Treatment of atopic dermatitis

1 . A method of treating atopic dermatitis (AD) in a human subject comprising administering to the subject a therapeutically effective amount of an anti-OX40L antibody, or antigen-binding fragment thereof,

wherein the antibody or antigen-binding fragment thereof comprises:

(a) the HCDR1 amino acid sequence of SEQ ID NO: 42;

(b) the HCDR2 amino acid sequence of SEQ ID NO: 44;

(c) the HCDR3 amino acid sequence of SEQ ID NO: 46;

(d) the LCDR1 amino acid sequence of SEQ ID NO: 56;

(e) the LCDR2 amino acid sequence of SEQ ID NO: 58; and

(f) the LCDR3 amino acid sequence of SEQ ID NO: 60,

wherein the antibody or antigen-binding fragment thereof is administered subcutaneously as a fixed dose during a maintenance phase at a frequency of every 12 weeks (Q12W).

2 . The method according to claim 1 , wherein

the antibody or antigen-binding fragment thereof is a disease modifying drug optionally wherein after administering the disease modifying drug, the subject achieves an IGA-AD score of 0 or 1 for at least six months.

3 . The method according to claim 1 , wherein:

each dose of the antibody or antigen-binding fragment thereof is between about 20 mg and about 1000 mg; or

each dose of the antibody or antigen-binding fragment thereof is about 62.5 mg, about 125 mg, about 150 mg, about 250 mg, or about 500 mg.

4 . The method of claim 1 , wherein:

(a) the minimum blood serum concentration reached by the antibody or fragment thereof between any two injections (C min ) is at least 2.5 μg/ml, 2.6 μg/ml, at least 2.7 μg/ml, at least 2.8 μg/ml, at least 2.9 μg/ml, at least 3 μg/ml, at least 3.1 μg/ml, at least 3.2 μg/ml, at least 3.3 μg/ml, at least 3.4 μg/ml, at least 3.5 μg/ml, at least 3.6 μg/ml, at least 3.7 μg/ml, at least 3.8 μg/ml, at least 3.9 μg/ml, at least 4 μg/ml, at least 4.1 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, 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; or

(b) the maximum blood serum concentration reached by antibody or fragment thereof after administration of an injection and prior to administration of a subsequent injection (C max ) is at least 1.5 μg/ml, at least 2 μg/ml, at least 5 μg/ml, at least 10 μg/ml, at least 20 μg/ml, at least 30 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, at least 100 μg/ml, at least 150 μg/ml, at least 200 μg/ml, at least 300 μg/ml or at least 550 μg/ml; or

(c) blood serum concentrations of the antibody or fragment thereof during treatment range between about 4 g/mL and about 15 g/mL; or

(d) blood serum concentrations of the antibody or fragment thereof during treatment range between about 20 g/mL and about 45 g/mL; or

(e) blood serum concentrations of the antibody or fragment thereof during treatment range between about 5 g/mL and about 23 g/mL; or

(f) blood serum concentrations of the-antibody or fragment thereof during treatment are about 10 g/mL or below 10 g/mL; or

(g) the antibody or fragment thereof is administered via injection and the area under the serum concentration-time curve (AUC extrapolated to infinity [AUC 0-inf ]) following a first injection is from around 100,000 ng/ml*day to around 4,500,000 ng/ml*day or around 1,000,000 ng/ml*day to around 3,800,000 ng/ml*day.

5 . The method of claim 1 , further comprising an induction phase.

6 . The method of claim 5 , wherein:

each dose of the antibody or fragment thereof administered during the induction phase is about 500 mg, about 250 mg, about 125 mg or about 62.5 mg, optionally wherein each dose administered during the induction phase is at a frequency of every 4 weeks (Q4W); or

each dose of the antibody or fragment thereof administered during the maintenance phase is about 500 mg, about 250 mg, about 125 mg or about 62.5 mg.

7 . The method of claim 5 , wherein each dose of the antibody or fragment thereof administered during the induction phase is about 500 mg, and each dose of the antibody or antigen-binding fragment thereof administered during the maintenance phase is about 250 mg.

8 . The method of claim 5 , wherein each dose of the antibody or fragment thereof administered during the induction phase is about 250 mg, and each dose of the antibody or antigen-binding fragment thereof administered during the maintenance phase is about 250 mg.

