Methods for treating bullous pemphigoids using FCRN antagonists

Abstract

Provided herein are methods of treating bullous pemphigoids using an effective amount of a human neonatal Fc receptor (FcRn) antagonist. Also provided herein are FcRn antagonists for the treatment of pemphigus bullosa and for the manufacture of medicaments for the treatment of pemphigus bullosa.

Description

Technical Field

[0001] The present disclosure relates to methods of treating bullous pemphigoid (BP) using an antagonist of the human neonatal Fc receptor (FcRn), which in certain embodiments is igamod. Background Art

[0002] Bullous pemphigoid (BP) is the most common autoimmune blistering skin disease, with an estimated annual incidence of 2.4 to 23 cases per million individuals. However, in people aged >80 years, the incidence is 190 to 312 cases per million individuals. The disease has a poor prognosis, which is directly attributed to the advanced age of the patient population and the comorbidities that may be present in this population. A recent meta-analysis calculated that the relative risk of death in patients with BP over a 1-year period was 2.93 times that of the general population worldwide (adjusted for age and sex). Tedbirt B et al., J AMA Dermatol. 2021; 157(4): 421-430. Studies investigating all-cause mortality in patients with BP for more than 1 year reported that the mortality rate in the first year (20% to 27%) was higher than that in subsequent years (9% to 16%). The main causes of death are infection and cardiovascular disease, which can be attributed to both the older age of patients with BP and their use of corticosteroids and / or immunosuppressants.

[0003] In BP, damage to the dermal-epidermal junction by pathogenic autoantibodies results in the development of large, tight bullae on the skin, which progress to epidermal erosions, crusting, and urticarial plaque formation. If untreated, BP can eventually develop into life-threatening complications, including (but not limited to) severe infection, functional impairment of vital organs, and iatrogenic disease.

[0004] Corticosteroids (topical or oral) are currently the first-line therapy for patients with BP. For localized or mild / moderate severity of BP, medical authorities recommend the application of high doses of potent topical corticosteroids (such as clobetasol propionate, at doses of 20 to 40 g / day). Unfortunately, the use of such high doses of topical corticosteroids can result in substantial systemic absorption and severe skin atrophy.

[0005] For patients with widespread or moderate to severe BP, oral corticosteroid (OCS) therapy is the standard of care for most practitioners. Unfortunately, OCS causes significant toxicity to patients with BP because of the high cumulative corticosteroid exposure that is often required to successfully control the disease. Therefore, physicians treating patients with BP must provide optimal corticosteroid doses to successfully control the disease, achieve control of disease activity (CDA) or complete / partial remission (CR / PR), and prevent subsequent relapses, while also mitigating the adverse effects of corticosteroids by minimizing the amount they prescribe to their patients.

[0006] Alternative adjunctive therapies to corticosteroids have been evaluated in patients with severe BP or those who demonstrate corticosteroid resistance and include IVIg, plasma exchange, rituximab, omalizumab, dapsone, and tetracycline. These therapies have either shown inconsistent results, proven to be too complex and / or expensive, induced significant side effects in their respective populations of patients with BP, or produced encouraging results, but a large proportion of patients who responded to treatment ultimately relapsed shortly thereafter.

[0007] Thus, there is an unmet need in the art for new and improved BP treatment options that provide rapid CDA and relief, minimize (or even prevent) relapses, and allow for tapering or elimination of corticosteroid therapy. Summary of the invention

[0008] The present disclosure generally relates to methods for treating bullous pemphigoid (BP) with neonatal Fc receptor (FcRn) antagonists.

[0009] In one aspect, provided herein is a method for treating BP in a subject in need thereof, the method comprising administering to the subject an effective amount of a human FcRn antagonist.

[0010] In some embodiments, the FcRn antagonist comprises two, three, or four FcRn binding regions.

[0011] In some embodiments, the FcRn antagonist comprises or consists of a variant Fc region or an FcRn binding fragment thereof. In some embodiments, the variant Fc region or an FcRn binding fragment thereof binds to FcRn with a higher affinity at pH 6.0 than the corresponding wild-type Fc region. In some embodiments, the variant Fc region or an FcRn binding fragment thereof binds to FcRn with a higher affinity at pH 7.4 than the corresponding wild-type Fc region.

[0012] In some embodiments, the variant Fc region comprises or consists of two Fc domains that form a homodimer or heterodimer.In some embodiments, the FcRn antagonist comprises an Fc region comprising amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively.

[0013] In some embodiments, the variant Fc region comprises or consists of a first Fc domain and a second Fc domain that form a homodimer or a heterodimer. In some embodiments, the first Fc domain and / or the second Fc domain comprises amino acids Y, T, E, K, and F located at EU positions 252, 254, 256, 433, and 434, respectively. In some embodiments, the first Fc domain and / or the second Fc domain comprises amino acids Y, T, E, K, F, and Y located at EU positions 252, 254, 256, 433, 434, and 436, respectively.

[0014] In some embodiments, the amino acid sequence of at least one of the Fc domains is selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3. In some embodiments, the amino acid sequence of both of the Fc domains is independently selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3. In some embodiments, the FcRn antagonist is igamod.

[0015] In some embodiments, the first Fc domain and / or the second Fc domain comprises an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3. In some embodiments, the first Fc domain and the second Fc domain comprise an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3. In some embodiments, the FcRn antagonist is igamod.

[0016] In some embodiments, the FcRn antagonist is an anti-FcRn antibody. In some embodiments, the anti-FcRn antibody is selected from the group consisting of rozanolixizumab, nipocalimab, orilanolimab, and batoclimab.

[0017] In some embodiments, the FcRn antagonist is administered to a subject at a fixed dose of 20 mg to 20,000 mg or at a dose of 0.2 mg / kg to 200 mg / kg. In some embodiments, the FcRn antagonist is administered to a subject at a fixed dose of 200 mg to 20,000 mg or at a dose of 2 mg / kg to 200 mg / kg.

[0018] In some embodiments, the FcRn antagonist is administered subcutaneously once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 20 mg to 20,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 200 mg to 20,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg or 2000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

[0019] In some embodiments, the FcRn antagonist is first administered subcutaneously twice on the same day at a fixed dose of about 1000 mg. In some embodiments, for the first two administrations, the FcRn antagonist is administered subcutaneously at a fixed dose of about 2000 mg, and then at a fixed dose of about 1000 mg. In some embodiments, for the first two administrations, the FcRn antagonist is administered subcutaneously at a fixed dose of 2000 mg, and then at a fixed dose of 1000 mg.

[0020] In some embodiments, the first two administrations of the FcRn antagonist are subcutaneous administrations at a fixed dose of about 1000 mg twice on the same day. In some embodiments, the first two administrations of the FcRn antagonist are subcutaneous administrations at a fixed dose of 1000 mg twice on the same day.

[0021] In some embodiments, the FcRn antagonist is agamod. In some embodiments, agamod is administered subcutaneously once a week at a fixed dose of 800 to 1200 mg. In some embodiments, agamod is administered subcutaneously once a week at a fixed dose of about 1000 mg. In some embodiments, agamod is administered subcutaneously once a week at a fixed dose of 1000 mg.

[0022] In certain embodiments, the FcRn antagonist is co-deployed with hyaluronidase and administered subcutaneously. In certain embodiments, the hyaluronidase is recombinant human hyaluronidase PH20 (rHuPH20). In certain embodiments, rHuPH20 is administered once a week at a dosage of 2000U / mL. In certain embodiments, rHuPH20 is administered once a week at about 11,000U or about 22,000U.

[0023] In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks at a dose of 0.2 mg / kg to 200 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks at a dose of 2 mg / kg to 200 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks at a dose of 3 mg / kg to 60 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks at a dose of 5 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks at a dose of 10 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks at a dose of 25 mg / kg.

[0024] In some embodiments, the FcRn antagonist is first administered intravenously and then subcutaneously. In some embodiments, the FcRn antagonist is first administered intravenously and then subcutaneously at a fixed dose of 20 mg to 20,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is first administered intravenously and then subcutaneously at a fixed dose of 200 mg to 20,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is first administered intravenously and then subcutaneously at a fixed dose of 1000 mg or 2000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

[0025] In some embodiments, the FcRn antagonist is administered for 52 weeks or less. In some embodiments, the FcRn antagonist is administered for 36 weeks or less.

[0026] In some embodiments, the FcRn antagonist is administered for at least 26 weeks.

[0027] In some embodiments, the FcRn antagonist is administered for at least 36 weeks.

[0028] In some embodiments, the method disclosed herein further comprises administering a dose of corticosteroids to the subject. In some embodiments, the dose of corticosteroids is reduced after disease control or complete remission has been achieved. In some embodiments, the dose of corticosteroids is reduced after disease control has lasted for at least two weeks.

[0029] In some embodiments, after two weeks of sustained disease control, the dose of corticosteroids is reduced from 0.5 mg / kg / day prednisone equivalents to 0.3 mg / kg / day prednisone equivalents, from 0.3 mg / kg / day prednisone equivalents to 0.2 mg / kg / day prednisone equivalents, from 0.2 mg / kg / day prednisone equivalents to 0.15 mg / kg / day prednisone equivalents, and from 0.15 mg / kg / day prednisone equivalents to 0.1 mg / kg / day prednisone equivalents.

[0030] In some embodiments, after two weeks of sustained disease control, the dose of corticosteroids is reduced from 0.75 mg / kg / day prednisone equivalents to 0.5 mg / kg / day prednisone equivalents, from 0.5 mg / kg / day prednisone equivalents to 0.3 mg / kg / day prednisone equivalents, from 0.3 mg / kg / day prednisone equivalents to 0.2 mg / kg / day prednisone equivalents, from 0.2 mg / kg / day prednisone equivalents to 0.15 mg / kg / day prednisone equivalents, and from 0.15 mg / kg / day prednisone equivalents to 0.1 mg / kg / day prednisone equivalents.

[0031] In some embodiments, after two weeks of sustained disease control, the dose of corticosteroids is reduced from 1 mg / kg / day prednisone equivalents to 0.75 mg / kg / day prednisone equivalents, from 0.75 mg / kg / day prednisone equivalents to 0.5 mg / kg / day prednisone equivalents, from 0.5 mg / kg / day prednisone equivalents to 0.3 mg / kg / day prednisone equivalents, from 0.3 mg / kg / day prednisone equivalents to 0.2 mg / kg / day prednisone equivalents, from 0.2 mg / kg / day prednisone equivalents to 0.15 mg / kg / day prednisone equivalents, and from 0.15 mg / kg / day prednisone equivalents to 0.1 mg / kg / day prednisone equivalents.

[0032] In some embodiments, each dose of corticosteroid is maintained for at least two weeks before further dose reduction. In some embodiments, each dose of corticosteroid is maintained for at least two weeks as long as no new lesions appear.

[0033] In some embodiments, once the subject receives a prednisone equivalent dose of 0.1 mg / kg / day, the daily dose of corticosteroids is further reduced by 2.5 mg of prednisone equivalent dose every two weeks for one or more two-week periods. In some embodiments, the daily dose of corticosteroids is reduced by 2.5 mg of prednisone equivalent dose every two weeks for one or more two-week periods until the daily dose of corticosteroids is zero, resulting in the interruption of corticosteroid therapy. In some embodiments, each daily dose is maintained for two weeks as long as no new lesions appear.

[0034] In some embodiments, once the subject receives 0.1 mg / kg / day of prednisone equivalents, the daily dose of corticosteroids is further reduced by 1 mg of prednisone equivalents per week for one or more one-week periods. In some embodiments, the daily dose of corticosteroids is reduced by 1 mg of prednisone equivalents per week for one or more one-week periods until the daily dose of corticosteroids is zero, resulting in interruption of corticosteroid therapy. In some embodiments, each daily dose is maintained for one week as long as no new lesions appear.

[0035] In some embodiments, the corticosteroid is prednisone.

[0036] In some embodiments, the BP is selected from the group consisting of newly diagnosed BP, recurrent BP, and refractory BP.

[0037] In some embodiments, the subject is diagnosed with moderate to severe BP, mild BP, moderate BP, or severe BP.

[0038] In some embodiments, the subject has a detectable serum level of anti-BP180 antibody or anti-BP230 antibody or both. In some embodiments, the subject exhibits a decrease in serum levels of anti-BP180 antibody or anti-BP230 antibody after administration of an FcRn antagonist. In some embodiments, the decrease in serum levels of anti-BP180 antibody or anti-BP230 antibody after administration of an anti-FcRn antagonist is at least 10%, at least 25%, at least 50%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% of the serum level of anti-BP180 antibody or anti-BP230 antibody of the subject before administration of the anti-FcRn antagonist. In some embodiments, after administration of an FcRn antagonist, the serum level of anti-BP180 antibody or anti-BP230 antibody is undetectable.

[0039] In some embodiments, the FcRn antagonist is administered until disease control, partial remission or complete remission is achieved. In some embodiments, the subject achieves complete remission. In some embodiments, the subject achieves complete remission within 1 month, within 2 months, within 3 months, within 4 months, within 5 months, within 6 months, within 9 months or within 1 year. In some embodiments, the subject achieves complete remission within about 3 to 6 months. In some embodiments, the subject's complete remission lasts for at least 2 months. In some embodiments, the subject's complete remission lasts for at least 6 months.

[0040] In some embodiments, the subject remains in complete remission in the absence of oral corticosteroids. In some embodiments, the subject remains in complete remission for at least eight weeks in the absence of oral corticosteroids. In some embodiments, at the end of the 36-week treatment period, the subject remains in complete remission in the absence of corticosteroids for at least eight weeks.

[0041] In some embodiments, BP recurrence is prevented after achieving remission from BP, wherein the prevention of BP recurrence persists for at least 36 weeks after initiation of FcRn antagonist administration.

[0042] In some embodiments, the subject has an IGA-BP score of 0 or 1 after administration of the FcRn antagonist. In some embodiments, the subject has an IGA-BP score of 0 or 1 in the absence of oral corticosteroids for at least eight weeks. In some embodiments, at the end of the 36-week treatment period, the subject has an IGA-BP score of 0 or 1 in the absence of oral corticosteroids for at least eight weeks.

[0043] In some embodiments, the subject has an IGA-BP score of 0 following administration of the FcRn antagonist. In some embodiments, the subject has an IGA-BP score of 0 in the absence of oral corticosteroids for at least eight weeks. In some embodiments, at the end of the 36-week treatment period, the subject has an IGA-BP score of 0 in the absence of oral corticosteroids for at least eight weeks.

[0044] Also provided herein is an FcRn antagonist for use in treating BP, wherein the treatment is performed according to any of the methods disclosed herein.

[0045] Also provided herein is an FcRn antagonist for use in the manufacture of a medicament for the treatment of BP, wherein the treatment is performed according to any of the methods disclosed herein.

[0046] Also provided herein is a method for monitoring the efficacy of treatment of BP in a subject following treatment with a first FcRn antagonist, the method comprising: a) measuring in vitro the serum level of anti-BP180 antibody and / or anti-BP230 antibody in a blood sample taken from the subject; and b) comparing the serum level of anti-BP180 antibody and / or anti-BP230 antibody with a reference value associated with BP in the subject, wherein if the serum level of anti-BP180 antibody and / or anti-BP230 antibody in the sample is greater than or equal to the reference value, the treatment is ineffective, and wherein if the serum level of anti-BP180 antibody and / or anti-BP230 antibody is less than the reference value, the treatment is effective.

[0047] Also provided herein is a method of treating BP in a subject who has received a first FcRn antagonist and is receiving a corticosteroid dosing regimen, the method comprising: a) administering to the subject an effective amount of a second FcRn antagonist; b) measuring in vitro the serum level of anti-BP180 antibody and / or anti-BP230 antibody in a blood sample taken from the subject; and c) comparing the serum level of anti-BP180 antibody and / or anti-BP230 antibody to a reference value associated with BP in the subject, wherein if the serum level of anti-BP180 antibody and / or anti-BP230 antibody in the sample is greater than or equal to the reference value, maintaining the corticosteroid dosing regimen, or wherein if the serum level of anti-BP180 antibody and / or anti-BP230 antibody is less than the reference value, gradually reducing the corticosteroid dosing regimen.

[0048] Also provided herein is a method for treating BP in a subject, the method comprising: (a) administering to the subject one or more initial doses of an effective amount of a first FcRn antagonist; and (b) administering to the subject one or more additional doses of an effective amount of a second FcRn antagonist if, after step (a), the subject's serum level of anti-BP180 antibodies and / or anti-BP230 antibodies is greater than or equal to a reference value associated with the subject's BP, or discontinuing treatment with the first FcRn antagonist if, after step (a), the subject's serum level of anti-BP180 antibodies and / or anti-BP230 antibodies is less than a reference value associated with the subject's active disease.

[0049] Also provided herein is a method for treating BP in a subject, the method comprising: administering to the subject an effective amount of a second FcRn antagonist, wherein the subject's BP has recurred following prior therapy with a first FcRn antagonist, and wherein the subject has a serum level of anti-BP180 antibody and / or anti-BP230 antibody greater than or equal to a reference value associated with the subject's BP.

[0050] Also provided herein is a method for determining whether a subject who has previously been treated for BP with a first FcRn antagonist requires further treatment with a second FcRn antagonist, the method comprising: a) measuring in vitro the serum level of anti-BP180 antibody and / or anti-BP230 antibody in a blood sample taken from the subject; and b) comparing the serum level of anti-BP180 antibody and / or anti-BP230 antibody with a reference value associated with BP in the subject, wherein if the serum level of anti-BP180 antibody and / or anti-BP230 antibody in the sample is greater than or equal to the reference value, the subject requires further treatment with a second FcRn antagonist.

[0051] In some embodiments, the subject was previously treated with the first FcRn antagonist at a fixed dose of about 200 mg to about 20,000 mg, or at a dose of 2 mmg / kg to 200 mmg / kg.

[0052] In some embodiments, the subject was previously treated with a first FcRn antagonist administered intravenously at a dose of 20 mmg / kg to 100 mmg / kg.

[0053] In some embodiments, the subject was previously treated with a first FcRn antagonist administered intravenously at a dose of 3 mmg / kg to 60 mmg / kg.

[0054] In some embodiments, the effective amount of the second FcRn antagonist is a higher dose compared to the previous treatment with the first FcRn antagonist.

[0055] In some embodiments, the effective amount of the second FcRn antagonist is a lower dose compared to the prior treatment with the first FcRn antagonist.

[0056] In some embodiments, the effective amount of the second FcRn antagonist is administered at a fixed dose of about 200 mg to about 20,000 mg, or at a dose of 2 mg / kg to 200 mg / kg.

[0057] In some embodiments, an effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of about 750 mg to about 3000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

[0058] In some embodiments, an effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of about 1000 mg or about 2000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

[0059] In some embodiments, the first FcRn antagonist and the second FcRn antagonist are each the same FcRn antagonist. In some embodiments, the FcRn antagonist comprises a variant Fc region or its FcRn binding fragment or consists of the variant Fc region or its FcRn binding fragment. In some embodiments, the variant Fc region or its FcRn binding fragment binds to FcRn with a higher affinity at pH 6.0 and / or 7.4 compared to the corresponding wild-type Fc region. In some embodiments, the variant Fc region comprises two Fc domains forming homodimers or heterodimers or consists of the two Fc domains. In some embodiments, the FcRn antagonist is an Fc region comprising amino acids Y, T, E, K, F and Y located at EU positions 252, 254, 256, 433, 434 and 436, respectively. In some embodiments, the FcRn antagonist is Agamod.

[0060] In some embodiments, the first FcRn antagonist and the second FcRn antagonist are each different FcRn antagonists. In some embodiments, the first FcRn antagonist or the second FcRn antagonist comprises a variant Fc region or its FcRn binding fragment or consists of the variant Fc region or its FcRn binding fragment. In some embodiments, compared with the corresponding wild-type Fc region, the variant Fc region or its FcRn binding fragment binds to FcRn with higher affinity at pH 6.0 and / or 7.4. In some embodiments, the variant Fc region comprises two Fc domains forming homodimers or heterodimers or consists of the two Fc domains. In some embodiments, the first FcRn antagonist or the second FcRn antagonist is an Fc region comprising amino acids Y, T, E, K, F and Y located at EU positions 252, 254, 256, 433, 434 and 436, respectively. In some embodiments, the first FcRn antagonist or the second FcRn antagonist is igamod.

[0061] In some embodiments, the amino acid sequence of at least one of the Fc domains is selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3. In some embodiments, the amino acid sequence of both of the Fc domains is independently selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3.

[0062] In some embodiments, the first FcRn antagonist is an anti-FcRn antibody and the second FcRn antagonist is igamod.

[0063] In some embodiments, the first FcRn antagonist is an anti-FcRn antibody and the second FcRn antagonist comprises the amino acid sequence of SEQ ID NO: 1, 2, or 3.

[0064] In some embodiments, the anti-FcRn antibody is rozanolimab, nicallimab, onorimumab, or bartolimumab.

[0065] In some embodiments, the patient has not been previously treated with igamod.

[0066] In some embodiments, the subject has one or more physical symptoms of BP following treatment with the first FcRn antagonist.

[0067] In some embodiments, the subject has a serum level of anti-BP180 antibody or anti-BP230 antibody that correlates with recurrence of BP.

[0068] Also provided herein is a method of treating BP in a subject in need thereof, the method comprising administering to the subject an effective amount of a human FcRn antagonist and a corticosteroid, wherein the cumulative oral dose of the corticosteroid administered to the subject does not exceed 100 mg / kg, does not exceed 75 mg / kg, does not exceed 50 mg / kg, or does not exceed 25 mg / kg.

[0069] Also provided herein is a method of treating BP in a subject in need thereof, the method comprising administering to the subject an effective amount of a human FcRn antagonist and a corticosteroid, wherein the oral prednisone equivalent dose of the corticosteroid administered to the subject does not exceed 1 mg / kg / day, does not exceed 0.75 mg / kg / day, does not exceed 0.5 mg / kg / day, does not exceed 0.3 mg / kg / day, does not exceed 0.25 mg / kg / day, does not exceed 0.2 mg / kg / day, does not exceed 0.15 mg / kg / day, or does not exceed 0.1 mg / kg / day.

[0070] Also provided herein is a method of treating BP in a subject in need thereof, the method comprising administering to the subject an effective amount of a human FcRn antagonist and a corticosteroid, wherein the oral prednisone equivalent dose of the corticosteroid administered to the subject does not exceed 12.5 mg / day or does not exceed 10 mg / day. BRIEF DESCRIPTION OF THE DRAWINGS

[0071] Figure 1A to Figure 1B Data on clinical disease activity in an anti-hNC16A IgG-induced acute prophylactic BP mouse model are shown. Adult hNC16A mice were injected intraperitoneally (ip) with normal human control IgG (NHC) or anti-hNC16A IgG (250 μg / g body weight) followed by intravenous (iv) injection of the agamod analog HEL-ABDEG (60 μg / g body weight) or PBS control and clinical examinations were performed 3 days after injection. Figure 1A: Injection of anti-hNC16A IgG antibody (α-NC16A IgG) resulted in the development of ear skin lesions, whereas the skin of HEL-ABDEG-treated mice looked similar to that of mice injected with normal human control (NHC) IgG. Figure 1B Disease activity scores are shown. *p<0.01, n=8 per group.

[0072] Figure 2 Histopathological data of skin lesions in an acute prophylactic BP mouse model induced by anti-hNC16A IgG are shown. Representative images of routine histological examination of mouse skin with H / E staining (upper figure marked as ac: 200-fold magnification; lower figure marked as df: 400-fold magnification). Compared with mice receiving PBS control (left figure), mice injected with pathogenic anti-hNC16A IgG treated with HEL-ABDEG did not show dermal-epidermal separation (upper middle figure), and skin neutrophil infiltration was significantly reduced (lower middle figure). Mice injected with normal human IgG control (NHC) and subsequently treated with PBS did not show dermal-epidermal separation.

[0073] Figure 3 Indirect immunofluorescence (IIF) staining showing lesions in an acute preventive BP mouse model showed reduced neutrophil infiltration in HEL-ABDEG treated mice. Compared with PBS treated control mice (2nd column from left, upper figure marked as b), the skin of mice treated with HEL-ABDEG showed a significant reduction in infiltrating neutrophils (2nd column from left, middle figure marked as f), as demonstrated by IIF (200 times magnification). Skin injected with NHC IgG showed no neutrophil infiltration (2nd column from left, lower figure marked as j).

[0074] FIG. 4A to FIG. 4B Data from an anti-hNC16A IgG-induced acute therapeutic BP mouse model are shown. Adult hNC16A mice were injected ip with anti-hNC16A (250 μg / g body weight). Three days later, mice were injected iv with HEL-ABDEG (60 μg / g body weight) or PBS control. Mice were examined on days 10 and 17 (7 and 14 days after HEL-ABDEG injection, respectively). On day 10 (7 days after treatment), mice treated with HEL-ABDEG showed a significant reduction in clinical disease activity compared to controls ( Figure 4A ) and infiltrative neutropenia ( Figure 4B ), as demonstrated by IIF. Figure 4A , *p=0.026, PBS control group n=8, HEL-ABDEG treatment group n=6.

[0075] Figure 5Schematic representation of the 2-part Phase 2 / 3 study protocol to investigate the efficacy, safety, tolerability, immunogenicity, participant-reported outcome measures (including QoL assessments), PK, and PD of agamod PH20 SC in adult participants with moderate-to-severe BP (BALLAD). BP: bullous pemphigoid; CDA: control of disease activity; CR: complete remission; EFG: agamod; HCP: healthcare provider; OCS: oral corticosteroids; PR: partial remission; SC: subcutaneous. *Rescue therapy may also be initiated if a participant relapses twice or experiences steroid toxicity, or any serious adverse event deemed by the investigator to be related to OCS therapy. These participants will discontinue agamod therapy but will continue to attend study visits during the 36-week treatment period while receiving rescue therapy.

[0076] Figure 6 is a schematic diagram depicting the treatment regimen for participants in ARGX-113-2010 (the study described in Example 3). 8w=8 weeks; BL=baseline; BP=bullous pemphigoid; CR=complete remission; EFG PH20 SC=agamod co-formulated with rHuPH20 for subcutaneous injection (dosing formulation); EoTP=end of treatment period (visit; ARGX-113-2009); IMP=investigational medicinal product; OCS=oral corticosteroids; PR=partial remission; rHuPH20=recombinant human hyaluronidase PH20; TCS=topical corticosteroids; W36=week 36 of ARGX-113-2009 (EoTP visit). DETAILED DESCRIPTION

[0077] The present disclosure provides engineered FcRn antagonists and methods for their use in treating bullous pemphigoid (BP). Advantageously, the methods disclosed herein allow for rapid treatment of the disease, as well as the potential for tapering and even discontinuation of corticosteroids after achieving clinical remission.

