered 4 weeks after the final induction injection; and (c) wherein the second maintenance injection and each subsequent maintenance injection are administered 4 weeks after the previous maintenance injection. The method described can: (a) Includes the administration of at least seven induction injections; (b) wherein the first maintenance injection is administered 12 weeks after the final induction injection; and (c) wherein the second maintenance injection and each subsequent maintenance injection are administered 12 weeks after the previous maintenance injection. The method described can: (a) Includes the administration of at least seven induction injections; (b) wherein the first maintenance injection is administered 16 weeks after the last induction injection; and (c) wherein the second maintenance injection and each subsequent maintenance injection are administered 16 weeks after the previous maintenance injection. The method described can: (a) Includes the administration of at least seven induction injections; (b) wherein the first maintenance injection is administered 24 weeks after the last induction injection; and (c) wherein the second maintenance injection and each subsequent maintenance injection are administered 24 weeks after the previous maintenance injection.

[0180] According to one embodiment, the method is a method of treating an inflammatory disease, inflammatory disorder, immune-mediated disease, immune-mediated disorder, or inflammatory skin disorder in a human subject, the method comprising administering a therapeutically effective amount of an antibiotic. An OX40L antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof is administered once every 4 weeks, or once every 12 weeks, or once every 6 months.

[0181] According to another embodiment, the method is a method of treating an inflammatory disease, inflammatory disorder, immune-mediated disease, immune-mediated disorder, 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 once every 4 weeks or once every 12 weeks or once every 6 months.

[0182] According to another embodiment, the method is a method of treating an inflammatory disease, inflammatory disorder, immune-mediated disease, immune-mediated disorder, 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 once every 4 weeks or once every 12 weeks or once every 6 months.

[0183] In yet other configurations, the above-described embodiments are provided, comprising administering a therapeutically effective amount of an OX40L antagonist antibody or antigen-binding fragment thereof. Loading and treatment dosage

[0184] The method may include: (a) Administer a first injection as a loading dose of the antibody or fragment thereof, followed by (b) Administer at least a second injection as a first therapeutic dose of the antibody or fragment thereof.

[0185] The second injection can be given 3 to 5 weeks after the first injection.

[0186] The method may further comprise administering at least a third injection as a therapeutic dose of the antibody or fragment thereof. The third injection can be given 3 to 5 weeks after the second injection.

[0187] The method may further comprise administering at least a fourth injection as a therapeutic dose of the antibody or fragment thereof. The fourth injection can be given 3 to 5 weeks after the third injection.

[0188] The method may include administering a fifth injection as a therapeutic dose. The fifth injection can be given 3 to 5 weeks after the fourth injection.

[0189] The method may further comprise administering a sixth injection as a therapeutic dose. The sixth treatment dose can be administered 3 to 5 weeks after the fifth injection.

[0190] Each injection as a therapeutic dose can be administered 4 weeks after the previous therapeutic dose.

[0191] The number of injections as a therapeutic dose may be any suitable number to achieve the clinical goal, and thus any suitable number of injections as a therapeutic dose may be involved. Therefore, the number of injections used as a therapeutic dose can be determined by the clinician. For example, the treatment number may be at least 6, at least 7, at least 8, at least 9, or at least 10. For some individuals, an undetermined number of injections may be administered as a therapeutic dose.

[0192] The loading dose may contain up to three times the quality of the antibody or fragment thereof as a therapeutic dose with each subsequent injection. The loading dose may contain greater than 2 times and up to 3 times the quality of the antibody or fragment thereof as a therapeutic dose with each subsequent injection. The loading dose may contain up to twice the mass of the antibody or fragment thereof as a therapeutic dose with each subsequent injection. The loading dose may contain up to 1.5 times the mass of antibody or fragment thereof as a therapeutic dose with each subsequent injection.

[0193] Each therapeutic dose may contain the same quality of antibody or antibody fragment as each therapeutic dose.

[0194] Loading doses can be between 100 and 600 mg; between 150 and 550 mg; or between 200 and 500 mg. Loading doses can be 200 mg or 500 mg.

[0195] 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.

[0196] Advantages of some embodiments arise from the favorable safety profile of the antibody or fragment thereof. This allows a wide range of therapeutic doses to be used for loading doses that may not be appropriate for other antibodies, where higher doses may, for example, lead to toxicity or unacceptable side effects. Any dose described herein can be used as a loading dose. Any dosage described herein can be used as a therapeutic dosage. Any dose described herein can be used as a therapeutic dose, and twice the therapeutic dose is used as the loading dose. For example: a loading dose of 500 mg could be combined with a therapeutic dose of 250 mg; a loading dose of 250 mg could be combined with a therapeutic dose of 125 mg; or a loading dose of 125 mg could be combined with a therapeutic dose of 62.5 mg. KY1005 has a particularly favorable safety profile, and loading doses can be used when the therapeutic dose is any of the doses described herein.

[0197] The first maintenance injection as a maintenance dose can be administered between 4 and 8 months after the last injection as a therapeutic dose. One or more further maintenance injections as maintenance doses are administered at intervals between 4 and 8 months.

[0198] Administration can be intravenous. For embodiments specifically including loading doses and therapeutic doses, the injection may be subcutaneous. This article discloses data from a randomized, double-blind, placebo-controlled Phase 2a clinical trial of moderate to severe AD administered by intravenous injection. Pharmacokinetic properties

[0199] In some embodiments, administered antibodies or fragments thereof have been found to exhibit surprisingly consistent pharmacokinetic (PK) parameter estimates in IV and subcutaneous population PK models. One advantage observed is linear PK (apart from some non-linearity seen in healthy individuals at low doses such as approximately 0.45 mg / kg), allowing the PK model to be described as "linear binary" for both intravenous and subcutaneous administration. Room distribution model”. Here, the term "linear" refers to clearance - encompassing the clearance rate (CL) and the clearance rate from the central chamber to the second chamber (Q1) - both of which are shown to be linear in the data disclosed here. The same findings apply to both AD patients and healthy patients. Without being bound by theory, this may be related to the poor performance of OX40L such that the clearance rate does not change based on drug concentration (or therefore time).

[0200] In some embodiments, the administered antibodies or fragments thereof have been found to exhibit surprisingly low immunogenicity. One component of a harmful immune response to therapeutic proteins is the formation of anti-drug antibodies (ADA). The consequences of immune responses to therapeutic proteins range from transient onset of ADA without any clinical significance to severe life-threatening conditions. Potential clinical consequences of unwanted immune responses include loss of efficacy of the therapeutic protein and severe acute immune effects, such as allergic reactions. ADA can affect the efficacy of a therapeutic protein by interfering with the pharmacodynamic interaction between the therapeutic protein and its target or by changing its pharmacokinetic profile.

[0201] For example, the European Medicines Agency (EMA) Guideline on Immunogenicity assessment of therapeutic proteins (May 18, 2017, EMEA / CHMP / BMWP / 42832 / 2005 Rev1, Human As stated by the Committee for Medicinal Products for Human Use (CHMP), products administered intravenously may be less immunogenic than drugs administered subcutaneously. Therefore, it is surprising that the population PK profiles for the treatments of some embodiments are so similar between the intravenous and subcutaneous dosing regimen scenarios (based on a single subcutaneous dose). It is evident from the information disclosed in this article that there is no meaningful ADA effect.

[0202] Important factors that influence the immunogenicity of therapeutic proteins often include the source (e.g., foreign or human) and nature (endogenous protein, post-translational modifications) of the active substance, significant modifications of the therapeutic protein (e.g., PEGylation and fusion proteins). ), product-related (e.g., degradation products, impurities, aggregates) and process-related impurities (host cell proteins, lipids or DNA, microbial contaminants), formulations (excipients), and drug and / or formulations associated with primary Interactions between product packaging (e.g., containers, closures).

[0203] Without being bound by theory, an antibody or fragment thereof administered according to some embodiments may advantageously maintain the native conformation of the antibody or fragment thereof. Denaturation and aggregation of therapeutic proteins may potentially trigger an immune response. Aggregation and adduct formation of proteins can reveal novel epitopes or lead to the formation of multivalent epitopes, which may stimulate the immune system. In addition, aggregation can enhance protein-specific immune responses and lead to the formation of ADA. Higher molecular weight (MW) aggregates are more likely to elicit an immune response than lower molecular weight aggregates. The antibody or fragment thereof may exhibit advantageously low aggregation and adduct formation, especially higher MW aggregates as administered according to some embodiments.

[0204] Other factors that influence the immunogenicity of a therapeutic protein include the properties of the active ingredient. Therapeutic proteins that are similar to endogenous human proteins may result from changes in amino acid sequence compared to the endogenous protein or changes in protein structure (as a result of post-translational modifications) or during the manufacturing process of the drug substance and / or drug product, Other changes in all steps of storage and administration trigger an immune response. T cell epitopes are small linear peptides and therefore can be modified by differences in amino acid sequences between the endogenous protein and the therapeutic protein. Therefore, analysis to identify potential T cell epitopes may help select novel proteins or peptides for development. Glycosylation can affect the physicochemical and biological properties of proteins. The presence or absence and structure of the carbohydrate moiety may have both direct and indirect effects on the immunogenicity of the therapeutic protein; the glycan itself may induce an immune response (e.g., glycans of non-human origin), or its presence may Affecting the conformation of a protein in such a way that the protein becomes immunogenic. In some embodiments, administration of antibodies or fragments thereof may advantageously minimize such properties and thus minimize immunogenicity.

[0205] The antibody or fragment thereof may be capable of exhibiting one or more pharmacokinetic properties selected from the group consisting of: (a) a clearance rate (CL) of about 0.05 to about 0.18 L / day; (b) Absorption constant (ka) of about 0.11 to about 0.33 L / day; (c) a volume (Vc) of central chamber volume of about 1.6 to about 5.0 L; (d) a second (peripheral chamber) volume (Vp1) of about 1.2 to about 3.6 L; (e) a clearance rate (Q) from the central chamber to the second chamber of about 0.31 to about 0.93 L / day; and (f) Bioavailability from about 0.6 to about 1.0 (Fabs1).

[0206] The antibody or fragment thereof may have 1, 2, 3, 4, 5 or 6 of the pharmacokinetic properties (a) to (f).

[0207] The antibody or fragment thereof may exhibit 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 a clearance rate (CL) of 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.

[0208] The antibody or fragment thereof may exhibit 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 or Absorption constant (ka) of 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.

[0209] The antibody or fragment thereof may exhibit 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 a volume (Vc) of the central chamber volume of 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 chamber volume (Vc) of approximately 3.3 L.

[0210] The antibody or fragment thereof may exhibit 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 a second (peripheral chamber) volume (Vp1) of about 2.3 to about 2.5 L. The antibody or fragment thereof may exhibit a second (peripheral compartment) volume (Vp1) of approximately 2.4 L.

[0211] The antibody or fragment thereof may exhibit 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 clearance rate (Q1) from the central chamber to the second chamber. The antibody or fragment thereof may exhibit a clearance rate (Q1) from the central chamber to the second chamber of about 0.62 L / day.

[0212] The antibody or fragment thereof can 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.

[0213] Pharmacokinetic properties can be induced by administration of a single dose of the antibody or fragment thereof. Pharmacokinetic properties may alternatively result from administration of more than one dose (eg, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) of the antibody or fragment thereof. The antibody or fragment thereof can be administered to an individual such that the antibody or fragment thereof is present in the individual at steady state levels.

[0214] Pharmacokinetic properties can be determined based on samples from a single individual. Pharmacokinetic properties may alternatively be determined based on population samples, such as mixed populations (e.g., healthy and unhealthy), AD populations, or moderate to severe AD populations.

[0215] The pharmacokinetic properties can be determined using a two-compartment model. The two-compartment model may be a linear two-compartment model. In a linear two-compartment model, CL and Q1 can be linearly related to the concentration of the antibody or its fragment.

[0216] 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. Antibodies or fragments thereof may possess the six pharmacokinetic properties described above as determined using a two-compartment model.

[0217] Pharmacokinetic properties can be induced by administration of antibodies of their fragments by intravenous injection or by subcutaneous injection. Pharmacokinetic properties can be induced by administration of any dose or combination of doses described herein.

[0218] The method may further comprise obtaining one or more blood samples from the individual, and optionally measuring the serum concentration achieved by the antibody or fragment thereof. patient population

[0219] An individual is a human individual. The individual may be a male individual. The individual may be a female individual. The individual may 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 between about 40 and about 60 years old. The individuals may be 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. Individuals can be 44 years old. The individual weight may be approximately 92 kg. An individual may weigh between about 40 and about 210 kg. An individual may weigh between about 50 and 200 kg, about 60 and about 150 kg; or about 75 kg and about 100 kg. Individual weight may be approximately 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.

[0220] The age of the individual may be selected from up to 6 years old; from 6 years old to 12 years old; from 12 years old to 18 years old; at least 18 years old; and less than 75 years old. The individual may be at least 18 years old and / or less than 75 years old. Individuals may be 6 months to 11 years old. The age of the individual may be 12 to 17 years old.

[0221] The individual may be a patient of an inflammatory disease or an inflammatory disorder. Individuals may have immune-mediated diseases or immune-mediated disorders. The individual may be a patient of an inflammatory skin disease or an inflammatory skin disorder.

[0222] Individuals may be type 2 sufferers. Individuals may be high in type 2 patients. Individuals may be low type 2 patients. Individuals may be non-type 2 patients. The individual may be a patient with a mixed inflammatory response.

[0223] The individual may be diagnosed with atopic dermatitis at least one year prior to administration of the antibody or fragment thereof. The individual 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 by topical prescriptions and / or systemic therapies or those therapies may be inappropriate.

[0224] The individual may be a patient with moderate to severe atopic dermatitis who is a candidate for systemic therapy. The individual may be a patient with moderate to severe atopic dermatitis whose disease is not adequately controlled by topical prescription therapies or those therapies are inappropriate.

[0225] The individual can be defined by biomarker levels. The biomarker level may be any suitable biomarker level known in the art or described elsewhere herein. topical corticosteroids

[0226] Topical corticosteroids are a type of steroid medication that are applied directly to the skin to reduce inflammation and irritation. Topical corticosteroids may be used to treat AD, for example, to reduce swelling, redness, and itching during flare-ups. If used appropriately, serious side effects of topical corticosteroids tend to be minimal, although they have been reported. However, as the only treatment for AD in many individuals, they may not be effective enough, especially when AD is moderate to severe. The methods described herein benefit from the use of topical corticosteroids and, according to embodiments of the methods, treatment with an anti-OX40L antibody or antigen-binding fragment thereof.