9 . The method of claim 5 , wherein each dose administered during the induction phase is at a frequency of every 4 weeks (Q4W).

10 . The method of claim 1 , wherein:

(a) the antibody or fragment thereof exhibits one or more pharmacokinetic properties selected from the group consisting of:

(i) a rate of clearance (CL) of about 0.05 to about 0.18 L/day;

(ii) an absorption constant (k a ) of about 0.11 to about 0.33 L/day;

(iii) a volume of central compartment volume (Vc) of about 1.6 to about 5.0 L;

(iv) a second (peripheral compartment) volume (Vp1) of about 1.2 to about 3.6 L;

(v) a rate of clearance from the central compartment to the second compartment (Q) of about 0.31 to about 0.93 L/day; and

(vi) a bioavailability (Fabs1) of about 0.6 to about 1.0; or

(b) the subject is at least 18 years of age and/or less than 75 years of age; or

(c) the atopic dermatitis is moderate-to-severe atopic dermatitis; or

(d) the atopic dermatitis is moderate-to-severe atopic dermatitis and wherein the subject is a patient candidate for systemic therapy; or

(e) the atopic dermatitis is moderate-to-severe atopic dermatitis and wherein the subject is a patient whose disease is not adequately controlled with topical prescription therapies or a patient for whom topical prescription therapies are not advisable; or

(f) the atopic dermatitis is resistant, non-responsive, or inadequately responsive to treatment by either topical corticosteroids and/or systemic therapies; or

(g) either topical corticosteroids and/or systemic therapies are not advisable for the subject; or

(h) the subject has had an inadequate response to, was intolerant to, or is refractory to one or more topical corticosteroids.

11 . The method of claim 10 , wherein the atopic dermatitis is moderate-to-severe atopic dermatitis.

12 . The method of claim 10 , wherein the subject is a patient whose disease is not adequately controlled with topical prescription therapies or is a patient for whom topical prescription therapies are not advisable.

13 . The method of claim 10 , wherein the atopic dermatitis is not adequately controlled in a patient with systemic therapies or wherein systemic therapies are not advisable for a patient.

14 . The method according to claim 1 , further comprising administering a therapeutically effective amount of one or more topical corticosteroids.

15 . The method of claim 14 , wherein the topical corticosteroid is selected from the group consisting of betamethasone dipropionate, clobetasol propionate, dexamethasone, methylprednisolone, methylprednisolone aceponate, mometasone furoate, diflorasone diacetate, halobetasol propionate, amcinonide, augmented betamethasone dipropionate, fluocinonide, halcinonide, triamcinolone acetonide, betamethasone valerate, clocortolone pivalate, desoximetasone, fluocinolone acetonide, flurandrenolide, fluticasone propionate, hydrocortisone butyrate, hydrocortisone probutate, hydrocortisone valerate, prednicarbate, alclometasone dipropionate, desonide, hydrocortisone, and hydrocortisone acetate.

16 . The method of claim 1 , wherein the administration of the anti-OX40L antibody, or antigen-binding fragment thereof results in at least one improvement selected from the group consisting of:

a. a decrease from baseline in validated investigator global assessment atopic dermatitis (vIGA-AD) score of at least 2 points;

b. achieving clear or almost clear skin (vIGA-AD 0/1) from baseline;

c. a decrease from baseline in eczema area and severity index (EASI) score of at least 50%;

d. a decrease from baseline in EASI score of at least 75%;

e. achieving EASI-75;

f. achieving EASI-90;

g. achieving an improvement of at least 3 points in pruritus numerical rating scale, (NRS) score;

h. achieving an improvement of at least 4 points in pruritus NRS score,

i. a decrease from baseline in SCORAD (SCORing Atopic Dermatitis) index score of at least 50%,

j. a decrease from baseline in SCORAD index score of at least 55%;

k. a decrease from baseline in affected BSA (Body Surface Area) score of at least 60%; and

l. a decrease from baseline in affected BSA score of at least 70%.