[0078] definition

[0079] As used herein, the term "FcRn" refers to the neonatal Fc receptor. Exemplary FcRn molecules include human FcRn encoded by the FCGRT gene as shown in RefSeq NM 004107. The amino acid sequence of the corresponding protein is shown in RefSeq NP_004098.

[0080] As used herein, the term "FcRn antagonist" refers to any agent that specifically binds to FcRn and inhibits the binding of immunoglobulins to FcRn (e.g., human FcRn). In one embodiment, the FcRn antagonist is an Fc region (e.g., a variant Fc region disclosed herein) that specifically binds to FcRn and inhibits the binding of immunoglobulins to FcRn through the Fc region. In one embodiment, the FcRn antagonist is not a full-length IgG antibody. In one embodiment, the FcRn antagonist comprises an antigen binding site and a variant Fc region that binds to a target antigen. In one embodiment, the FcRn antagonist is an Fc fragment that comprises or consists of an Fc region and lacks an antigen binding site. In one embodiment, the term "FcRn antagonist" refers to an antibody or antigen-binding fragment thereof that specifically binds to FcRn via its antigen binding domain or via its Fc region and inhibits the binding of the Fc region of an immunoglobulin (e.g., an IgG autoantibody) to FcRn.

[0081] As used herein, the terms "antibody" and "antibodies" include full-length antibodies, antigen-binding fragments of full-length antibodies, and molecules comprising antibody CDRs, VH regions, or VL regions. Examples of antibodies include monoclonal antibodies, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain-antibody heavy chain pairs, intrabodies, heteroconjugate antibodies, antibody drug conjugates, single domain antibodies (sdAb), monovalent antibodies, single chain antibodies or single chain Fv (scFv), camelid antibodies, affinity antibody molecules, humanized antibodies, VHH fragments, Fab fragments, F(ab') 2 Antibodies may be any type of immunoglobulin molecule (e.g., IgG, IgE, IgM, IgD, IgA, or IgY), any class (e.g., IgG 1 IgG 2 IgG 3 IgG 4 , IgA 1 or IgA 2 ) or any subclass (e.g., IgG 2a or IgG 2b ).

[0082] As used herein, the term "Fc domain" refers to the portion of a single immunoglobulin heavy chain that starts at the hinge region and ends at the C-terminus of an antibody. Thus, a complete Fc domain comprises at least a portion of a hinge (e.g., upper, middle and / or lower hinge region) domain, a CH2 domain, and a CH3 domain. In some embodiments, the term "Fc domain" refers to the portion of a single immunoglobulin heavy chain that comprises both the CH2 domain and the CH3 domain of an antibody. In some embodiments, the Fc domain comprises at least a portion of a hinge region (e.g., upper, middle and / or lower hinge region), a CH2 domain, and a CH3 domain. In some embodiments, the Fc domain does not comprise a hinge region.

[0083] As used herein, the term "hinge region" refers to the portion of the heavy chain molecule that joins the CH1 domain to the CH2 domain. In some embodiments, the hinge region is up to 70 amino acid residues in length. In some embodiments, the hinge region comprises approximately 11 to 17 amino acid residues and is flexible, thereby allowing the two N-terminal antigen binding regions to move independently. In some embodiments, the hinge region is 12 amino acid residues in length. In some embodiments, the hinge region is 15 amino acid residues in length. In some embodiments, the hinge region is 62 amino acid residues in length. The hinge region can be subdivided into three different domains: upper, middle and lower hinge domains. The FcRn antagonists of the present disclosure may include all or any portion of the hinge region. In some embodiments, the hinge region is from an IgG1 antibody. In some embodiments, the hinge region comprises the amino acid sequence of EPKSCDKTHTCPPCP (SEQID NO: 12).

[0084] As used herein, the term "Fc region" refers to the portion of an immunoglobulin formed by the Fc domains of its two heavy chains. The Fc region may be a wild-type Fc region (native Fc region) or a variant Fc region. The native Fc region is a homodimer. The Fc region may be derived from any natural immunoglobulin. In some embodiments, the Fc region is formed by IgA, IgD, IgE or IgG heavy chain constant regions. In some embodiments, the Fc region is formed by IgG heavy chain constant regions. In some embodiments, the IgG heavy chain constant region is an IgG1, IgG2, IgG3 or IgG4 heavy chain constant region. In some embodiments, the Fc region is formed by an IgG1 heavy chain constant region. In some embodiments, the IgG1 heavy chain constant region comprises G1m1 (a), G1m2 (x), G1m3 (f) or G1m17 (z) allotypes. See, e.g., Jefferis and Lefranc, mAbs; 2009; 1(4): 332-338, and de Taeye et al., Front Immunol. 2020; 11: 740, which are incorporated herein by reference in their entireties.

[0085] As used herein, the term "variant Fc region" refers to an Fc region that has one or more changes relative to a native Fc region. The changes may include amino acid substitutions, additions and / or deletions, attachment of additional moieties, and / or changes in native glycans. The term encompasses heterodimeric Fc regions in which each of the constituent Fc domains is different. The term also encompasses single-chain Fc regions in which the constituent Fc domains are linked together by a linker moiety.

[0086] As used herein, the term "FcRn binding fragment" refers to a portion of the Fc region sufficient to confer FcRn binding.

[0087] As used herein, the term "EU position" refers to the amino acid position of the Fc region in the EU numbering convention, which is described in Edelman, GM et al., Proc. Natl. Acad. USA, 1969; 63, 78-85 and Rabat et al., in "Sequences of Proteins of Immunological Interest," U. Sept. Health and Human Services, 5th Edition, 1991.

[0088] As used herein, the term "baseline" refers to a measurement (e.g., frequency of B cells, IgG levels) of a patient (e.g., a patient's blood) prior to the first administration (e.g., intravenous or subcutaneous administration) of a treatment (e.g., an FcRn antagonist).

[0089] As used herein, the term "autoantibody-mediated disease" refers to any disease or condition in which the underlying pathology is caused, at least in part, by pathogenic IgG autoantibodies.

[0090] As used herein, the terms "treat," "treating," and "treatment" refer to therapeutic or preventive measures as described herein. "Therapeutic" methods employ the administration of antibodies to a subject having a disease or condition or susceptible to such a disease or condition in order to prevent, cure, delay, lessen the severity of, or ameliorate one or more symptoms of the disease or condition or a recurring disease or condition, or in order to prolong the survival of the subject beyond the expected survival in the absence of such treatment.

[0091] As used herein, the term "effective amount" in the context of administering a therapy to a subject refers to that amount of the therapy that achieves the desired prophylactic or therapeutic effect.

[0092] As used herein, the term "dose" or "administration" refers to the amount of a pharmaceutical agent administered to a subject in a single administration.

[0093] As used herein, the terms "fixed dose" or "uniform dose" both refer to a dose that does not vary based on characteristics of the subject (e.g., weight, e.g., within a set range; sex; age, e.g., within a set range; etc.).

[0094] As used herein, the term "minimal OCS therapy" refers to an oral prednisone dose (or prednisone equivalent dose) of ≤ 0.10 mg / kg / day.

[0095] As used herein, the term "prednisone equivalent dose" means a dose of prednisone or an equivalent dose of a systemic corticosteroid other than prednisone. Systemic corticosteroids are well known and include compounds of various potencies and formulations. They are generally formulated as injections or pills. Examples of commercially available systemic corticosteroids include, but are not limited to, betamethasone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, prednisolone, and triamcinolone.

[0096] As used herein, the term "control of disease activity" or "CDA" refers to the point at which new lesions cease to form and already formed lesions begin to heal and symptoms of pruritus begin to abate.

[0097] As used herein, the term "treatment failure" refers to the absence of CDA after administering one or more treatments for a specified length of time. In some aspects, "treatment failure" refers to the absence of CDA despite receiving at least 4 consecutive weekly doses of Agamod PH20 SC with or without concurrent BP therapy. In some aspects, "treatment failure" refers to the absence of CDA after administering at least 4 consecutive weekly doses of Agamod PH20 SC with or without oral prednisone at 0.75 mg / kg / day (or equivalent OCS) for 3 weeks. Optionally, a fourth week of oral prednisone 0.75 mg / kg / day or 1 mg / kg / day (based on clinical judgment) therapy can be added before declaring treatment failure.

[0098] As used herein, the term "transient lesions" refers to new lesions that heal within 1 week or itch that persists for less than 1 week.

[0099] As used herein, the term "non-transient lesions" may be defined as new lesions that do not heal within 1 week or that persist for more than 1 week with pruritus.

[0100] As used herein, the term "remission" refers to complete remission or partial remission.

[0101] As used herein, the term "complete remission" or "CR" refers to the absence of new lesions, complete healing of existing lesions, and the absence of pruritus.

[0102] As used herein, the term "partial response" or "PR" refers to the presence of only new, transient lesions.

[0103] As used herein, the term "relapse" or "flare-up" refers to a patient with BP who has physical symptoms of BP and / or an increase in markers after a period of remission of BP. In some aspects, the term "relapse" or "flare-up" refers to the occurrence of any of the following in a patient who has achieved CDA: the appearance of 3 or more new lesions (such as blisters, eczematous lesions, or urticaria plaques) within 1 month (4 weeks); the appearance of at least 1 large (>10cm diameter) eczematous lesion that does not heal within 1 week; the appearance of urticaria plaques that do not heal within 1 week; the extension / enlargement of established lesions; and / or new daily itching symptoms or increased intensity of daily itching symptoms.

[0104] As used herein, the term "subject" or "patient" or "participant" includes any human or non-human animal. In one embodiment, the subject or patient or participant is a human or non-human mammal. In one embodiment, the subject or patient or participant is a human.

[0105] As used herein, when referring to a measurable value, such as a dosage, the term "about" or "approximately" encompasses variations of ±20%, ±15%, ±10%, ±5%, ±1%, or ±0.1% of a given value or range, as long as it is suitable for performing the methods disclosed herein.

[0106] Bullous Pemphigoid (BP)

[0107] BP is a subepidermal autoimmune blistering disease (AIBD) that primarily affects the elderly. It is a chronic disease that significantly affects morbidity and quality of life (QoL); in addition, the disease may spontaneously worsen even when patients are treated with current standards of care. The pathogenesis of BP is driven by IgG and IgE autoantibodies against the hemidesmosomal proteins BP180 and BP230, which are key antigens for pathogenic autoantibodies. These pathogenic autoantibodies are thought to cause direct interference with autoantigen adhesion, activation of complement, recruitment of inflammatory cells (e.g., eosinophils), and release of proteolytic enzymes, leading to skin blistering and pruritus. IgG autoantibodies against BP180 and BP230 have been shown to induce BP-like symptoms in animal models, and disease activity correlates with serum levels of anti-BP180 autoantibodies. Schmidt E et al., Arch Dermatol. 2000; 136(2): 174-178; Masmoudi W et al., Br J Dermatol. 2021; 184(6): 1106-1112. Anti-BP180 autoantibodies mainly recognize the extracellular 16th non-collagenous domain (NC16A) of the molecule.

[0108] Currently, there are no therapies specifically licensed for the treatment of patients with BP. The current standard of care for BP is treatment with topical corticosteroids or OCS, either of which can be combined with conventional immunosuppressant therapy. Unfortunately, corticosteroid therapy for patients with BP often results in comorbidities that can be severe or even life-threatening, especially in elderly patients. As a result, patients with BP have a higher mortality rate than their peers, even when their disease is being treated. Replacement therapies that target IgG (e.g., IV administration of immune globulin [IVIg], plasma exchange, or protein A immunoadsorption) or biologics (e.g., rituximab, omalizumab) have shown potential in a small number of patients with BP. However, the efficacy and safety of these treatments have not been evaluated in registration studies. Amagai M et al., J Dermatol Sci. 2017;85(2):77-84; Kasperkiewicz M et al., J Am Acad Dermatol. 2014;71(5):1018-1020; Jafari SMS et al., Front Immunol. 2019;10:1919.

[0109] In BP, patients usually achieve control of disease activity (CDA), partial remission (PR), or complete remission (CR) only after a few weeks of treatment; sometimes even months of treatment are required to achieve CR or PR. In addition, patients with BP often relapse within a few months of achieving remission.

[0110] Assessment of BP disease status and efficacy of BP treatment can be measured using validated scales developed by experts in the field, including:

[0111] (1) Investigator's Global Assessment of Bullous Pemphigoid (IGA-BP) - The IGA-BP is a new assessment tool developed in 2021 by medical experts in the field of AIBD and is currently being used (along with the BPDAI) in other clinical studies of BP therapies. The IGA classifies the severity of BP on an ordinal scale of 0 (clear) to 4 (severe). An IGA-BP score of 0 (clear) indicates that there are no signs of active disease (no blisters, erythema, or erosions). An IGA-BP score of 1 (almost clear) indicates that no blisters or erosions are present and there are very limited erythema, eczema, or urticaria lesions. An IGA-BP score of 2 (mild) indicates that there are a few (<10) blisters or erosions and / or a few erythema, eczema, or urticaria lesions (involving less than 10% of the body surface area) and there are no large areas of erosion (>5 cm) or no large blisters (>5 cm). An IGA-BP score of 3 (moderate) indicates the presence of multiple (10 to 29) blisters or erosions and / or the presence of multiple erythematous, eczematous, or urticarial lesions (involving 10-30% of the body surface area) and / or the presence of up to 2 large erosive areas (>5 cm) or large blisters (>5 cm). An IGA-BP score of 4 (severe) indicates the presence of extensive (≥30) blisters or erosions and / or the presence of extensive erythematous, eczematous, or urticarial lesions (involving >30% of the body surface area) and / or the presence of 3 or more large erosive areas (>5 cm) or large blisters (>5 cm).

[0112] (2) Bullous Pemphigoid Disease Area Index (BPDAI) - The BPDAI is an internationally recognized tool for objectively measuring disease activity. The BPDAI distinguishes scores for skin (erosions / blistering and urticaria / erythema) and mucosal activity at multiple anatomical locations. In addition, a separate score for lesions (e.g., pigmentation) is recorded to account for healing lesions. The BPDAI classifies the severity of BP in the skin and mucosa on a numerical scale of 0 (clear) to 120 (most severe).

[0113] (3) Itch Numerical Rating Scale (Itch NRS) - Itch symptoms of BP will be indicated by the participant on the Itch NRS, recording the average and worst score of itch experienced in the past 24 hours. An Itch NRS score of 0 indicates no itch; <3 indicates mild itch; ≥3 to <7 indicates moderate itch; ≥7 to <9 indicates severe itch; and ≥9 indicates very severe itch.

[0114] (4) EuroQoL 5 Dimensions 5 Levels (EQ-5D-5L) - EQ-5D-5L is a standardized measure of health status developed by the EuroQoL Group to provide a simple, universal measure of health for clinical and economic assessment. The descriptive system includes 5 dimensions (mobility, self-care, usual activities, pain / discomfort, and anxiety / depression). Each dimension now has 5 levels: no problem, slight problem, moderate problem, severe problem, and extreme problem.

[0115] (5) Dermatology Life Quality Index (DLQI) - The DLQI consists of 10 questions concerning participants' perceptions of the impact of skin disease in the past week on different aspects of their health-related QoL. The impact of each aspect on QoL rating is rated qualitatively, ranging from "not at all" to "very much."

[0116] (6) Autoimmune Bullous Disease Quality of Life (ABQoL) Questionnaire - The ABQoL was developed and validated to determine the impact of AIBD and its treatment on patients' daily lives. It is a series of 17 questions that address participants' perceptions of how AIBD affects their daily lives, including comfort, hygiene, diet, appearance, social interactions, sexual activity, and employment.

[0117] FcRn antagonists

[0118] FcRn antagonists useful in the methods and uses provided herein can include any molecule that binds to and inhibits FcRn, including but not limited to any anti-FcRn antibody, any anti-FcRn binding region, or any Fc domain or Fc region.

[0119] In some embodiments, the FcRn antagonists disclosed herein comprise two, three, or four FcRn binding regions, such as Fc regions. In some embodiments, the FcRn antagonists disclosed herein comprise a combination of one or more Fc regions and one or more Fab regions.

[0120] Any Fc region can be changed to produce a variant Fc region for use in the methods disclosed herein. In general, the Fc region or its FcRn binding fragment is from a human immunoglobulin. However, it should be understood that the Fc region can be derived from the immunoglobulin of any other mammalian species, including, for example, camel species, rodents (e.g., mice, rats, rabbits, guinea pigs) or non-human primates (e.g., orangutans, macaques) species. In addition, the Fc region or its portion can be derived from any immunoglobulin class, including IgM, IgG, IgD, IgA and IgE, and any immunoglobulin isotype, including IgG1, IgG2, IgG3 and IgG4. In one embodiment, the Fc region is an IgG Fc region (e.g., human IgG region). In one embodiment, the Fc region is an IgG1 Fc region (e.g., human IgG1 region). In one embodiment, the Fc region is a chimeric Fc region including a portion of several different Fc regions. Suitable examples of chimeric Fc regions are described in US2011 / 0243966A1, which is incorporated herein by reference in its entirety. A variety of Fc region gene sequences (eg, human constant region gene sequences) are available in the form of publicly available deposits.

[0121] The Fc region may be further truncated or internally deleted to generate a minimal FcRn binding fragment thereof. The ability of the Fc region fragment to bind to FcRn may be determined using any art-recognized binding assay (eg, ELISA).

[0122] To enhance the manufacturability of the FcRn antagonists disclosed herein, preferably, the constituent Fc region does not contain any non-disulfide-linked cysteine ​​residues. Thus, in one embodiment, the Fc region does not contain free cysteine ​​residues.

[0123] Any Fc variant or FcRn binding fragment thereof that specifically binds to FcRn with increased affinity and reduced pH dependence relative to the native (i.e., wild-type) Fc region can be used in the methods disclosed herein. In one embodiment, the variant Fc region comprises amino acid changes, substitutions, insertions and / or deletions that confer the desired characteristics. In some embodiments, the FcRn antagonist comprises a variant Fc region or its FcRn binding fragment or consists of the variant Fc region or its FcRn binding fragment, which binds to FcRn with higher affinity at pH 5.5 compared to the corresponding wild-type Fc region. In some embodiments, the FcRn antagonist comprises a variant Fc region or its FcRn binding fragment or consists of the variant Fc region or its FcRn binding fragment, which binds to FcRn with higher affinity at pH 6.0 and / or pH 7.4 compared to the corresponding wild-type Fc region. In some embodiments, the FcRn antagonist comprises or consists of a variant Fc region, or an FcRn binding fragment thereof, that binds to FcRn with higher affinity at both acidic and neutral pH.

[0124] In some embodiments, the variant Fc region is derived from the Fc region of any natural immunoglobulin. In some embodiments, the natural immunoglobulin is a human immunoglobulin. In some embodiments, the immunoglobulin is IgA, IgD, IgE or IgG. In some embodiments, the immunoglobulin is IgG. In some embodiments, the immunoglobulin is human IgA, human IgD, human IgE or human IgG. In some embodiments, the immunoglobulin is human IgG. In some embodiments, IgG is IgG1, IgG2, IgG3 or IgG4. In some embodiments, human IgG is human IgG1, human IgG2, human IgG3 or human IgG4. In some embodiments, the variant Fc region is different from the human IgG1 Fc region. In some embodiments, the human IgG1 Fc region comprises G1m1 (a), G1m2 (x), G1m3 (f) or G1m17 (z) allotypes.

[0125] In one embodiment, the variant Fc region or FcRn binding fragment thereof consists of two Fc domains.In one embodiment, the FcRn antagonist is an Fc region comprising amino acids Y, T, E, K, F and Y at EU positions 252, 254, 256, 433, 434 and 436, respectively.

[0126] In one embodiment, the variant Fc region comprises or consists of a first Fc domain and a second Fc domain that form a homodimer or heterodimer. In one embodiment, the first Fc domain and / or the second Fc domain comprise amino acids Y, T, E, K and F located at EU positions 252, 254, 256, 433 and 434, respectively. In one embodiment, the first Fc domain and / or the second Fc domain comprise amino acids Y, T, E, K, F and Y located at EU positions 252, 254, 256, 433, 434 and 436, respectively.

[0127] In some embodiments, the FcRn antagonists disclosed herein comprise or consist of at least one Fc domain, wherein the amino acid sequence of the at least one Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 13 provided in Table 1 below.

[0128] Table 1

[0129]

[0130] In some embodiments, an FcRn antagonist disclosed herein comprises or consists of a variant Fc region comprising or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first Fc domain and the second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 13.

[0131] In some embodiments, the FcRn antagonists disclosed herein comprise or consist of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first Fc domain and the second Fc domain comprises or consists of an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 1-3 and 14-31. In some embodiments, the dimer is a heterodimer or a homodimer.

[0132] Table 2

[0133]

[0134]

[0135]

[0136] In one embodiment, the first Fc domain and / or the second Fc domain comprises an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3. In one embodiment, the first Fc domain and the second Fc domain comprise an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3.

[0137] In one embodiment, the first Fc domain and / or the second Fc domain comprises an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 1, 2, 3 and 30. In one embodiment, the first Fc domain and the second Fc domain comprise an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 1, 2, 3 and 30.

[0138] In some embodiments, the FcRn antagonist comprises a population of FcRn antagonist molecules. In some embodiments, the FcRn antagonist comprising a first Fc domain and a second Fc domain is the predominant FcRn antagonist molecule in the population of FcRn antagonist molecules, and the first Fc domain and the second Fc domain comprise an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 1, 2, and 3. In some embodiments, the FcRn antagonist comprising a first Fc domain and a second Fc domain is the predominant FcRn antagonist molecule in the population of FcRn antagonist molecules, and the first Fc domain and the second Fc domain comprise an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 1, 2, 3, and 30. In some embodiments, the predominant FcRn antagonist molecules comprise at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% of the population of FcRn antagonist molecules.

[0139] In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 1. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 1. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 2. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 2. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 3. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 3. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 30. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 30.

[0140] In one embodiment, the FcRn antagonist consists of a variant Fc region, wherein the variant Fc region comprises two Fc domains, wherein the amino acid sequence of each of the Fc domains is independently selected from SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3. In one embodiment, the FcRn antagonist consists of a variant Fc region, wherein the variant Fc region comprises two Fc domains, wherein the amino acid sequence of each of the Fc domains is independently selected from SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 30.

[0141] In certain embodiments, the variant Fc region is a heterodimer in which the constituent Fc domains are different from each other. Methods for producing Fc heterodimers are known in the art (see, e.g., US 8,216,805, which is incorporated herein by reference in its entirety). In one embodiment, the FcRn antagonist consists of a variant Fc region, wherein the variant Fc region consists of two Fc domains forming a heterodimer, wherein the amino acid sequence of each of the Fc domains is independently selected from SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3. In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 1, and the amino acid sequence of the second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 3. In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 2, and the amino acid sequence of the second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 3. In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 3, and the amino acid sequence of the second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2.

[0142] In one embodiment, the FcRn antagonist consists of a variant Fc region, wherein the variant Fc region consists of two Fc domains forming a heterodimer, wherein the amino acid sequence of each of the Fc domains is independently selected from SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 or SEQ ID NO: 30. In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 1, and the amino acid sequence of the second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3 or SEQ ID NO: 30. In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 2, and the amino acid sequence of the second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 3, or SEQ ID NO: 30. In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 3, and the amino acid sequence of the second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 30. In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 30, and the amino acid sequence of the second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3.

[0143] In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a homodimer, wherein the amino acid sequence of each of the Fc domains comprises or consists of the amino acid sequence of SEQ ID NO: 1.

[0144] In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains comprises or consists of the amino acid sequence of SEQ ID NO: 2.

[0145] In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains comprises or consists of the amino acid sequence of SEQ ID NO: 3.

[0146] In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains comprises or consists of the amino acid sequence of SEQ ID NO: 30.

[0147] In some embodiments, the FcRn antagonist comprises glycans on one or both of the Fc domains. In some embodiments, the FcRn antagonist molecule comprises glycans at EU position 297 on one or both of the Fc domains. In some embodiments, the glycans comprise N-glycans. In some embodiments, the N-glycans comprise G0F N-glycans, G1F N-glycans, G2F N-glycans, or G0 N-glycans.

[0148] In some embodiments, the FcRn antagonist comprises or consists of a population of FcRn antagonists, wherein at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, or at least 57% of the population of Fc domains of the FcRn antagonists comprise galactose. In some embodiments, the population comprises or consists of an FcRn antagonist, wherein at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the population of Fc domains of the FcRn antagonists comprises fucose.

[0149] In some embodiments, the FcRn antagonist lacks an amino acid at EU position 441 of one or both of the Fc domains. In some embodiments, the FcRn antagonist comprises a glycine and a lysine at EU positions 440 and 441, respectively. In some embodiments, the FcRn antagonist lacks an amino acid at EU positions 440 and 441. In some embodiments, the FcRn antagonist comprises an amidated proline at EU position 439. In some embodiments, the FcRn antagonist lacks an amino acid at EU positions 440 and 441 and comprises an amidated proline at EU position 439.

[0150] In some embodiments, the FcRn antagonist comprises aspartic acid, lysine, threonine, histidine, threonine, and cysteine ​​at EU positions 221, 222, 223, 224, 225, and 226, respectively. In some embodiments, the FcRn antagonist lacks an amino acid at EU position 221, and comprises lysine, threonine, histidine, threonine, and cysteine ​​at EU positions 222, 223, 224, 225, and 226, respectively. In some embodiments, the FcRn antagonist lacks amino acids at EU positions 221 and 222, and comprises threonine, histidine, threonine, and cysteine ​​at EU positions 223, 224, 225, and 226, respectively. In some embodiments, the FcRn antagonist lacks amino acids at EU positions 221-224, and comprises threonine and cysteine ​​at EU positions 225 and 226, respectively. In some embodiments, the FcRn antagonist lacks amino acids at EU positions 221, 222, 223, 224, 225, and 226.

[0151] In some embodiments, the FcRn antagonist is a population of FcRn antagonist molecules. In some embodiments, the population of FcRn antagonist molecules comprises or consists of multiple subpopulations of FcRn antagonist molecules. In some embodiments, the population of FcRn antagonist molecules comprises or consists of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 subpopulations. In some embodiments, the population of FcRn antagonist molecules comprises or consists of 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 subpopulations.