[0227] The atopic dermatitis may be resistant to, unresponsive or inadequately responsive to treatment with topical corticosteroids and / or systemic therapies or those therapies may be inappropriate, or the individual may be resistant to one or more topical corticosteroids. Inadequate steroid response, intolerance, or refractory treatment. The atopic dermatitis may not be adequately controlled or respond poorly to topical corticosteroid treatment. Individuals may have an inadequate response to, be intolerant of, or be refractory to one or more topical corticosteroids. The individual may also be being treated with one or more topical corticosteroids. The antibodies or fragments thereof can be used with topical corticosteroids. Individuals may have been treated with one or more topical corticosteroids.

[0228] The method may further comprise administering a therapeutically effective amount of one or more topical corticosteroids. The one or more topical corticosteroids can be administered prior to the anti-OX40L antibody or antigen-binding fragment thereof. The first injection of anti-OX40L antibody or antigen-binding fragment thereof can be administered on the day the individual 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 the one or more topical corticosteroids.

[0229] A clinical decision may be made to discontinue treatment with the one or more topical corticosteroids, or an individual may discontinue treatment for a variety of reasons. For example, an individual may have an inadequate response to the one or more topical corticosteroids, be intolerant to the one or more topical corticosteroids, or be refractory to the one or more topical corticosteroids. The likely time course for discontinuing treatment may depend on the reason for discontinuing treatment. For example, it may be apparent to the clinician that the patient is intolerant to the one or more topical corticosteroids, such that the decision to discontinue treatment can be made relatively quickly. It may take longer to identify a patient who is refractory to or inadequately responsive to one or more topical corticosteroids, and therefore the decision to discontinue treatment for these reasons may be less rapid. Causes may be loss of primary efficacy, loss of secondary efficacy, or intolerance. Major loss of efficacy may be without seeing a response to initiation of treatment. In this case, treatment may be discontinued quickly. Secondary efficacy failure may occur when a patient loses responsiveness and fails to respond to further treatment, which may occur at any time after an initial response is observed, such as after six months, one year, 18 months or two years. . Intolerance can occur at any time after treatment is started, and in some cases it may be apparent early on, while in other cases it may be evident some time later when adverse events begin to manifest themselves.

[0230] May be administered at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or 4 to 6 months after the first administration of one or more topical corticosteroids A clinical decision is made to discontinue treatment with the one or more topical corticosteroids or the individual may discontinue treatment therewith.

[0231] The one or more topical corticosteroids can be administered following the anti-OX40L antibody or antigen-binding fragment thereof. The first dose of one or more topical corticosteroids can be administered on the day the individual discontinues treatment with the anti-OX40L antibody or antigen-binding fragment thereof. The first dose of the topical corticosteroid(s) may be administered on the day the clinical decision is made to discontinue treatment with the anti-OX40L antibody or antigen-binding fragment thereof.

[0232] Can be made at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or between 4 and 6 months after administration of the first injection of the anti-OX40L antibody or antigen-binding fragment thereof It is a clinical decision to discontinue treatment with the anti-OX40 antibody or antigen-binding fragment thereof or the individual may discontinue treatment with it.

[0233] In many cases, individuals may undergo treatment with a combination of topical corticosteroids and an anti-OX40L antibody or antigen-binding fragment thereof. However, in some cases, the one or more topical corticosteroids and the anti-OX40L antibody or antigen-binding fragment thereof are administered sequentially, and the administration of the one or more topical corticosteroids is consistent with the administration of the one or more topical corticosteroids. The time period between injections of the anti-OX40 antibody or antigen-binding fragment thereof 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.

[0234] The one or more topical corticosteroids can be administered concurrently with the anti-OX40L antibody or antigen-binding fragment thereof. Concurrent administration may include overlapping dosing regimens and / or co-administration.

[0235] The topical corticosteroid can be any suitable topical corticosteroid. The topical corticosteroid can be selected from the group consisting of corycortisol dipropionate, becloasone propionate, dexamethasone, methyladrenocorticosterone, methyladrenocorticosterone acetate, mometasone furoate, and diacetate. difluxazone, halobetasol propionate, amcinonide, triamcinolone dipropionate, triamcinolone acetonide, triamcinolone acetonide, triamcinolone valerate Cortisol, chlorocotolone pivalate, cortisol dehydrogenase, fluocinolone acetonide, fludroxone, fluticortisol propionate, corticosterone butyrate, butyric acid Hydrocortisone, hydrocortisone valerate, prednicate, aclomethasone dipropionate, desonide, hydrocortisone, and hydrocortisone acetate. The topical corticosteroids can be selected from the group consisting of cassava cortisol dipropionate, cassava corticosteroid dipropionate; gentamicin sulfate, becloasone propionate, dexamethasone, methyladrenocorticosterone, and methacrylate acetate. Adrenocorticosterone and mometasone furoate. The topical corticosteroid may be corynocortisol dipropionate, optionally wherein said corynocortisol dipropionate is combined with gentamicin sulfate.

[0236] Topical corticosteroids may be formulated as a cream, ointment, gel, foam, solution, lotion, or gel. Topical corticosteroids can be applied twice daily or once daily. Topical corticosteroids can be applied once a week or twice a week.

[0237] The duration of topical corticosteroid administration can be of any suitable length to achieve the clinical goals, and thus can involve any suitable number of administrations. Therefore, the duration of topical corticosteroids can be determined by the clinician. For some individuals, topical corticosteroid administration can be uncertain.

[0238] In yet other configurations, the above-described embodiments are provided, comprising administering a therapeutically effective amount of an OX40L antagonist antibody or antigen-binding fragment thereof. calcineurin inhibitor

[0239] Topical calcineurin inhibitors (TCIs) work by altering the immune system and have been developed to treat atopic dermatitis. There are two types available: tacrolimus ointment (Protopic) for moderate to severe atopic dermatitis and pimecrolimus cream (Elidel) for mild to moderate atopic dermatitis. "Topical" means application to the skin. "Calcineurin inhibitors" means that they block the enzyme calcineurin, which may contribute to the onset of atopic dermatitis. TCIs are used to treat atopic dermatitis in adults and children older than 2 years who have an inadequate response to or intolerance to conventional treatments, such as topical steroids. They can be used to treat and prevent attacks. The methods described herein benefit from the use of topical calcineurin inhibitors and, according to embodiments of the methods, treatment with anti-OX40L antibodies or antigen-binding fragments thereof.

[0240] The atopic dermatitis may be resistant to, non-responsive or under-responsive to treatment with topical calcineurin inhibitors and / or systemic therapies or those therapies may be inappropriate, or the individual may be resistant to one or Insufficient response, intolerance, or refractory treatment to various topical calcineurin inhibitors. The atopic dermatitis may not be adequately controlled or respond poorly to treatment with topical calcineurin inhibitors. Individuals may have an inadequate response to, be intolerant to, or be refractory to one or more topical calcineurin inhibitors. The individual may also be being treated with one or more topical calcineurin inhibitors. The antibodies or fragments thereof can be used with topical calcineurin inhibitors. Individuals may have been treated with one or more topical calcineurin inhibitors.

[0241] The method may further comprise administering a therapeutically effective amount of one or more topical calcineurin inhibitors. The one or more topical calcineurin inhibitors can be administered prior to the anti-OX40L antibody or antigen-binding fragment thereof. The first injection of anti-OX40L antibody or antigen-binding fragment thereof can be administered on the day the individual discontinues treatment with one or more topical calcineurin inhibitors. 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 the one or more topical calcineurin inhibitors.

[0242] A clinical decision may be made to discontinue treatment with one or more topical calcineurin inhibitors, or an individual may discontinue treatment for a variety of reasons. For example, an individual may have an inadequate response to the one or more calcineurin inhibitors, be intolerant to the one or more topical calcineurin inhibitors, or be a patient with more than one topical calcineurin inhibitor. Refractory to phosphatase inhibitors. The likely time course for discontinuing treatment may depend on the reason for discontinuing treatment. For example, it may be apparent to the clinician that the patient is intolerant to the one or more topical calcineurin inhibitors, such that the decision to discontinue treatment can be made relatively quickly. It may take longer to identify a patient who is refractory to or inadequately responsive to one or more topical calcineurin inhibitors, and therefore the decision to discontinue treatment for these reasons may be less rapid. Causes may be loss of primary efficacy, loss of secondary efficacy, or intolerance. Major loss of efficacy may be without seeing a response to initiation of treatment. In this case, treatment may be discontinued quickly. Secondary efficacy failure may occur when a patient loses responsiveness and fails to respond to further treatment, which may occur at any time after an initial response is observed, such as after six months, one year, 18 months or two years. . Intolerance can occur at any time after treatment is started, and in some cases it may be apparent early on, while in other cases it may be evident some time later when adverse events begin to manifest themselves.

[0243] Can be administered at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or 4 to A clinical decision to discontinue treatment with one or more topical calcineurin inhibitors is made at 6 months.

[0244] The one or more topical calcineurin inhibitors can be administered following the anti-OX40L antibody or antigen-binding fragment thereof. The first dose of one or more topical calcineurin inhibitors can be administered on the day the individual discontinues treatment with the anti-OX40L antibody or antigen-binding fragment thereof. The first administration of the one or more topical calcineurin inhibitors may be administered on the day the clinical decision is made to discontinue treatment with the anti-OX40L antibody or antigen-binding fragment thereof.

[0245] Can be made at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or between 4 and 6 months after administration of the first injection of the anti-OX40L antibody or antigen-binding fragment thereof It is a clinical decision to discontinue treatment with the anti-OX40 antibody or antigen-binding fragment thereof or the individual may discontinue treatment with it.

[0246] In many cases, individuals may undergo treatment with a combination of both a topical calcineurin inhibitor and an anti-OX40L antibody or antigen-binding fragment thereof. However, in some cases, the one or more topical calcineurin inhibitors and the anti-OX40L antibody or antigen-binding fragment thereof are administered sequentially, and the one or more topical calcineurin inhibitors are administered The time period between the administration of the phosphatase inhibitor and the injection of the anti-OX40 antibody or antigen-binding fragment thereof 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 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.

[0247] The one or more topical calcineurin inhibitors can be administered concurrently with the anti-OX40L antibody or antigen-binding fragment thereof. Concurrent administration may include overlapping dosing regimens and / or co-administration.

[0248] The topical calcineurin inhibitor can be any suitable topical calcineurin inhibitor. Topical calcineurin inhibitors can be tacrolimus ointment or pimecrolimus cream, such as tacrolimus ointment.

[0249] Topical calcineurin inhibitors may be formulated as a cream, ointment, gel, foam, solution, lotion, or gel. Topical calcineurin inhibitors can be applied twice daily or once daily. Topical calcineurin inhibitors can be applied two to three times per week.

[0250] The duration of topical calcineurin inhibitor administration can be of any suitable length to achieve the clinical goals, and thus can involve any suitable number of administrations. Therefore, the duration of topical calcineurin inhibitor use can be determined by the clinician. For some individuals, topical calcineurin inhibitor administration can be uncertain.

[0251] In yet other configurations, the above-described embodiments are provided, comprising administering a therapeutically effective amount of an OX40L antagonist antibody or antigen-binding fragment thereof. Other co-treatments

[0252] Any other suitable treatment for the treatment of atopic dermatitis may characterize an individual for treatment and / or use in combination with an antibody or fragment thereof according to the methods described herein.

[0253] The individual may also be being treated with one or more topical antihistamines. The antibodies or fragments thereof can be used with one or more topical antihistamines.

[0254] The individual may also be being treated with one or more oral steroids. The antibodies or fragments thereof can be used with one or more oral steroids. disease severity

[0255] When evaluating patients with atopic dermatitis, there are several different methods that can be used to assign disease severity. Thus, each method of assigning disease severity can inform patient selection for method embodiments. Each method of assigning disease severity can be used to monitor individual treatment for method embodiments. Each method of assigning disease severity can be used to transition patients from induction to maintenance. Each method of assigning disease severity can be used to identify treatments that are disease-modifying. Each method of assigning disease severity can be performed as described below and / or in the Examples, as applicable. Methods of assigning disease severity include: EASI (including EASI75 and EASI90)

[0256] The EASI is a continuous scale (0 (no disease) to 72 (most severe disease)) used to assess the severity and extent of atopic dermatitis. This is described for example 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. Methods for determining the EASI score are known and may be described below and / or in the Examples (as applicable).

[0257] In the EASI, researchers rated the severity of four disease features of AD (erythema, infiltrates / papules, exfoliation, and lichenification) on a scale of 0 (none) to 3 (severe). The scores for each of the four body regions (head, arms, torso, and legs) were summed. The percentages of body surface area (BSA) allocated to each body part are 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 area. Additionally, each body region is assigned an area score of 0 to 6 based on the percentage of skin affected by AD in that area: 0 (none), 1 (1% to 9%), 2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%) or 6 (90% to 100%). Each body area score is multiplied by the affected area. The resulting EASI scores ranged from 0 to 72 points, with the highest scores indicating worse AD severity.

[0258] It is recommended that AD severity based on EASI scores should be classified as follows: 0 = resolved; 0.1 to 1.0 = almost resolved; 1.1 to 7.0 = mild; 7.1 to 21.0 = moderate; 21.1 to 50.0 = severe; 50.1 to 72.0 = very severe. EASI50 represents an improvement of ≥50% compared with baseline. EASI75 indicates an improvement of ≥75% compared with baseline. EASI90 indicates ≥90% improvement compared to baseline. EASI100 indicates 100% improvement compared to baseline.

[0259] The overall minimal clinically important difference (MCID) was considered to be 6.6 points. Baseline Score - EASI

[0260] Atopic dermatitis can be assessed by determining a baseline EASI score. Determination of baseline EASI score can include: (a) Select body regions from the following: head and neck; trunk, including genital areas; upper limbs; and lower limbs, including buttocks; (b) assess the extent of atopic dermatitis in the selected body region and assign a regional score based on the extent of atopic dermatitis in the selected body region; (c) Assess the severity of each of the following signs in selected body areas: 1. Erythema, 2. Edema and / or papules, 3. Exfoliation of epidermis, and 4. Lichenification, As well as assigning a severity score to each sign in the selected body region; (d) Determine the overall score for the selected body region based on the selected score for the region and the severity score for each sign in the selected body region; (e) Repeat steps (b) through (d) for each remaining body region; and (f) Determine the baseline EASI score based on the total score for each body region.

[0261] The baseline EASI score can be any score indicative of moderate to severe AD. The baseline EASI score may be at least 12.1, at least 16.1, or at least 21.1. Baseline EASI score can be at least 16.1.