17 . The method of claim 1 , wherein:

(a) the atopic dermatitis has been assessed by determining a baseline EASI score; or

(b) the atopic dermatitis has been assessed by determining a baseline EASI score and wherein the post-administration EASI score is maintained, without additional administration of the anti-OX40L antibody, or antigen-binding fragment thereof, for:

(i) at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after administration of the last injection; or

(ii) at least about 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169, or 253 days; or

(c) the atopic dermatitis has been assessed by determining a baseline EASI score and wherein the post-administration EASI is determined at least around 113 days after administering a first injection of the antibody or fragment thereof and wherein the post-administration EASI is EASI50, EASI75, EASI90 or EASI100; or

(d) the atopic dermatitis has been assessed by determining a baseline EASI score and wherein the post-administration EASI is determined at least around 169 days after administering a first injection of the antibody or fragment thereof and wherein the post-administration EASI is EASI50, EASI75, EASI90 or EASI100; or

(e) the atopic dermatitis has been assessed by determining a baseline EASI score and wherein the post-administration EASI is determined at least around 253 days after administering a first injection of the antibody or fragment thereof and wherein the post-administration EASI a is EASI50, EASI75, EASI90 or EASI100; or

(f) the atopic dermatitis has been assessed by determining a baseline EASI score and wherein the atopic dermatitis is treated as evidenced by a reduction in the EASI score by at least 40% after the third injection as a treatment dose and wherein the reduction in EASI score is persistent for at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after administration of the last injection as a treatment dose.

18 . The method of claim 1 , wherein the atopic dermatitis has been assessed by determining a baseline vIGA-AD score, and wherein:

(a) the post-administration vIGA-AD score is 0 or 1; or

(b) the post-administration vIGA-AD score is maintained, without additional administration of the anti-OX40L antibody, or antigen-binding fragment thereof, for:

(i) at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after administration of the last injection; or

(ii) at least about 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, 169 or 253 days; or

(c) the post-administration vIGA-AD is determined at least around 113 days after administering a first injection of the antibody or fragment thereof and wherein the post-administration vIGA-AD AD is:

(i) a vIGA-AD score of 0 or 1, and/or

(ii) reduced at least 2 points relative to the baseline vIGA-AD score; or

(d) the post-administration vIGA-AD is determined at least around 169 days after administering a first injection of the antibody or fragment thereof and wherein the post-administration vIGA-AD is:

(i) a vIGA-AD score of 0 or 1, and/or

(ii) reduced at least 2 points relative to the baseline vIGA-AD score; or

(e) the post-administration vIGA-AD is determined at least around 253 days after administering a first injection of the antibody or fragment thereof and wherein the post-administration vIGA-AD is:

(i) A vIGA-AD score of 0 or 1, and/or

(ii) reduced at least 2 points relative to the baseline vIGA-AD score; or

(f) the atopic dermatitis is treated as evidenced by a reduction in the vIGA-AD score by at least 2 points after the third injection as a treatment dose and wherein the reduction in vIGA-AD score is persistent for at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after administration of the last injection as a treatment dose.

19 . The method of claim 1 , wherein

the anti-OX40L antibody or antigen-binding fragment thereof comprises the heavy chain variable (VH) domain of SEQ ID NO: 34; or

the anti-OX40L antibody or antigen-binding fragment thereof comprises the light chain variable (VL) domain of SEQ ID NO: 48; or

the anti-OX40L antibody or antigen-binding fragment thereof comprises the VH domain of SEQ ID NO: 34 and the VL domain of SEQ ID NO: 48.

20 . The method of claim 1 , wherein the subject is classified as a Th2 AD patient and/or a non-Th2 AD patient; or

comprising selecting a subject having atopic dermatitis.

21 . The method of claim 1 , further comprising administering an initial dose of about 500 mg and one or more secondary doses of about 250 mg each, wherein each of the initial dose and the one or more secondary doses are administered prior to the maintenance phase.

22 . The method of claim 21 , wherein each dose of the antibody or antigen-binding fragment thereof administered during the maintenance phase is about 250 mg.

23 . The method of claim 1 , wherein a decrease of serum levels of one or more of IL-13, IL-22, IL-17A, IL-31 and IgE are achieved.

24 . The method of claim 1 , wherein the anti-OX40L antibody or antigen-binding fragment thereof comprises the heavy chain of SEQ ID NO: 62 and the light chain of SEQ ID NO: 64.

25 . The method of claim 1 , wherein the anti-OX40L antibody is amlitelimab.

26 . The method of claim 1 , wherein the anti-OX40L antibody or antigen-binding fragment thereof is administered using a prefilled syringe, a pen delivery device or an autoinjector delivery device.

27 . The method of claim 1 , wherein each dose of the antibody or antigen-binding fragment thereof administered during the maintenance phase is about 250 mg.