[0152] In some embodiments, the first subset of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of both the first Fc domain and the second Fc domain comprises or consists of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:3.

[0153] In some embodiments, the second subset of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first Fc domain and the second Fc domain comprises or consists of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NOs: 3 and 22, respectively.

[0154] In some embodiments, the third subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first Fc domain and the second Fc domain comprises or consists of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NOs: 3 and 19, respectively.

[0155] In some embodiments, the fourth subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of both the first Fc domain and the second Fc domain comprises or consists of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:3, and wherein two asparagine residues in each FcRn antagonist molecule in the fourth subpopulation are deaminated.

[0156] In some embodiments, the fifth subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first Fc domain and the second Fc domain comprises or consists of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NOs: 3 and 19, respectively, and wherein one asparagine residue in each FcRn antagonist molecule in the fifth subpopulation is deaminated.

[0157] In some embodiments, a sixth subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first Fc domain and the second Fc domain comprises or consists of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NOs: 2 and 3, respectively.

[0158] In some embodiments, the seventh subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first Fc domain and the second Fc domain comprises or consists of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NOs: 2 and 3, respectively, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the seventh subpopulation is oxidized.

[0159] In some embodiments, the eighth subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of both the first Fc domain and the second Fc domain comprise or consist of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:2.

[0160] In some embodiments, the ninth subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first Fc domain and the second Fc domain comprises or consists of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NOs: 3 and 16, respectively.

[0161] In some embodiments, the tenth subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first Fc domain and the second Fc domain comprises or consists of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NOs: 2 and 3, respectively, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the tenth subpopulation is oxidized.

[0162] In some embodiments, the eleventh subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of both the first Fc domain and the second Fc domain comprises or consists of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 3, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the eleventh subpopulation is oxidized.

[0163] In some embodiments, the first subset of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of both the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence of SEQ ID NO: 3.

[0164] In some embodiments, the second subset of FcRn antagonist molecules comprises or consists of a variant Fc region, which variant Fc region comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first Fc domain and the second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 3 and 22, respectively.

[0165] In some embodiments, the third subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region, which variant Fc region comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first Fc domain and the second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 3 and 19, respectively.

[0166] In some embodiments, the fourth subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of both the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence of SEQ ID NO: 3, and wherein two asparagine residues in each FcRn antagonist molecule in the fourth subpopulation are deaminated.

[0167] In some embodiments, the fifth subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or consist of the amino acid sequences of SEQ ID NOs: 3 and 19, respectively, and wherein one asparagine residue in each FcRn antagonist molecule in the fifth subpopulation is deaminated.

[0168] In some embodiments, a sixth subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or consist of the amino acid sequences of SEQ ID NOs: 2 and 3, respectively.

[0169] In some embodiments, the seventh subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or consist of the amino acid sequences of SEQ ID NOs: 2 and 3, respectively, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the seventh subpopulation is oxidized.

[0170] In some embodiments, the eighth subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of both the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence of SEQ ID NO: 2.

[0171] In some embodiments, the ninth subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region, which variant Fc region comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or consist of the amino acid sequences of SEQ ID NOs: 3 and 16, respectively.

[0172] In some embodiments, the tenth subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or consist of the amino acid sequences of SEQ ID NOs: 2 and 3, respectively, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the tenth subpopulation is oxidized.

[0173] In some embodiments, the eleventh subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of both the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence of SEQ ID NO: 3, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the eleventh subpopulation is oxidized.

[0174] In some embodiments, the FcRn antagonist molecule population comprises a combination of the first subgroup and one of the second subgroup, the third subgroup, the fourth subgroup, the fifth subgroup, the sixth subgroup, the seventh subgroup, the eighth subgroup, the ninth subgroup, the tenth subgroup, or the eleventh subgroup. In some embodiments, the FcRn antagonist molecule population comprises a combination of the first subgroup and two of the second subgroup, the third subgroup, the fourth subgroup, the fifth subgroup, the sixth subgroup, the seventh subgroup, the eighth subgroup, the ninth subgroup, the tenth subgroup, or the eleventh subgroup. In some embodiments, the FcRn antagonist molecule population comprises a combination of the first subgroup and three of the second subgroup, the third subgroup, the fourth subgroup, the fifth subgroup, the sixth subgroup, the seventh subgroup, the eighth subgroup, the ninth subgroup, the tenth subgroup, or the eleventh subgroup. In some embodiments, the population of FcRn antagonist molecules comprises or consists of a combination of the first subgroup and four of the second subgroup, the third subgroup, the fourth subgroup, the fifth subgroup, the sixth subgroup, the seventh subgroup, the eighth subgroup, the ninth subgroup, the tenth subgroup, or the eleventh subgroup. In some embodiments, the population of FcRn antagonist molecules comprises or consists of a combination of the first subgroup and five of the second subgroup, the third subgroup, the fourth subgroup, the fifth subgroup, the sixth subgroup, the seventh subgroup, the eighth subgroup, the ninth subgroup, the tenth subgroup, or the eleventh subgroup. In some embodiments, the population of FcRn antagonist molecules comprises or consists of a combination of the first subgroup and six of the second subgroup, the third subgroup, the fourth subgroup, the fifth subgroup, the sixth subgroup, the seventh subgroup, the eighth subgroup, the ninth subgroup, the tenth subgroup, or the eleventh subgroup. In some embodiments, the population of FcRn antagonist molecules comprises a combination of or consists of the first subgroup and seven of the second subgroup, the third subgroup, the fourth subgroup, the fifth subgroup, the sixth subgroup, the seventh subgroup, the eighth subgroup, the ninth subgroup, the tenth subgroup, or the eleventh subgroup. In some embodiments, the population of FcRn antagonist molecules comprises a combination of or consists of the first subgroup and eight of the second subgroup, the third subgroup, the fourth subgroup, the fifth subgroup, the sixth subgroup, the seventh subgroup, the eighth subgroup, the ninth subgroup, the tenth subgroup, or the eleventh subgroup. In some embodiments, the population of FcRn antagonist molecules comprises a combination of or consists of the first subgroup and nine of the second subgroup, the third subgroup, the fourth subgroup, the fifth subgroup, the sixth subgroup, the seventh subgroup, the eighth subgroup, the ninth subgroup, the tenth subgroup, or the eleventh subgroup. In some embodiments, the population of FcRn antagonist molecules comprises or consists of a combination of the first subpopulation and all of the second subpopulation, the third subpopulation, the fourth subpopulation, the fifth subpopulation, the sixth subpopulation, the seventh subpopulation, the eighth subpopulation, the ninth subpopulation, the tenth subpopulation, or the eleventh subpopulation.

[0175] In some embodiments, the population comprises or consists of a first subgroup and a second subgroup. In some embodiments, the population comprises or consists of a first subgroup and a third subgroup. In some embodiments, the population comprises or consists of a first subgroup and a fourth subgroup. In some embodiments, the population comprises or consists of a first subgroup and a fifth subgroup. In some embodiments, the population comprises or consists of a first subgroup and a sixth subgroup. In some embodiments, the population comprises or consists of a first subgroup and a seventh subgroup. In some embodiments, the population comprises or consists of a first subgroup and an eighth subgroup. In some embodiments, the population comprises or consists of a first subgroup and a ninth subgroup. In some embodiments, the population comprises or consists of a first subgroup and a tenth subgroup. In some embodiments, the population comprises or consists of a first subgroup and an eleventh subgroup. In some embodiments, the above-listed population further comprises or consists of 1, 2, 3, 4, 5, 6, 7, 8, or 9 additional subgroups. In some embodiments, these additional subgroups are one or more of the above-mentioned subgroups.

[0176] In some embodiments, the population comprises or consists of the first subpopulation and the seventh subpopulation, the ninth subpopulation, or the eleventh subpopulation. In some embodiments, the population comprises or consists of the first subpopulation, the seventh subpopulation, the ninth subpopulation, and the eleventh subpopulation.

[0177] In some embodiments, the first subpopulation accounts for 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% of the population of FcRn antagonist molecules. In some embodiments, the first subpopulation accounts for about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90% of the population of FcRn antagonist molecules. In some embodiments, the first subpopulation accounts for 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% of the population of FcRn antagonist molecules. In some embodiments, the first subpopulation accounts for 40%-90%, 50%-80%, or 55%-70% of the population of FcRn antagonist molecules. In some embodiments, the first subpopulation comprises 56.9%-68.3% or 59.5%-67.9% of the population of FcRn antagonist molecules.

[0178] In some embodiments, the second subpopulation accounts for less than 3.0%, less than 2.5%, less than 2.0%, less than 1.5%, less than 1% or less than 0.5% of the population of FcRn antagonist molecules. In some embodiments, the second subpopulation accounts for about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1% or about 0.5% of the population of FcRn antagonist molecules. In some embodiments, the second subpopulation accounts for 3.0%, 2.5%, 2.0%, 1.5%, 1% or 0.5% of the population of FcRn antagonist molecules. In some embodiments, the second subpopulation accounts for 0.5%-3.0%, 1.0%-2.5% or 1.0%-2.0% of the population of FcRn antagonist molecules. In some embodiments, the second subpopulation accounts for 0.8%-2.0% or 0.8%-2.1% of the population of FcRn antagonist molecules.

[0179] In some embodiments, the third subpopulation accounts for less than 3.0%, less than 2.5%, less than 2.0%, less than 1.5%, less than 1% or less than 0.5% of the population of FcRn antagonist molecules. In some embodiments, the third subpopulation accounts for about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1% or about 0.5% of the population of FcRn antagonist molecules. In some embodiments, the third subpopulation accounts for 3.0%, 2.5%, 2.0%, 1.5%, 1% or 0.5% of the population of FcRn antagonist molecules. In some embodiments, the third subpopulation accounts for 0.5%-3.0%, 1.0%-2.5% or 1.0%-2.0% of the population of FcRn antagonist molecules. In some embodiments, the third subpopulation accounts for 1.1%-2.1% or 1.0%-1.9% of the population of FcRn antagonist molecules.

[0180] In some embodiments, the fourth subpopulation accounts for less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of the population of FcRn antagonist molecules. In some embodiments, the fourth subpopulation accounts for about 5%, about 4%, about 3%, about 2%, or about 1% of the population of FcRn antagonist molecules. In some embodiments, the fourth subpopulation accounts for 5%, 4%, 3%, 2%, or 1% of the population of FcRn antagonist molecules. In some embodiments, the fourth subpopulation accounts for 1%-5%, 2%-4%, or 2%-3% of the population of FcRn antagonist molecules. In some embodiments, the fourth subpopulation accounts for 2.1%-3.2% or 2.0%-3.1% of the population of FcRn antagonist molecules.

[0181] In some embodiments, the fifth subpopulation accounts for less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, or less than 5% of the population of FcRn antagonist molecules. In some embodiments, the fifth subpopulation accounts for about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, or about 5% of the population of FcRn antagonist molecules. In some embodiments, the fifth subpopulation accounts for 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5% of the population of FcRn antagonist molecules. In some embodiments, the fifth subpopulation accounts for 5%-12%, 6%-10%, or 7%-8% of the population of FcRn antagonist molecules. In some embodiments, the fifth subpopulation accounts for 6.8%-9.4% or 6.9%-8.7% of the population of FcRn antagonist molecules.

[0182] In some embodiments, the sixth subpopulation accounts for less than 17%, less than 16%, less than 15%, less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, or less than 6% of the population of FcRn antagonist molecules. In some embodiments, the sixth subpopulation accounts for about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, or about 6% of the population of FcRn antagonist molecules. In some embodiments, the sixth subpopulation accounts for 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, or 6% of the population of FcRn antagonist molecules. In some embodiments, the sixth subpopulation accounts for 7%-17%, 10%-15%, or 11%-12% of the population of FcRn antagonist molecules. In some embodiments, the sixth subpopulation comprises 7.0%-14.0% or 10.0%-14.4% of the population of FcRn antagonist molecules.

[0183] In some embodiments, the seventh subpopulation accounts for less than 6.0%, less than 5.5%, less than 5.0%, less than 4.5%, less than 4.0%, less than 3.5%, less than 3.0%, less than 2.5%, less than 2.0%, less than 1.5%, less than 1% or less than 0.5% of the population of FcRn antagonist molecules. In some embodiments, the seventh subpopulation accounts for about 6.0%, about 5.5%, about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1% or about 0.5% of the population of FcRn antagonist molecules. In some embodiments, the seventh subpopulation accounts for 6.0%, 5.5%, 5.0%, 4.5%, 4.0%, 3.5%, 3.0%, 2.5%, 2.0%, 1.5%, 1% or 0.5% of the population of FcRn antagonist molecules. In some embodiments, the seventh subpopulation comprises 0.5%-5.5%, 1.0%-3.0% or 1.5%-2.5% of the population of FcRn antagonist molecules. In some embodiments, the seventh subpopulation comprises 1.5%-5.5% or 1.4%-4.9% of the population of FcRn antagonist molecules.

[0184] In some embodiments, the eighth subpopulation accounts for less than 7.5%, less than 7.0%, less than 6.5%, less than 6.0%, less than 5.5%, less than 5.0%, less than 4.5%, less than 4.0%, less than 3.5%, less than 3.0%, or less than 2.5% of the population of FcRn antagonist molecules. In some embodiments, the eighth subpopulation accounts for about 7.5%, about 7.0%, about 6.5%, about 6.0%, about 5.5%, about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, or about 2.5% of the population of FcRn antagonist molecules. In some embodiments, the eighth subpopulation accounts for 7.5%, 7.0%, 6.5%, 6.0%, 5.5%, 5.0%, 4.5%, 4.0%, 3.5%, 3.0%, or 2.5% of the population of FcRn antagonist molecules. In some embodiments, the eighth subpopulation comprises 2.5%-7.5%, 3.0%-5.0% or 3.5%-4.5% of the population of FcRn antagonist molecules. In some embodiments, the eighth subpopulation comprises 2.9%-7.4% or 3.0%-6.3% of the population of FcRn antagonist molecules.

[0185] In some embodiments, the ninth subpopulation accounts for less than 3.5%, less than 3.0%, less than 2.5%, less than 2.0%, less than 1.5%, less than 1% or less than 0.5% of the population of FcRn antagonist molecules. In some embodiments, the ninth subpopulation accounts for about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1% or about 0.5% of the population of FcRn antagonist molecules. In some embodiments, the ninth subpopulation accounts for 3.5%, 3.0%, 2.5%, 2.0%, 1.5%, 1% or 0.5% of the population of FcRn antagonist molecules. In some embodiments, the ninth subpopulation accounts for 0.5%-3.5%, 1.5%-2.0% or 1.0%-1.5% of the population of FcRn antagonist molecules. In some embodiments, the ninth subpopulation accounts for 0.4%-3.2% or 0.5%-2.6% of the population of FcRn antagonist molecules.

[0186] In some embodiments, the tenth subpopulation accounts for less than 2.0%, less than 1.5%, less than 1%, or less than 0.5% of the population of FcRn antagonist molecules. In some embodiments, the tenth subpopulation accounts for about 2.0%, about 1.5%, about 1%, or about 0.5% of the population of FcRn antagonist molecules. In some embodiments, the tenth subpopulation accounts for 2.0%, 1.5%, 1%, or 0.5% of the population of FcRn antagonist molecules. In some embodiments, the tenth subpopulation accounts for 0.5%-2.0%, 0.5%-1.5%, or 1.0%-1.5% of the population of FcRn antagonist molecules.

[0187] In some embodiments, the eleventh subpopulation accounts for less than 2.0%, less than 1.5%, less than 1%, or less than 0.5% of the population of FcRn antagonist molecules. In some embodiments, the eleventh subpopulation accounts for about 2.0%, about 1.5%, about 1%, or about 0.5% of the population of FcRn antagonist molecules. In some embodiments, the eleventh subpopulation accounts for 2.0%, 1.5%, 1%, or 0.5% of the population of FcRn antagonist molecules. In some embodiments, the eleventh subpopulation accounts for 0.5%-2.0%, 0.5%-1.5%, or 1.0%-1.5% of the population of FcRn antagonist molecules.

[0188] In some embodiments, the FcRn antagonist molecule population comprises one or more FcRn antagonists described herein. In some embodiments, the FcRn antagonist is any of those described in U.S. Patent Application No. 63 / 383,599 filed on November 14, 2022, which is incorporated herein by reference in its entirety. In some embodiments, the FcRn antagonist is a population of FcRn antagonists, as described in U.S. Patent Application No. 63 / 383,599 filed on November 14, 2022, which is incorporated herein by reference in its entirety.

[0189] In one embodiment, the FcRn antagonist is agamod (CAS Reg. No. 1821402-21-4). As used herein, the term "agamod" is interchangeable with "agamod α". In some embodiments, agamod is agamod α-fcab.

[0190] In one embodiment, the anti-FcRn antibody is rozanolimab (UCB7665), nicalizumab (M281), onorimumab (ALXN1830 / SYNT001), or bartolimumab (IMVT-1401 / RVT1401 / HBM9161).

[0191] In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is nikalimab, also known as M281. Nicalimab is a full-length "Fc dead" IgG1 monoclonal antibody. Nicalimab is administered by intravenous infusion in a Phase 2 clinical trial for the treatment of myasthenia gravis (MG), warm antibody autoimmune hemolytic anemia (WAIHA), and hemolytic disease of the fetus and the newborn (HDFN). Nicalimab comprises the light chain (SEQ ID NO: 4) and heavy chain (SEQ ID NO: 5) sequences listed in Table 3 below:

[0192] Table 3. Heavy and light chain sequences of nikalimab

[0193]

[0194] In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is rozanolimab, also known as UCB 7665. Rozanolimab is a full-length humanized IgG4 monoclonal antibody. Rozanolimab is administered by subcutaneous infusion in ongoing clinical trials for MG, immune thrombocytopenia (ITP), and chronic inflammatory demyelinating polyneuropathy (CIDP). Rozanolimab comprises the light chain (SEQ ID NO: 6) and heavy chain (SEQ ID NO: 7) sequences shown in Table 4 below:

[0195] Table 4. Heavy and light chain sequences of Rozanolimumab

[0196]

[0197] In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is Onorimab, also known as SYNT001. Onorimab is another full-length humanized IgG4 monoclonal antibody. Onorimab is administered by intravenous infusion in a Phase 2 clinical trial for the treatment of WAIHA. Onorimab comprises the light chain (SEQ ID NO: 8) and heavy chain (SEQ ID NO: 9) sequences shown in Table 5 below:

[0198] Table 5. Heavy and light chain sequences of Onorimab

[0199]

[0200] In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is Bartolimab, also known as IMVT1401 / RVT1401 / HBM9161. Bartolimab is a full-length "Fc-null" IgG1 monoclonal antibody. Bartolimab is administered by subcutaneous injection in an ongoing Phase 2 clinical trial for the treatment of MG and Graves' ophthalmopathy. Bartolimab comprises the light chain (SEQ ID NO: 10) and heavy chain (SEQ ID NO: 11) sequences shown in Table 6 below:

[0201] Table 6. Heavy and light chain sequences of Batolimumab

[0202]

[0203] Pharmaceutical composition

[0204] In one aspect, the present disclosure provides a pharmaceutical composition comprising an FcRn antagonist, which is used in a method for treating bullous pemphigoid (BP). In certain embodiments, these compositions comprise a variant Fc region or its FcRn binding fragment or consist of the variant Fc region or its FcRn binding fragment, which specifically binds to FcRn, particularly human FcRn, with increased affinity and reduced pH dependence relative to the native Fc region. In other embodiments, the FcRn antagonist composition is an antibody or its antigen-binding fragment, which specifically binds to FcRn via its antigen-binding domain and inhibits the binding of the Fc region of an immunoglobulin to FcRn. In general, these FcRn antagonists inhibit the binding of Fc-containing agents (e.g., antibodies and immunoadhesins) to FcRn in vivo, which results in an increase in the degradation rate of Fc-containing agents and a decrease in the serum levels of these agents.

[0205] In one embodiment, the FcRn antagonist is agamod. Aggremod (ARGX-113) is a modified human immunoglobulin (Ig) γ (IgG) 1 derived Fc, which is a za allotype and binds to human FcRn with nanomolar affinity. Aggremod comprises an IgG1 Fc region (comprising the residues of SEQ ID NO: 2) and has been sequenced using ABDEG. TM The invention relates to a novel IgG inhibitor that is engineered to increase its affinity for FcRn at both physiological and acidic pH. Vaccaro C et al., Nat Biotechnol. 2005; 23(10): 1283. See also U.S. Patent No. 10,316,073, which is incorporated herein by reference in its entirety. The increased affinity of igamod for FcRn at both acidic and physiological pH results in the blockade of FcRn-mediated IgG recycling.

[0206] The molecular weight of Agamode is about 54kDa, which is about one-third of the molecular weight (MW about 150kDa) of full-length IgG. Therefore, 10mg Agamode is about 185nmol, so that the dosage of 10mg Agamode / kg body weight corresponds to about 185nmol Agamode / kg body weight, and the dosage of 25mg Agamode / kg body weight corresponds to about 462.5nmol Agamode / kg body weight. In contrast, the dosage of 10mg full-length IgG antibody / kg body weight corresponds to about 67nmol / kg body weight. In addition, the Agamode of 1000mg fixed dose corresponds to the fixed dose of about 18,500nmol Agamode, and the Agamode of 2000mg fixed dose corresponds to the fixed dose of about 37,000nmol Agamode.

[0207] Due to the increased affinity for FcRn at both acidic and neutral pH, agamod blocks the formation of FcRn / IgG complexes, which leads to the degradation of endogenous IgG (including autoantibodies that cause IgG-mediated autoimmune diseases). This blockade of FcRn by agamod leads to a rapid and substantial reduction in autoantibody levels, which is the basis of therapeutic strategies for treating autoimmune indications, where IgG autoantibodies are expected to play a central role in disease pathology, e.g., conditions such as BP.

[0208] Agamod is a prescription drug for myasthenia gravis, which is approved in the United States and Europe for the treatment of adults with systemic myasthenia gravis (gMG) who are positive for anti-acetylcholine receptor (AChR) antibodies, and in Japan for the treatment of adults with gMG who have not responded adequately to steroid or non-steroidal immunosuppressive therapy (IST). Agamod is being developed for both intravenous (IV) and subcutaneous (SC) administration routes for multiple indications. For SC administration, in certain embodiments, Agamod can be administered alone. Alternatively, for SC administration, in certain embodiments, Agamod can be co-formulated with hyaluronidase, such as, in particular, rHuPH20 for administration. Co-formulated materials will allow for administration of larger volumes.

[0209] rHuPH20 is a commercial product of Halozyme Recombinant (hyaluronidase human injection), called The product was approved by the FDA for marketing in the United States in December 2005. It is a tissue permeability regulator indicated as an adjuvant in SC fluid administration to achieve hydration, to increase the dispersion and absorption of other injected drugs, and to improve the reabsorption of radiopaque agents in SC urography.

[0210] rHuPH20 is a recombinant human hyaluronidase produced by Chinese hamster ovary (CHO) cells that have been genetically engineered to contain a DNA plasmid encoding a soluble fragment of human hyaluronidase (posterior head protein 20 [PH20]).

[0211] HZ202 rHuPH20 DS is currently and other biopharmaceuticals co-formulated with rHuPH20 DS. Thus, in certain embodiments, HZ202 rHuPH20 DS is used in an agamod / rHuPH20 co-formulated product for SC administration (ie, agamod PH20 SC).

[0212] SC injection volumes are typically limited to 2.5 mL due to concerns about injection pain associated with excessive volumes. rHuPH20 has been shown to provide a solution to the volume limitations associated with rapid SC injections. rHuPH20 acts locally and temporarily to depolymerize hyaluronic acid, a gel-like substance found in the subcutaneous layer of the skin. This causes a decrease in resistance to fluid flow and may increase the dispersion and absorption of injected drugs and fluids, allowing larger volumes to be injected with limited swelling or pain. rHuPH20 has been shown to allow rapid absorption of relatively large volumes (10 mL) when administered SC. Shpilberg O et al., Br J Cancer. 2013; 109(6): 1556-1561. When 10 mL of IgG solution was administered SC using 2000 U / mL of rHuPH20, very little injection site swelling was observed, whereas large injection site swelling was observed when 10 mL of IgG solution was injected without rHuPH20. Shpilberg O et al. Br J Cancer 2013;109(6):1556-1561.

[0213] rHuPH20 is transient and is not systemically absorbed. It has been shown not to exert long-term local effects. The half-life of rHuPH20 in the skin is less than 30 minutes. Due to the rapid natural turnover of hyaluronic acid, hyaluronic acid levels in the subcutaneous tissue return to normal within 24 to 48 hours.

[0214] rHuPH20 is approved in the U.S. and Europe for use in combination with other active ingredients (RITUXAN HYCELA for non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) TM / MABTHERA TM SC [rituximab] and HERCEPTIN HYLECTA TM / HERCEPTIN TM SC [trastuzumab]) was co-formulated for SC administration with an enzyme concentration of 2000 U / mL and an injectable volume ranging from 5 to 13.4 mL.

[0215] In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of about 20 mg to about 20,000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of about 200 mg to about 20,000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of about 300 mg to about 6000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of about 750 mg to about 3000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of about 1000 mg to about 2500 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of about 1000 mg to about 2000 mg.

[0216] In some embodiments, the pharmaceutical formulation comprises an amount of 20 mg to 20,000 mg of an FcRn antagonist. In some embodiments, the pharmaceutical formulation comprises an amount of 200 mg to 20,000 mg of an FcRn antagonist. In some embodiments, the pharmaceutical formulation comprises an amount of 300 mg to 6000 mg of an FcRn antagonist. In some embodiments, the pharmaceutical formulation comprises an amount of 750 mg to 3000 mg of an FcRn antagonist. In some embodiments, the pharmaceutical formulation comprises an amount of 1000 mg to 2500 mg of an FcRn antagonist. In some embodiments, the pharmaceutical formulation comprises an amount of 1000 mg to 2000 mg of an FcRn antagonist.

[0217] In some embodiments, the pharmaceutical formulation comprises about 1000 mg or about 2000 mg of the FcRn antagonist. In some embodiments, the pharmaceutical formulation comprises 1000 mg or 2000 mg of the FcRn antagonist. In some embodiments, the FcRn antagonist is igamod.