[0262] The first injection of the anti-OX40L antibody or fragment thereof can be administered on the same day as the baseline EASI score is determined.

[0263] Some embodiments of the method may further include determining a baseline EASI score. Clinical Results - EASI

[0264] Some embodiments of the method may further comprise 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. Post-administration EASI scores are expected to be obtained at least 7 days or at least 15 days after the first injection of the antibody or fragment thereof, which is the earliest that changes in the EASI score can be reliably observed due to the effects of the antibody or fragment thereof, however Any clinically appropriate delay from administration to assessment may be used. The antibody or fragment thereof may be administered at least about 7 days, 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 after the first injection of the antibody or fragment thereof and / or at least approximately 253 days post-dose to determine 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 EASI scores after casting. Post-administration EASI scores can be determined at the end of the induction period.

[0265] The post-voting EASI score can be less than or equal to 21.0. Post-administration EASI scores can indicate that AD is no longer severe AD. The post-voting EASI score can be less than or equal to 16.0. Post-administration EASI scores can be less than or equal to 16.0, less than or equal to 15.0, less than or equal to 14.0, less than or equal to 13.0, less than or equal to 12.0, less than or equal to 11.0, less than or equal to 10.0, less than or equal to 9.0, less than or equal to 8.0 , less than or equal to 7.0, less than or equal to 6.0, less than or equal to 5.0, less than or equal to 4.0, less than or equal to 3.0, less than or equal to 2.0, less than or equal to 1.0, or approximately 0. Post-administration EASI scores can indicate that AD is no longer moderate AD. Post-administration EASI scores can be less than or equal to 7.0 or less than or equal to 1.0. Post-administration EASI scores can indicate mild AD. Post-injection EASI scores can indicate that AD is almost cured. Relative to the baseline EASI score, the EASI score after administration can be reduced by at least 10%, at least 25%, or at least 50%. Relative to the baseline EASI score, the EASI score after administration can be 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.

[0266] Some embodiments of the method may further comprise assessing atopic dermatitis by determining one or more further post-administration EASI scores. The antibody or fragment thereof may be administered 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 The EASI score is determined 253 days after the one or more further administrations. The one or more further can be determined 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. EASI scores after casting. The one or more further post-dose EASI scores may be determined at the end of the induction period.

[0267] The one or more further post-administration EASI scores may be less than or equal to 21.0. The one or more further post-dose EASI scores may indicate that AD is no longer severe AD. The one or more further post-administration EASI scores may be less than or equal to 16.0, less than or equal to 15.0, less than or equal to 14.0, less than or equal to 13.0, less than or equal to 12.0, less than or equal to 11.0, less than or equal to 10.0, less than or equal to 9.0, less than or equal to 8.0, less than or equal to 7.0, less than or equal to 6.0, less than or equal to 5.0, less than or equal to 4.0, less than or equal to 3.0, less than or equal to 2.0, less than or equal to 1.0, or about 0. The one or more further post-dose EASI scores may indicate that AD is no longer moderate AD. The one or more further post-administration EASI scores may be less than or equal to 7.0 or less than or equal to 1.0. The one or more further post-administration EASI scores may indicate that the AD is mild AD. The one or more further post-administration EASI scores may indicate that AD is nearly resolved. The one or more further administrations may reduce the EASI score by at least 10%, at least 25%, or at least 50% relative to the baseline EASI score. The one or more further administrations result in a decrease in the EASI score of 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. Relative to the baseline EASI score, the one or more further administrations reduces the EASI score 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 anti-OX40L antibodies or antigen-binding fragments thereof, EASI scores can be maintained after administration: (a) At least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after the last injection; or (b) At least approximately 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169 or 253 days. Determination of the post-dose EASI score and / or the one or more further post-dose EASI scores may include: (a) Select body regions from the following: head and neck; trunk, including genital areas; upper limbs; and lower limbs, including buttocks; (b) assess the extent of atopic dermatitis in the selected body region and assign a regional score based on the extent of atopic dermatitis in the selected body region; (c) Assess the severity of each of the following signs in selected body areas: 1. Erythema, 2. Edema and / or papules, 3. Exfoliation of epidermis, and 4. Lichenification, As well as assigning a severity score to each sign in the selected body region; (d) Determine the overall score for the selected body region based on the selected score for the region and the severity score for each sign in the selected body region; (e) Repeat steps (b) through (d) for each remaining body region; and (f) Determine the baseline EASI score based on the total score for each body region.

[0268] Post-administration EASI and / or further post-administration EASI can be determined at least approximately 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 EASI can be EASI50, EASI75, EASI90 or EASI100. Post-administration EASI and / or further post-administration EASI can be determined at least approximately 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 EASI can be EASI50, EASI75, EASI90 or EASI100. Post-administration EASI and / or further post-administration EASI can be determined at least approximately 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 EASI can be EASI50, EASI75, EASI90 or EASI100. The atopic dermatitis can be treated, as evidenced by a decrease in the EASI score of at least 40% after the third injection as a therapeutic dose, and after the administration of the last injection as a therapeutic dose, the EASI The decrease in score lasts for at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months.

[0269] According to certain embodiments, administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in a reduction in EASI score. Some embodiments include methods of treatment that result in administration of an anti-OX40L antibody or antigen-binding fragment thereof (e.g., subcutaneous administration of a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by administration of 250 mg of anti-OX40L antibody or antigen-binding fragment thereof). EASI scores on days 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, 253 or later after OX40L antibody or its antigen-binding fragment) A reduction from baseline of at least approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or more. Relative to the baseline EASI score, the EASI score after administration 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%. A 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 disclosed herein at any time point or between any time points. In certain exemplary embodiments, administering an anti-OX40L antibody, or antigen-binding fragment thereof, to an individual results in an EASI score relative to baseline, optionally at approximately day 113 after the first administration of the anti-OX40L antibody, or antigen-binding fragment thereof. Reduce by at least 15%, at least 20%, or at least 30%. In certain exemplary embodiments, administering an anti-OX40L antibody, or antigen-binding fragment thereof, to an individual results in an EASI score relative to baseline, optionally at approximately day 113 after the first administration of the anti-OX40L antibody, or antigen-binding fragment thereof. Reduce by at least 40% or at least 45%.

[0270] According to certain embodiments, administering to a patient a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof, results in an increase in the amount of the anti-OX40L antibody, or antigen-binding fragment thereof (e.g., subcutaneously administered about 62.5 mg, 125 mg, 250 mg or 500 mg loading dose followed by administration of 250 mg of anti-OX40L antibody or antigen-binding fragment thereof) on days 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85 , 113, 169, 253 days or later, a reduction in EASI score equal to or greater than the minimal clinically important difference (MCID). Researchers Global Assessment - Atopic Dermatitis (IGA-AD)

[0271] The physician-assigned IGA-AD scale, which ranges from 0-4, was developed by Eli Lilly in collaboration with multiple atopic dermatitis clinical experts and has been reviewed and approved by the FDA. Methods for determining IGA-AD scores are known and may be described below and / or in the Examples, as applicable.

[0272] The distribution of different scores is summarized in Table 1a below. [Score] [morphological description] 0 - healed There were no signs of inflammation of atopic dermatitis (no erythema, no induration / papule, no oozing / crusting). Postinflammatory hyperpigmentation and / or hypopigmentation may be present. 1 - Almost healed Barely noticeable erythema and / or barely noticeable indurations / papules. No oozing or crusting. 2 - Mild Mild but definite erythema (pink), and / or mild but definite nodules / papules. No oozing or crusting. 3 - Moderate Clearly perceptible erythema (dark red) and / or clearly perceptible indurations / papules. There may be oozing and crusting. 4 - Severe Visible erythema (dark or bright red) and / or conspicuous nodules / papules. The range of diseases is wide. There may be oozing or crusting. [surface] [1a] [:] [IGA-AD] [Score]

[0273] Therefore, a decrease in IGA-AD score is associated with an improvement in signs and / or symptoms Baseline Score - IGA-AD

[0274] Atopic dermatitis can be assessed by determining a baseline IGA-AD score. Determination of the baseline IGA-AD score may include describing the overall appearance of AD lesions at a given time point by: (a) Assign a score of 0 when the most applicable morphological description is - elimination: · Absence of inflammatory signs of atopic dermatitis (no erythema, no indurations / papules, no lichenification, no oozing / crusting); post-inflammatory hyperpigmentation and / or hypopigmentation may be present; (b) Assign a score of 1 when the most applicable morphological description is - nearly healed: · Barely noticeable erythema and / or barely noticeable induration / papule without oozing or crusting; (c) Assign a score of 2 - Mild when the most applicable morphological description is: · Mild but definite erythema (pink), and / or slight but definite induration / papule; no oozing or crusting; (d) Assign a score of 3 - Moderate when the most applicable morphological description is: · Clearly perceptible erythema (dark red) and / or clearly perceptible indurations / papules; oozing and crusting may be present; (e) A score of 4 is assigned when the most applicable morphological description is: - Severe: · Prominent erythema (dark or bright red) and / or prominent indurations / papules; disease is widespread; oozing or crusting may be present.

[0275] The baseline IGA-AD score can be any score indicative of moderate to severe AD. Baseline IGA-AD score can be 3 or 4.

[0276] The first injection of anti-OX40L antibody or fragment thereof can be administered on the same day that the baseline IGA-AD score is determined.

[0277] Some embodiments of the method may further include determining a baseline IGA-AD score. Clinical Results - IGA-AD

[0278] Some embodiments of the method may further comprise 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. Post-administration IGA-AD scores are expected to be obtained at least 7 days after the first injection of the antibody or fragment thereof, or at least 15 days after administration of the antibody or fragment thereof, which is the earliest that the IGA-AD score can be reliably observed due to the effects of the antibody or fragment thereof of variation, however any clinically appropriate delay from administration to assessment may be used. The antibody or fragment thereof may be administered at least about 7 days, 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 after the first injection of the antibody or fragment thereof and / or at least approximately 253 days post-administration to determine the 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 IGA-AD score after the throw. Post-administration IGA-AD scores can be determined at the end of the induction period.

[0279] The IGA-AD score can be 0 or 1 after casting. Post-administration IGA-AD scores can indicate that AD is no longer severe AD. Post-administration IGA-AD scores can indicate that AD is no longer moderate AD. The IGA-AD score after administration can indicate that AD is almost cured. Relative to the baseline IGA-AD score, the post-administration IGA-AD score 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 IGA-AD score can be reduced by at least 2 points after administration. Relative to the baseline IGA-AD score, the post-administration IGA-AD score decreases 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 anti-OX40L antibodies or antigen-binding fragments thereof, the IGA-AD score can be maintained after administration: (a) At least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after the last injection; or (b) At least approximately 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169 or 253 days.

[0280] Some embodiments of the method may further comprise assessing atopic dermatitis by determining one or more further post-administration IGA-AD scores. The antibody or fragment thereof may be administered 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 The IGA-AD score is determined 253 days after the one or more further administrations. The one or more further administrations are determined approximately 29 days, approximately 57 days, approximately 85 days, approximately 113 days, approximately 169 days, and / or approximately 253 days after administration of the first injection of the antibody or fragment thereof. Post-IGA-AD score. The one or more further post-administration IGA-AD scores can be determined at the end of the induction period.

[0281] The IGA-AD score may be 0 or 1 after the one or more further administrations. The one or more further post-administration IGA-AD scores may indicate that AD is no longer severe AD. The one or more further post-administration IGA-AD scores may indicate that AD is no longer moderate AD. The one or more further post-administration IGA-AD scores may indicate that AD is nearly resolved. The one or more further administrations may reduce the IGA-AD score 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 further administrations may reduce the IGA-AD score by at least 2 points relative to the baseline IGA-AD score.

[0282] Determination of the post-administration IGA-AD score and / or the one or more further post-administration IGA-AD scores may include describing the overall appearance of the AD lesion at a given time point by: (a) Assign a score of 0 when the most applicable morphological description is - elimination: · Absence of inflammatory signs of atopic dermatitis (no erythema, no indurations / papules, no oozing / crusting); post-inflammatory hyperpigmentation and / or hypopigmentation may be present; (b) Assign a score of 1 when the most applicable morphological description is - nearly healed: · Barely noticeable erythema and / or barely noticeable induration / papule, without oozing or crusting; (c) Assign a score of 2 - Mild when the most applicable morphological description is: · Mild but definite erythema (pink), and / or slight but definite induration / papule; no oozing or crusting; (d) Assign a score of 3 - Moderate when the most applicable morphological description is: · Clearly perceptible erythema (dark red) and / or clearly perceptible indurations / papules; oozing and crusting may be present; (e) A score of 4 is assigned when the most applicable morphological description is: - Severe: · Prominent erythema (dark or bright red) and / or prominent indurations / papules; disease is widespread; oozing or crusting may be present.

[0283] Post-administration IGA-AD and / or further post-administration IGA-AD can be determined at least about 113 days after administration of the first injection of the antibody or fragment thereof, and post-administration IGA-AD and / or further post-administration IGA-AD After administration of IGA-AD can be: (a) IGA-AD score of 0 or 1, and / or (b) A decrease in IGA-AD score of at least 2 points relative to said baseline.

[0284] Post-administration IGA-AD and / or further post-administration IGA-AD can be determined at least about 169 days after administration of the first injection of the antibody or fragment thereof, and wherein post-administration IGA-AD and / or After further administration IGA-AD can be: (a) IGA-AD score of 0 or 1, and / or (b) A decrease in IGA-AD score of at least 2 points relative to said baseline.

[0285] Post-administration IGA-AD and / or further post-administration IGA-AD can be determined at least about 253 days after administration of the first injection of the antibody or fragment thereof, and wherein post-administration IGA-AD and / or After further administration IGA-AD can be: (a) IGA-AD score of 0 or 1, and / or (b) A decrease in IGA-AD score of at least 2 points relative to said baseline.

[0286] The atopic dermatitis can be treated as evidenced by a decrease in the IGA-AD score of at least 2 points after administration of the third injection as a therapeutic dose, and wherein after administration of the final injection as a therapeutic dose, The reduction in IGA-AD score lasts for at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months.

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

[0288] According to certain embodiments, administering to a patient a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof, results in an increase in the amount of the anti-OX40L antibody, or antigen-binding fragment thereof (e.g., subcutaneously administered about 62.5 mg, 125 mg, 250 mg or 500 mg loading dose followed by administration of 250 mg of anti-OX40L antibody or antigen-binding fragment thereof) on days 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85 , 113, 169, 253 days or later, a reduction in IGA-AD score equal to or greater than the minimal clinically important difference (MCID). Validated Investigator-wide Assessment - Atopic Dermatitis (vIGA-AD)

[0289] The physician-assigned vIGA-AD scale, which ranges from 0-4, was developed by Eli Lilly in collaboration with multiple atopic dermatitis clinical experts and has been reviewed and approved by the FDA. Additional 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 25 April 2020. The vIGA-AD scale corresponds to the IGA-AD scale, but further takes into account lichenification. Methods for determining vIGA-AD scores are known and may be described below and / or in the Examples, as applicable.