28 . The method of claim 1 , wherein each dose of the antibody or antigen-binding fragment thereof administered during the maintenance phase is about 150 mg.

29 . The method of claim 1 , wherein each dose of the antibody or antigen-binding fragment thereof administered during the maintenance phase is about 125 mg.

30 . The method of claim 1 , wherein each dose of the antibody or antigen-binding fragment thereof administered during the maintenance phase is about 62.5 mg.

31 . The method of claim 1 , wherein the anti-OX40L antibody or antigen-binding fragment thereof comprises the heavy chain variable (VH) domain of SEQ ID NO: 34 and the light chain variable (VL) domain of SEQ ID NO: 48.

32 . The method of claim 1 , wherein the subject is 12 years of age to 18 years of age.

33 . The method of claim 1 , wherein the subject is at least 18 years of age.

34 . The method of claim 1 , wherein the subject has previously received a systemic therapy.

35 . The method of claim 1 , wherein the subject has not previously received a systemic therapy.

36 . A method of treating moderate-to-severe atopic dermatitis (AD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-OX40L antibody or antigen-binding fragment thereof, wherein the anti-OX40L antibody or antigen-binding fragment thereof comprises three heavy chain complementary determining region (CDR) sequences comprising SEQ ID NOs: 42, 44, and 46, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 56, 58, and 60, respectively, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously as a fixed dose during a maintenance phase at a frequency of every 12 weeks (Q12W).

37 . The method of claim 36 , wherein the subject achieves a decrease from baseline in eczema area and severity index (EASI) score of at least a 75% reduction (EASI-75), or a decrease from baseline in EASI score of at least a 90% reduction (EASI-90).

38 . The method of claim 36 , wherein the subject achieves a decrease from baseline in SCORing Atopic Dermatitis (SCORAD) index score of at least 50%, or wherein the subject achieves a decrease from baseline in SCORAD index score of at least 55%.

39 . The method of claim 36 , wherein the anti-OX40L antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 34, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 48.

40 . The method of claim 39 , wherein the antibody is amlitelimab.

41 . The method of claim 36 , further comprising one or more induction doses.

42 . The method of claim 36 , wherein a decrease of serum levels of one or more of IL-13, IL-22, IL-17A, IL-31 and IgE are achieved.

43 . The method of claim 36 , wherein the anti OX40L antibody or antigen-binding fragment thereof comprises the heavy chain of SEQ ID NO: 62 and the light chain of SEQ ID NO: 64.

44 . The method of claim 36 , further comprising administering an initial dose of about 500 mg and one or more secondary doses of about 250 mg each, wherein each of the initial dose and the one or more secondary doses are administered prior to the maintenance phase.

45 . The method of claim 36 , further comprising administering to the subject one or more topical corticosteroids.

46 . The method of claim 36 , wherein the subject is 12 years of age to 18 years of age.

47 . The method of claim 36 , wherein the subject is at least 18 years of age.

48 . The method of claim 36 , wherein the subject is a patient whose disease is not adequately controlled with topical prescription therapies or is a patient for whom topical prescription therapies are not advisable.

49 . The method of claim 36 , wherein the atopic dermatitis is not adequately controlled in a patient with systemic therapies or wherein systemic therapies are not advisable for a patient.

50 . The method of claim 36 , wherein the subject has previously received a systemic therapy.

51 . The method of claim 36 , wherein the subject has not previously received a systemic therapy.

52 . A method of treating atopic dermatitis (AD) in a human subject comprising administering to the subject an anti-OX40L antibody or antigen-binding fragment thereof,

wherein the antibody or antigen-binding fragment thereof comprises:

(a) the HCDR 1 amino acid sequence of SEQ ID NO: 42;

(b) the HCDR 2 amino acid sequence of SEQ ID NO: 44;

(c) the HCDR 3 amino acid sequence of SEQ ID NO: 46;

(d) the LCDR 1 amino acid sequence of SEQ ID NO: 56;

(e) the LCDR 2 amino acid sequence of SEQ ID NO: 58; and

(f) the LCDR 3 amino acid sequence of SEQ ID NO: 60;

wherein the antibody or antigen-binding fragment thereof is administered subcutaneously as a fixed dose of 250 mg; 150 mg; 125 mg; or 62.5 mg during a maintenance phase at a frequency of every 12 weeks (Q12W).