[0218] In some embodiments, the pharmaceutical formulation comprises an amount of about 800 mg to about 1200 mg of igatimod. In some embodiments, the pharmaceutical formulation comprises about 1000 mg of igatimod. In some embodiments, the pharmaceutical formulation comprises 1000 mg of igatimod.

[0219] In some embodiments, the pharmaceutical formulation comprises about 10 mg / mL to about 200 mg / mL igamod. In some embodiments, the pharmaceutical formulation comprises 10 mg / mL to 200 mg / mL igamod.

[0220] In some embodiments, the pharmaceutical formulation comprises about 20 mg / mL igatimod. In some embodiments, the pharmaceutical formulation comprises 20 mg / mL igatimod.

[0221] In some embodiments, the pharmaceutical formulation comprises about 180 mg / mL igatimod. In some embodiments, the pharmaceutical formulation comprises 180 mg / mL igatimod.

[0222] In some embodiments, the pharmaceutical formulation further comprises a hyaluronidase. In some embodiments, the hyaluronidase is a recombinant human hyaluronidase PH20 (rHuPH20).

[0223] Hyaluronidase can be present in the pharmaceutical formulation in any suitable amount. In one embodiment, the amount of hyaluronidase is about 1000U / mL to about 3000U / mL. In one embodiment, the amount of hyaluronidase is about 1000U / mL, about 1500U / mL, about 2000U / mL, about 2500U / mL or about 3000U / mL. In one embodiment, the amount of hyaluronidase is 2000U / mL.

[0224] In some embodiments, rHuPH20 is present in the pharmaceutical formulation in an amount of about 11,000 U or about 22,000 U. In some embodiments, rHuPH20 is present in the pharmaceutical formulation in an amount of 11,000 U or 22,000 U.

[0225] In any of the above embodiments, the pharmaceutical formulation can be in unit dosage form.

[0226] In one embodiment, the unit dosage form comprises the FcRn antagonist in the form of a dry formulation for dissolution, such as a lyophilized powder, a freeze-dried powder, or a water-free concentrate. In one embodiment, the dry formulation is contained in a hermetically sealed container, such as a vial, an ampoule, or a sachet.

[0227] In one embodiment, the unit dosage form comprises an FcRn antagonist in the form of a liquid formulation (e.g., in the form of an injectable or infusible solution). In one embodiment, the liquid formulation is contained in a hermetically sealed container, such as a vial, a sachet, a prefilled syringe, a prefilled auto-injector, or a cartridge for a reusable syringe or applicator.

[0228] In one embodiment, the unit dose of each vial may contain 0.5 mL, 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, 10 mL, 15 mL or 20 mL of an FcRn antagonist in the range of about 500 mg to about 2500 mg or about 1000 mg to about 2000 mg. In one embodiment, these formulations may be adjusted to a desired concentration by adding a sterile diluent to each vial.

[0229] The formulations disclosed herein include bulk pharmaceutical compositions that can be used to make pharmaceutical compositions (e.g., compositions suitable for administration to subjects or patients), which can be used to prepare unit dosage forms. In one embodiment, the compositions of the present invention are pharmaceutical compositions. Such compositions comprise a preventive or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., FcRn antagonists of the present invention or other prophylactic or therapeutic agents) and a pharmaceutically acceptable carrier. In one embodiment, these pharmaceutical compositions are formulated to be suitable for intravenous administration to a subject. In one embodiment, these pharmaceutical compositions are formulated to be suitable for subcutaneous administration to a subject.

[0230] method

[0231] In one aspect, methods for treating bullous pemphigoid (BP) using an FcRn antagonist are provided. In one aspect, provided herein is a method for treating BP in a subject in need thereof, the method comprising administering to the subject an effective amount of a human neonatal Fc receptor (FcRn) antagonist.

[0232] In some embodiments, BP is mild BP, moderate BP or severe BP. In some embodiments, BP is moderate BP or severe BP. In some embodiments, BP is moderate to severe BP. In certain embodiments, the FcRn antagonist is Agamod. An important goal and feature of the methods disclosed herein is to reduce or even eliminate the use of potentially toxic agents such as corticosteroids (e.g., prednisone) in the treatment of BP. Another important goal and feature of the methods disclosed herein is the rapid onset of disease control. Another important goal and feature of the methods disclosed herein is to achieve lasting complete remission on minimal or no treatment, preferably without the use of potentially toxic agents, such as corticosteroids (e.g., prednisone). Effective treatment of BP using FcRn antagonists may include at least one of the elements in the group consisting of the following items: reduction of skin blistering, reduction of itching, improvement of QoL (quality of life), safety and / or tolerability of FcRn antagonists, and steroid-sparing effects.

[0233] In certain embodiments, the severity of BP can be characterized by the investigator's overall assessment of bullous pemphigoid (IGA-BP). In certain embodiments, BP can be characterized as severe BP (e.g., IGA-BP score is 4). In certain embodiments, BP can be characterized as moderate BP (e.g., IGA-BP score is 3). In certain embodiments, BP can be characterized as mild BP (e.g., IGA-BP score is 2). In certain embodiments, BP can be characterized as almost clear (e.g., IGA-BP score is 1). In certain embodiments, BP can be characterized as clear (e.g., IGA-BP score is 0). In certain embodiments, BP can be characterized as moderate to severe BP (e.g., IGA-BP score is 3 or 4). In certain embodiments, an IGA-BP score of 0 or 1 indicates effective treatment of BP. In certain embodiments, an IGA-BP score of 0 indicates effective treatment of BP.

[0234] In some embodiments, BP is newly diagnosed BP, recurrent BP or refractory BP. Recurrent BP refers to any of the following conditions in patients who have achieved control of disease activity (CDA): 3 or more new lesions (such as blisters, eczematous lesions or urticaria plaques) within 1 month (4 weeks); at least 1 large (>10cm diameter) eczematous lesion that does not heal within 1 week; urticaria plaques that do not heal within 1 week; extension / enlargement of established lesions; and / or new daily pruritus symptoms or increased intensity of daily pruritus symptoms. Refractory BP refers to BP that cannot be controlled by current therapy. In some embodiments, refractory BP refers to BP that cannot be controlled by corticosteroids. In some embodiments, refractory BP refers to BP that cannot be controlled by immunosuppressants. In some embodiments, refractory BP refers to BP that cannot be controlled by corticosteroids and immunosuppressants. In some embodiments, refractory BP refers to BP that cannot be controlled by corticosteroids and immunosuppressants. In some embodiments, refractory BP refers to failure to achieve disease control with full therapeutic doses of systemic treatment (e.g., prednisone 1.5mg / kg / day for 3 weeks).

[0235] In some embodiments, the FcRn antagonist is administered at a fixed dose of about 20 mg to about 20,000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 200 mg to about 20,000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 300 mg to about 6000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 750 mg to about 3000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 1000 mg to about 2500 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 1000 mg to about 2000 mg. In some embodiments, the FcRn antagonist is agamod.

[0236] In some embodiments, the FcRn antagonist is administered at a fixed dose of 20 mg to 20,000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 200 mg to 20,000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 300 mg to 6000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 750 mg to 3000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 1000 mg to 2500 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 1000 mg to 2000 mg. In some embodiments, the FcRn antagonist is agamod.

[0237] In some embodiments, the FcRn antagonist is administered at a fixed dose of about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 500 mg, about 750 mg, about 1000 mg, about 1500 mg, about 2000 mg, about 2500 mg, about 3000 mg, about 4000 mg, about 5000 mg, about 6000 mg, about 7000 mg, about 8000 mg, about 9000 mg, about 10,000 mg, about 11,000 mg, about 12,000 mg, about 13,000 mg, about 14,000 mg, about 15,000 mg, about 16,000 mg, about 17,000 mg, about 18,000 mg, about 19,000 mg, or about 20,000 mg. In some embodiments, the FcRn antagonist is igamod.

[0238] In some embodiments, the FcRn antagonist is administered at a fixed dose of 20 mg, 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, 500 mg, 750 mg, 1000 mg, 1500 mg, 2000 mg, 2500 mg, 3000 mg, 4000 mg, 5000 mg, 6000 mg, 7000 mg, 8000 mg, 9000 mg, 10,000 mg, 11.000 mg, 12,000 mg, 13,000 mg, 14,000 mg, 15,000 mg, 16,000 mg, 17,000 mg, 18,000 mg, 19,000 mg or 20,000 mg. In some embodiments, the FcRn antagonist is igamod.

[0239] In some embodiments, the FcRn antagonist is administered at a dose of about 0.2 mg / kg to about 200 mg / kg. In some embodiments, the FcRn antagonist is administered at a dose of about 2 mg / kg to about 200 mg / kg. In some embodiments, the FcRn antagonist is administered at a dose of about 2 mg / kg to about 120 mg / kg. In some embodiments, the FcRn antagonist is administered at a dose of about 3 mg / kg to about 60 mg / kg. In some embodiments, the FcRn antagonist is administered at a dose of about 10 mg / kg to about 25 mg / kg. In some embodiments, the FcRn antagonist is agamod.

[0240] In some embodiments, the FcRn antagonist is administered at a dose of 0.2 mg / kg to 200 mg / kg. In some embodiments, the FcRn antagonist is administered at a dose of about 2 mg / kg to about 200 mg / kg. In some embodiments, the FcRn antagonist is administered at a dose of 2 mg / kg to 120 mg / kg. In some embodiments, the FcRn antagonist is administered at a dose of 3 mg / kg to 60 mg / kg. In some embodiments, the FcRn antagonist is administered at a dose of 10 mg / kg to 25 mg / kg. In some embodiments, the FcRn antagonist is agamod.

[0241] In some embodiments, the FcRn antagonist is administered at about 0.2 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 12.5 mg / kg, about 15 mg / kg, about 17.5 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about In some embodiments, the FcRn antagonist is igamod.

[0242] In some embodiments, the FcRn antagonist is administered at 0.2 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 12.5 mg / kg, 15 mg / kg, 17.5 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 5 In some embodiments, the FcRn antagonist is igamod.

[0243] In some embodiments, the FcRn antagonist is administered intravenously. In some embodiments, the FcRn antagonist is administered intravenously once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is agamod.

[0244] In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks at a dosage of about 0.2 mg / kg to about 200 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks at a dosage of about 2 mg / kg to about 200 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks at a dosage of about 2 mg / kg to about 120 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks at a dosage of about 3 mg / kg to about 60 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks at a dosage of about 10 mg / kg to about 25 mg / kg. In some embodiments, the FcRn antagonist is agamod.

[0245] In some embodiments, the FcRn antagonist is administered at about 0.2 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 12.5 mg / kg, about 15 mg / kg, about 17.5 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg. In some embodiments, the FcRn antagonist is agamod, for example, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, about 100 mg / kg, about 110 mg / kg, about 120 mg / kg, about 130 mg / kg, about 140 mg / kg, about 150 mg / kg, about 160 mg / kg, about 170 mg / kg, about 180 mg / kg, about 190 mg / kg or about 200 mg / kg is administered intravenously once a week or once every two weeks. In some embodiments, the FcRn antagonist is agamod.

[0246] In some embodiments, the FcRn antagonist is administered at 0.2 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 12.5 mg / kg, 15 mg / kg, 17.5 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, A dose of 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, 100 mg / kg, 110 mg / kg, 120 mg / kg, 130 mg / kg, 140 mg / kg, 150 mg / kg, 160 mg / kg, 170 mg / kg, 180 mg / kg, 190 mg / kg or 200 mg / kg is administered intravenously once a week or once every two weeks. In some embodiments, the FcRn antagonist is igamod.

[0247] In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks at a dose of about 10 mg / kg to about 30 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks at a dose of about 10 mg / kg to about 25 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks at a dose of about 10 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks at a dose of about 15 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks at a dose of about 20 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks at a dose of about 25 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks at a dose of about 30 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks at a dose of 10 mg / kg to 30 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks at a dose of 10 mg / kg to 25 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks at a dose of 10 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks at a dose of 15 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks at a dose of 20 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks at a dose of 25 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks at a dose of 30 mg / kg. In some embodiments, the FcRn antagonist is Agamod.

[0248] In some embodiments, the FcRn antagonist is administered subcutaneously. In some embodiments, the FcRn antagonist is administered subcutaneously once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is agamod.

[0249] In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 20 mg to about 20,000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 100 mg to about 10,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg to 2000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is Agamod.

[0250] In some embodiments, the FcRn antagonist is administered subcutaneously once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks at a fixed dose of about 20 mg, about 50 mg, about 100 mg, about 250 mg, about 500 mg, about 750 mg, about 1000 mg, about 1500 mg, about 2000 mg, about 3000 mg, about 4000 mg, about 5000 mg, about 6000 mg, about 7000 mg, about 8000 mg, about 9000 mg, about 10,000 mg, about 11,000 mg, about 12,000 mg, about 13,000 mg, about 14,000 mg, about 15,000 mg, about 16,000 mg, about 17,000 mg, about 18,000 mg, about 19,000 mg, or about 20,000 mg. In some embodiments, the FcRn antagonist is igamod.

[0251] In some embodiments, the FcRn antagonist is administered subcutaneously once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks at a fixed dose of 20 mg, 50 mg, 100 mg, 250 mg, 500 mg, 750 mg, 1000 mg, 1500 mg, 2000 mg, 3000 mg, 4000 mg, 5000 mg, 6000 mg, 7000 mg, 8000 mg, 9000 mg, 10,000 mg, 11.000 mg, 12,000 mg, 13,000 mg, 14,000 mg, 15,000 mg, 16,000 mg, 17,000 mg, 18,000 mg, 19,000 mg, or 20,000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg or 2000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is igamod.

[0252] In some embodiments, the FcRn antagonist is administered subcutaneously once a week or once every two weeks at a fixed dose of about 750 mg to about 3000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week or once every two weeks at a fixed dose of about 1000 mg to about 2000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week or once every two weeks at a fixed dose of about 1000 mg or about 2000 mg. In some embodiments, the FcRn antagonist is agamod.

[0253] In some embodiments, the FcRn antagonist is administered subcutaneously once a week or once every two weeks at a fixed dose of 750 mg to 3000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week or once every two weeks at a fixed dose of 1000 mg to 2000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week or once every two weeks at a fixed dose of 1000 mg or 2000 mg. In some embodiments, the FcRn antagonist is agamod.

[0254] In some embodiments, the FcRn antagonist is first administered subcutaneously twice on the same day at a fixed dose of about 1000 mg. In some embodiments, the FcRn antagonist is first administered subcutaneously twice on the same day at a fixed dose of 1000 mg. In some embodiments, the FcRn antagonist is agamod.

[0255] In some embodiments, for the first two administrations, the FcRn antagonist is administered subcutaneously at a fixed dose of about 2000 mg, and then subcutaneously at a fixed dose of about 1000 mg. In some embodiments, for the first two administrations, the FcRn antagonist is administered subcutaneously at a fixed dose of 2000 mg, and then subcutaneously at a fixed dose of 1000 mg. In some embodiments, the first two administrations of the FcRn antagonist are subcutaneously administered twice on the same day at a fixed dose of about 1000 mg. In some embodiments, the first two administrations of the FcRn antagonist are subcutaneously administered twice on the same day at a fixed dose of 1000 mg. In some embodiments, the FcRn antagonist is agamod.

[0256] In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a fixed dose of about 750 mg to about 1750 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a fixed dose of about 800 mg to about 1200 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a fixed dose of about 750 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a fixed dose of about 800 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a fixed dose of about 1000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a fixed dose of about 1200 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a fixed dose of about 1250 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a fixed dose of about 1500 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a fixed dose of about 1750 mg. In some embodiments, the FcRn antagonist is igamod.

[0257] In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a fixed dose of 750 mg to 1750 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a fixed dose of 800 mg to 1200 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a fixed dose of 750 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a fixed dose of 800 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a fixed dose of 1000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a fixed dose of 1200 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a fixed dose of 1250 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a fixed dose of 1500 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a fixed dose of 1750 mg. In some embodiments, the FcRn antagonist is agamod.

[0258] In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a dose of about 10 mg / kg to about 25 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a dose of about 10 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a dose of about 15 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a dose of about 20 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a dose of about 25 mg / kg. In some embodiments, the FcRn antagonist is agamod.

[0259] In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a dose of 10 mg / kg to 25 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a dose of 10 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a dose of 15 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a dose of 20 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a dose of 25 mg / kg. In some embodiments, the FcRn antagonist is agamod.

[0260] In some embodiments, the FcRn antagonist is first administered intravenously and then subcutaneously. In some embodiments, the FcRn antagonist is first administered intravenously and then subcutaneously at a fixed dose of 100 mg to 10,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is first administered intravenously and then subcutaneously at a fixed dose of 1000 mg or 2000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is agamod.

[0261] In some embodiments, one or more doses of the FcRn antagonist are administered intravenously and a subsequent dose of the FcRn antagonist is administered subcutaneously. In some embodiments, one or more doses of the FcRn antagonist are administered intravenously and a subsequent dose of the FcRn antagonist is administered subcutaneously, with a fixed dose of 100 mg to 10,000 mg, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, one or more doses of the FcRn antagonist are administered intravenously and a subsequent dose of the FcRn antagonist is administered subcutaneously, with a fixed dose of 1000 mg or 2000 mg, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is agamod.

[0262] In some embodiments, the FcRn antagonist is administered for 6, 12, 26, 36, or 52 weeks or less. In some embodiments, the FcRn antagonist is administered for 36 weeks or less. In some embodiments, the FcRn antagonist is administered for 52 weeks or less. In some embodiments, the FcRn antagonist is administered for at least 6, 12, 26, 36, or 52 weeks. In some embodiments, the FcRn antagonist is administered for at least 36 weeks. In some embodiments, the FcRn antagonist is administered for at least 52 weeks.

[0263] In some embodiments, the FcRn antagonist is administered once weekly in disease control or complete remission.

[0264] In some embodiments, the FcRn antagonist is rozanolimab. In some embodiments, rozanolimab is administered subcutaneously or intravenously. In some embodiments, rozanolimab is administered at a dose of about 0.2 mg / kg to about 200 mg / kg or at a fixed dose of about 20 mg to about 20,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

[0265] In some embodiments, rozanolizumab is administered at about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg g, about 25mg / kg, about 26mg / kg, about 27mg / kg, about 28mg / kg, about 29mg / kg, about 30mg / kg, about 31mg / kg, about 32mg / kg, about 33mg / kg, about 34mg / kg, about 35mg / kg, about 36mg / kg, about 37mg / kg, about 38mg / kg, about 39mg / kg, about 40mg / kg, about 41mg / kg, about 42mg / kg, about 43mg / kg, about 44mg / kg, about 45mg / kg, about 46mg / kg, about 47mg / kg, about 48mg / kg, about 49mg / kg, about 50mg / kg, about 51mg / kg, about 52mg / kg, about 53mg / kg, about 54mg / kg, about 55mg / kg, about 56mg / kg, about 57mg / kg, about 58mg / kg, about 59mg / kg, about 60mg / kg, about 61mg / kg, about 62mg / kg, about 63mg / kg, about 64mg / kg, about 65mg / kg, about 66mg / kg, about 67mg / kg, about 68mg / kg, about 69mg / kg, about 70mg / kg, about 71mg / kg, about 72mg / kg, about 73mg / kg, about 74mg / kg, about 75mg / kg, about 76mg / kg or about 100 mg / kg once a week.

[0266] In some embodiments, rozanolizumab is administered at about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg g, about 25mg / kg, about 26mg / kg, about 27mg / kg, about 28mg / kg, about 29mg / kg, about 30mg / kg, about 31mg / kg, about 32mg / kg, about 33mg / kg, about 34mg / kg, about 35mg / kg, about 36mg / kg, about 37mg / kg, about 38mg / kg, about 39mg / kg, about 40mg / kg, about 41mg / kg, about 42mg / kg, about 43mg / kg, about 44mg / kg, about 45mg / kg, about 46mg / kg, about 47mg / kg, about 48mg / kg, about 49mg / kg, about 50mg / kg, about 51mg / kg, about 52mg / kg, about 53mg / kg, about 54mg / kg, about 55mg / kg, about 56mg / kg, about 57mg / kg, about 58mg / kg, about 59mg / kg, about 60mg / kg, about 61mg / kg, about 62mg / kg, about 63mg / kg, about 64mg / kg, about 65mg / kg, about 66mg / kg, about 67mg / kg, about 68mg / kg, about 69mg / kg, about 70mg / kg, about 71mg / kg, about 72mg / kg, about 73mg / kg, about 74mg / kg, about 75mg / kg, about 76mg / kg or about 100 mg / kg once every two weeks.

[0267] In some embodiments, rozanolizumab is administered at about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg g, about 25mg / kg, about 26mg / kg, about 27mg / kg, about 28mg / kg, about 29mg / kg, about 30mg / kg, about 31mg / kg, about 32mg / kg, about 33mg / kg, about 34mg / kg, about 35mg / kg, about 36mg / kg, about 37mg / kg, about 38mg / kg, about 39mg / kg, about 40mg / kg, about 41mg / kg, about 42mg / kg, about 43mg / kg, about 44mg / kg, about 45mg / kg, about 46mg / kg, about 47mg / kg, about 48mg / kg, about 49mg / kg, about 50mg / kg, about 51mg / kg, about 52mg / kg, about 53mg / kg, about 54mg / kg, about 55mg / kg, about 56mg / kg, about 57mg / kg, about 58mg / kg, about 59mg / kg, about 60mg / kg, about 61mg / kg, about 62mg / kg, about 63mg / kg, about 64mg / kg, about 65mg / kg, about 66mg / kg, about 67mg / kg, about 68mg / kg, about 69mg / kg, about 70mg / kg, about 71mg / kg, about 72mg / kg, about 73mg / kg, about 74mg / kg, about 75mg / kg, about 76mg / kg or about 100 mg / kg once every three weeks.

[0268] In some embodiments, rozanolizumab is administered at about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg g, about 25mg / kg, about 26mg / kg, about 27mg / kg, about 28mg / kg, about 29mg / kg, about 30mg / kg, about 31mg / kg, about 32mg / kg, about 33mg / kg, about 34mg / kg, about 35mg / kg, about 36mg / kg, about 37mg / kg, about 38mg / kg, about 39mg / kg, about 40mg / kg, about 41mg / kg, about 42mg / kg, about 43mg / kg, about 44mg / kg, about 45mg / kg, about 46mg / kg, about 47mg / kg, about 48mg / kg, about 49mg / kg, about 50mg / kg, about 51mg / kg, about 52mg / kg, about 53mg / kg, about 54mg / kg, about 55mg / kg, about 56mg / kg, about 57mg / kg, about 58mg / kg, about 59mg / kg, about 60mg / kg, about 61mg / kg, about 62mg / kg, about 63mg / kg, about 64mg / kg, about 65mg / kg, about 66mg / kg, about 67mg / kg, about 68mg / kg, about 69mg / kg, about 70mg / kg, about 71mg / kg, about 72mg / kg, about 73mg / kg, about 74mg / kg, about 75mg / kg, about 76mg / kg or about 100 mg / kg once every four weeks.

[0269] In some embodiments, rozanolizumab is administered at about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg g, about 25mg / kg, about 26mg / kg, about 27mg / kg, about 28mg / kg, about 29mg / kg, about 30mg / kg, about 31mg / kg, about 32mg / kg, about 33mg / kg, about 34mg / kg, about 35mg / kg, about 36mg / kg, about 37mg / kg, about 38mg / kg, about 39mg / kg, about 40mg / kg, about 41mg / kg, about 42mg / kg, about 43mg / kg, about 44mg / kg, about 45mg / kg, about 46mg / kg, about 47mg / kg, about 48mg / kg, about 49mg / kg, about 50mg / kg, about 51mg / kg, about 52mg / kg, about 53mg / kg, about 54mg / kg, about 55mg / kg, about 56mg / kg, about 57mg / kg, about 58mg / kg, about 59mg / kg, about 60mg / kg, about 61mg / kg, about 62mg / kg, about 63mg / kg, about 64mg / kg, about 65mg / kg, about 66mg / kg, about 67mg / kg, about 68mg / kg, about 69mg / kg, about 70mg / kg, about 71mg / kg, about 72mg / kg, about 73mg / kg, about 74mg / kg, about 75mg / kg, about 76mg / kg or about 100 mg / kg once a month.

[0270] In some embodiments, the FcRn antagonist is nikalimab. In some embodiments, nikalimab is administered subcutaneously or intravenously. In some embodiments, nikalimab is administered at a dose of about 0.2 mg / kg to about 200 mg / kg or at a fixed dose of about 20 mg to about 20,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

[0271] In some embodiments, nikalimab is administered at about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg. , about 25mg / kg, about 26mg / kg, about 27mg / kg, about 28mg / kg, about 29mg / kg, about 30mg / kg, about 31mg / kg, about 32mg / kg, about 33mg / kg, about 34mg / kg, about 35mg / kg, about 36mg / kg, about 37mg / kg, about 38mg / kg, about 39mg / kg, about 40mg / kg, about 41mg / kg, about 42mg / kg, about 43mg / kg, about 44mg / kg, about 45mg / kg, about 46mg / kg, about 47mg / kg, about 48mg / kg, about 49mg / kg, about 50mg / kg kg, about 51mg / kg, about 52mg / kg, about 53mg / kg, about 54mg / kg, about 55mg / kg, about 56mg / kg, about 57mg / kg, about 58mg / kg, about 59mg / kg, about 60mg / kg, about 61mg / kg, about 62mg / kg, about 63mg / kg, about 64mg / kg, about 65mg / kg, about 66mg / kg, about 67mg / kg, about 68mg / kg, about 69mg / kg, about 70mg / kg, about 71mg / kg, about 72mg / kg, about 73mg / kg, about 74mg / kg, about 75mg / kg, about 76mg / kg or about 100 mg / kg once a week.