[0290] The distribution of different scores is summarized in Table 1b below. [Score] [morphological description] 0 - healed There were no inflammatory signs of atopic dermatitis (no erythema, no induration / papules, no lichenification, no oozing / crusting). Postinflammatory hyperpigmentation and / or hypopigmentation may be present. 1 - Almost healed Barely noticeable erythema, barely noticeable indurations / papules, and / or minimal lichenification. No oozing or crusting. 2 - Mild Mild but definite erythema (pink), mild but definite indurations / papules, and / or mild but definite lichenification. No oozing or crusting. 3 - Moderate Clearly perceptible erythema (dark red), clearly perceptible indurations / papules, and / or clearly perceptible lichenification. There may be oozing and crusting. 4 - Severe Prominent erythema (dark or bright red), prominent nodules / papules, and / or significant lichenification. The range of diseases is wide. There may be oozing or crusting. [surface] [1b] [:] [vIGA-AD] [Score]

[0291] Therefore, a decrease in vIGA-AD score is associated with an improvement in signs and / or symptoms. Baseline score - vIGA-AD

[0292] Atopic dermatitis can be assessed by determining the baseline vIGA-AD score. Determination of the baseline vIGA-AD score may include describing the overall appearance of AD lesions at a given time point by: (a) Assign a score of 0 when the most applicable morphological description is - elimination: · Absence of inflammatory signs of atopic dermatitis (no erythema, no indurations / papules, no lichenification, no oozing / crusting); post-inflammatory hyperpigmentation and / or hypopigmentation may be present; (b) Assign a score of 1 when the most applicable morphological description is - nearly healed: · Barely noticeable erythema, barely noticeable indurations / papules, and / or minimal lichenification; no oozing or crusting; (c) Assign a score of 2 - Mild when the most applicable morphological description is: · Mild but definite erythema (pink), mild but definite induration / papule, and / or mild but definite lichenification; no oozing or crusting; (d) Assign a score of 3 - Moderate when the most applicable morphological description is: · Clearly detectable erythema (dark red), clearly detectable indurations / papules, and / or clearly detectable lichenification; oozing and crusting may be present; (e) A score of 4 is assigned when the most applicable morphological description is: - Severe: · Prominent erythema (dark or bright red), prominent indurations / papules, and / or significant lichenification; disease is widespread; oozing or crusting may be present.

[0293] The baseline vIGA-AD score can be any score indicative of moderate to severe AD. Baseline vIGA-AD score can be 3 or 4.

[0294] The first injection of anti-OX40L antibody or fragment thereof can be administered on the same day that the baseline vIGA-AD score is determined.

[0295] Some embodiments of the method may further include determining a baseline vIGA-AD score. Clinical Results - vIGA-AD

[0296] Some embodiments of the method may further comprise assessing atopic dermatitis by determining a post-administration vIGA-AD score at least 15 days after administration of the first injection of the antibody or fragment thereof. Post-administration vIGA-AD scores are expected to be obtained at least 7 days after the first injection of the antibody or fragment thereof, or at least 15 days after administration of the antibody or fragment thereof, which is the earliest that the vIGA-AD score can be reliably observed due to the effects of the antibody or fragment thereof of variation, however any clinically appropriate delay from administration to assessment may be used. The antibody or fragment thereof may be administered at least about 7 days, 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 after the first injection of the antibody or fragment thereof and / or at least approximately 253 days post-administration to determine the vIGA-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 vIGA-AD scores after administration. Post-administration vIGA-AD scores can be determined at the end of the induction period.

[0297] The vIGA-AD score can be 0 or 1 after casting. Post-administration vIGA-AD scores can indicate that AD is no longer severe AD. Post-administration vIGA-AD scores can indicate that AD is no longer moderate AD. The vIGA-AD score after administration can indicate that AD is almost cured. Relative to the baseline vIGA-AD score, the vIGA-AD score after administration 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 vIGA-AD score, the vIGA-AD score can be reduced by at least 2 points after administration. Relative to the baseline vIGA-AD score, the vIGA-AD score after administration decreases 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 anti-OX40L antibodies or antigen-binding fragments thereof, vIGA-AD scores can be maintained following administration: (a) At least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after the last injection; or (b) At least approximately 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169 or 253 days.

[0298] Some embodiments of the method may further comprise assessing atopic dermatitis by determining one or more further post-administration vIGA-AD scores. The antibody or fragment thereof may be administered 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 vIGA-AD scores were determined 253 days after the one or more further administrations. The one or more further administrations are determined approximately 29 days, approximately 57 days, approximately 85 days, approximately 113 days, approximately 169 days, and / or approximately 253 days after administration of the first injection of the antibody or fragment thereof. Post-vIGA-AD score. The one or more further post-administration vIGA-AD scores can be determined at the end of the induction period.

[0299] The vIGA-AD score may be 0 or 1 after the one or more further administrations. The one or more further post-administration vIGA-AD scores may indicate that AD is no longer severe AD. The one or more further post-administration vIGA-AD scores may indicate that AD is no longer moderate AD. The one or more further post-administration vIGA-AD scores may indicate that AD is nearly resolved. The one or more further administrations may reduce the vIGA-AD score 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 may decrease by at least 2 points relative to the baseline vIGA-AD score after the one or more further administrations.

[0300] Determination of the post-administration vIGA-AD score and / or the one or more further post-administration vIGA-AD scores may include describing the overall appearance of the AD lesion at a given time point by: (a) Assign a score of 0 when the most applicable morphological description is - elimination: · Absence of inflammatory signs of atopic dermatitis (no erythema, no indurations / papules, no lichenification, no oozing / crusting); post-inflammatory hyperpigmentation and / or hypopigmentation may be present; (b) Assign a score of 1 when the most applicable morphological description is - nearly healed: · Barely noticeable erythema, barely noticeable indurations / papules, and / or minimal lichenification; no oozing or crusting; (c) Assign a score of 2 - Mild when the most applicable morphological description is: · Mild but definite erythema (pink), mild but definite induration / papule, and / or mild but definite lichenification; no oozing or crusting; (d) Assign a score of 3 - Moderate when the most applicable morphological description is: · Clearly detectable erythema (dark red), clearly detectable indurations / papules, and / or clearly detectable lichenification; oozing and crusting may be present; (e) A score of 4 is assigned when the most applicable morphological description is: - Severe: · Prominent erythema (dark or bright red), prominent indurations / papules, and / or significant lichenification; disease is widespread; oozing or crusting may be present.

[0301] 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 post-administration vIGA-AD and / or further post-administration vIGA-AD Post-administration of vIGA-AD can be: (a) vIGA-AD score of 0 or 1, and / or (b) A decrease in vIGA-AD score of at least 2 points relative to said baseline.

[0302] 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 wherein post-administration vIGA-AD and / or After further administration vIGA-AD can be: (a) vIGA-AD score of 0 or 1, and / or (b) A decrease in vIGA-AD score of at least 2 points relative to said baseline.

[0303] Post-administration vIGA-AD and / or further post-administration vIGA-AD can be determined at least about 253 days after administration of the first injection of the antibody or fragment thereof, and wherein post-administration vIGA-AD and / or After further administration vIGA-AD can be: (a) vIGA-AD score of 0 or 1, and / or (b) A decrease in vIGA-AD score of at least 2 points relative to said baseline.

[0304] The atopic dermatitis can be treated as evidenced by a decrease in the vIGA-AD score of at least 2 points after administration of the third injection as a therapeutic dose, and wherein after administration of the final injection as a therapeutic dose, The reduction in 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.

[0305] According to certain embodiments, administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in a decrease in vIGA-AD score. Some examples include

[0306] A treatment method that results in administration of an anti-OX40L antibody or an antigen-binding fragment thereof (e.g., subcutaneous administration of a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by administration of 250 mg of an anti-OX40L antibody or an antigen-binding fragment thereof vIGA-AD score on days 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, 253 or later after antigen-binding fragment) relative to baseline Reduce by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more. Relative to the baseline vIGA-AD score, the vIGA-AD score after administration 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%. A decrease in post-administration vIGA-AD score relative to baseline vIGA-AD score can be derived from any baseline vIGA-AD score at any time point or between any time points disclosed herein and any post-administration vIGA-AD score. . In certain exemplary embodiments, administering an anti-OX40L antibody, or antigen-binding fragment thereof, to an individual results in a relative vIGA-AD score, optionally at about day 113 after the first administration of the anti-OX40L antibody, or antigen-binding fragment thereof. A reduction of at least 15%, at least 20%, or at least 30% from baseline.

[0307] According to certain embodiments, administering to a patient a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof, results in an increase in the amount of the anti-OX40L antibody, or antigen-binding fragment thereof (e.g., subcutaneously administered about 62.5 mg, 125 mg, 250 mg or 500 mg loading dose followed by administration of 250 mg of anti-OX40L antibody or antigen-binding fragment thereof) on days 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85 , 113, 169, 253 days or later, the reduction in vIGA-AD score was equal to or greater than the minimal clinically important difference (MCID).

[0308] According to certain embodiments, administering to a patient a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof, results in an increase in the amount of the anti-OX40L antibody, or antigen-binding fragment thereof (e.g., subcutaneously administered about 62.5 mg, 125 mg, 250 mg or 500 mg loading dose followed by administration of 250 mg of anti-OX40L antibody or antigen-binding fragment thereof) produced resolved skin on at least day 113.

[0309] According to certain embodiments, administering to a patient a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof, results in an increase in the amount of the anti-OX40L antibody, or antigen-binding fragment thereof (e.g., subcutaneously administered about 62.5 mg, 125 mg, 250 mg or 500 mg loading dose, followed by administration of 250 mg of anti-OX40L antibody or antigen-binding fragment thereof) produced resolved skin at least day 169.

[0310] According to certain embodiments, administering to a patient a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof, results in an increase in the amount of the anti-OX40L antibody, or antigen-binding fragment thereof (e.g., subcutaneously administered about 62.5 mg, 125 mg, 250 mg or 500 mg loading dose followed by administration of 250 mg of anti-OX40L antibody or antigen-binding fragment thereof) produced resolved skin on at least day 253.

[0311] According to certain embodiments, administering to a patient a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof, results in an increase in the amount of the anti-OX40L antibody, or antigen-binding fragment thereof (e.g., subcutaneously administered about 62.5 mg, 125 mg, 250 mg or 500 mg loading dose followed by administration of 250 mg of anti-OX40L antibody or antigen-binding fragment thereof) produced nearly healed skin at least on day 113.

[0312] According to certain embodiments, administering to a patient a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof, results in an increase in the amount of the anti-OX40L antibody, or antigen-binding fragment thereof (e.g., subcutaneously administered about 62.5 mg, 125 mg, 250 mg or 500 mg loading dose followed by administration of 250 mg of anti-OX40L antibody or antigen-binding fragment thereof) produced nearly healed skin at least day 169 after administration.

[0313] According to certain embodiments, administering to a patient a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof, results in an increase in the amount of the anti-OX40L antibody, or antigen-binding fragment thereof (e.g., subcutaneously administered about 62.5 mg, 125 mg, 250 mg or 500 mg loading dose followed by administration of 250 mg of anti-OX40L antibody or antigen-binding fragment thereof) produced nearly healed skin at least on day 253.

[0314] According to certain embodiments, administering to a patient a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof, results in an increase in the amount of the anti-OX40L antibody, or antigen-binding fragment thereof (e.g., subcutaneously administered about 62.5 mg, 125 mg, 250 mg or 500 mg loading dose, followed by administration of 250 mg of anti-OX40L antibody or antigen-binding fragment thereof) resulting in healed skin or nearly healed skin on at least day 113.

[0315] According to certain embodiments, administering to a patient a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof, results in an increase in the amount of the anti-OX40L antibody, or antigen-binding fragment thereof (e.g., subcutaneously administered about 62.5 mg, 125 mg, 250 mg or 500 mg loading dose, followed by administration of 250 mg of anti-OX40L antibody or antigen-binding fragment thereof) resulting in resolved skin or nearly resolved skin on at least day 169.

[0316] According to certain embodiments, administering to a patient a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof, results in an increase in the amount of the anti-OX40L antibody, or antigen-binding fragment thereof (e.g., subcutaneously administered about 62.5 mg, 125 mg, 250 mg or 500 mg loading dose, followed by administration of 250 mg of anti-OX40L antibody or antigen-binding fragment thereof) resulting in healed skin or nearly healed skin on at least day 253.

[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 healed skin or nearly healed skin at least 2 months after administration of the last injection.

[0318] 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 healed skin or nearly healed skin at least 3 months after administration of the last injection.

[0319] 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 healed skin or nearly healed skin at least 4 months after administration of the last injection.

[0320] 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 healed skin or nearly healed skin at least 5 months after administration of the last injection.

[0321] 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 healed skin or nearly healed skin at least 6 months after administration of the last injection. Numerical Rating Scale (NRS) for Pruritus

[0322] 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 NRS scores are known and may be described below and / or in the Examples (as applicable). Determination of the baseline NRS score involves the individual providing a numerical rating on a scale from "0" for no itch to "10" for the worst itch imaginable for the most severe itching in the past 24 hours. The question asked of individuals in English was "On a scale of "0" (no itch) to "10" (worst itch imaginable), what was your worst itch in the past 24 hours?" Individuals are asked to mark only one digit on a scale from 0 to 10.

[0323] If at least 4 values ​​are available, the average of the absolute NRS values ​​is calculated for each week, i.e. the corresponding day and the previous 6 days. For these averages, calculate the absolute change from baseline. Baseline values ​​are those assessed on Day 1. The value for Early Termination Visit is used for the actual date on which the Early Termination Visit was performed.

[0324] The most appropriate definition of a responder to pruritus NRS was considered to be in the range of 2 to 4 points. Baseline Score - NRS: Pruritus / itching

[0325] Atopic dermatitis can be assessed by determining a baseline NRS score. Determination of the baseline NRS score may include the individual providing a numerical rating on a scale of 0 to 10 of the worst itch imaginable in the past 24 hours, where "0" is no itch and "10" is the worst itch imaginable. . Determination of the baseline NRS score may include the patient providing a numerical rating of the worst itching in the past 24 hours once a day for 7 days, and taking the average numerical rating as the baseline NRS score.