[0272] In some embodiments, nikalimab is administered at about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg. , about 25mg / kg, about 26mg / kg, about 27mg / kg, about 28mg / kg, about 29mg / kg, about 30mg / kg, about 31mg / kg, about 32mg / kg, about 33mg / kg, about 34mg / kg, about 35mg / kg, about 36mg / kg, about 37mg / kg, about 38mg / kg, about 39mg / kg, about 40mg / kg, about 41mg / kg, about 42mg / kg, about 43mg / kg, about 44mg / kg, about 45mg / kg, about 46mg / kg, about 47mg / kg, about 48mg / kg, about 49mg / kg, about 50mg / kg kg, about 51mg / kg, about 52mg / kg, about 53mg / kg, about 54mg / kg, about 55mg / kg, about 56mg / kg, about 57mg / kg, about 58mg / kg, about 59mg / kg, about 60mg / kg, about 61mg / kg, about 62mg / kg, about 63mg / kg, about 64mg / kg, about 65mg / kg, about 66mg / kg, about 67mg / kg, about 68mg / kg, about 69mg / kg, about 70mg / kg, about 71mg / kg, about 72mg / kg, about 73mg / kg, about 74mg / kg, about 75mg / kg, about 76m or about 100 mg / kg once every two weeks.

[0273] In some embodiments, nikalimab is administered at about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg. , about 25mg / kg, about 26mg / kg, about 27mg / kg, about 28mg / kg, about 29mg / kg, about 30mg / kg, about 31mg / kg, about 32mg / kg, about 33mg / kg, about 34mg / kg, about 35mg / kg, about 36mg / kg, about 37mg / kg, about 38mg / kg, about 39mg / kg, about 40mg / kg, about 41mg / kg, about 42mg / kg, about 43mg / kg, about 44mg / kg, about 45mg / kg, about 46mg / kg, about 47mg / kg, about 48mg / kg, about 49mg / kg, about 50mg / kg kg, about 51mg / kg, about 52mg / kg, about 53mg / kg, about 54mg / kg, about 55mg / kg, about 56mg / kg, about 57mg / kg, about 58mg / kg, about 59mg / kg, about 60mg / kg, about 61mg / kg, about 62mg / kg, about 63mg / kg, about 64mg / kg, about 65mg / kg, about 66mg / kg, about 67mg / kg, about 68mg / kg, about 69mg / kg, about 70mg / kg, about 71mg / kg, about 72mg / kg, about 73mg / kg, about 74mg / kg, about 75mg / kg, about 76m or about 100 mg / kg once every three weeks.

[0274] In some embodiments, nikalimab is administered at about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg. , about 25mg / kg, about 26mg / kg, about 27mg / kg, about 28mg / kg, about 29mg / kg, about 30mg / kg, about 31mg / kg, about 32mg / kg, about 33mg / kg, about 34mg / kg, about 35mg / kg, about 36mg / kg, about 37mg / kg, about 38mg / kg, about 39mg / kg, about 40mg / kg, about 41mg / kg, about 42mg / kg, about 43mg / kg, about 44mg / kg, about 45mg / kg, about 46mg / kg, about 47mg / kg, about 48mg / kg, about 49mg / kg, about 50mg / kg kg, about 51mg / kg, about 52mg / kg, about 53mg / kg, about 54mg / kg, about 55mg / kg, about 56mg / kg, about 57mg / kg, about 58mg / kg, about 59mg / kg, about 60mg / kg, about 61mg / kg, about 62mg / kg, about 63mg / kg, about 64mg / kg, about 65mg / kg, about 66mg / kg, about 67mg / kg, about 68mg / kg, about 69mg / kg, about 70mg / kg, about 71mg / kg, about 72mg / kg, about 73mg / kg, about 74mg / kg, about 75mg / kg, about 76m or about 100 mg / kg once every four weeks.

[0275] In some embodiments, nikalimab is administered at about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg. , about 25mg / kg, about 26mg / kg, about 27mg / kg, about 28mg / kg, about 29mg / kg, about 30mg / kg, about 31mg / kg, about 32mg / kg, about 33mg / kg, about 34mg / kg, about 35mg / kg, about 36mg / kg, about 37mg / kg, about 38mg / kg, about 39mg / kg, about 40mg / kg, about 41mg / kg, about 42mg / kg, about 43mg / kg, about 44mg / kg, about 45mg / kg, about 46mg / kg, about 47mg / kg, about 48mg / kg, about 49mg / kg, about 50mg / kg kg, about 51mg / kg, about 52mg / kg, about 53mg / kg, about 54mg / kg, about 55mg / kg, about 56mg / kg, about 57mg / kg, about 58mg / kg, about 59mg / kg, about 60mg / kg, about 61mg / kg, about 62mg / kg, about 63mg / kg, about 64mg / kg, about 65mg / kg, about 66mg / kg, about 67mg / kg, about 68mg / kg, about 69mg / kg, about 70mg / kg, about 71mg / kg, about 72mg / kg, about 73mg / kg, about 74mg / kg, about 75mg / kg, about 76mg / kg or about 100 mg / kg once a month.

[0276] In some embodiments, the FcRn antagonist is Onorimumab. In some embodiments, Onorimumab is administered subcutaneously or intravenously. In some embodiments, Onorimumab is administered once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks at a dosage of about 0.2 mg / kg to about 200 mg / kg or with a fixed dose of about 20 mg to about 20,000 mg.

[0277] In some embodiments, onorimab is administered at about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg. , about 25mg / kg, about 26mg / kg, about 27mg / kg, about 28mg / kg, about 29mg / kg, about 30mg / kg, about 31mg / kg, about 32mg / kg, about 33mg / kg, about 34mg / kg, about 35mg / kg, about 36mg / kg, about 37mg / kg, about 38mg / kg, about 39mg / kg, about 40mg / kg, about 41mg / kg, about 42mg / kg, about 43mg / kg, about 44mg / kg, about 45mg / kg, about 46mg / kg, about 47mg / kg, about 48mg / kg, about 49mg / kg, about 50mg / kg kg, about 51mg / kg, about 52mg / kg, about 53mg / kg, about 54mg / kg, about 55mg / kg, about 56mg / kg, about 57mg / kg, about 58mg / kg, about 59mg / kg, about 60mg / kg, about 61mg / kg, about 62mg / kg, about 63mg / kg, about 64mg / kg, about 65mg / kg, about 66mg / kg, about 67mg / kg, about 68mg / kg, about 69mg / kg, about 70mg / kg, about 71mg / kg, about 72mg / kg, about 73mg / kg, about 74mg / kg, about 75mg / kg, about 76mg / kg or about 100 mg / kg once a week.

[0278] In some embodiments, onorimab is administered at about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg. , about 25mg / kg, about 26mg / kg, about 27mg / kg, about 28mg / kg, about 29mg / kg, about 30mg / kg, about 31mg / kg, about 32mg / kg, about 33mg / kg, about 34mg / kg, about 35mg / kg, about 36mg / kg, about 37mg / kg, about 38mg / kg, about 39mg / kg, about 40mg / kg, about 41mg / kg, about 42mg / kg, about 43mg / kg, about 44mg / kg, about 45mg / kg, about 46mg / kg, about 47mg / kg, about 48mg / kg, about 49mg / kg, about 50mg / kg kg, about 51mg / kg, about 52mg / kg, about 53mg / kg, about 54mg / kg, about 55mg / kg, about 56mg / kg, about 57mg / kg, about 58mg / kg, about 59mg / kg, about 60mg / kg, about 61mg / kg, about 62mg / kg, about 63mg / kg, about 64mg / kg, about 65mg / kg, about 66mg / kg, about 67mg / kg, about 68mg / kg, about 69mg / kg, about 70mg / kg, about 71mg / kg, about 72mg / kg, about 73mg / kg, about 74mg / kg, about 75mg / kg, about 76m or about 100 mg / kg once every two weeks.

[0279] In some embodiments, onorimab is administered at about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg. , about 25mg / kg, about 26mg / kg, about 27mg / kg, about 28mg / kg, about 29mg / kg, about 30mg / kg, about 31mg / kg, about 32mg / kg, about 33mg / kg, about 34mg / kg, about 35mg / kg, about 36mg / kg, about 37mg / kg, about 38mg / kg, about 39mg / kg, about 40mg / kg, about 41mg / kg, about 42mg / kg, about 43mg / kg, about 44mg / kg, about 45mg / kg, about 46mg / kg, about 47mg / kg, about 48mg / kg, about 49mg / kg, about 50mg / kg kg, about 51mg / kg, about 52mg / kg, about 53mg / kg, about 54mg / kg, about 55mg / kg, about 56mg / kg, about 57mg / kg, about 58mg / kg, about 59mg / kg, about 60mg / kg, about 61mg / kg, about 62mg / kg, about 63mg / kg, about 64mg / kg, about 65mg / kg, about 66mg / kg, about 67mg / kg, about 68mg / kg, about 69mg / kg, about 70mg / kg, about 71mg / kg, about 72mg / kg, about 73mg / kg, about 74mg / kg, about 75mg / kg, about 76m or about 100 mg / kg once every three weeks.

[0280] In some embodiments, onorimab is administered at about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg. , about 25mg / kg, about 26mg / kg, about 27mg / kg, about 28mg / kg, about 29mg / kg, about 30mg / kg, about 31mg / kg, about 32mg / kg, about 33mg / kg, about 34mg / kg, about 35mg / kg, about 36mg / kg, about 37mg / kg, about 38mg / kg, about 39mg / kg, about 40mg / kg, about 41mg / kg, about 42mg / kg, about 43mg / kg, about 44mg / kg, about 45mg / kg, about 46mg / kg, about 47mg / kg, about 48mg / kg, about 49mg / kg, about 50mg / kg kg, about 51mg / kg, about 52mg / kg, about 53mg / kg, about 54mg / kg, about 55mg / kg, about 56mg / kg, about 57mg / kg, about 58mg / kg, about 59mg / kg, about 60mg / kg, about 61mg / kg, about 62mg / kg, about 63mg / kg, about 64mg / kg, about 65mg / kg, about 66mg / kg, about 67mg / kg, about 68mg / kg, about 69mg / kg, about 70mg / kg, about 71mg / kg, about 72mg / kg, about 73mg / kg, about 74mg / kg, about 75mg / kg, about 76m or about 100 mg / kg once every four weeks.

[0281] In some embodiments, onorimab is administered at about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg. , about 25mg / kg, about 26mg / kg, about 27mg / kg, about 28mg / kg, about 29mg / kg, about 30mg / kg, about 31mg / kg, about 32mg / kg, about 33mg / kg, about 34mg / kg, about 35mg / kg, about 36mg / kg, about 37mg / kg, about 38mg / kg, about 39mg / kg, about 40mg / kg, about 41mg / kg, about 42mg / kg, about 43mg / kg, about 44mg / kg, about 45mg / kg, about 46mg / kg, about 47mg / kg, about 48mg / kg, about 49mg / kg, about 50mg / kg kg, about 51mg / kg, about 52mg / kg, about 53mg / kg, about 54mg / kg, about 55mg / kg, about 56mg / kg, about 57mg / kg, about 58mg / kg, about 59mg / kg, about 60mg / kg, about 61mg / kg, about 62mg / kg, about 63mg / kg, about 64mg / kg, about 65mg / kg, about 66mg / kg, about 67mg / kg, about 68mg / kg, about 69mg / kg, about 70mg / kg, about 71mg / kg, about 72mg / kg, about 73mg / kg, about 74mg / kg, about 75mg / kg, about 76mg / kg or about 100 mg / kg once a month.

[0282] In some embodiments, onorimab is administered intravenously at a dose of about 30 mg / kg once a week for three weeks and then administered intravenously at a dose of 10 mg / kg every other week.

[0283] In some embodiments, the FcRn antagonist is Bartolimumab. In some embodiments, Bartolimumab is administered subcutaneously or intravenously. In some embodiments, Bartolimumab is administered at a dose of about 0.2 mg / kg to about 200 mg / kg or at a fixed dose of about 20 mg to about 20,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

[0284] In some embodiments, Batolimumab is administered at about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg. , about 25mg / kg, about 26mg / kg, about 27mg / kg, about 28mg / kg, about 29mg / kg, about 30mg / kg, about 31mg / kg, about 32mg / kg, about 33mg / kg, about 34mg / kg, about 35mg / kg, about 36mg / kg, about 37mg / kg, about 38mg / kg, about 39mg / kg, about 40mg / kg, about 41mg / kg, about 42mg / kg, about 43mg / kg, about 44mg / kg, about 45mg / kg, about 46mg / kg, about 47mg / kg, about 48mg / kg, about 49mg / kg, about 50mg / kg kg, about 51mg / kg, about 52mg / kg, about 53mg / kg, about 54mg / kg, about 55mg / kg, about 56mg / kg, about 57mg / kg, about 58mg / kg, about 59mg / kg, about 60mg / kg, about 61mg / kg, about 62mg / kg, about 63mg / kg, about 64mg / kg, about 65mg / kg, about 66mg / kg, about 67mg / kg, about 68mg / kg, about 69mg / kg, about 70mg / kg, about 71mg / kg, about 72mg / kg, about 73mg / kg, about 74mg / kg, about 75mg / kg, about 76mg / kg or about 100 mg / kg once a week.

[0285] In some embodiments, Batolimumab is administered at about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg. , about 25mg / kg, about 26mg / kg, about 27mg / kg, about 28mg / kg, about 29mg / kg, about 30mg / kg, about 31mg / kg, about 32mg / kg, about 33mg / kg, about 34mg / kg, about 35mg / kg, about 36mg / kg, about 37mg / kg, about 38mg / kg, about 39mg / kg, about 40mg / kg, about 41mg / kg, about 42mg / kg, about 43mg / kg, about 44mg / kg, about 45mg / kg, about 46mg / kg, about 47mg / kg, about 48mg / kg, about 49mg / kg, about 50mg / kg kg, about 51mg / kg, about 52mg / kg, about 53mg / kg, about 54mg / kg, about 55mg / kg, about 56mg / kg, about 57mg / kg, about 58mg / kg, about 59mg / kg, about 60mg / kg, about 61mg / kg, about 62mg / kg, about 63mg / kg, about 64mg / kg, about 65mg / kg, about 66mg / kg, about 67mg / kg, about 68mg / kg, about 69mg / kg, about 70mg / kg, about 71mg / kg, about 72mg / kg, about 73mg / kg, about 74mg / kg, about 75mg / kg, about 76m or about 100 mg / kg once every two weeks.

[0286] In some embodiments, Batolimumab is administered at about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg. , about 25mg / kg, about 26mg / kg, about 27mg / kg, about 28mg / kg, about 29mg / kg, about 30mg / kg, about 31mg / kg, about 32mg / kg, about 33mg / kg, about 34mg / kg, about 35mg / kg, about 36mg / kg, about 37mg / kg, about 38mg / kg, about 39mg / kg, about 40mg / kg, about 41mg / kg, about 42mg / kg, about 43mg / kg, about 44mg / kg, about 45mg / kg, about 46mg / kg, about 47mg / kg, about 48mg / kg, about 49mg / kg, about 50mg / kg kg, about 51mg / kg, about 52mg / kg, about 53mg / kg, about 54mg / kg, about 55mg / kg, about 56mg / kg, about 57mg / kg, about 58mg / kg, about 59mg / kg, about 60mg / kg, about 61mg / kg, about 62mg / kg, about 63mg / kg, about 64mg / kg, about 65mg / kg, about 66mg / kg, about 67mg / kg, about 68mg / kg, about 69mg / kg, about 70mg / kg, about 71mg / kg, about 72mg / kg, about 73mg / kg, about 74mg / kg, about 75mg / kg, about 76m or about 100 mg / kg once every three weeks.

[0287] In some embodiments, Batolimumab is administered at about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg. , about 25mg / kg, about 26mg / kg, about 27mg / kg, about 28mg / kg, about 29mg / kg, about 30mg / kg, about 31mg / kg, about 32mg / kg, about 33mg / kg, about 34mg / kg, about 35mg / kg, about 36mg / kg, about 37mg / kg, about 38mg / kg, about 39mg / kg, about 40mg / kg, about 41mg / kg, about 42mg / kg, about 43mg / kg, about 44mg / kg, about 45mg / kg, about 46mg / kg, about 47mg / kg, about 48mg / kg, about 49mg / kg, about 50mg / kg kg, about 51mg / kg, about 52mg / kg, about 53mg / kg, about 54mg / kg, about 55mg / kg, about 56mg / kg, about 57mg / kg, about 58mg / kg, about 59mg / kg, about 60mg / kg, about 61mg / kg, about 62mg / kg, about 63mg / kg, about 64mg / kg, about 65mg / kg, about 66mg / kg, about 67mg / kg, about 68mg / kg, about 69mg / kg, about 70mg / kg, about 71mg / kg, about 72mg / kg, about 73mg / kg, about 74mg / kg, about 75mg / kg, about 76m or about 100 mg / kg once every four weeks.

[0288] In some embodiments, Batolimumab is administered at about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg. , about 25mg / kg, about 26mg / kg, about 27mg / kg, about 28mg / kg, about 29mg / kg, about 30mg / kg, about 31mg / kg, about 32mg / kg, about 33mg / kg, about 34mg / kg, about 35mg / kg, about 36mg / kg, about 37mg / kg, about 38mg / kg, about 39mg / kg, about 40mg / kg, about 41mg / kg, about 42mg / kg, about 43mg / kg, about 44mg / kg, about 45mg / kg, about 46mg / kg, about 47mg / kg, about 48mg / kg, about 49mg / kg, about 50mg / kg kg, about 51mg / kg, about 52mg / kg, about 53mg / kg, about 54mg / kg, about 55mg / kg, about 56mg / kg, about 57mg / kg, about 58mg / kg, about 59mg / kg, about 60mg / kg, about 61mg / kg, about 62mg / kg, about 63mg / kg, about 64mg / kg, about 65mg / kg, about 66mg / kg, about 67mg / kg, about 68mg / kg, about 69mg / kg, about 70mg / kg, about 71mg / kg, about 72mg / kg, about 73mg / kg, about 74mg / kg, about 75mg / kg, about 76mg / kg or about 100 mg / kg once a month.

[0289] In one embodiment, the method further comprises administering an effective amount of a corticosteroid and / or an immunosuppressant (such as methotrexate, mycophenolate mofetil (MMF), azathioprine, cyclophosphamide, doxycycline, and dapsone) to the subject. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of 2.5 mg / day to 20 mg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of 5 mg / day to 20 mg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of 7.5 mg / day to 20 mg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of 8 mg / day to 15 mg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of 10 mg / day to 15 mg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 20 mg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 10 mg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 7.5 mg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 5 mg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 2.5 mg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 1 mg / kg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 0.75 mg / kg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 0.5 mg / kg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 0.4 mg / kg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 0.3 mg / kg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 0.25 mg / kg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 0.2 mg / kg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 0.15 mg / kg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 0.1 mg / kg / day.

[0290] Corticosteroids can be oral corticosteroids, topical corticosteroids or both oral corticosteroids and topical corticosteroids. In certain embodiments, corticosteroids are oral corticosteroids. Examples of oral corticosteroids include but are not limited to betamethasone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, prednisolone and triamcinolone. In certain embodiments, corticosteroids are topical corticosteroids. Topical corticosteroids are well-known and include compounds of various effects and formulations. These are usually formulated as ointments, creams, oils, lotions, shampoos, foams and / or gels. Examples of commercially available topical corticosteroids include alclometasone dipropionate, amcinonide, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, desonide, desoximetasone, diflucortolone valerate, diflorasone diacetate, fluocinolone acetonide, fluocinolone acetonide, flurandrenolide, fluticasone propionate, halcinonide, halobetasol propionate, hydrocortisone, hydrocortisone 17-butyrate, hydrocortisone acetate, hydrocortisone valerate, methylprednisolone acetate, mometasone furoate, prednicarbate, and triamcinolone acetonide. Topical corticosteroids can be conveniently applied topically to the affected area or lesion in need of treatment, thereby limiting adverse systemic effects of corticosteroid therapy.

[0291] In one embodiment, during or after treatment with an FcRn antagonist, the subject's corticosteroid dosage regimen is gradually reduced. In one embodiment, gradually reducing the corticosteroid regimen is to reduce the dosage of the corticosteroid or reduce its frequency of administration. In one embodiment, the dosage of the corticosteroid is reduced after CDA is achieved or alleviated (partially or completely). In one embodiment, the dosage of the corticosteroid is reduced after CDA has lasted for at least two weeks. In one embodiment, the dosage of the corticosteroid is reduced by following a gradually reduced schedule. This article provides an example of a gradually reduced schedule that can be used to reduce the dosage of the corticosteroid. It will be appreciated by those skilled in the art that the gradually reduced schedule can vary and can be adjusted according to multiple subject-specific factors, such as the appearance of the initial corticosteroid dosage, new lesions or other BP symptoms, the overall health of the subject, etc.

[0292] In some embodiments, after two weeks of continued CDA, the daily dose of prednisone (or equivalent OCS) is reduced from 0.5 mg / kg / day to 0.3 mg / kg / day, from 0.3 mg / kg / day to 0.2 mg / kg / day, from 0.2 mg / kg / day to 0.15 mg / kg / day, and from 0.15 mg / kg / day to 0.1 mg / kg / day. In some embodiments, each daily dose of prednisone (or equivalent OCS) is maintained for at least two weeks before further dose reduction. In some embodiments, the daily dose of prednisone (or equivalent OCS) is maintained at 0.3 mg / kg / day for at least 2 weeks, then maintained at 0.2 mg / kg / day for at least 2 weeks, then maintained at 0.15 mg / kg / day for at least 2 weeks, and then maintained at 0.1 mg / kg / day for at least 2 weeks. In some embodiments, the daily dose of prednisone (or equivalent OCS) is maintained at 0.3 mg / kg / day for at least 2 weeks, then maintained at 0.2 mg / kg / day for at least 2 weeks, then maintained at 0.15 mg / kg / day for at least 2 weeks, and then maintained at 0.1 mg / kg / day for at least 8 weeks. In some embodiments, each daily dose is maintained for two weeks as long as no new lesions appear.

[0293] In some embodiments, after two weeks of sustained disease control, the daily dose of prednisone (or equivalent OCS) is reduced from 0.75 mg / kg / day to 0.5 mg / kg / day, from 0.5 mg / kg / day to 0.3 mg / kg / day, from 0.3 mg / kg / day to 0.2 mg / kg / day, from 0.2 mg / kg / day to 0.15 mg / kg / day, and from 0.15 mg / kg / day to 0.1 mg / kg / day. In some embodiments, each daily dose of prednisone (or equivalent OCS) is maintained for at least two weeks before further dose reduction. In some embodiments, the daily dose of prednisone (or equivalent OCS) is maintained at 0.5 mg / kg / day for at least 2 weeks, then maintained at 0.3 mg / kg / day for at least 2 weeks, then maintained at 0.2 mg / kg / day for at least 2 weeks, then maintained at 0.15 mg / kg / day for at least 2 weeks, and then maintained at 0.1 mg / kg / day for at least 2 weeks. In some embodiments, the daily dose of prednisone (or equivalent OCS) is maintained at 0.5 mg / kg / day for at least 2 weeks, then maintained at 0.3 mg / kg / day for at least 2 weeks, then maintained at 0.2 mg / kg / day for at least 2 weeks, then maintained at 0.15 mg / kg / day for at least 2 weeks, and then maintained at 0.1 mg / kg / day for at least 8 weeks. In some embodiments, each daily dose is maintained for two weeks as long as no new lesions appear.

[0294] In some embodiments, after two weeks of sustained disease control, the daily dose of prednisone (or equivalent OCS) is reduced from 1 mg / kg / day to 0.75 mg / kg / day, from 0.75 mg / kg / day to 0.5 mg / kg / day, from 0.5 mg / kg / day to 0.3 mg / kg / day, from 0.3 mg / kg / day to 0.2 mg / kg / day, from 0.2 mg / kg / day to 0.15 mg / kg / day, and from 0.15 mg / kg / day to 0.1 mg / kg / day. In some embodiments, each daily dose of prednisone (or equivalent OCS) is maintained for at least two weeks before further dose reduction. In some embodiments, the daily dose of prednisone (or equivalent OCS) is maintained at 0.75mg / kg / day for at least 2 weeks, then maintained at 0.5mg / kg / day for at least 2 weeks, then maintained at 0.3mg / kg / day for at least 2 weeks, then maintained at 0.2mg / kg / day for at least 2 weeks, then maintained at 0.15mg / kg / day for at least 2 weeks, and then maintained at 0.1mg / kg / day for at least 2 weeks. In some embodiments, the daily dose of prednisone (or equivalent OCS) is maintained at 0.75mg / kg / day for at least 2 weeks, then maintained at 0.5mg / kg / day for at least 2 weeks, then maintained at 0.3mg / kg / day for at least 2 weeks, then maintained at 0.2mg / kg / day for at least 2 weeks, then maintained at 0.15mg / kg / day for at least 2 weeks, and then maintained at 0.1mg / kg / day for at least 8 weeks. In some embodiments, each daily dose is maintained for two weeks as long as no new lesions appear.

[0295] After being maintained at 0.1 mg / kg / day for at least 2 weeks, the daily dose of prednisone (or equivalent OCS) can be optionally further reduced by 2.5 mg every two weeks for one or more two-week periods. In some embodiments, the daily dose of prednisone (or equivalent OCS) is maintained at 0.1 mg / kg / day for at least 8 weeks, and then further reduced by 2.5 mg every two weeks for one or more two-week periods. In some embodiments, the daily dose of prednisone (or equivalent OCS) is reduced by 2.5 mg every two weeks for one or more two-week periods until the daily dose of prednisone (or equivalent OCS) is zero (i.e., interruption of corticosteroid therapy). In some embodiments, each daily dose is maintained for two weeks as long as no new lesions appear.

[0296] Alternatively, after being maintained at 0.1 mg / kg / day for at least 2 weeks, the daily dose of prednisone (or equivalent OCS) can be optionally further reduced by 1 mg per week for one or more time periods of one week. In some embodiments, the daily dose of prednisone (or equivalent OCS) is maintained at 0.1 mg / kg / day for at least 8 weeks, and then further reduced by 1 mg per week for one or more time periods of one week. In some embodiments, the daily dose of prednisone (or equivalent OCS) is reduced by 1 mg per week for one or more time periods of one week until the daily dose of prednisone (or equivalent OCS) is zero (i.e., interruption of corticosteroid therapy). In some embodiments, each daily dose is maintained for one week as long as no new lesions occur.

[0297] In some embodiments, the FcRn antagonist is administered during the induction phase and the maintenance phase. In certain embodiments, during the induction phase, the FcRn antagonist is administered once a week or more frequently, for example, twice a week or once every other day. In certain embodiments, during the induction phase, the FcRn antagonist is administered at a frequency lower than once a week, for example, once every other week. In certain embodiments, (i) during the induction phase, the FcRn antagonist is administered once a week simultaneously with a corticosteroid and / or an immunosuppressant; and (ii) during the maintenance phase, the FcRn antagonist dose is reduced by 1 and / or the FcRn antagonist dosing interval is extended, for example, to once every two weeks, with or without the use of corticosteroids and / or immunosuppressants. In certain embodiments, during the maintenance phase, the corticosteroid dose is reduced and / or the corticosteroid dosing interval is extended. In some embodiments, (i) during the induction phase, the FcRn antagonist is administered at a dose of 1000 mg once per week; and (ii) during the maintenance phase, the FcRn antagonist is administered at a dose of 1000 mg once every two weeks.

[0298] In some embodiments, the FcRn antagonist is administered during the induction phase and the consolidation phase. In certain embodiments, during the induction phase, the FcRn antagonist is administered once a week or more frequently, for example, twice a week or once every other day. In certain embodiments, during the induction phase, the FcRn antagonist is administered at a frequency lower than once a week, for example, once every other week. In certain embodiments, (i) during the induction phase, the FcRn antagonist is administered once a week and a corticosteroid (e.g., 0.5 mg prednisone / kg / day or equivalent OCS) is administered until the disease is controlled, and (ii) during the consolidation phase, the FcRn antagonist dose is reduced and / or the FcRn antagonist dosing interval is extended, for example, extended to once every two weeks, and / or the corticosteroid dose is reduced and / or the corticosteroid dosing interval is extended to the consolidation end dose or the dosing interval that effectively prevents the appearance of new lesions.

[0299] In certain embodiments, (i) during the induction phase, the FcRn antagonist is administered once weekly and a corticosteroid (e.g., 0.5 mg prednisone / kg / day or equivalent OCS) is administered until disease control, and (ii) during the consolidation phase, the FcRn antagonist dose is reduced and / or the FcRn antagonist dosing interval is extended, e.g., to once every two weeks, to the end-of-consolidation dose, or to a dosing interval effective to prevent the appearance of new lesions.

[0300] In certain embodiments, (i) during the induction phase, the FcRn antagonist is administered once weekly and a corticosteroid (e.g., 0.5 mg prednisone / kg / day or equivalent OCS) is administered until disease control, and (ii) during the consolidation phase, the corticosteroid dose is reduced and / or the corticosteroid dosing interval is extended to the end-of-consolidation dose or to a dosing interval effective to prevent the appearance of new lesions.

[0301] In certain embodiments, (i) during the induction phase, the FcRn antagonist is administered once a week and a corticosteroid (e.g., 0.5 mg prednisone / kg / day or equivalent OCS) is administered until disease control, and (ii) during the consolidation phase, the FcRn antagonist dose is reduced and / or the FcRn antagonist dosing interval is extended, e.g., to once every two weeks, and the corticosteroid dose is reduced and / or the corticosteroid dosing interval is extended to the end-of-consolidation dose or to a dosing interval effective to prevent the appearance of new lesions.

[0302] In some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously at a fixed dose of about 750 mg to about 3000 mg. In some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously at a fixed dose of about 750 mg to about 2000 mg. In some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously at a fixed dose of about 750 mg. In some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously at a fixed dose of about 1000 mg. In some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously at a fixed dose of about 1250 mg. In some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously at a fixed dose of about 1500 mg. In some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously at a fixed dose of about 1750 mg. In some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously at a fixed dose of about 2000 mg.

[0303] In some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg. In some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 2000 mg. In some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg. In some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg. In some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously at a fixed dose of 1250 mg. In some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously at a fixed dose of 1500 mg. In some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously at a fixed dose of 1750 mg. In some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously at a fixed dose of 2000 mg.

[0304] In some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously at a dose of about 10 mg / kg to about 25 mg / kg. In some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously at a dose of about 10 mg / kg. In some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously at a dose of about 15 mg / kg; in some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously at a dose of about 20 mg / kg; in some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously at a dose of about 25 mg / kg.

[0305] In some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously at a dose of 10 mg / kg to 25 mg / kg. In some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously at a dose of 10 mg / kg; in some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously at a dose of 15 mg / kg; in some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously at a dose of 20 mg / kg; in some embodiments, during the induction period, the FcRn antagonist is administered subcutaneously at a dose of 25 mg / kg.

[0306] In some embodiments, during the induction period, the FcRn antagonist is administered intravenously at a dose of about 10 mg / kg to about 25 mg / kg. In some embodiments, during the induction period, the FcRn antagonist is administered intravenously at a dose of about 10 mg / kg. In some embodiments, during the induction period, the FcRn antagonist is administered intravenously at a dose of about 15 mg / kg; in some embodiments, during the induction period, the FcRn antagonist is administered intravenously at a dose of about 20 mg / kg; in some embodiments, during the induction period, the FcRn antagonist is administered intravenously at a dose of about 25 mg / kg.

[0307] In some embodiments, during the induction period, the FcRn antagonist is administered intravenously at a dose of 10 mg / kg to 25 mg / kg. In some embodiments, during the induction period, the FcRn antagonist is administered intravenously at a dose of 10 mg / kg; in some embodiments, during the induction period, the FcRn antagonist is administered intravenously at a dose of 15 mg / kg; in some embodiments, during the induction period, the FcRn antagonist is administered intravenously at a dose of 20 mg / kg; in some embodiments, during the induction period, the FcRn antagonist is administered intravenously at a dose of 25 mg / kg.

[0308] In some embodiments, during the consolidation period, the FcRn antagonist is administered once a week or less frequently. For example, in certain embodiments, during the consolidation period, the FcRn antagonist is administered once every 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days; or once every 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks. In certain embodiments, during the consolidation period, the FcRn antagonist is administered once every 7 days to 8 days, 7 days to 9 days, 7 days to 10 days, 7 days to 11 days, 7 days to 12 days, 7 days to 13 days, 7 days to 14 days, 7 days to 15 days, 7 days to 16 days, 7 days to 17 days, 7 days to 18 days, 7 days to 19 days, 7 days to 20 days, or 7 days to 21 days. In certain embodiments, during the consolidation phase, the FcRn antagonist is administered at intervals of every 8 to 9 days, 8 to 10 days, 8 to 11 days, 8 to 12 days, 8 to 13 days, 8 to 14 days, 8 to 15 days, 8 to 16 days, 8 to 17 days, 8 to 18 days, 8 to 19 days, 8 to 20 days, or 8 to 21 days. In certain embodiments, during the consolidation phase, the FcRn antagonist is administered at intervals of every 9 to 10 days, 9 to 11 days, 9 to 12 days, 9 to 13 days, 9 to 14 days, 9 to 15 days, 9 to 16 days, 9 to 17 days, 9 to 18 days, 9 to 19 days, 9 to 20 days, or 9 to 21 days. In certain embodiments, during the consolidation phase, the FcRn antagonist is administered at intervals of every 10 to 11 days, 10 to 12 days, 10 to 13 days, 10 to 14 days, 10 to 15 days, 10 to 16 days, 10 to 17 days, 10 to 18 days, 10 to 19 days, 10 to 20 days, or 10 to 21 days. In certain embodiments, during the consolidation phase, the FcRn antagonist is administered at intervals of every 11 to 12 days, 11 to 13 days, 11 to 14 days, 11 to 15 days, 11 to 16 days, 11 to 17 days, 11 to 18 days, 11 to 19 days, 11 to 20 days, or 11 to 21 days. In certain embodiments, during the consolidation phase, the FcRn antagonist is administered at intervals of every 12 to 13 days, 12 to 14 days, 12 to 15 days, 12 to 16 days, 12 to 17 days, 12 to 18 days, 12 to 19 days, 12 to 20 days, or 12 to 21 days. In certain embodiments, during the consolidation phase, the FcRn antagonist is administered at intervals of every 13 to 14 days, 13 to 15 days, 13 to 16 days, 13 to 17 days, 13 to 18 days, 13 to 19 days, 13 to 20 days, or 13 to 21 days.In certain embodiments, during the consolidation period, the FcRn antagonist is administered once every 14 to 15 days, 14 to 16 days, 14 to 17 days, 14 to 18 days, 14 to 19 days, 14 to 20 days, or 14 to 21 days. In certain embodiments, during the consolidation period, the FcRn antagonist is administered once every 15 to 16 days, 15 to 17 days, 15 to 18 days, 15 to 19 days, 15 to 20 days, or 15 to 21 days. In certain embodiments, during the consolidation period, the FcRn antagonist is administered once every 16 to 17 days, 16 to 18 days, 16 to 19 days, 16 to 20 days, or 16 to 21 days. In certain embodiments, during the consolidation period, the FcRn antagonist is administered once every 17 to 18 days, 17 to 19 days, 17 to 20 days, or 17 to 21 days. In certain embodiments, during the consolidation period, the FcRn antagonist is administered once every 18 to 19 days, 18 to 20 days, or 18 to 21 days. In certain embodiments, during the consolidation period, the FcRn antagonist is administered once every 19 to 20 days, or 19 to 21 days.

[0309] In some embodiments, during the consolidation phase, the FcRn antagonist is administered once a week or once every 2 weeks.

[0310] In some embodiments, the method further comprises a maintenance period, wherein during the maintenance period, the consolidation end dose or dosing interval of the FcRn antagonist and / or corticosteroid continues until complete clearance of the lesion.

[0311] In some embodiments, during the maintenance period, the FcRn antagonist is administered once a week or less frequently. For example, in certain embodiments, during the maintenance period, the FcRn antagonist is administered once every 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days; or once every 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks. In certain embodiments, during the maintenance period, the FcRn antagonist is administered once every 7 days to 8 days, 7 days to 9 days, 7 days to 10 days, 7 days to 11 days, 7 days to 12 days, 7 days to 13 days, 7 days to 14 days, 7 days to 15 days, 7 days to 16 days, 7 days to 17 days, 7 days to 18 days, 7 days to 19 days, 7 days to 20 days, or 7 days to 21 days. In certain embodiments, during the maintenance period, the FcRn antagonist is administered at intervals of every 8 to 9 days, 8 to 10 days, 8 to 11 days, 8 to 12 days, 8 to 13 days, 8 to 14 days, 8 to 15 days, 8 to 16 days, 8 to 17 days, 8 to 18 days, 8 to 19 days, 8 to 20 days, or 8 to 21 days. In certain embodiments, during the maintenance period, the FcRn antagonist is administered at intervals of every 9 to 10 days, 9 to 11 days, 9 to 12 days, 9 to 13 days, 9 to 14 days, 9 to 15 days, 9 to 16 days, 9 to 17 days, 9 to 18 days, 9 to 19 days, 9 to 20 days, or 9 to 21 days. In certain embodiments, during the maintenance period, the FcRn antagonist is administered at intervals of every 10 to 11 days, 10 to 12 days, 10 to 13 days, 10 to 14 days, 10 to 15 days, 10 to 16 days, 10 to 17 days, 10 to 18 days, 10 to 19 days, 10 to 20 days, or 10 to 21 days. In certain embodiments, during the maintenance period, the FcRn antagonist is administered at intervals of every 11 to 12 days, 11 to 13 days, 11 to 14 days, 11 to 15 days, 11 to 16 days, 11 to 17 days, 11 to 18 days, 11 to 19 days, 11 to 20 days, or 11 to 21 days. In certain embodiments, during the maintenance period, the FcRn antagonist is administered once every 12 to 13 days, 12 to 14 days, 12 to 15 days, 12 to 16 days, 12 to 17 days, 12 to 18 days, 12 to 19 days, 12 to 20 days, or 12 to 21 days. In certain embodiments, during the maintenance period, the FcRn antagonist is administered once every 13 to 14 days, 13 to 15 days, 13 to 16 days, 13 to 17 days, 13 to 18 days, 13 to 19 days, 13 to 20 days, or 13 to 21 days.In certain embodiments, during the maintenance period, the FcRn antagonist is administered once every 14 to 15 days, 14 to 16 days, 14 to 17 days, 14 to 18 days, 14 to 19 days, 14 to 20 days, or 14 to 21 days. In certain embodiments, during the maintenance period, the FcRn antagonist is administered once every 15 to 16 days, 15 to 17 days, 15 to 18 days, 15 to 19 days, 15 to 20 days, or 15 to 21 days. In certain embodiments, during the maintenance period, the FcRn antagonist is administered once every 16 to 17 days, 16 to 18 days, 16 to 19 days, 16 to 20 days, or 16 to 21 days. In certain embodiments, during the maintenance period, the FcRn antagonist is administered once every 17 to 18 days, 17 to 19 days, 17 to 20 days, or 17 to 21 days. In certain embodiments, during the maintenance period, the FcRn antagonist is administered once every 18 to 19 days, 18 to 20 days, or 18 to 21 days. In certain embodiments, during the maintenance period, the FcRn antagonist is administered once every 19 to 20 days, or 19 to 21 days.

[0312] In some embodiments, during the maintenance period, the FcRn antagonist is administered once a week. In some embodiments, during the maintenance period, the FcRn antagonist is administered once every two weeks.

[0313] In some embodiments, during the maintenance period, corticosteroids are administered at a dose of ≤ 0.1 mg / kg / day prednisone or equivalent OCS.

[0314] In some embodiments, during the maintenance phase, the FcRn antagonist is administered subcutaneously once weekly at a dose of 1000 mg and the corticosteroid is administered at a dose of ≤ 0.1 mg / kg / day of prednisone or equivalent OCS.

[0315] In one embodiment, the subject has a serum level of pathogenic IgG autoantibodies associated with BP. In one embodiment, the pathogenic IgG autoantibodies are anti-BP180 antibodies and / or anti-BP230 antibodies. In some embodiments, the anti-BP180 antibodies are anti-NC16A antibodies. In one embodiment, the level of pathogenic IgG autoantibodies is measured by ELISA or addressable laser bead immunoassay (ALBIA). In one embodiment, the serum level of pathogenic IgG autoantibodies is compared to the baseline level of the subject.

[0316] In one embodiment, BP is newly diagnosed BP, recurrent BP or refractory BP. In some embodiments, the subject is diagnosed with moderate BP or severe BP. In some embodiments, the subject is diagnosed with moderate to severe BP. In some embodiments, the subject is diagnosed according to the IGA-BP scale. In some embodiments, the subject has an IGA-BP score of 3 or 4.

[0317] In some embodiments, the treatment of BP is characterized by a reduction in autoantibodies. In some embodiments, the autoantibody is an anti-BP180 autoantibody. In some embodiments, after administration of one or more of the treatments described herein, the prevalence of anti-BP180 autoantibodies is reduced by at least 10%, at least 25%, at least 50%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%. In some embodiments, after administration of one or more of the treatments described herein, no anti-BP180 autoantibodies are detected in the subject. In some embodiments, the treatment is administration of an effective amount of an FcRn antagonist. In some embodiments, the treatment is administration of an effective amount of agamod. In some embodiments, the anti-BP180 autoantibody is an anti-NC16A autoantibody.

[0318] In some embodiments, the autoantibody is an anti-BP230 autoantibody. In some embodiments, the prevalence of anti-BP230 autoantibodies is reduced by at least 10%, at least 25%, at least 50%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% after administration of one or more of the treatments described herein. In some embodiments, anti-BP230 autoantibodies are undetectable in the subject after administration of one or more of the treatments described herein. In some embodiments, the treatment is administration of an effective amount of an FcRn antagonist. In some embodiments, the treatment is administration of an effective amount of agamod.

[0319] In some embodiments, the treatment of BP is characterized by changes in BP disease state. Various terms are used to describe BP disease state and are defined elsewhere herein. In some embodiments, changes in BP disease state are characterized as one or more of the following: control of disease activity (CDA), partial remission (PR), complete remission (CR), relapse and / or treatment failure. In some embodiments, CDA, PR or CR are achieved after administering one or more of the treatments described herein. In some embodiments, after administering one or more of the treatments described herein, CDA, PR or CR are observed within ≤36 weeks, ≤26 weeks, ≤12 weeks, ≤6 weeks or ≤3 weeks. In some embodiments, CDA, PR or CR are maintained in the absence of corticosteroid therapy. In some embodiments, after stopping corticosteroid therapy, CDA, PR or CR are maintained for at least 2 weeks, at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks or at least 26 weeks.

[0320] In some embodiments, treatment prevents BP recurrence. In some embodiments, treatment prevents BP recurrence for at least 2 weeks, at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 26 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, or at least 52 weeks. In some embodiments, treatment is administration of an effective amount of an FcRn antagonist. In some embodiments, treatment is administration of an effective amount of agamod.

[0321] In some embodiments, after initiation of treatment with an FcRn antagonist, the treatment prevents recurrence of BP for at least 2 weeks, at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 26 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, or at least 52 weeks after achieving remission from BP. In some embodiments, initiation of treatment with an FcRn antagonist is the first administration of an effective amount of an FcRn antagonist. In some embodiments, initiation of treatment with an FcRn antagonist is the first administration of an effective amount of an agamod.

[0322] In some embodiments, after achieving remission from BP, the treatment prevents BP recurrence within at least 4 weeks after achieving remission from BP. In some embodiments, after achieving remission from BP, the treatment prevents BP recurrence within at least 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, or 52 weeks after achieving remission from BP.

[0323] In some embodiments, CR is achieved at a corticosteroid dose of ≤ about 5 mg prednisone / kg / day or equivalent OCS. In some embodiments, CR is achieved at a corticosteroid dose of ≤ about 3 mg prednisone / kg / day or equivalent OCS. In some embodiments, CR is achieved at a corticosteroid dose of ≤ about 2 mg prednisone / kg / day or equivalent OCS. In some embodiments, CR is achieved at a corticosteroid dose of ≤ about 1 mg prednisone / kg / day or equivalent OCS. In some embodiments, CR is achieved at a corticosteroid dose of ≤ about 0.5 mg prednisone / kg / day or equivalent OCS. In some embodiments, CR is achieved at a corticosteroid dose of ≤ about 0.4 mg prednisone / kg / day or equivalent OCS. In some embodiments, CR is achieved at a corticosteroid dose of ≤ about 0.3 mg prednisone / kg / day or equivalent OCS. In some embodiments, CR is achieved at a corticosteroid dose of ≤ about 0.2 mg prednisone / kg / day or equivalent OCS. In some embodiments, CR is achieved at a corticosteroid dose of ≤ about 0.1 mg prednisone / kg / day or equivalent OCS.

[0324] In some embodiments, CR is achieved at a corticosteroid dose of ≤5 mg prednisone / kg / day or equivalent OCS. In some embodiments, CR is achieved at a corticosteroid dose of ≤3 mg prednisone / kg / day or equivalent OCS. In some embodiments, CR is achieved at a corticosteroid dose of ≤2 mg prednisone / kg / day or equivalent OCS. In some embodiments, CR is achieved at a corticosteroid dose of ≤1 mg prednisone / kg / day or equivalent OCS. In some embodiments, CR is achieved at a corticosteroid dose of ≤0.5 mg prednisone / kg / day or equivalent OCS. In some embodiments, CR is achieved at a corticosteroid dose of ≤0.4 mg prednisone / kg / day or equivalent OCS. In some embodiments, CR is achieved at a corticosteroid dose of ≤0.3 mg prednisone / kg / day or equivalent OCS. In some embodiments, CR is achieved at a corticosteroid dose of ≤0.2 mg prednisone / kg / day or equivalent OCS. In some embodiments, CR is achieved at a corticosteroid dose of ≤ 0.1 mg prednisone / kg / day or equivalent OCS.

[0325] In some embodiments, CR is achieved at a corticosteroid dose of ≤ about 20 mg prednisone / day or equivalent OCS. In some embodiments, CR is achieved at a corticosteroid dose of ≤ about 15 mg prednisone / day or equivalent OCS. In some embodiments, CR is achieved at a corticosteroid dose of ≤ about 10 mg prednisone / day or equivalent OCS. In some embodiments, CR is achieved at a corticosteroid dose of ≤ about 5 mg prednisone / day or equivalent OCS. In some embodiments, CR is achieved at a corticosteroid dose of ≤ about 3 mg prednisone / day or equivalent OCS. In some embodiments, CR is achieved at a corticosteroid dose of ≤ about 2 mg prednisone / day or equivalent OCS.

[0326] In some embodiments, CR is achieved at a corticosteroid dose of ≤10 mg prednisone / day or equivalent OCS. In some embodiments, CR is achieved at a corticosteroid dose of ≤5 mg prednisone / day or equivalent OCS. In some embodiments, CR is achieved at a corticosteroid dose of ≤3 mg prednisone / day or equivalent OCS. In some embodiments, CR is achieved at a corticosteroid dose of ≤2 mg prednisone / day or equivalent OCS.

[0327] In some embodiments, CR is achieved in the absence of corticosteroids.

[0328] In some embodiments, CR is maintained at a corticosteroid dose of ≤ about 20 mg prednisone / day or OCS equivalent. In some embodiments, CR is maintained at a corticosteroid dose of ≤ about 15 mg prednisone / day or OCS equivalent. In some embodiments, CR is maintained at a corticosteroid dose of ≤ about 10 mg prednisone / day or OCS equivalent. In some embodiments, CR is maintained at a corticosteroid dose of ≤ about 5 mg prednisone / day or OCS equivalent. In some embodiments, CR is maintained at a corticosteroid dose of ≤ about 2 mg prednisone / day or OCS equivalent. In some embodiments, CR remission is maintained at a corticosteroid dose of ≤ about 1 mg prednisone / kg / day or OCS equivalent. In some embodiments, CR is maintained at a corticosteroid dose of ≤ about 0.5 mg prednisone / kg / day or OCS equivalent. In some embodiments, CR is maintained at a corticosteroid dose of ≤ about 0.4 mg prednisone / kg / day or OCS equivalent. In some embodiments, CR is maintained at a corticosteroid dose of ≤ about 0.3 mg prednisone / kg / day or equivalent OCS. In some embodiments, CR is maintained at a corticosteroid dose of ≤ about 0.2 mg prednisone / kg / day or equivalent OCS. In some embodiments, CR is maintained at a corticosteroid dose of ≤ about 0.1 mg prednisone / kg / day or equivalent OCS.

[0329] In some embodiments, CR is maintained at a corticosteroid dose of ≤20 mg prednisone / day or equivalent OCS. In some embodiments, CR is maintained at a corticosteroid dose of ≤15 mg prednisone / day or equivalent OCS. In some embodiments, CR is maintained at a corticosteroid dose of ≤10 mg prednisone / day or equivalent OCS. In some embodiments, CR is maintained at a corticosteroid dose of ≤5 mg prednisone / day or equivalent OCS. In some embodiments, CR is maintained at a corticosteroid dose of ≤2 mg prednisone / day or equivalent OCS. In some embodiments, CR is maintained at a corticosteroid dose of ≤1 mg prednisone / kg / day or equivalent OCS. In some embodiments, CR is maintained at a corticosteroid dose of ≤0.5 mg prednisone / kg / day or equivalent OCS. In some embodiments, CR is maintained at a corticosteroid dose of ≤0.4 mg prednisone / kg / day or equivalent OCS. In some embodiments, CR is maintained at a corticosteroid dose of ≤0.3 mg prednisone / kg / day or equivalent OCS. In some embodiments, CR is maintained at a corticosteroid dose of ≤ 0.2 mg prednisone / kg / day or equivalent OCS. In some embodiments, CR is maintained at a corticosteroid dose of ≤ 0.1 mg prednisone / kg / day or equivalent OCS.

[0330] In some embodiments, CR is maintained in the absence of corticosteroids.

[0331] In some embodiments, the treatment of BP is characterized by a decrease in the investigator's overall assessment of bullous pemphigoid (IGA-BP). In some embodiments, after administering one or more of the treatments described herein, IGA-BP is reduced by 1 point, 2 points, 3 points, or 4 points. In some embodiments, after administering one or more of the treatments described herein, IGA-BP is reduced from 3 or 4 to 0 or 1. In some embodiments, after administering one or more of the treatments described herein, IGA-BP is reduced from 3 or 4 to 0. In some embodiments, an IGA-BP score of 0 or 1 is maintained under the lowest OCS therapy. In some embodiments, an IGA-BP score of 0 or 1 is maintained under the lowest OCS therapy for at least 2 weeks, at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 26 weeks. In some embodiments, an IGA-BP score of 0 or 1 is maintained in the absence of corticosteroid therapy. In some embodiments, an IGA-BP score of 0 or 1 is maintained for at least 2 weeks, at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 26 weeks after cessation of corticosteroid therapy. In some embodiments, treatment is administration of an effective amount of an FcRn antagonist. In some embodiments, treatment is administration of an effective amount of igamod.

[0332] In some embodiments, the treatment of BP is characterized by a reduction in the bullous pemphigoid disease area index (BPDAI). In some embodiments, after administering one or more of the treatments described herein, BPDAI is reduced by at least 5%, 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 70%, at least 80%, at least 90%, at least 95% or 100%. In some embodiments, BPDAI is reduced to ≤36, ≤24, ≤18, ≤12, ≤8, ≤4 or 0. In some embodiments, treatment is the administration of an effective amount of an FcRn antagonist. In some embodiments, treatment is the administration of an effective amount of Aijiamod.

[0333] In some embodiments, the treatment of BP is characterized by a decrease in the Itch Numerical Rating Scale (Itch NRS) score. In some embodiments, after administration of one or more of the treatments described herein, the Itch NRS score is reduced by at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, or at least 10 points. In some embodiments, after administration of one or more of the treatments described herein, the Itch NRS score is <7, <6, <5, <4, <3, <2, or <1. In some embodiments, after administration of one or more of the treatments described herein, the Itch NRS score is 0, 1, or 2. In some embodiments, the treatment is the administration of an effective amount of an FcRn antagonist. In some embodiments, the treatment is the administration of an effective amount of agamod.

[0334] In some embodiments, the treatment of BP is characterized by an improvement in quality of life. In some embodiments, quality of life is assessed by one or more of the following: EuroQoL 5-dimensional 5-level (EQ-5D-5L), Dermatology Life Quality Index (DLQI) and / or Autoimmune Bullous Disease Quality of Life (ABQoL). In some embodiments, after administration of one or more of the treatments described herein, quality of life improves by at least 5%, 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 70%, at least 80%, at least 90% or at least 95%. In some embodiments, treatment is administration of an effective amount of an FcRn antagonist. In some embodiments, treatment is administration of an effective amount of agamod.

[0335] In some embodiments, the treatment of BP is characterized by an improvement in the glucocorticoid toxicity index (GTI). In some embodiments, after administration of one or more of the treatments described herein, the GTI score is reduced by at least 5%, 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 70%, at least 80%, at least 90%, at least 95% or 100%. In some embodiments, treatment is administration of an effective amount of an FcRn antagonist. In some embodiments, treatment is administration of an effective amount of agamod.