[0326] The baseline NRS score can be any score associated with moderate to severe AD cases. Although AD is often associated with itching, the NRS itself does not measure the severity of AD. It is possible to have severe AD without pruritus. However, pruritus may contribute to the severity of AD, for example, exfoliation is a sign assessed when determining the EASI score. Therefore, NRS can be a relevant descriptor of AD. The baseline NRS score can be selected from at least 3 points, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, 6 to 9 points, and 7 to 8 points.

[0327] 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.

[0328] Some embodiments may further include determining a baseline NRS score. Clinical Outcome - NRS: Pruritus / Pruritus

[0329] Some embodiments may further include assessing atopic dermatitis by determining a post-administration NRS (Numerical Rating Scale) score following administration of the first injection of the antibody or fragment thereof. Any clinically appropriate delay from administration to assessment may be used. In cases such as JAKi, changes in NRS scores are quickly observed, and some topical creams can provide immediate improvement. The post-administration NRS score can be determined within 2 hours, within 6 hours, within 12 hours, within 24 hours, within 24 hours, or within 7 days of administration of the first injection of the antibody or fragment thereof. Although NRS measures onset of effect more quickly than other disease severity measures, post-administration NRS scores can be determined on a similar time scale to one or more other disease severity measures, which is clinically advantageous. The antibody or fragment thereof may be administered 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 NRS score determined after 253 days of administration. Post-administration NRS can be determined at 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 Score. Post-administration NRS scores were determined at the end of the induction period.

[0330] The NRS score after casting can be from 0 to 7. Relative to the baseline NRS score, the NRS score after administration can be 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 point. Relative to the baseline NRS score, the NRS score can be reduced by at least 3 points or at least 4 points after administration. Relative to the baseline NRS score, the NRS score after administration 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%. Without additional administration of anti-OX40L antibody or antigen-binding fragment thereof, the NRS score can be maintained after administration: (a) At least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after the last injection; or (b) At least approximately 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169 or 253 days.

[0331] Some embodiments may further include assessing atopic dermatitis by determining one or more further post-administration NRS scores. The antibody or fragment thereof may be administered 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 The NRS score is determined 253 days after the one or more further administrations. The one or more further can be determined 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. NRS score after casting. The one or more further post-administration NRS scores may be determined at the end of the induction period.

[0332] The NRS score may be from 0 to 7 after the one or more further administrations. Relative to the baseline NRS score, the one or more further administrations may reduce the NRS score 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. The NRS score after one or more further administrations may be: (a) A reduction of at least 3 points relative to the baseline NRS score, wherein the baseline NRS score is selected from the group consisting of at least 3 points, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, 6 to 9 points and 7 to 8 points; or (b) A reduction of at least 4 points relative to said baseline NRS score, wherein said baseline NRS score is selected from the group consisting of at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, 6 to 9 points, and 7 to 8 points.

[0333] Determination of the post-administration NRS score and / or the one or more further post-administration NRS scores may include the individual providing a value on a scale of 0 to 10 for the most severe itching within the past 24 hours. Rating, where "0" is no itching and "10" is the worst itching imaginable.

[0334] The post-administration NRS and / or further post-administration NRS can be determined at least about 113 days after administration of the first injection of the antibody or fragment thereof, and wherein the post-administration NRS and / or further post-administration NRS Can be: (a) A reduction of at least 3 points relative to the baseline NRS score, wherein the baseline NRS score is selected from the group consisting of at least 3 points, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, 6 to 9 points and 7 to 8 points; or (b) A reduction of at least 4 points relative to said baseline NRS score, wherein said baseline NRS score is selected from the group consisting of at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, 6 to 9 points, and 7 to 8 points.

[0335] The post-administration NRS and / or further post-administration NRS can be determined at least about 169 days after administration of the first injection of the antibody or fragment thereof, and wherein the post-administration NRS and / or further post-administration NRS Can be: (a) A reduction of at least 3 points relative to the baseline NRS score, wherein the baseline NRS score is selected from the group consisting of at least 3 points, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, 6 to 9 points and 7 to 8 points; or (b) A reduction of at least 4 points relative to said baseline NRS score, wherein said baseline NRS score is selected from the group consisting of at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, 6 to 9 points, and 7 to 8 points.

[0336] The post-administration NRS and / or further post-administration NRS can be determined at least about 253 days after administration of the first injection of the antibody or fragment thereof, and wherein the post-administration NRS and / or further post-administration NRS Can be: (a) A reduction of at least 3 points relative to the baseline NRS score, wherein the baseline NRS score is selected from the group consisting of at least 3 points, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, 6 to 9 points and 7 to 8 points; or (b) A reduction of at least 4 points relative to said baseline NRS score, wherein said baseline NRS score is selected from the group consisting of at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, 6 to 9 points, and 7 to 8 points.

[0337] The atopic dermatitis can be treated as demonstrated by a decrease in the NRS score of at least 4 points after the third injection as a therapeutic dose. The reduction in NRS score may persist 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 therapeutic dose.

[0338] According to certain embodiments, administering 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 administration of an anti-OX40L antibody or antigen-binding fragment thereof (e.g., subcutaneous administration of a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by administration of 250 mg of anti-OX40L antibody or antigen-binding fragment thereof). Relative NRS scores on days 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, 253 or later after OX40L antibody or its antigen-binding fragment) A reduction from baseline of at least approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or more. Relative to the baseline NRS score, the NRS score after administration 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%. A decrease 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, administering an anti-OX40L antibody, or antigen-binding fragment thereof, to an individual results in a NRS score relative to baseline, optionally at approximately day 113 after the first administration of the anti-OX40L antibody, or antigen-binding fragment thereof. Reduce by at least 15%, at least 20%, or at least 30%.

[0339] According to certain embodiments, administering to a patient a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof, results in an increase in the amount of the anti-OX40L antibody, or antigen-binding fragment thereof (e.g., subcutaneously administered about 62.5 mg, 125 mg, 250 mg or 500 mg loading dose followed by administration of 250 mg of anti-OX40L antibody or antigen-binding fragment thereof) on days 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85 , 113, 169, 253 days or later, the reduction in NRS score is equal to or greater than the minimal clinically important difference (MCID). Patient Oriented (PO) Eczema Metric (POEM)

[0340] 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 Dec;140(12) Described in :1513-9. Methods for determining POEM scores are known and may be described below and / or in the Examples (as applicable).

[0341] Seven events (dryness, itching, flaking, cracking, sleep deprivation, bleeding, and extravasation) were assessed using a five-point scale based on their frequency within the past week. Each of the seven questions is equally weighted and scored from 0 to 4. Possible scores for each question are: 0 (zero days), 1 (1 to 2 days), 2 (3 to 4 days), 3 (5 to 6 days), and 4 (every day). The highest total score is 28. If a question is not answered, its score is 0, and the scores are totaled and expressed in the usual way, up to a maximum of 28. If two or more questions are unanswered, the questionnaire will not be scored. If two or more response options are selected, the response option with the highest score should be recorded.

[0342] High scores indicate poor quality of life. 0 to 2 indicates healed or nearly healed skin, 3 to 7 indicates mild eczema, 8 to 16 indicates moderate eczema, 17 to 24 indicates severe eczema, and 25 to 28 indicates very severe eczema. It is believed that the overall average MCID of POEM is 3.4 points. Baseline Score - POEM

[0343] Atopic dermatitis can be assessed by determining a baseline POEM (Patient-Orientated Eczema Measure) score. Determination of the baseline POEM score may include the individual providing a rating of how often their eczema caused the following events during the most recent week: i. Itchy skin, ii. Sleep disorders, iii. Skin bleeding, iv. Extravasation or exudation of clear fluid from the skin, v. cracked skin, vi. Skin flaking, and vii. Skin feels dry or rough.

[0344] Frequency ratings can be selected from: i. "zero day", ii. “1-2 days”, iii. “3-4 days”, iv. “5-6 days”, and v. "Every day".

[0345] The method may further include: Assign 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, and "1-2 days" is assigned a score of 2 The assigned score is 1, and the "zero day" assigned score is 0, and The frequency rating scores are added together to calculate the POEM score.

[0346] A baseline POEM score of 0 to 2 can indicate resolved or nearly resolved eczema; a baseline POEM score of 3 to 7 can indicate mild eczema; a baseline POEM score of 8 to 16 can indicate moderate eczema; and a baseline POEM score of 8 to 16 can indicate moderate eczema. A score of 17 to 24 can indicate severe eczema, and a POEM baseline score of 25 to 28 can indicate very severe eczema.

[0347] The baseline POEM score can be any score indicative of moderate to severe or very severe AD. The POEM baseline score can be selected from: 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 to 28, 8 to 24, 8 to 16, 17 to 24 and 25 to 28.

[0348] 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.

[0349] Some embodiments may further include determining a baseline POEM score. Clinical Results - POEM

[0350] Some embodiments may 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. Post-administration POEM scores are expected to be obtained at least 7 days after the first injection of the antibody or its fragments, or at least 15 days after the first injection of the antibody or its fragments. Changes in POEM scores can be reliably observed due to the effects of the antibody or its fragments, but can be obtained from Admit any clinically appropriate delay to assessment. The antibody or fragment thereof may be administered at least about 7 days, 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 after the first injection of the antibody or fragment thereof and / or at least approximately 253 days post-dose to determine POEM 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 POEM score after casting. Post-administration POEM scores can be determined at the end of the induction period.

[0351] Post-administration POEM score can be selected from 0 to 2; 3 to 7; 8 to 16; 17 to 24 and 25 to 28. Post-administration POEM scores can indicate that AD is no longer very severe AD. Post-administration POEM scores can indicate that AD is no longer severe AD. Post-administration POEM scores can indicate that AD is no longer moderate AD. Post-administration POEM scores can indicate mild AD. The POEM score after administration can indicate that AD is almost cured. Relative to the baseline POEM score, the POEM score after administration can be 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 point. Relative to the baseline POEM score, the POEM score can be reduced by at least 2 points or at least 3 points after administration. Relative to the baseline POEM score, the POEM score after administration 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%. Without additional administration of anti-OX40L antibodies or antigen-binding fragments thereof, POEM scores can be maintained after administration: (a) At least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after the last injection; or (b) At least approximately 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169 or 253 days.

[0352] Some embodiments may further include assessing atopic dermatitis by determining one or more further post-administration POEM scores. The antibody or fragment thereof may be administered 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 The POEM score is determined 253 days after the one or more further administrations. The one or more further can be determined 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. POEM score after casting. The one or more further post-administration POEM scores may be determined at the end of the induction period.

[0353] The one or more further post-administration POEM scores may be selected from 0 to 2; 3 to 7; 8 to 16; 17 to 24 and 25 to 28. The one or more further post-dose POEM scores may indicate that AD is no longer very severe AD. The one or more further post-dose POEM scores may indicate that AD is no longer severe AD. The one or more further post-dose POEM scores may indicate that AD is no longer moderate AD. The one or more further post-administration POEM scores may indicate that the AD is mild AD. The one or more further post-administration POEM scores may indicate that AD is nearly resolved. Relative to the baseline POEM score, the one or more further administrations may reduce the POEM score 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 or 10 points. The POEM score may be reduced by at least 2 points or at least 3 points after the one or more further administrations relative to the baseline POEM score.

[0354] Determination of the post-administration POEM score and / or the one or more further post-administration POEM scores may include the individual providing a frequency rating of how often their eczema caused the following events in the past week: i. Itchy skin, ii. Sleep disorders, iii. Skin bleeding, iv. Extravasation or exudation of clear fluid from the skin, v. cracked skin, vi. Skin flaking, and vii. Skin feels dry or rough.

[0355] Frequency ratings can be selected from: i. "zero day", ii. “1-2 days”, iii. “3-4 days”, iv. “5-6 days”, and v. "Every day".

[0356] The method may further include: Assign 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, and "1-2 days" is assigned a score of 2 The assigned score is 1, and the "zero day" assigned score is 0, and The frequency rating scores are added together to calculate the POEM score.

[0357] Post-administration POEM and / or further post-administration POEM can be determined at least about 113 days after administration of the first injection of the antibody or fragment thereof, and wherein relative to the baseline POEM score, the post-administration POEM POEM and / or MOEM decreases by at least 2 points or by at least 3 points after further administration.

[0358] Post-administration POEM and / or further post-administration POEM can be determined at least approximately 169 days after administration of the first injection of the antibody or fragment thereof, and wherein relative to the baseline POEM score, the post-administration POEM POEM and / or MOEM decreases by at least 2 points or by at least 3 points after further administration.

[0359] Post-administration POEM and / or further post-administration POEM can be determined at least approximately 253 days after administration of the first injection of the antibody or fragment thereof, and wherein relative to the baseline POEM score, the post-administration POEM POEM and / or MOEM decreases by at least 2 points or by at least 3 points after further administration.

[0360] The atopic dermatitis can be treated as demonstrated by a decrease in the POEM score of at least 2 points after the third injection as a therapeutic dose. The reduction in POEM score may persist 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 therapeutic dose.

[0361] According to certain embodiments, administering 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 administration of an anti-OX40L antibody or antigen-binding fragment thereof (e.g., subcutaneous administration of a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by administration of 250 mg of anti-OX40L antibody or antigen-binding fragment thereof). POEM scores on days 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, 253 or later after OX40L antibody or antigen-binding fragment thereof) A reduction from baseline of at least approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or more. Relative to the baseline POEM score, the POEM score after administration 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%. A reduction in post-administration POEM score relative to 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, administering an anti-OX40L antibody, or antigen-binding fragment thereof, to an individual results in a POEM score relative to baseline, optionally at approximately day 113 after the first administration of the anti-OX40L antibody, or antigen-binding fragment thereof. Reduce by at least 15%, at least 20%, or at least 30%.

[0362] According to certain embodiments, administering to a patient a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof, results in an increase in the amount of the anti-OX40L antibody, or antigen-binding fragment thereof (e.g., subcutaneously administered about 62.5 mg, 125 mg, 250 mg or 500 mg loading dose followed by administration of 250 mg of anti-OX40L antibody or antigen-binding fragment thereof) on days 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85 , 113, 169, 253 days or later, a reduction in POEM score equal to or greater than the minimal clinically important difference (MCID). Affected body surface area (BSA)

[0363] BSA can also be used to describe the scope of AD. Methods for determining BSA scores are known and may be described below and / or in the Examples (as applicable). BSA typically uses the "Rule of Nine", dividing body area into 9% (or a fraction thereof) - see Table 2 below. Alternative calculations can be made for children and adults associated with different body proportions as indicated in Table 2. Calculate the extent of each individual area, and then total.