[0336] In one aspect, a method of treating BP in a subject in need thereof is provided, the method comprising administering to the subject an effective amount of a human FcRn antagonist and a corticosteroid, wherein the cumulative oral dose of the corticosteroid administered to the subject does not exceed 100 mg / kg. In some embodiments, the cumulative oral dose of the corticosteroid does not exceed 75 mg / kg. In some embodiments, the cumulative oral dose of the corticosteroid does not exceed 50 mg / kg. In some embodiments, the cumulative oral dose of the corticosteroid does not exceed 25 mg / kg. In some embodiments, the corticosteroid is prednisone. In some embodiments, the cumulative oral dose of the corticosteroid is a cumulative oral prednisone equivalent dose.

[0337] In one aspect, a method of treating BP in a subject in need thereof is provided, the method comprising administering to the subject an effective amount of a human FcRn antagonist and a corticosteroid, wherein the oral prednisone equivalent dose of the corticosteroid administered to the subject does not exceed 1 mg / kg / day. In some embodiments, the oral prednisone equivalent dose of the corticosteroid administered to the subject does not exceed 0.75 mg / kg / day. In some embodiments, the oral prednisone equivalent dose of the corticosteroid administered to the subject does not exceed 0.5 mg / kg / day. In some embodiments, the oral prednisone equivalent dose of the corticosteroid administered to the subject does not exceed 0.3 mg / kg / day. In some embodiments, the oral prednisone equivalent dose of the corticosteroid administered to the subject does not exceed 0.25 mg / kg / day. In some embodiments, the oral prednisone equivalent dose of the corticosteroid administered to the subject does not exceed 0.2 mg / kg / day. In some embodiments, the oral prednisone equivalent dose of the corticosteroid administered to the subject does not exceed 0.15 mg / kg / day. In some embodiments, the oral prednisone equivalent dose of the corticosteroid administered to the subject does not exceed 0.1 mg / kg / day. In some embodiments, the corticosteroid is prednisone.

[0338] In one aspect, a method of treating BP in a subject in need thereof is provided, the method comprising administering to the subject an effective amount of a human FcRn antagonist and a corticosteroid, wherein the oral prednisone equivalent dose of the corticosteroid administered to the subject does not exceed 12.5 mg / day. In some embodiments, the oral prednisone equivalent dose of the corticosteroid administered to the subject does not exceed 10 mg / day. In some embodiments, the corticosteroid is prednisone.

[0339] In one aspect, provided herein is a method for monitoring treatment of BP in a subject following treatment with an FcRn antagonist, the method comprising: a) measuring autoantibodies in a blood sample taken from the subject; and b) comparing the autoantibody value to a reference value associated with BP in the subject, wherein if the autoantibody in the sample is less than or equal to the reference value, the subject is in remission of BP.

[0340] In one aspect, provided herein is a method for monitoring the efficacy of treatment of BP in a subject after treatment with a first FcRn antagonist, the method comprising: a) measuring in vitro the serum level of BP180 antibody and / or BP230 antibody in a blood sample taken from the subject; and b) comparing the serum level of BP180 antibody and / or BP230 antibody with a reference value associated with BP in the subject, wherein if the serum level of BP180 antibody and / or BP230 antibody in the sample is greater than or equal to the reference value, then the treatment is ineffective, and wherein if the serum level of BP180 antibody and / or BP230 antibody in the sample is less than the reference value, then the treatment is effective. In some embodiments, the BP180 antibody is an NC16A antibody.

[0341] In one aspect, provided herein is a method for treating BP in a subject who has received a first FcRn antagonist and is receiving a corticosteroid dosing regimen, the method comprising: a) administering an effective amount of a second FcRn antagonist to the subject; b) measuring the serum level of BP180 antibody and / or BP230 antibody in a blood sample taken from the subject in vitro; and c) comparing the serum level of BP180 antibody and / or BP230 antibody to a reference value associated with BP in the subject, wherein if the serum level of BP180 antibody and / or BP230 antibody in the sample is greater than or equal to the reference value, the corticosteroid dosing regimen is maintained, or wherein if the serum level of BP180 antibody and / or BP230 antibody is less than the reference value, the corticosteroid dosing regimen is gradually reduced. In some embodiments, the BP180 antibody is an NC16A antibody.

[0342] In one aspect, provided herein is a second FcRn antagonist for use in a method of treating BP in a subject who has received a first FcRn antagonist and is receiving a corticosteroid dosing regimen, wherein: a) an effective amount of the second FcRn antagonist is administered to the subject; b) serum levels of BP180 antibody and / or BP230 antibody are measured in vitro in a blood sample taken from the subject; and c) the serum levels of BP180 antibody and / or BP230 antibody are compared to a reference value associated with BP in the subject, wherein if the serum level of BP180 antibody and / or BP230 antibody in the sample is greater than or equal to the reference value, the corticosteroid dosing regimen is maintained, and wherein if the serum level of BP180 antibody and / or BP230 antibody is less than the reference value, the corticosteroid dosing regimen is gradually reduced. In some embodiments, the BP180 antibody is an NC16A antibody.

[0343] In some embodiments, the corticosteroid dosing regimen is gradually reduced to a lower dose or a lower dosing frequency. In one embodiment, the method further comprises administering an effective amount of a second FcRn antagonist to the subject if the serum level of BP180 antibody and / or BP230 antibody in the sample is greater than or equal to the reference value. In one embodiment, the method further comprises administering an effective amount of a second FcRn antagonist to the subject if the serum level of BP180 antibody and / or BP230 antibody in the sample is greater than or equal to the reference value. In some embodiments, the BP180 antibody is an NC16A antibody.

[0344] In one aspect, a method for treating BP in a subject is also provided, the method comprising: (a) administering to the subject one or more initial doses of an effective amount of a first FcRn antagonist, (b) administering to the subject one or more additional doses of an effective amount of a second FcRn antagonist if the subject's serum level of BP180 antibody and / or BP230 antibody after step (a) is greater than or equal to a reference value associated with the subject's BP, or discontinuing treatment with the first FcRn antagonist if the subject's serum level of BP180 antibody and / or BP230 antibody after step (a) is less than a reference value associated with the subject's active disease. In some embodiments, the BP180 antibody is an NC16A antibody.

[0345] In one aspect, provided herein is an FcRn antagonist for use in a method of treating BP in a subject, wherein (a) one or more initial doses of an effective amount of a first FcRn antagonist are administered to the subject, and (b) if the subject's serum level of BP180 antibody and / or BP230 antibody after step (a) is greater than or equal to a reference value associated with the subject's BP, one or more additional doses of an effective amount of a second FcRn antagonist are administered to the subject, or if the subject's serum level of BP180 antibody and / or BP230 antibody after step (a) is less than a reference value associated with the subject's BP, use of the first FcRn antagonist is discontinued. In some embodiments, the BP180 antibody is an NC16A antibody.

[0346] In one embodiment, the effective amount of the first FcRn antagonist is a dose of about 10 mg / kg to about 30 mg / kg administered intravenously.

[0347] In one embodiment, the effective amount of the first FcRn antagonist is a dose of about 750 mg to about 3000 mg administered subcutaneously.

[0348] In one aspect, provided herein is a method for determining whether a subject who has previously been treated for BP with a first FcRn antagonist requires further treatment with a second FcRn antagonist, the method comprising: a) measuring in vitro the serum level of BP180 antibody and / or BP230 antibody in a blood sample taken from the subject; and b) comparing the serum level of BP180 antibody and / or BP230 antibody with a reference value associated with BP in the subject, wherein if the serum level of BP180 antibody and / or BP230 antibody in the sample is greater than or equal to the reference value, the subject requires further treatment with a second FcRn antagonist. In some embodiments, the BP180 antibody is an NC16A antibody.

[0349] In one aspect, provided herein is a method for treating BP in a subject, the method comprising: administering to the subject an effective amount of a second FcRn antagonist, wherein the subject's BP has recurred after prior therapy with a first FcRn antagonist, and wherein the subject has a serum level of BP180 antibody and / or BP230 antibody greater than or equal to a reference value associated with the subject's BP. In some embodiments, the BP180 antibody is an NC16A antibody.

[0350] In one aspect, provided herein is a second FcRn antagonist for use in a method of treating BP in a subject, wherein the BP has recurred in the subject following prior therapy with a first FcRn antagonist, and wherein the subject has a serum level of BP180 antibody and / or BP230 antibody greater than or equal to a reference value associated with the subject's BP. In some embodiments, the BP180 antibody is an NC16A antibody.

[0351] In one aspect, provided herein is a method for treating BP in a subject, the method comprising administering to the subject an effective amount of a second FcRn antagonist, wherein the BP has recurred in the subject following prior therapy with a first FcRn antagonist, and wherein the effective amount of the FcRn antagonist is determined based on the serum level of BP180 antibody and / or BP230 antibody in a blood sample taken from the subject. In some embodiments, the BP180 antibody is an NC16A antibody.

[0352] In one aspect, provided herein is a second FcRn antagonist for use in a method of treating BP in a subject, wherein the BP has recurred in the subject following prior therapy with a first FcRn antagonist, the method comprising administering to the subject an effective amount of the second FcRn antagonist, wherein the effective amount is determined based on the serum level of BP180 antibody and / or BP230 antibody in a blood sample taken from the subject. In some embodiments, the BP180 antibody is an NC16A antibody.

[0353] In one aspect, provided herein is a method for monitoring the efficacy of a treatment of a subject after treatment with a first FcRn antagonist, wherein the subject suffers from BP, the method comprising: a) measuring in vitro the serum level of BP180 antibody and / or BP230 antibody in a blood sample taken from the subject; and b) comparing the serum level of BP180 antibody and / or BP230 antibody with a reference value associated with BP for the subject, wherein if the serum level of BP180 antibody and / or BP230 antibody in the sample is greater than or equal to the reference value, then the treatment is ineffective, or wherein if the serum level of BP180 antibody and / or BP230 antibody is less than the reference value, then the treatment is effective. In some embodiments, the BP180 antibody is an NC16A antibody.

[0354] In one aspect, the present invention provides a method for monitoring the relief of BP in a subject after treatment with a first FcRn antagonist, the method comprising: a) measuring the serum level of BP180 antibody and / or BP230 antibody in a blood sample taken from the subject in vitro; and b) comparing the serum level of BP180 antibody and / or BP230 antibody with a reference value associated with BP in the subject, wherein if the serum level of BP180 antibody and / or BP230 antibody in the sample is lower than or equal to the reference value, the subject is in relief of BP. In some embodiments, the BP180 antibody is an NC16A antibody.

[0355] BP180 antibody and BP230 antibody are not usually present in the serum of healthy individuals (i.e., individuals who do not suffer from BP or other autoantibody-mediated diseases). Therefore, in one embodiment, the reference value is an undetectable serum level of BP180 antibody and / or BP230 antibody. In some embodiments, the BP180 antibody is NC16A antibody.

[0356] In some embodiments, the reference value is about 10%, 11%, 12%, 13%, 14%, 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%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111 %, 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% or 90%. In some embodiments, the BP180 antibody is an NC16A antibody.

[0357] In some embodiments, the reference value is 10%, 11%, 12%, 13%, 14%, 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%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111 %, 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% or 90%. In some embodiments, the BP180 antibody is an NC16A antibody.

[0358] In some embodiments, the reference value is about 10%, 11%, 12%, 13%, 14%, 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%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, %, 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% or 90%. In some embodiments, the BP180 antibody is an NC16A antibody.

[0359] In one embodiment, the reference value is 10%, 11%, 12%, 13%, 14%, 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%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111 %, 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% or 90%. In some embodiments, the BP180 antibody is an NC16A antibody.

[0360] In one embodiment, the reference value is about 10%, 11%, 12%, 13%, 14%, 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% higher than the lowest serum level of BP180 antibody or BP230 antibody measured in a subject following treatment of BP with a first FcRn antagonist. %, 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% or 90%. In some embodiments, the BP180 antibody is an NC16A antibody.

[0361] In one embodiment, the reference value is 10%, 11%, 12%, 13%, 14%, 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% higher than the lowest serum level of BP180 antibody or BP230 antibody measured in the subject after treatment of BP with the first FcRn antagonist. %, 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% or 90%. In some embodiments, the BP180 antibody is an NC16A antibody.

[0362] In one embodiment, the reference value is about 2 times, 2.1 times, 2.2 times, 2.3 times, 2.4 times, 2.5 times, 2.6 times, 2.7 times, 2.8 times, 2.9 times, 3 times, 3.1 times, 3.2 times, 3.3 times, 3.4 times, 3.5 times, 3.6 times, 3.7 times, 3.8 times, the lowest serum level of BP180 antibody or BP230 antibody measured in a subject after treatment of BP with a first FcRn antagonist. In some embodiments, the BP180 antibody is an NC16A antibody.

[0363] In one embodiment, the reference value is 2 times, 2.1 times, 2.2 times, 2.3 times, 2.4 times, 2.5 times, 2.6 times, 2.7 times, 2.8 times, 2.9 times, 3 times, 3.1 times, 3.2 times, 3.3 times, 3.4 times, 3.5 times, 3.6 times, 3.7 times, 3.8 times, the lowest serum level of BP180 antibody or BP230 antibody measured in the subject after treatment of BP with the first FcRn antagonist. In some embodiments, the BP180 antibody is an NC16A antibody.

[0364] In one embodiment, the subject was previously treated with a first FcRn antagonist administered intravenously at a dose of about 10 mg / kg to about 30 mg / kg. In one embodiment, the subject was previously treated with a first FcRn antagonist administered intravenously at a dose of about 10 mg / kg. In one embodiment, the subject was previously treated with a first FcRn antagonist administered intravenously at a dose of about 15 mg / kg. In one embodiment, the subject was previously treated with a first FcRn antagonist administered intravenously at a dose of about 20 mg / kg. In one embodiment, the subject was previously treated with a first FcRn antagonist administered intravenously at a dose of about 25 mg / kg. In one embodiment, the subject was previously treated with a first FcRn antagonist administered intravenously at a dose of about 30 mg / kg.

[0365] In one embodiment, the subject is previously treated with a first FcRn antagonist administered intravenously at a dose of about 10 mg / kg to about 30 mg / kg once a week. In one embodiment, the subject is previously treated with a first FcRn antagonist administered intravenously at a dose of about 10 mg / kg once a week. In one embodiment, the subject is previously treated with a first FcRn antagonist administered intravenously at a dose of about 15 mg / kg once a week. In one embodiment, the subject is previously treated with a first FcRn antagonist administered intravenously at a dose of about 20 mg / kg once a week. In one embodiment, the subject is previously treated with a first FcRn antagonist administered intravenously at a dose of about 25 mg / kg once a week. In one embodiment, the subject is previously treated with a first FcRn antagonist administered intravenously at a dose of about 30 mg / kg once a week.

[0366] In one embodiment, the subject is previously treated with a first FcRn antagonist administered intravenously at a dose of about 10 mg / kg to about 30 mg / kg once every two weeks. In one embodiment, the subject is previously treated with a first FcRn antagonist administered intravenously at a dose of about 10 mg / kg once every two weeks. In one embodiment, the subject is previously treated with a first FcRn antagonist administered intravenously at a dose of about 15 mg / kg once every two weeks. In one embodiment, the subject is previously treated with a first FcRn antagonist administered intravenously at a dose of about 20 mg / kg once every two weeks. In one embodiment, the subject is previously treated with a first FcRn antagonist administered intravenously at a dose of about 25 mg / kg once every two weeks. In one embodiment, the subject is previously treated with a first FcRn antagonist administered intravenously at a dose of about 30 mg / kg once every two weeks.

[0367] In one embodiment, the subject was previously treated with a first FcRn antagonist administered subcutaneously at a dose of about 750 mg to about 3000 mg. In one embodiment, the subject was previously treated with a first FcRn antagonist administered subcutaneously at a dose of about 750 mg. In one embodiment, the subject was previously treated with a first FcRn antagonist administered subcutaneously at a dose of about 1000 mg. In one embodiment, the subject was previously treated with a first FcRn antagonist administered subcutaneously at a dose of about 1250 mg. In one embodiment, the subject was previously treated with a first FcRn antagonist administered subcutaneously at a dose of about 1500 mg. In one embodiment, the subject was previously treated with a first FcRn antagonist administered subcutaneously at a dose of about 1750 mg. In one embodiment, the subject was previously treated with a first FcRn antagonist administered subcutaneously at a dose of about 2000 mg.

[0368] In one embodiment, the subject is previously treated with a first FcRn antagonist administered subcutaneously at a dose of about 750 mg to about 3000 mg once a week. In one embodiment, the subject is previously treated with a first FcRn antagonist administered subcutaneously at a dose of about 750 mg once a week. In one embodiment, the subject is previously treated with a first FcRn antagonist administered subcutaneously at a dose of about 1000 mg once a week. In one embodiment, the subject is previously treated with a first FcRn antagonist administered subcutaneously at a dose of about 1250 mg once a week. In one embodiment, the subject is previously treated with a first FcRn antagonist administered subcutaneously at a dose of about 1500 mg once a week. In one embodiment, the subject is previously treated with a first FcRn antagonist administered subcutaneously at a dose of about 1750 mg once a week. In one embodiment, the subject is previously treated with a first FcRn antagonist administered subcutaneously at a dose of about 2000 mg once a week.

[0369] In one embodiment, the subject was previously treated with a first FcRn antagonist administered subcutaneously at a dose of about 750 mg to about 3000 mg once every two weeks. In one embodiment, the subject was previously treated with a first FcRn antagonist administered subcutaneously at a dose of about 750 mg once every two weeks. In one embodiment, the subject was previously treated with a first FcRn antagonist administered subcutaneously at a dose of about 1000 mg once every two weeks. In one embodiment, the subject was previously treated with a first FcRn antagonist administered subcutaneously at a dose of about 1250 mg once every two weeks. In one embodiment, the subject was previously treated with a first FcRn antagonist administered subcutaneously at a dose of about 1500 mg once every two weeks. In one embodiment, the subject was previously treated with a first FcRn antagonist administered subcutaneously at a dose of about 1750 mg once every two weeks. In one embodiment, the subject was previously treated with a first FcRn antagonist administered subcutaneously at a dose of about 2000 mg once every two weeks.

[0370] In one embodiment, the subject was also previously treated with a corticosteroid or an immunosuppressant such as dapsone. In one embodiment, the subject was previously treated with prednisone.

[0371] In one embodiment, the subject was previously treated with prednisone at a dose of 7.5 mg / day to 20 mg / day. In one embodiment, the subject was previously treated with prednisone at a dose of 8 mg / day to 15 mg / day. In one embodiment, the subject was previously treated with prednisone at a dose of 10 mg / day to 15 mg / day.

[0372] In one embodiment, the subject was previously treated with a dose of ≤5 mg / kg / day of prednisone. In one embodiment, the subject was previously treated with a dose of ≤3 mg / kg / day of prednisone. In one embodiment, the subject was previously treated with a dose of ≤2 mg / kg / day of prednisone. In one embodiment, the subject was previously treated with a dose of ≤1 mg / kg / day of prednisone. In one embodiment, the subject was previously treated with a dose of ≤0.5 mg / kg / day of prednisone. In one embodiment, the subject was previously treated with a dose of ≤0.4 mg / kg / day of prednisone. In one embodiment, the subject was previously treated with a dose of ≤0.3 mg / kg / day of prednisone. In one embodiment, the subject was previously treated with a dose of ≤0.2 mg / kg / day of prednisone. In one embodiment, the subject was previously treated with a dose of ≤0.1 mg / kg / day of prednisone.

[0373] In one embodiment, the effective amount of the second FcRn antagonist is a higher dose compared to the previous treatment with the first FcRn antagonist. In one embodiment, the effective amount of the second FcRn antagonist is a lower dose compared to the previous treatment with the first FcRn antagonist.

[0374] In one embodiment, an effective amount of the second FcRn antagonist is administered more frequently than in a previous treatment with the first FcRn antagonist. In one embodiment, an effective amount of the second FcRn antagonist is administered less frequently than in a previous treatment with the first FcRn antagonist.

[0375] In one embodiment, the effective amount of the second FcRn antagonist is administered intravenously at a dosage of about 10 mg / kg to about 30 mg / kg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In one embodiment, the effective amount of the second FcRn antagonist is administered intravenously at a dosage of 10 mg / kg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In one embodiment, the effective amount of the second FcRn antagonist is administered intravenously at a dosage of 15 mg / kg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In one embodiment, the effective amount of the second FcRn antagonist is administered intravenously at a dosage of 20 mg / kg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In one embodiment, the effective amount of the second FcRn antagonist is administered intravenously at a dosage of 25 mg / kg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In one embodiment, the effective amount of the second FcRn antagonist is administered intravenously at a dose of 30 mg / kg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

[0376] In one embodiment, the effective amount of the second FcRn antagonist is administered intravenously at a dose of about 10 mg / kg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In one embodiment, the effective amount of the second FcRn antagonist is administered intravenously at a dose of about 15 mg / kg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In one embodiment, the effective amount of the second FcRn antagonist is administered intravenously at a dose of about 20 mg / kg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In one embodiment, the effective amount of the second FcRn antagonist is administered intravenously at a dose of about 25 mg / kg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In one embodiment, the effective amount of the second FcRn antagonist is administered intravenously at a dose of about 30 mg / kg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

[0377] In one embodiment, the effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of about 750 mg to about 3000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg or 2000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In one embodiment, the effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of about 750 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In one embodiment, the effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of about 1000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In one embodiment, the effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of about 1250 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In one embodiment, the effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of about 1500 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In one embodiment, the effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of about 1750 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In one embodiment, the effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of about 2000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

[0378] In one embodiment, the effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg once a week, every two weeks, every three weeks, every four weeks, every month or every six weeks. In one embodiment, the effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg once a week, every two weeks, every three weeks, every four weeks, every month or every six weeks. In one embodiment, the effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of 1250 mg once a week, every two weeks, every three weeks, every four weeks, every month or every six weeks. In one embodiment, the effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of 1500 mg once a week, every two weeks, every three weeks, every four weeks, every month or every six weeks. In one embodiment, the effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of 1750 mg once a week, every two weeks, every three weeks, every four weeks, every month or every six weeks. In one embodiment, the effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of 2000 mg once a week, every two weeks, every three weeks, every four weeks, monthly, or every six weeks.

[0379] In one embodiment, the method further includes administering an effective amount of a corticosteroid or an immunosuppressant to the subject. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 2 mg / kg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 1 mg / kg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 0.5 mg / kg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 0.4 mg / kg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 0.3 mg / kg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 0.25 mg / kg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 0.2 mg / kg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 0.1 mg / kg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 0.05 mg / kg / day.

[0380] In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 20 mg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 15 mg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 10 mg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 7.5 mg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 5 mg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 4 mg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 3 mg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 2 mg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 1 mg / day. In one embodiment, an effective amount of a corticosteroid is administered at a dosage of about 0.5 mg / day.

[0381] In one embodiment, the subject's corticosteroid dosing regimen is gradually reduced based on the serum level of BP180 antibody or BP230 antibody in the subject with BP. In some embodiments, the BP180 antibody is an NC16A antibody. In one embodiment, the gradually reduced corticosteroid regimen is to reduce the dose of the corticosteroid or reduce its administration frequency. In one embodiment, the gradually reduced corticosteroid dose is ≤2 mg prednisone / kg / day or equivalent OCS. In one embodiment, the gradually reduced corticosteroid dose is less than or equal to about 1.5, 1.0, 0.75, 0.5 or 0.2 mg prednisone / kg / day or equivalent OCS. In one embodiment, the gradually reduced corticosteroid dose is ≤0.5 mg prednisone / kg / day or equivalent OCS. In one embodiment, the gradually reduced corticosteroid dose is ≤0.1 mg prednisone / kg / day or equivalent OCS.

[0382] In one embodiment, the serum level of BP180 antibody or BP230 antibody is measured by ELISA or addressable laser bead immunoassay (ALBIA).In some embodiments, the BP180 antibody is NC16A antibody.

[0383] In one embodiment, the first FcRn antagonist and the second FcRn antagonist are each the same FcRn antagonist. In one embodiment, the first FcRn antagonist and the second FcRn antagonist are each different FcRn antagonists.

[0384] In one embodiment, the FcRn antagonist is an Fc region comprising amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively. In one embodiment, the first FcRn antagonist or the second FcRn antagonist is an Fc region comprising amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively.

[0385] In one embodiment, the FcRn antagonist is igatimod. In one embodiment, the first FcRn antagonist or the second FcRn antagonist is igatimod.

[0386] In one embodiment, the FcRn antagonist comprises the amino acid sequence of SEQ ID NO: 1, 2 or 3. In one embodiment, the first FcRn antagonist or the second FcRn antagonist comprises the amino acid sequence of SEQ ID NO: 1, 2 or 3.

[0387] In one embodiment, the FcRn antagonist is an anti-FcRn antibody. In one embodiment, the first FcRn antagonist is an anti-FcRn antibody. In one embodiment, the second FcRn antagonist is an anti-FcRn antibody.

[0388] In one embodiment, the anti-FcRn antibody is rozanolimab (UCB7665), nicalizumab (M281), onorimumab (ALXN1830 / SYNT001), or bartolimumab (IMVT-1401 / RVT1401 / HBM9161).

[0389] In one embodiment, the first FcRn antagonist is an anti-FcRn antibody and the second FcRn antagonist is igamod. In one embodiment, the first FcRn antagonist is an anti-FcRn antibody and the second FcRn antagonist comprises the amino acid sequence of SEQ ID NO: 1, 2 or 3. In one embodiment, the anti-FcRn antibody is rozanolimab (UCB7665), nikalizumab (M281), onorimumab (ALXN1830 / SYNT001) or bartolimumab (IMVT-1401 / RVT1401 / HBM9161). In one embodiment, the patient has not been previously treated with igamod.

[0390] In one embodiment, the first FcRn antagonist is selected from the group consisting of: rozanolimab (UCB7665), nikalizumab (M281), onorimumab (ALXN1830 / SYNT001), or bartolimumab (IMVT-1401 / RVT1401 / HBM9161) and the second FcRn antagonist is an Fc region comprising amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively. In one embodiment, the first FcRn antagonist is selected from the group consisting of rozanolimab (UCB7665), nikalizumab (M281), onorimumab (ALXN1830 / SYNT001), or bartolimumab (IMVT-1401 / RVT1401 / HBM9161) and the second FcRn antagonist is igamod.