[0364] Table 2 - BSA 9-point scale [body parts] [estimate] [BSA] [aldult] [Children] whole left arm 9% 9% whole right arm 9% 9% whole head 9% 18% whole chest 9% 9% entire abdomen 9% 9% entire back 18% 18% Whole left leg 18% 13.5% Whole right leg 18% 13.5% groin 1% 1%

[0365] BSA or its variants are part of EASI, SCORAD and POSCORAD. BSA itself cannot be considered indicative of disease severity because patients may have coverage for many low-grade diseases or limited coverage for more clinically problematic high-grade diseases. Nonetheless, after treatment, a decrease in BSA compared to baseline levels may indicate clinical improvement when there is no increase in AD severity (optionally measured by surrogate methods described herein) in areas that still exhibit AD involvement. . Baseline Score - BSA

[0366] Atopic dermatitis can be assessed by determining a baseline BSA (Body Surface Area) score. Determination of baseline BSA score can include: (a) Assign a BSA value to each of the following body parts: (a) The entire left arm, (b) the entire right arm, (c) the entire head, (d) the entire chest, (e) Entire abdomen, (f) the entire back, (g) The entire left leg, (h) the entire right leg, and (i) groin, (b) Estimate the proportion of each body area affected by atopic dermatitis, (c) multiply the proportion of each body part affected by dermatitis by the BSA value for said body part to provide the affected BSA value for each body part, and (d) Add the affected BSA values ​​for the body parts together to provide a BSA score.

[0367] The baseline BSA score can be any score associated with moderate to severe AD cases. BSA by itself may not measure the severity of AD. There may be high coverage at low severity levels, meaning that the overall AD severity may not be very high. However, BSA may contribute to the severity of AD, for example, by assigning the percentage of body surface area that is part of determining the EASI score. Therefore, BSA can be the relevant descriptor of AD. 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%.

[0368] The first injection of the anti-OX40L antibody or fragment thereof can be administered on the same day that the baseline BSA score is determined.

[0369] Some embodiments may further include determining a baseline BSA score. Clinical Results - BSA

[0370] Some embodiments may 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. Post-administration BSA scores are expected to be obtained at least 7 days or at least 15 days after the first injection of the antibody or its fragment, which is the earliest that changes in the BSA score can be reliably observed due to the effects of the antibody or its fragment, but can be obtained using Admit any clinically appropriate delay to assessment. The antibody or fragment thereof may be administered at least about 7 days, 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 after the first injection of the antibody or fragment thereof and / or at least approximately 253 days post-dose to determine BSA 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 BSA score after casting. Post-administration BSA scores can be determined at the end of the induction period.

[0371] Post-administration BSA score can be selected from: 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%. Post-administration BSA scores can indicate that AD is no longer severe AD. Post-administration BSA scores can indicate that AD is no longer moderate AD. Post-administration BSA scores can indicate mild AD. Post-administration BSA scores can indicate that AD is nearly cured. Relative to the baseline BSA score, the BSA score after administration can be reduced by at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, 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 60% points, at least 70% points, at least 80% points or at least 90% points. Relative to the baseline BSA score, the BSA score can be reduced by at least 5% after administration. The post-administration BSA score can be reduced by at least 10% relative to the baseline BSA score, where the baseline BSA score is at least 10%. Relative to the baseline BSA score, the post-administration BSA score 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%. Without additional administration of anti-OX40L antibodies or antigen-binding fragments thereof, BSA scores can be maintained following administration: (a) At least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after the last injection; or (b) At least approximately 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169 or 253 days.

[0372] Some embodiments may further include assessing atopic dermatitis by determining one or more further post-administration BSA scores. The antibody or fragment thereof may be administered 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 The BSA score is determined 253 days after the one or more further administrations. The one or more further can be determined 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. BSA score after casting. The one or more further post-administration BSA scores may be determined at the end of the induction period.

[0373] The one or more further post-administration BSA scores may be selected from: 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-dose BSA scores may indicate that AD is no longer severe AD. The one or more further post-dose BSA scores may indicate that AD is no longer moderate AD. The one or more further post-administration BSA scores may indicate that the AD is mild AD. The one or more further post-dose BSA scores may indicate that AD is nearly resolved. The one or more further post-administration BSA scores may decrease the BSA score by at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, or at least 7% relative to the baseline BSA score. points, at least 8% 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 60% points, at least 70% points, at least 80% points or at least 90% points. The one or more further administrations may reduce the BSA score by at least 10% relative to the baseline BSA score.

[0374] Determination of the post-dose BSA score and / or the one or more further post-dose BSA scores may include: (a) Assign a BSA value to each of the following body parts: (a) The entire left arm, (b) the entire right arm, (c) the entire head, (d) the entire chest, (e) Entire abdomen, (f) the entire back, (g) The entire left leg, (h) the entire right leg, and (i) groin, (b) Estimate the proportion of each body area affected by atopic dermatitis, (c) multiply the proportion of each body part affected by dermatitis by the BSA value for said body part to provide the affected BSA value for each body part, and (d) Add the affected BSA values ​​for the body parts together to provide a BSA score.

[0375] The post-administration BSA and / or further post-administration BSA may be determined at least approximately 113 days after administration of the first injection of the antibody or fragment thereof, and the post-administration BSA and / or further post-administration BSA may be determined relative to the baseline BSA score. or the BSA may be reduced by at least 10% following further administration. The post-administration BSA and / or further post-administration BSA may be determined at least approximately 169 days after administration of the first injection of the antibody or fragment thereof, and the post-administration BSA and / or further post-administration BSA may be determined relative to the baseline BSA score. or the BSA may be reduced by at least 10% following further administration. 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, and wherein the post-administration BSA and / or the post-administration BSA are determined relative to the baseline BSA score. / or the BSA can be reduced by at least 10% after said further administration.

[0376] The atopic dermatitis can be treated as demonstrated by a decrease in BSA score of at least 10% after the third injection as a therapeutic dose. The reduction in BSA score may persist 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 therapeutic dose.

[0377] According to certain embodiments, administering 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 administration of an anti-OX40L antibody or antigen-binding fragment thereof (e.g., subcutaneous administration of a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by administration of 250 mg of anti-OX40L antibody or antigen-binding fragment thereof). Relative BSA scores on days 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, 253 or later after OX40L antibody or its antigen-binding fragment) A reduction from baseline of at least approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or more. Relative to the baseline BSA score, the post-administration BSA score 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%. A decrease in post-administration BSA score relative to baseline BSA score can be derived from any baseline BSA score and any post-administration BSA score disclosed herein at any time point or between any time points. In certain exemplary embodiments, administering an anti-OX40L antibody, or antigen-binding fragment thereof, to an individual results in a BSA score relative to baseline, optionally at approximately day 113 after the first administration of the anti-OX40L antibody, or antigen-binding fragment thereof. Reduce by at least 20%, at least 30%, or at least 35%.

[0378] According to certain embodiments, administering to a patient a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof, results in an increase in the amount of the anti-OX40L antibody, or antigen-binding fragment thereof (e.g., subcutaneously administered about 62.5 mg, 125 mg, 250 mg or 500 mg loading dose followed by administration of 250 mg of anti-OX40L antibody or antigen-binding fragment thereof) on days 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85 , 113, 169, 253 days or later, a reduction in BSA score equal to or greater than the minimal clinically important difference (MCID). Atopic Dermatitis Scoring (SCORAD) Index

[0379] 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 symptoms, and symptoms.

[0380] Methods for determining the SCORAD index are known and may be described below and / or in the Examples (as applicable).

[0381] The extent of AD was assessed as a percentage of each defined body area and reported as the sum of all areas. The maximum score is 100%. A four-point scale (ie, none = 0, mild = 1, moderate = 2, severe = 3) was used to assess the severity of six specific symptoms of AD (redness, swelling, oozing / crusting, excoriation, Skin thickening / lichenification, dryness), with a maximum possible total of 18 points. Symptoms (itching and insomnia) were recorded by the patient or caregiver on a visual analog scale, where 0 is no symptoms and 10 is the worst symptom imaginable, and the highest possible score is 20. The highest possible SCORAD score is 103; higher scores indicate a worse or more severe condition.

[0382] A SCORAD difference of 8.7 points was estimated to be a minimal clinically important difference (MCID) in 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). Baseline Score - SCORAD Index

[0383] Atopic dermatitis can be assessed by determining a baseline SCORAD (SCORing Atopic Dermatitis) index score. Determination of the baseline SCORAD index can include: (a) Estimate the extent of said atopic dermatitis as a percentage of the affected body area to provide an extent score "A", (b) Evaluate the intensity of the following clinical signs to provide an intensity score of "B": (i) Erythema, (ii) Edema / Papules, (iii) oozing / crusting, (iv) Exfoliation of epidermis, (v) Lichenification, and (vi) drying; (c) Evaluate the severity of the following symptoms to provide a severity score of "C": (i) pruritus, and (ii) lack of sleep; as well as (d) Calculate a baseline SCORAD index using the range score "A", the intensity score "B" and the severity score "C".

[0384] Determination of the baseline SCORAD index may further include assigning to each clinical sign a sign intensity level selected from a group consisting of: i. "does not exist" ii. "mild" iii. "Moderate", and iv. "Severe".

[0385] Determination of the baseline SCORAD index can further include: A sign intensity score is assigned to each sign intensity level, where "severe" is assigned a score of 3, "moderate" is assigned a score of 2, "mild" is assigned a score of 1, and "absent" is assigned a score of 0, and The sign intensity scores are added together to calculate the intensity score "B".

[0386] Determination of the baseline SCORAD index may include the individual or caregiver providing a numerical rating on a scale of 0 to 10 of the severity of symptoms of pruritus and sleep deprivation during the past 3 days and / or nights, where "0" is Asymptomatic and "10" is the worst symptom imaginable. Determination of the baseline SCORAD index may further include adding together numerical ratings of symptom severity for pruritus and sleep loss to calculate a severity score "C".

[0387] Determination of the baseline SCORAD index may include calculating the baseline SCORAD index using the following formula: SCORAD index = A / 5 + 7B / 2 + C.

[0388] The baseline SCORAD index can be any index indicative of moderate to severe AD. A baseline SCORAD index of 0 to 24 can indicate mild disease; a baseline SCORAD index of 25 to 50 can indicate moderate disease; and a baseline SCORAD index of 51 to 103 can indicate severe disease. The baseline SCORAD index can 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.

[0389] 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.

[0390] Some embodiments may further include determining a baseline SCORAD index. Based on clinical results - SCORAD

[0391] Some embodiments may 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. Post-administration SCORAD index is expected to be obtained at least 7 days or at least 15 days after the first injection of the antibody or its fragment. Changes in the SCORAD index due to the effects of the antibody or its fragment can be reliably observed, but it can be used from Admit any clinically appropriate delay to assessment. The antibody or fragment thereof may be administered at least about 7 days, 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 after the first injection of the antibody or fragment thereof and / or at least approximately 253 days post-dose to determine the 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 Post-investment SCORAD index. The post-administration SCORAD index can be determined at the end of the induction period.

[0392] Post-administration SCORAD index can be selected from: 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. Relative to the baseline SCORAD index, the SCORAD index after administration can be 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 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 can be reduced by at least 20 points after administration. The SCORAD index after administration can indicate that AD is no longer very severe AD. The SCORAD index after administration can indicate that AD is no longer severe AD. The SCORAD index after administration can indicate that AD is no longer moderate AD. The SCORAD index after administration can indicate that AD is mild AD. The SCORAD index after administration can show that AD is almost cured. Relative to the baseline SCORAD index, the SCORAD index after administration 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%. Without additional administration of anti-OX40L antibodies or antigen-binding fragments thereof, the SCORAD index can be maintained after administration: (a) At least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after the last injection; or (b) At least approximately 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169 or 253 days.

[0393] Some embodiments may further include assessing atopic dermatitis by determining one or more further post-administration SCORAD indices. The antibody or fragment thereof may be administered 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 The SCORAD index is determined 253 days after the one or more further administrations. The one or more further can be determined 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. Post-investment SCORAD index. The one or more further post-administration SCORAD indices can be determined at the end of the induction period.

[0394] The one or more further post-administration SCORAD indices may be selected from: 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. Relative to the baseline SCORAD index, the one or more further administrations can reduce the SCORAD index 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 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. The one or more further administrations may reduce the SCORAD index by at least 20 points relative to the baseline SCORAD index. The one or more further post-administration SCORAD indices may indicate that AD is no longer very severe AD. The one or more further post-administration SCORAD indices may indicate that AD is no longer severe AD. The one or more further post-administration SCORAD indices may indicate that AD is no longer moderate AD. The one or more further post-administration SCORAD indices may indicate that the AD is mild AD. The SCORAD index after one or more further administrations may indicate that AD is nearly resolved.

[0395] Determination of the post-administration SCORAD index and / or the one or more further post-administration SCORAD indexes may include: (a) Estimate the extent of said atopic dermatitis as a percentage of the affected body area to provide an extent score "A", (b) Evaluate the intensity of the following clinical signs to provide an intensity score of "B": (i) Erythema, (ii) Edema / Papules, (iii) oozing / crusting, (iv) Exfoliation of epidermis, (v) Lichenification, and (vi) drying; (c) Evaluate the severity of the following symptoms to provide a severity score of "C": (i) pruritus, and (ii) lack of sleep; as well as (d) Calculate a SCORAD index using the range score "A", the intensity score "B" and the severity score "C".

[0396] Determination of the post-administration SCORAD index and / or the one or more further post-administration SCORAD indices may further comprise assigning to each clinical sign a sign intensity level selected from the group consisting of: i. "does not exist" ii. "mild" iii. "Moderate", and iv. "Severe".

[0397] Determination of the post-administration SCORAD index and / or the one or more further post-administration SCORAD indexes may further include: A sign intensity score is assigned to each sign intensity level, where "severe" is assigned a score of 3, "moderate" is assigned a score of 2, "mild" is assigned a score of 1, and "absent" is assigned a score of 0, and The sign intensity scores are added together to calculate the intensity score "B".

[0398] Determination of the post-administration SCORAD index and / or the one or more further post-administration SCORAD indexes may include the individual or caregiver providing symptom severity of pruritus and sleep deprivation over the past 3 days and / or nights. A numerical rating on a scale of 0 to 10, where "0" is no symptoms and "10" is the worst symptoms imaginable. The method may further comprise adding together the numerical ratings of symptom severity of pruritus and sleep loss to calculate a severity score "C".

[0399] Determination of the post-administration SCORAD index and / or the one or more further post-administration SCORAD indexes includes calculating the SCORAD index using the following formula: SCORAD index = A / 5 + 7B / 2 + C.

[0400] Post-administration SCORAD and / or further post-administration SCORAD can be determined at least about 113 days after administration of the first injection of the antibody or fragment thereof, and wherein the post-administration SCORAD and / or the post-administration SCORAD are determined relative to a baseline SCORAD index. / or the SCORAD may be reduced by at least 20 points upon further administration. Post-administration SCORAD and / or further post-administration SCORAD can be determined at least about 169 days after administration of the first injection of the antibody or fragment thereof, and wherein the post-administration SCORAD and / or the post-administration SCORAD are determined relative to a baseline SCORAD index. / or the SCORAD may be reduced by at least 20 points upon further administration. Post-administration SCORAD and / or further post-administration SCORAD can be determined at least about 253 days after administration of the first injection of the antibody or fragment thereof, and wherein the post-administration SCORAD and / or the post-administration SCORAD are determined relative to a baseline SCORAD index. / or the SCORAD may be reduced by at least 20 points upon further administration. The atopic dermatitis can be treated as demonstrated by a decrease in the SCORAD index of at least 20 points after the third injection as a therapeutic dose. The reduction in SCORAD index may persist 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 therapeutic dose.

[0401] According to certain embodiments, administering 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. Some embodiments include methods of treatment that result in administration of an anti-OX40L antibody or antigen-binding fragment thereof (e.g., subcutaneous administration of a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg, followed by administration of 250 mg of anti-OX40L antibody or antigen-binding fragment thereof). SCORAD index on days 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, 253 or later after OX40L antibody or antigen-binding fragment thereof) A reduction from baseline of at least approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or more. Relative to the baseline SCORAD index, the SCORAD index after administration 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%. A decrease in post-administration SCORAD index relative to baseline SCORAD index can be derived from any baseline SCORAD index and any post-administration SCORAD index disclosed herein at any time point or between any time points. In certain exemplary embodiments, administering an anti-OX40L antibody, or antigen-binding fragment thereof, to an individual results in a SCORAD index relative to baseline, optionally at approximately day 113 after the first administration of the anti-OX40L antibody, or antigen-binding fragment thereof. Reduce by at least 20%, at least 30%, or at least 35%.

[0402] According to certain embodiments, administering to a patient a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof, results in an increase in the amount of the anti-OX40L antibody, or antigen-binding fragment thereof (e.g., subcutaneously administered about 62.5 mg, 125 mg, 250 mg or 500 mg loading dose followed by administration of 250 mg of anti-OX40L antibody or antigen-binding fragment thereof) on days 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85 , 113, 169, 253 days or later, the reduction in SCORAD index was equal to or greater than the minimal clinically important difference (MCID). Patient-Oriented Atopic Dermatitis Score (POSCORAD)

[0403] POSCORAD is derived from SCORAD and can be easily used by patients without any special experience. POSCORAD was created for patients to help patients or caregivers track the course of disease and the effectiveness of treatment. POSCORAD has been validated in multiple studies, including Vourc'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.

[0404] POSCORAD is available as software for mobile devices and computers. Regular (weekly) use of POSCORAD software allows patients to create curves that represent fluctuations in their disease between consultations.

[0405] Methods for determining the PO-SCORAD index are known and may be described below and / or in the Examples (where applicable). Baseline Score - PO-SCORAD

[0406] Atopic dermatitis can be assessed by determining a baseline PO-SCORAD (Patient Oriented Score of Atopic Dermatitis) index score. Determination of the baseline PO-SCORAD index can include: (a) Estimate the extent of said atopic dermatitis as a percentage of the affected body area to provide an extent score "A", (b) Evaluate the intensity of the following clinical signs to provide an intensity score of "B": (i) redness, (ii) swelling, (iii) Exudation / scarring, (iv) scratches, (v) skin thickening, and (vi) drying; (c) Evaluate the severity of the following symptoms to provide a severity score of "C": (i) itching, and (ii) Difficulty sleeping as well as (d) Calculate a baseline PO-SCORAD index using the range score "A", the intensity score "B" and the severity score "C".

[0407] Input for steps (a), (b) and (c) may be provided by the individual or a caregiver. Inputs from steps (a), (b), and (c) can be entered into the computer program through a graphical user interface by the individual or caregiver. The extent of atopic dermatitis can be estimated by a computer program as a percentage of the affected body area to provide an extent score of "A".

[0408] Determination of the baseline PO-SCORAD index may include the individual or caregiver providing a sign intensity score for each clinical sign, selected from: i. "0" ii. "1" iii. “2”, and iv. "3"; where "0" is the lowest intensity, and "3" is the highest intensity; and wherein said sign intensity scores are added together to calculate the intensity score "B". A computer program can be used to add the physical strength scores together to calculate a strength score "B".

[0409] Determination of the baseline PO-SCORAD index may include the individual or caregiver providing a numerical rating on a 0 to 10 scale of symptom severity of itching and difficulty sleeping during the past 2 days and / or nights, where "0" is none Symptoms and "10" are the worst symptoms imaginable. The method may further comprise adding together the numerical ratings of symptom severity of itching and sleep difficulty to calculate a severity score "C". Numerical symptom severity ratings of itching and sleep difficulty can be added together by a computer program to calculate a severity score of "C".

[0410] Determination of the baseline PO-SCORAD index may include calculating the baseline PO-SCORAD index using the following formula: PO-SCORAD index = A / 5 + 7B / 2 + C.

[0411] The baseline PO-SCORAD index can be any index indicative of moderate to severe AD. The baseline PO-SCORAD index can 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.

[0412] 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.

[0413] Some embodiments may further include determining a baseline PO-SCORAD index. Based on clinical results - PO-SCORAD

[0414] Some embodiments may 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. The post-administration PO-SCORAD index is expected to be obtained at least 7 days after the first injection of the antibody or its fragment, or at least 15 days after the first injection of the antibody or its fragment, which is the earliest when changes in the PO-SCORAD score can be reliably observed due to the effects of the antibody or its fragment. However, any clinically appropriate delay from administration to assessment may be used. The antibody or fragment thereof may be administered at least about 7 days, 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 after the first injection of the antibody or fragment thereof and / or at least approximately 253 days post-dose to determine the 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 Post-administration PO-SCORAD index. Post-administration PO-SCORAD index can be determined at the end of the induction period.

[0415] Post-administration PO-SCORAD index can be selected from: 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. Relative to the baseline PO-SCORAD index, the PO-SCORAD index after administration can be 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 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 can be reduced by at least 20 points after administration. The PO-SCORAD index after administration can indicate that AD is no longer very severe AD. The PO-SCORAD index after administration can indicate that AD is no longer severe AD. The PO-SCORAD index after administration can indicate that AD is no longer moderate AD. The PO-SCORAD index after administration can indicate that AD is mild AD. The PO-SCORAD index after administration can indicate that AD is almost cured. Relative to the baseline PO-SCORAD index, the PO-SCORAD index after administration 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%. Without additional administration of anti-OX40L antibodies or antigen-binding fragments thereof, the PO-SCORAD index can be maintained after administration: (a) At least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after the last injection; or (b) At least approximately 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169 or 253 days.

[0416] Some embodiments may further include assessing atopic dermatitis by determining one or more further post-administration PO-SCORAD indices. The antibody or fragment thereof may be administered 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 The PO-SCORAD index was determined 253 days after the one or more further administrations. The one or more further can be determined 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. Post-administration PO-SCORAD index. The one or more further post-administration PO-SCORAD indices can be determined at the end of the induction period.

[0417] The one or more further post-administration PO-SCORAD indices are selected from: 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. Relative to the baseline PO-SCORAD index, the one or more further administrations may reduce the PO-SCORAD index 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 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. One or more doses that reduce the PO-SCORAD index by at least 20 points compared to the baseline PO-SCORAD index.

[0418] Determination of the post-administration PO-SCORAD index and / or the one or more further post-administration PO-SCORAD indexes may include: (a) Estimate the extent of said atopic dermatitis as a percentage of the affected body area to provide an extent score "A", (b) Evaluate the intensity of the following clinical signs to provide an intensity score of "B": (i) redness, (ii) swelling, (iii) Exudation / scarring, (iv) scratches, (v) skin thickening, and (vi) drying; (c) Evaluate the severity of the following symptoms to provide a severity score of "C": (i) itching, and (ii) difficulty sleeping; as well as (d) Calculate a PO-SCORAD index using the range score "A", the intensity score "B" and the severity score "C".

[0419] Input for steps (a), (b) and (c) may be provided by the individual or a caregiver. Inputs from steps (a), (b), and (c) can be entered into the computer program through a graphical user interface by the individual or caregiver. The extent of atopic dermatitis can be estimated by a computer program as a percentage of the affected body area to provide an extent score of "A".

[0420] Determination of the post-administration PO-SCORAD index may include the individual or caregiver providing a sign intensity score for each clinical sign, selected from: i. "0" ii. "1" iii. “2”, and iv. "3"; where "0" is the lowest intensity, and "3" is the highest intensity; and wherein said sign intensity scores are added together to calculate the intensity score "B". A computer program can be used to add the physical strength scores together to calculate a strength score "B".

[0421] Determination of the post-administration PO-SCORAD index may include the individual or caregiver providing a numerical rating on a scale of 0 to 10, with "0", of symptom severity of itching and difficulty sleeping during the past 2 days and / or nights. are asymptomatic and "10" is the most severe symptom imaginable. The method may further comprise adding together the numerical ratings of symptom severity of itching and sleep difficulty to calculate a severity score "C". Numerical symptom severity ratings of itching and sleep difficulty can be added together by a computer program to calculate a severity score of "C".

[0422] Determination of the post-administration PO-SCORAD index and / or the one or more further post-administration PO-SCORAD indexes may include calculating the PO-SCORAD index using the following equation: PO-SCORAD index = A / 5 + 7B / 2+C.

[0423] Post-administration PO-SCORAD and / or further post-administration PO-SCORAD can be determined at least about 113 days after administration of the first injection of the antibody or fragment thereof, and wherein relative to the baseline PO-SCORAD index, the post-administration PO-SCORAD The PO-SCORAD after said administration and / or the PO-SCORAD after said further administration may be reduced by at least 20 points. 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, and wherein relative to the baseline PO-SCORAD index, the post-administration PO-SCORAD The PO-SCORAD after said administration and / or the PO-SCORAD after said further administration may be reduced by at least 20 points. 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, and wherein the PO-SCORAD index relative to the baseline The PO-SCORAD after said administration and / or the PO-SCORAD after said further administration may be reduced by at least 20 points. The atopic dermatitis can be treated as demonstrated by a decrease in the PO-SCORAD index of at least 20 points after the third injection as a therapeutic dose. The reduction in PO-SCORAD index may persist 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 therapeutic dose. According to certain embodiments, administering a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof to a patient results in a decrease in PO-SCORAD index. In some embodiments, the method of treatment results in administering a loading dose of about 62.5 mg, 125 mg, 250 mg, or 500 mg subcutaneously followed by administration of an anti-OX40L antibody, or antigen-binding fragment thereof, followed by administration of 250 mg of anti-OX40L antibody or antigen-binding fragment thereof. PO-SCORAD on day 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, 253 or later after OX40L antibody or antigen-binding fragment thereof Index decrease from baseline by at least approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more many. Relative to the baseline PO-SCORAD index, the PO-SCORAD index after administration 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%. A decrease in post-administration PO-SCORAD index relative to baseline PO-SCORAD index can be derived from any baseline PO-SCORAD index disclosed herein at any time point or between any time points and from any post-administration PO-SCORAD index. . In certain exemplary embodiments, administering an anti-OX40L antibody, or antigen-binding fragment thereof, to an individual results in a relative PO-SCORAD index, optionally at about day 113 after the first administration of the anti-OX40L antibody, or antigen-binding fragment thereof. A reduction of at least 15%, at least 20%, or at least 30% from baseline.

[0424] According to certain embodiments, administering to a patient a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof, results in an increase in the amount of the anti-OX40L antibody, or antigen-binding fragment thereof (e.g., subcutaneously administered about 62.5 mg, 125 mg, 250 mg or 500 mg loading dose followed by administration of 250 mg of anti-OX40L antibody or antigen-binding fragment thereof) on days 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85 , 113, 169, 253 days or later, the reduction in PO-SCORAD index was equal to or greater than the minimal clinically important difference (MCID). Dermatology Life Quality Index (DLQI)

[0425] The DLQI was designed to measure health-related quality of life in patients with skin diseases, including atopic dermatitis. The DLQI 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 DQLI scores are known and may be described below and / or in the Examples (as applicable).

[0426] The DLQI consists of 10 questions regarding patients' perceptions of the impact of skin disease on different aspects of their health-related quality of life during the past week. The DLQI is designed for use in adults, that is, patients aged 16 years and above.

[0427] Each question is rated on a four-point Likert scale: Very large = 3 Very large = 2 Rarely = 1 Not at all = 0 Not relevant = 0 Question unanswered = 0

[0428] The DLQI is calculated by adding the scores for each question, giving a maximum of 30 and a minimum of 0. The higher the score, the more the quality of life is impaired. A score above 10 indicates that the patient's life is significantly affected by their skin disease.

[0429] The meaning of score: · 0-1 = No impact at all on patient’s life · 2-5 = Little impact on patient’s life · 6-10 = Moderate impact on patient’s life · 11-20 = Very significant impact on patient’s life · 21-30 = Great impact on patient’s life

[0430] For general inflammatory skin conditions, a change in DLQI score of at least four points is considered clinically important. In an alternative embodiment, a change in DLQI score from 2.2 to 6.9 points is considered clinically important.

[0431] Baseline Score - DQLI

[0432] Atopic dermatitis can be assessed by determining a baseline DQLI (Dermatology Quality of Life Index) score. Determination of a baseline DQLI score may include answers provided by the individual to the extent to which their skin problem has affected their life over the past week: i. How itchy, sore, painful or stinging their skin is, ii. The extent to which they feel embarrassed or uncomfortable because of their skin, iii. To what extent does their skin interfere with their shopping or caring for their home or garden, iv. The extent to which their skin affects the clothes they wear, v. The extent to which their skin affects any social or leisure activities, vi. The extent to which their skin makes it difficult for them to perform any exercise, vii. Does their skin prevent them from working or studying, or if not, to what extent is their skin a problem at work or studying, viii. The extent to which their skin causes problems for any of their close friends or relatives or their partners, ix. The extent to which their skin causes any sexual difficulties, x. How problematic is the treatment of their skin.

[0433] Each answer can be chosen from: i. "very big" ii. "very big" iii. "few" iv. "Not at all" v. "irrelevant".

[0434] The method may further include: Assign an answer score to each answer, where "very much" is assigned a score of 3, "very muc...

Claims

1. Use of an anti-OX40L antibody or its antigen-binding fragment for the preparation of a medicament for treating atopic dermatitis in human individuals, wherein the anti-OX40L antibody or its antigen-binding fragment comprises: (a) the HCDR1 amino acid sequence of SEQ ID NO: 36; the HCDR2 amino acid sequence of SEQ ID NO: 38; the HCDR3 amino acid sequence of SEQ ID NO: 40; the LCDR1 amino acid sequence of SEQ ID NO: 50; the LCDR2 amino acid sequence of AAS; and the LCDR3 amino acid sequence of SEQ ID NO: 54; or (b) the HCDR1 amino acid sequence of SEQ ID NO: 42; the HCDR2 amino acid sequence of SEQ ID NO: 44; the HCDR3 amino acid sequence of SEQ ID NO: 46; the LCDR1 amino acid sequence of SEQ ID NO: 56; the LCDR2 amino acid sequence of AAS or SEQ ID NO: 58; and the LCDR3 amino acid sequence of SEQ ID NO: 60; wherein the antibody or fragment thereof is administered by subcutaneous injection.

2. The use of an anti-OX40L antibody or its antigen-binding fragment thereof for the preparation of a medicament for treating inflammatory diseases, inflammatory disorders, immune-mediated diseases, immune-mediated disorders, inflammatory skin diseases, or inflammatory skin disorders in human individuals, wherein the anti-OX40L antibody or its antigen-binding fragment comprises: (a) the HCDR1 amino acid sequence of SEQ ID NO: 36; the HCDR2 amino acid sequence of SEQ ID NO: 38; the HCDR3 amino acid sequence of SEQ ID NO: 40; the LCDR1 amino acid sequence of SEQ ID NO: 50; the LCDR2 amino acid sequence of AAS; and the LCDR3 amino acid sequence of SEQ ID NO: 54; or (b) the HCDR1 amino acid sequence of SEQ ID NO: 42; the HCDR2 amino acid sequence of SEQ ID NO: 44; the HCDR3 amino acid sequence of SEQ ID NO: 46; the LCDR1 amino acid sequence of SEQ ID NO: 56; the LCDR2 amino acid sequence of AAS or SEQ ID NO: 58; and the LCDR3 amino acid sequence of SEQ ID NO: 60; wherein the antibody or fragment thereof is administered by subcutaneous injection.

3. Use of a glass vial, drug delivery device, pre-filled syringe, microinfusion set, pen delivery device, auto-injector, or kit comprising an anti-OX40L antibody or its antigen-binding fragment for the manufacture of a medicament for the treatment of atopic dermatitis, wherein the anti-OX40L antibody or its antigen-binding fragment comprises: (a) the HCDR1 amino acid sequence of SEQ ID NO: 36; the HCDR2 amino acid sequence of SEQ ID NO: 38; the HCDR3 amino acid sequence of SEQ ID NO: 40; the LCDR1 amino acid sequence of SEQ ID NO: 50; the LCDR2 amino acid sequence of AAS; and the LCDR3 amino acid sequence of SEQ ID NO: 54; or (b) the HCDR1 amino acid sequence of SEQ ID NO: 42; the HCDR2 amino acid sequence of SEQ ID NO: 44; the HCDR3 amino acid sequence of SEQ ID NO: 46; the LCDR1 amino acid sequence of SEQ ID NO: 56; the LCDR2 amino acid sequence of AAS or SEQ ID NO: 58; and the LCDR3 amino acid sequence of SEQ ID NO: 60; wherein the antibody or fragment thereof is administered by subcutaneous injection.

4. The use as described in claims 1, 2 or 3, wherein the antibody or a fragment thereof is a disease-modifying drug.

5. The use as described in claim 4, wherein after administration of the disease-modifying drug, the individual achieves an IGA-AD score of 0 or 1 for at least six months.

6. For the purposes described in claims 1, 2 or 3, wherein the antibody or fragment thereof is administered in the following manner: (i) at least twice at an interval of at least 2 to 6 months; (ii) at least twice at an interval of at least about 3 months; (iii) once every 4 weeks during the induction period and once every 12 weeks during the maintenance period; and / or (iv) once every 4 weeks, once every 12 weeks or once every 6 months.

7. The use as described in any of claims 1, 2 or 3, wherein the antibody or fragment thereof is administered every 12 weeks.

8. The use as described in claims 1, 2 or 3, wherein (i) each dose is from 20 mg to 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 from 0.7 mg / kg to 6 mg / kg; and / or (viii) the dose is from 1.4 mg / kg to 3 mg / kg.

9. The use as described in claims 1, 2 or 3, wherein (a) a first injection is administered as a loading dose of the antibody or a fragment thereof, and subsequently (b) at least a second injection is administered as a first therapeutic dose of the antibody or a fragment thereof.

10. The use as described in claim 9, wherein (i) the loading dose is between 200 mg and 500 mg; (ii) each therapeutic dose is between 100 and 250 mg; (iii) the loading dose is 500 mg and the therapeutic dose is 250 mg; and / or (iv) each therapeutic dose contains the same mass of antibody or antibody fragment as the therapeutic dose.

11. Uses as described in claims 1, 2 or 3, including an induction period and a maintenance period.

12. The use as claimed in claim 11, wherein (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 comprises the same mass of the antibody or a fragment thereof as each maintenance injection.

13. The use as claimed in claim 11, wherein the induction period comprises administering at least five induction period injections, wherein the first induction period injection is a 500 mg loading dose of the antibody or a fragment thereof, followed by at least four subsequent induction period injections, wherein each subsequent induction period injection is a 250 mg dose of the antibody or a fragment thereof, and wherein each subsequent induction period injection is administered 4 weeks after the previous induction period injection.

14. The use as described in claim 11, wherein the maintenance period comprises administering at least three maintenance injections, wherein each maintenance injection is a 250 mg dose of the antibody or a fragment thereof, wherein the first maintenance injection is administered at least four weeks after the final induction injection, and wherein the second maintenance injection and each subsequent maintenance injection are administered at least four weeks after the previous maintenance injection.

15. The use as claimed in claim 11, wherein (i) the induction period comprises administering at least five induction period injections, wherein each induction period injection is a dose of 250 mg of the antibody or a fragment thereof, and wherein the second induction period injection and each subsequent induction period injection are administered 4 weeks after the previous induction period injection; or (ii) the induction period comprises administering at least five induction period injections, wherein each induction period injection is a dose of 125 mg of the antibody or a fragment thereof, and wherein the second induction period injection and each subsequent induction period injection are administered 4 weeks after the previous induction period injection; or (iii) the induction period comprises administering at least five induction period injections, wherein each induction period injection is a dose of 62.5 mg of the antibody or a fragment thereof, and wherein the second induction period injection and each subsequent induction period injection are administered 4 weeks after the previous induction period injection.

16. The use as claimed in claim 11, wherein the maintenance period comprises administering at least three maintenance injections, wherein each maintenance injection is a 125 mg dose of the antibody or a fragment thereof, wherein the first maintenance injection is administered at least four weeks after the final induction injection, and wherein the second maintenance injection and each subsequent maintenance injection are administered at least four weeks after the previous maintenance injection.

17. The use as claimed in claim 11, wherein the maintenance period comprises administering at least three maintenance injections, wherein each maintenance injection is a dose of 62.5 mg of the antibody or a fragment thereof, wherein the first maintenance injection is administered at least four weeks after the final induction injection, and wherein the second maintenance injection and each subsequent maintenance injection are administered at least four weeks after the previous maintenance injection.

18. The use as described in claim 11, wherein (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 are administered 12 weeks after the previous maintenance injection.

19. For the purposes described in claim 1, 2 or 3, wherein the individual is at least 18 years old and / or less than 75 years old.

20. The use as described in claim 1 or 3, wherein the atopic dermatitis is moderate to severe atopic dermatitis.

21. The use as described in claim 20, wherein (i) the individual is a candidate patient for systemic therapy; and (ii) the subject is a patient whose disease is not adequately controlled by topical prescription therapy or those therapies are inappropriate.

22. The use as claimed in claim 1 or 3, wherein the atopic dermatitis is resistant, unresponsive, or poorly responsive to treatment with topical corticosteroids and / or systemic therapy, or such treatment is inappropriate, or wherein the individual is poorly responsive, intolerant, or refractory to one or more topical corticosteroids.

23. The use as described in claim 1, 2 or 3 further includes administering a therapeutically effective amount of one or more topical corticosteroids.

24. The use as described in claim 22 or 23, wherein (i) the topical corticosteroid is selected from betamethasone dipropionate, clobetasol propionate, dexamethasone, methylprednisolone, methylprednisolone aceponate, mometasone furoate, diflorasone diacetate, halobetasol propionate, amcinonide, potentiated betamethasone dipropionate, fluocinonide, halcinonide, triamcinolone acetonide, betamethasone valerate, and clocortolone. The topical corticosteroids are selected from the group consisting of pivalate, desoximetasone, fluocinolone acetonide, flurandrenolide, fluticasone propionate, hydrocortisone butyrate, hydrocortisone probutate, hydrocortisone valerate, prednicarbate, alclometasone dipropionate, desonide, hydrocortisone, and hydrocortisone acetate; and / or (ii) the topical corticosteroids are selected from the group consisting of beclomethasone dipropionate, beclomethasone dipropionate; gentamicin sulfate, beclomethasone propionate, dexamethasone, methylcorticosterone, methylcorticosterone acetate propionate, and mometasone furoate.

25. The use as described in claim 1 or 3, wherein administration of the anti-OX40L antibody or its antigen-binding fragment results in at least one improvement selected from the group consisting of: a. a reduction of at least 2 points in vIGA score relative to baseline, or b. skin that has reached or nearly reached healing relative to baseline (vIGA0 / 1).

26. The use as described in claim 1 or 3, wherein administration of the anti-OX40L antibody or its antigen-binding fragment results in at least one improvement selected from the group consisting of: a. a reduction of at least 50% in EASI score relative to baseline, or b. a reduction of at least 75% in EASI score relative to baseline, or c. achieving EASI-75, or d. achieving EASI-90, or e. achieving at least 3 points in the pruritus NRS, or f. achieving at least 4 points in the pruritus NRS, or g. a reduction of at least 50% in the SCORAD index relative to baseline, or h. a reduction of at least 55% in the SCORAD index relative to baseline, or u. a reduction of at least 60% in the affected BSA relative to baseline, or j. a reduction of at least 70% in the affected BSA relative to baseline.

27. The use as described in claim 1, 2 or 3, wherein administration of the anti-OX40L antibody or an antigen-binding fragment thereof results in a decrease in serum levels of at least one biomarker selected from the group consisting of IL-13, IL-22, IL-17A, IL-31 and IgE.

28. The use as described in claim 1, 2 or 3, wherein the reduction in serum level of at least one of the biomarkers 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 last dose and / or wherein the improvement of at least one of the biomarkers is maintained for at least 12 weeks or at least 24 weeks after the last dose.

29. The use as described in claim 1 or 2, wherein the atopic dermatitis is assessed by determining a baseline EASI score.

30. The use as described in claims 1, 2, or 3, wherein (i) without additional administration of the anti-OX40L antibody or its antigen-binding fragment, the post-administration EASI score is maintained at: (a) at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after 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; and / or (ii) the post-administration EASI and / or further post-administration EASI are determined at least about 113 days after the first injection of the antibody or its fragment, and wherein said post-administration EASI and / or further post-administration EASI is EASI50, EASI75, EASI90, or EASI100; and / or (iii) The post-administration EASI and / or further post-administration EASI are determined at least approximately 169 days after the first injection of the antibody or its fragment, and wherein the post-administration EASI and / or further post-administration EASI is EASI50, EASI75, EASI90, or EASI100; and / or (iv) the post-administration EASI and / or further post-administration EASI are determined at least approximately 253 days after the first injection of the antibody or its fragment, and wherein the post-administration EASI and / or further post-administration EASI is EASI50, EASI75, EASI90, or EASI100.

31. The use as claimed in claim 1 or 3, wherein the atopic dermatitis is treated by evidence of a reduction of at least 40% in the EASI score after a third injection as a therapeutic dose, and wherein the reduction in the 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 the last injection as a therapeutic dose.

32. The use as described in claim 1 or 3, wherein the atopic dermatitis is assessed by determining a baseline vIGA-AD score.

33. The use as described in claims 1, 2, or 3, wherein (i) the post-administration vIGA-AD score is 0 or 1; (ii) without additional administration of the anti-OX40L antibody or its antigen-binding fragment, the post-administration vIGA-AD score is maintained at: (a) at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after 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; and / or (iii) the post-administration vIGA-AD and / or further post-administration vIGA-AD are determined at least about 113 days after the first injection of the antibody or its fragment, and wherein 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) The post-injection vIGA-AD score is reduced by at least 2 points relative to the baseline vIGA-AD score; and / or (iv) the post-injection vIGA-AD and / or further post-injection vIGA-AD are determined at least approximately 169 days after the first injection of the antibody or a fragment thereof, and wherein the post-injection vIGA-AD and / or further post-injection vIGA-AD is: (a) a vIGA-AD score of 0 or 1, and / or (b) a reduction of at least 2 points relative to the baseline vIGA-AD score; and / or (v) the post-injection vIGA-AD and / or further post-injection vIGA-AD are determined at least approximately 253 days after the first injection of the antibody or a fragment thereof, and wherein the post-injection vIGA-AD and / or further post-injection vIGA-AD is: (a) a vIGA-AD score of 0 or 1, and / or (b) a reduction of at least 2 points relative to the baseline vIGA-AD score.

34. The use as claimed in claim 1 or 3, wherein the atopic dermatitis is treated by evidence of a reduction of at least 2 points in the vIGA-AD score after a third injection as a therapeutic dose, and 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 the final injection as a therapeutic dose.

35. The use as described in claim 1, 2 or 3 above, wherein the antibody or fragment thereof comprises a VH domain having the amino acid sequence of SEQ ID No: 34 and / or a VL domain having the amino acid sequence of SEQ ID No:

48.

36. The use as described in claim 1, 2 or 3 above, wherein the anti-OX40L antibody or a fragment thereof comprises a heavy chain having an amino acid sequence according to SEQ ID No: 62 and a light chain having an amino acid sequence according to SEQ ID No:

64.

37. The use as described in claim 1, 2 or 3 above, wherein the individual is classified as a Th2 AD patient and / or a non-Th2 AD patient.

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