[0391] Examples

[0392] The following examples are offered by way of illustration and not limitation.

[0393] Example 1: Efficacy of agamod analogs in an acute mouse model of bullous pemphigoid

[0394] Bullous pemphigoid (BP) is an autoimmune blistering disease that most commonly occurs in the elderly. BP patients have autoantibodies against two hemidesmosomal proteins, BP180 and BP230. Anti-BP180 autoantibodies primarily recognize the extracellular 16th non-collagenous domain (NC16A) of the molecule. Animal model studies using humanized NC16A mice have shown that anti-BP180 NC16A IgG is pathogenic (Liu et al., J Clin Invest. 1993; 92: 2480-2488; Nishie et al., Nat Med. 2007; 13: 378-383; Liu et al., J Autoimmun. 2008; 31: 331-338). The purpose of this study was to investigate the in vivo efficacy of an ibadimod analog (HEL-ABDEG) used in a mouse model to inhibit BP disease in an acute preventive and therapeutic BP mouse model. HEL-ABDEG is a full-length human IgG1 molecule comprising Y, T, E, K and F mutations at EU positions 252, 254, 256, 433 and 434 in the heavy chain.

[0395] A. Methods

[0396] Serum samples were collected from 2 patients with active BP (BP1 and BP2). The patients had signed informed consent and the samples were de-identified before being transferred to the laboratory. By routine histological examination, these patients had extensive tension blisters and dermal-epidermal separation, accompanied by inflammatory cell infiltration. Direct immunofluorescence showed IgG deposition in the basement membrane zone (BMZ) of the skin around the lesions. Indirect immunofluorescence (IIF) showed "roof staining" of salt-split human skin cryosections, where the IgG titers determined by IIF were 1:320 (BP1) and 1:640 (BP2), as described (Liu et al., J Autoimmun. 2008; 31:331-338).

[0397] hNC16A-specific total IgG was purified from BP patient serum using a protein G column followed by a hNC16A-specific glutathione sepharose column as described (Liu et al., J Autoimmun. 2008; 31: 331-338). The concentration of purified IgG was quantified by human IgG-specific ELISA (Invitrogen, catalog number BMS2091). The purity of hNC16A-specific IgG was 96% (BP1) and 92% (BP2). The purified anti-hNC16A IgG fractions from BP1 and BP2 were concentrated by ultrafiltration (Millipore), stored frozen in PBS, mixed 1:1 and used for in vivo experiments.

[0398] Humanized NC16A mice were generated by the UNC Animal Model Core as described by Liu et al. (J Autoimmun. 2008; 31: 331-338). Briefly, to generate humanized BP180 NC16A mice (hNC16A), the murine BP180 genomic segment encoding the NC14A domain (exons 17 to 18) was replaced with the human NC16A genomic sequence (exons 18 to 19). The targeting vector was electroporated into 129 / Ola mouse ES cells. After excision of the neo gene from the targeted locus by Flp treatment, neo-minus cells were microinjected into C57BL / 6J mouse blastocysts, which were then implanted into pseudopregnant recipients. Highly chimeric males were mated with B6 females to produce F1 heterozygotes (NC16A+ / -). Crossing F1+ / - produced F2 homozygotes that only expressed the mhBP180NC16A hybrid antigen (NC16A+ / +). NC16A+ / + mice were backcrossed to C57BL / 6J for >10 generations. C57BL / 6J mice were obtained from Jackson Laboratories.

[0399] To test whether the HEL-ABDEG antibody can effectively prevent the onset of BP disease, adult (8-10 weeks old; n=8 per group) humanized NC16A (hNC16A) mice generated by the Liu laboratory (as described in Liu et al., J Autoimmun. 2008; 31: 331-338) were injected intraperitoneally (ip) with pathogenic human anti-hNC16A IgG (250 μg / g body weight) and immediately followed by intravenous (iv) injection of HEL-ABDEG (60 μg / g body weight) or PBS control. A third group of mice was injected with normal human control IgG (250 μg / g body weight) followed by PBS. Mice were examined 3 days after treatment. Clinical disease activity scores were performed on ear skin lesions (as described below). After clinical examination, 2 animals in the PBS group and 3 animals in the HEL-ABDEG group were sacrificed, and skin lesion specimens were obtained for histopathology (as described below) and IIF (as described below).

[0400] To test whether the HEL-ABDEG antibody could effectively treat established progressive BP disease, adult (8-10 weeks old) hNC16A mice were injected ip with pathogenic anti-hNC16A IgG (250 μg / g body weight). Three days later, when mice developed clinical and histopathological signs of BP, mice were treated iv with HEL-ABDEG (60 μg / g body weight) or PBS control and examined on days 10 and 17 after anti-hNC16A IgG injection. Due to limited mouse availability and sex reassignment, 7 mice were used for the HEL-ABDEG group and 9 mice were used for the PBS control group. Two mice per group were sacrificed and skin lesion specimens were obtained for IIF.

[0401] The clinical disease score of the ear was measured as the sum of ear thickness + redness score + scaling score, as used by Lin et al. (J Invest Dermatol. 2018; 138(5): 1032-1043). The score was 0 = normal (i.e., untreated ear); 1 = mild; 2 = moderate; 3 = severe; 4 = very severe.

[0402] Skin sections were used for routine histological examination by light microscopy (H / E staining) to locate the site of lesions (dermal-epidermal separation) and neutrophil infiltration. Disease activity in adult mice was scored based on histological dermal-epidermal separation: (-) = no dermal-epidermal separation detected; (1+) = mild inflammatory reaction and <25% epidermal detachment; (2+) = strong inflammatory reaction and epidermal detachment involving 25% to 50% of the epidermis; and (3+) = strong inflammatory reaction with obvious epidermal detachment involving >50% of the epidermis.

[0403] For IIF, anti-hNC16A IgG (1 μg / mL) was incubated on skin sections of hNC16A mice. Anti-hNC16A IgG binding to BMZ was detected by AlexaFluor 594-conjugated goat anti-human IgG antibody (Life Technologies, catalog number A11014). In order to detect infiltrating neutrophils, skin sections were incubated with Ly6G (Biolegend, catalog number 127602) and then incubated with AlexaFluor 488 goat anti-rat (Life Technologies, catalog number A11006). Dapi was purchased from SigmaAldrich (catalog number D9542).

[0404] All the above tests were performed by an experimenter blinded to the treatments. Data were analyzed using Student's t-test with SigmaPlot software; p values ​​< 0.05 were considered significant.

[0405] B. Results

[0406] HEL-ABDEG treatment eliminates BP disease in an acute preventive BP model

[0407] Mice injected with pathogenic anti-hNC16A IgG developed typical BP skin lesions, while mice injected with both pathogenic anti-hNC16A IgG and HEL-ABDEG had a dramatic reduction in skin lesions, as shown in clinical ( Figure 1A to Figure 1B ) and histology ( Figure 2 ). The reduction in BP disease activity caused by HEL-ABDEG treatment was associated with a significant reduction in neutrophil infiltration in the skin ( Figure 2 and Figure 3 ).

[0408] HEL-ABDEG treatment abolishes BP disease in an acute therapeutic BP model

[0409] To test whether HEL-ABDEG showed efficacy in treating established BP disease, mice were first injected ip with pathogenic anti-hNC16A IgG. Three days later, when mice developed extensive BP disease, mice were treated iv with HEL-ABDEG (60 μg / g body weight) or PBS control. Compared with PBS control mice, mice treated with HEL-ABDEG showed significantly reduced skin lesions and less neutrophil infiltration on day 10 after anti-hNC16A IgG injection ( FIG. 4A to FIG. 4B ).

[0410] No clinical disease activity was observed in both HEL-ABDEG treated mice and PBS treated control mice on day 17. This could be explained by the fact that pathogenic anti-hNC16A IgG was cleared and / or the immunogenicity against HEL-ABDEG (not tested). Therefore, neutrophil infiltration was not examined on day 17.

[0411] C. Conclusion

[0412] Two acute mouse models were used to investigate the in vivo efficacy of HEL-ABDEG (an agamod analog) in inhibiting anti-hNC16A IgG-induced BP disease. In the acute preventive BP disease model, HEL-ABDEG-treated mice exhibited fewer skin lesions both clinically (p<0.01) and histologically, with reduced neutrophil skin infiltration compared to control mice treated with PBS.

[0413] In the acute therapeutic BP disease model, mice were treated 3 days after anti-hNC16A IgG administration. HEL-ABDEG-treated mice had a statistically significant reduction in disease activity on day 10 (p<0.05 compared to controls) and had fewer skin-infiltrating neutrophils compared to the control group, as demonstrated by IIF. The disease-inducing effect of pathogenic anti-hNC16A IgG antibodies disappeared on day 17, which may be due to immunogenicity or clearance of anti-hNC16A IgG. In fact, it was previously reported that the half-life of human IgG in mice is 6-8 days. Therefore, the results of this model must be interpreted with caution on day 17. Nevertheless, in this model, therapeutic treatment with HEL-ABDEG reduced the severity of the disease on day 10.

[0414] Example 2: Phase 2 / 3 Study of Agamod PH20 SC in Adult Participants with Bullous Pemphigoid (BALLAD)

[0415] BALLAD (ARGX-113-2009) is a seamlessly conducted 2-part, Phase 2 / 3, prospective, global, multicenter, randomized, double-blind, placebo-controlled study designed to investigate the efficacy, safety, tolerability, immunogenicity, participant-reported outcome measures (including measures assessing participant quality of life [QoL]), PK, and PD of agamod PH20 SC (agamod co-formulated with recombinant human PH20 for subcutaneous (SC) injection) in adult participants with moderate to severe BP. The study aims to demonstrate that agamod is an effective and safe treatment for BP, providing participants with control of disease activity (CDA) and ultimately remission, while reducing their cumulative exposure to OCS.

[0416] The study consists of 2 parts. Part A is a Phase 2 evaluation designed to provide proof of concept for the therapeutic activity of agamod PH20 SC in participants with BP. Part B is a Phase 3 evaluation designed to confirm the results obtained from Part A in a separate, larger group of participants with BP.

[0417] An interim analysis will be conducted during Part A (data available through Week 26 for all Part A participants) to assess the primary and several secondary endpoints, confirm the appropriate sample size for Part B of the study, and determine whether the efficacy results observed in Part A through Week 26 warrant continued study of agamod PH20 SC for the treatment of participants with BP (futility analysis).

[0418] Apart from differences in the primary objective, end points, and statistical analysis, Parts A and B were identical in schedule, structure, assessment, and conduct.

[0419] To facilitate SC injection of investigational medicinal product (IMP), participants will be administered either agamod PH20 SC, a solution of agamod co-formulated with rHuPH20, or a matching placebo with the same concentration of rHuPH20. rHuPH20 is currently used to co-formulate with approved therapeutic antibodies to facilitate SC injection volumes > 2 mL. Agamod, both as an IV formulation (agamod IV) and agamod PH20 SC, has been studied in nonclinical studies, clinical studies in healthy volunteers, and clinical studies in patients with IgG-driven autoimmune diseases (systemic myasthenia gravis [gMG], primary immune thrombocytopenia [ITP], chronic inflammatory demyelinating polyneuropathy [CIPD], and pemphigus).

[0420] In clinical studies that included PD assessments, agamod IV and agamod PH20 SC have been effective in reducing IgG antibodies. Available clinical data support the clinical benefit of agamod. Efficacy was demonstrated in a pivotal Phase 3 study (ARGX-113-1704) in participants with gMG, and clear signs of efficacy were demonstrated in Phase 2 studies in participants with primary ITP (ARGX-113-1603) or pemphigus (ARGX-113-1701).

[0421] The primary objective of BALLAD is to evaluate the efficacy of agamod PH20 SC in achieving sustained remission in participants with BP.

[0422] A. Research Design

[0423] Overall Design

[0424] Participants will be administered investigational medication (IMP: igamod PH20SC or placebo [PBO PH20 SC]) once weekly for 36 weeks during both parts of the study. All participants will also receive concurrent OCS therapy, either prednisone starting at 0.5 mg / kg / day at baseline, or an alternative OCS of equivalent dose strength. OCS doses will be adjusted throughout the study based on each participant's BP disease status.

[0425] A schematic diagram of the overall study design is shown in Figure 5 A brief description of the two parts of ARGX-113-2009 is as follows.

[0426] Part A – Phase 2

[0427] Approximately 40 adult participants with moderate to severe BP will be randomized to receive either agamod PH20 SC or PBO PH20 SC. The primary objective of Part A is to determine whether agamod PH20 SC is effective in treating participants with BP by assessing the primary endpoint of the study: the proportion of participants who are in CR while receiving agamod PH20 SC or placebo and who have discontinued OCS therapy for ≥8 weeks at Week 36. Additional objectives and endpoints of Part A are described below.

[0428] An interim analysis will be conducted based on data obtained for all Part A participants through the Week 26 visit. The interim analysis will be conducted to assess the primary endpoint, assess several secondary endpoints of the study, confirm the appropriate sample size for Part B of the study, and determine whether the efficacy results observed at Week 26 warrant continued study of agamod PH20 SC for the treatment of participants with BP (futility analysis).

[0429] The final analysis of the Part A data will be conducted after the last participant completes his or her last visit.

[0430] Part B – Phase 3

[0431] Part B is a Phase 3 confirmatory study in which approximately 120 adult participants with moderate to severe BP will be randomized to receive either agamod PH20 SC or PBO PH20 SC. The primary objective of Part B is to confirm the primary endpoint results of Part A (the proportion of participants who are in CR and have discontinued OCS therapy for ≥8 weeks at Week 36 while receiving agamod PH20 SC or placebo), but in a separate, larger group of participants with BP. The additional objectives and endpoints of Part B are described below. The proposed order of the key secondary endpoints of Part B may be adjusted based on the results obtained from the interim analysis of Part A.

[0432] Implementation of both Part A and Part B

[0433] Parts A and B of the study have different sample sizes; otherwise, both parts are identical in terms of schedule, structure, assessment, and conduct. Both Parts A and B have a screening period of up to 2 weeks (extendable to 3 weeks at the discretion of the investigator), followed by a 36-week treatment period during which participants will receive either agamod PH20 SC or placebo (PBOPH20 SC). Finally, all Part A and Part B participants who complete the end-of-treatment period (EoTP) visit at Week 36 will be offered the option to participate in an open-label extension (OLE) of the study or complete a 7-week no-treatment follow-up period (as described in Example 3 below).

[0434] To enter the study, participants must have a BP diagnosis that meets international BP diagnostic guidelines. Before participants are randomized to the study intervention, the diagnosis of BP must be confirmed by all three of the following methods:

[0435] - Clinical signs of BP (presence of bullae), presence or absence of urticaria, eczematous or erythematous plaques, and presence or absence of pruritus.

[0436] - Histopathology and direct immunofluorescence (DIF) of skin biopsy

[0437] - Serological testing by indirect immunofluorescence (IIF), chemiluminescent enzyme immunoassay (CLEIA), or ELISA.

[0438] In Part B, study participants will be stratified based on disease history (new diagnosis or relapse) and disease severity (moderate BP [Investigator Global Assessment of Bullous Pemphigoid {IGA-BP} score of 3] or severe BP [IGA-BP score of 4]). Participants will be randomized in a 1:1 ratio to receive either agamodulid PH20 SC or PBO PH20 SC as follows:

[0439] - Igamod PH20 SC will be administered by SC injection at a dose of 2000 mg on Days 1 and 8 (administered as 2 separate SC injections of 1000 mg each), followed by weekly SC injections of 1000 mg from Weeks 2 to 35.

[0440] - PBO PH20 SC (injection vehicle co-formulated with 2000 U / mL of rHuPH20) will be administered using the same protocol as above.

[0441] All participants will also receive concurrent OCS therapy, i.e., prednisone at a starting dose of 0.5 mg / kg / day at baseline, or an alternative OCS of equivalent dose strength. Throughout the study, the OCS dose will be adjusted based on each participant's BP disease status. BP disease status terms are defined elsewhere herein and the oral prednisone dose adjustment procedure is described below.

[0442] Efficacy and QoL measures to be assessed during the study (except for BP disease status assessment) include the following:

[0443] - Investigator's Global Assessment of Bullous Pemphigoid (IGA-BP)

[0444] - Bullous Pemphigoid Disease Area Index (BPDAI)

[0445] -Itch Numerical Rating Scale (Itch NRS)

[0446] -EuroQoL 5 dimensions 5 levels (EQ-5D 5L)

[0447] -Dermatology Life Quality Index (DLQI)

[0448] -Autoimmune Bullous Disease Quality of Life (ABQoL) Questionnaire.

[0449] The time points during the study at which these assessments were administered are provided in the Schedule of Activities (SoA) (Table S4).

[0450] PK metrics included quantification of igamod serum concentrations. PD metrics included quantification of total IgG serum levels, anti-BP1 80 and anti-BP230 antibodies, and IgE serum levels. See SoA (Table S4) for time points when PK and PD blood samples were collected during the study.

[0451] Immunogenicity measures included determination of both ADA against igamod in serum and antibodies against rHuPH20 in plasma. See SoA (Table S4) for time points during the study when immunogenicity blood samples were collected.

[0452] Safety measures for the study included the following:

[0453] -Physical examination

[0454] -Height, weight and vital signs measurements

[0455] -Electrocardiogram (ECG)

[0456] - Record medical, surgical and vaccination history

[0457] - Clinical safety laboratory testing including clinical chemistry, hematology, coagulation, urinalysis, and viral serology - Serum and urine pregnancy test (WOCBP) or follicle stimulating hormone (FSH) test for women of childbearing age to confirm postmenopausal status

[0458] - Glucocorticoid Toxicity Index (GTI), which consists of the Combined Glucocorticoid Toxicity Index (C-GTI) and the Glucocorticoid Toxicity Index Specific List (GTI SL)

[0459] - Adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) were recorded.

[0460] Additionally, selected study sites will participate in the following sub-studies:

[0461] - Photography Substudy: Site staff will take photographs of bullous lesions located in different anatomical areas of the participants at the investigator's discretion. As a guide, the time points of baseline, CDA, CR, and relapse are indicated; however, photographs may also be taken at intermediate time points.

[0462] Vaccination Response Substudy: This substudy will investigate the effects of agamod PH20 SC treatment on historical protective antibody titers and humoral and / or cellular responses to vaccines received during the study period in participants who provided additional consent to participate in this substudy.

[0463] The rationale for selecting the participant population

[0464] To ensure that the study population is demographically consistent with the general population of patients with BP (primarily occurring in those aged 65 years and older), ARGX 113-2009 study participants will include males and females of legal age of majority, with no upper age limit.

[0465] The sponsor designed the participant eligibility criteria for ARGX-113-2009 to comply with international guidelines for the diagnosis of BP, which will ensure that the study population is representative of the general population of patients with BP worldwide. Bernard P et al., Am J Clin Dermatol. 2017;389(10079):1630-1638; Witte M. et al., Front Med. 2018;5:296; DiLernia V et al., Derm Pract Concept. 2020;10(3):e2020050.

[0466] ARGX-113-2009 will compare the treatment arms of agamod PH20 SC to PBO PH20 SC. All participants will receive concomitant therapy with oral corticosteroids (OCS) (i.e., prednisone) starting at 0.5 mg / kg / day at baseline or an alternative OCS of equivalent dose strength. OCS dose will be adjusted throughout the study based on each participant's BP disease status.

[0467] ARGX-113-2009 will enroll participants with moderate to severe BP. This patient subgroup was chosen because it represents those patients in the general population with the greatest medical need for new BP treatment modalities that can reduce their cumulative OCS exposure. Bernard P et al., Am J Clin Dermatol. 2017; 389(10079): 1630-1638; Bernard P et al., Ann Dermatol Venereol. 2011; 138(3): 247-251; Feliciani C et al., Br J Dermatol. 2015; 172(4): 867-877.

[0468] The IGA-BP will be used to assess the severity of BP for each participant. It is a new assessment tool developed by AIBD experts in 2021 and is currently used (along with the BPDAI) in other clinical studies of BP. The IGA-BP classifies the severity of BP on a numerical scale of 0 to 4, where a score of 0 represents no obvious signs of BP and a score of 4 represents severe BP. Given that this study is designed to investigate the effects of agamodulin PH20 SC in participants with moderate to severe BP, ARGX-113-2009 will recruit participants with an IGA-BP score of 3 or 4.

[0469] Patients with BP may have comorbidities that may limit daily function. Moreover, ARGX-113-2009 will not have an upper age limit for participation; therefore, the sponsor anticipates that the study will include a large number of older participants with BP. In addition, the sponsor wants to ensure that study participants are able to adequately complete patient-reported outcome (PRO) assessments without placing any undue burden on them. Therefore, ARGX-113-2009 participants will be required to have a Karnofsky Physical Performance Index score of ≥60% (i.e., requires occasional assistance but is able to care for most needs or better).

[0470] Atypical types of BP and AIBD other than BP may have different pathogenesis and course from typical BP. Therefore, participants with other AIBD or atypical forms of BP will be excluded from participating in the study.

[0471] Participants with BP who have been treated with any systemic therapy other than corticosteroids but still wish to participate in the study will be required to complete a washout period before commencing study participation. The duration of these required washout periods is selected based on the known PK properties of each of these therapies (described further below). Prior therapy with conventional immunosuppressants (including but not limited to azathioprine, cyclophosphamide, methotrexate, and mycophenolate mofetil) or dapsone does not require a washout period; however, these therapies must be stopped prior to baseline.

[0472] Rationale for selecting oral corticosteroid dosing regimen

[0473] The initial oral prednisone dose of 0.5 mg / kg / day (or equivalent OCS) and subsequent dose adjustment regimen (described further below) are based on the recommendations of European and Japanese guidelines. Schmidt E et al., J Dtsch Dermatol Ges. 2020; 18(5): 516-526; Ujiie H et al., J Dermatol. 2019; 46(12): 1102-1135. The oral prednisone dose will be adjusted throughout the study according to each participant's current BP disease activity, with the goal of maintaining CDA and avoiding relapses.

[0474] Rationale for the primary end point

[0475] The primary endpoint was selected based on the BP disease state terminology described by Murrell et al., J Amer Acad Dermatol. 2012;66(3):479-485, where the term CR off therapy is defined as "the absence of new or established lesions or pruritus when the patient has stopped all therapy for at least 2 months." Both patients with BP and physicians who treat patients with this disease agree that achieving complete and stable absence of BP symptoms represents a clinically meaningful outcome that significantly improves the patient's quality of life. The only concomitant BP therapy allowed in ARGX-113-2009, in addition to IMP, is OCS; therefore, within the scope of this study, "discontinuation of OCS therapy" is considered equivalent to the AIBD expert definition of "discontinuation of therapy." In ARGX-113-2009, tapering of concomitant OCS therapy will be performed in a manner consistent with treatment guidelines, while weekly IMP dosing will continue until the end of the 36-week treatment period.

[0476] Gradually reducing and eventually eliminating concurrent OCS therapy reduces the risk of developing complications associated with steroid therapy. Avoiding such risks is particularly important for elderly patients (such as those with BP), who develop serious complications such as osteoporosis, diabetes, and glaucoma after long-term exposure to high doses of OCS. Joly P et al., N Engl J Med. 2002; 346(5): 321-327; Hull CM et al., Arch Dermatol. 2003; 139(2): 225-226; Bernard P et al., Ann Dermatol Venereol. 2011; 138(3): 173-181.

[0477] This study will assess whether participants remain in CR while receiving agamod PH20 SC or placebo and after stopping OCS for at least 8 weeks at the end of the 36-week treatment period. Achieving a sustained response to treatment is particularly important for patients with BP, as existing evidence suggests that many patients who achieve CR subsequently relapse within a few months. Bernard P et al., Arch Dermatol. 2009; 145(5): 537-542; Wang Y et al., Ann Med. 2018; 50(3): 234-239.

[0478] The choice of a 36-week treatment period was based on international BP treatment guidelines, which recommend that systemic steroid doses should be tapered to achieve minimal OCS therapy within 4–6 months after initiation of treatment and that OCS therapy can subsequently be discontinued after patients have been in CR for 3–6 months. Therefore, a treatment period of 36 weeks (approximately 9 months) was considered an appropriate duration to allow patients to achieve CR and discontinue concurrent OCS therapy.

[0479] Rationale for Key Secondary End Points

[0480] The rationale for selecting the key secondary efficacy endpoints for Part B is summarized below. [Note: These endpoints are “key” secondary endpoints (meaning they are subject to stratified testing and alpha control) during Part B only. They will be assessed as standard secondary efficacy endpoints (no stratified testing / alpha control) during Part A of the study.]

[0481] Cumulative OCS dose from baseline to week 36: Currently, the standard of care for moderate to severe BP is OCS. Unfortunately, exposure to high doses of OCS leads to an increased risk of developing serious comorbidities, especially in the elderly. Therefore, the goal of BP treatment is to reduce patients' cumulative exposure to OCS. Therefore, this endpoint was selected to determine whether participants administered agamod PH20 SC had lower cumulative OCS exposure values ​​than those administered PBO PH20 SC.

[0482] Proportion of participants who achieved an IGA-BP score of 0 and discontinued OCS therapy for ≥8 weeks at Week 36 while receiving agamod PH20 SC or placebo: This endpoint was chosen because an IGA-BP score of 0 represents the complete absence of BP skin lesions. The ability to remain free of clinical disease activity while limiting their long-term cumulative exposure to OCS is particularly important for elderly patients with BP, who are at high risk for developing serious comorbidities associated with long-term OCS exposure (e.g., osteoporosis, diabetes, glaucoma, etc.).

[0483] Proportion of participants who achieved CDA and remained relapse-free through Week 36 while receiving agamod PH20 SC or placebo: This endpoint was selected because it is important to determine whether treatment with agamod PH20 SC provides long-term and sustained relief of BP symptoms in participants with BP and whether agamod PH20 SC is effective in preventing relapses.

[0484] Proportion of participants in CR while receiving agamod PH20 SC or placebo who had received minimal OCS therapy for ≥8 weeks at Week 36: The ability to remain free of clinical disease activity while limiting their long-term cumulative exposure to OCS is particularly important for elderly patients with BP, who are susceptible to serious comorbidities associated with long-term OCS exposure (e.g., osteoporosis, diabetes, glaucoma, etc.).

[0485] Change from baseline in the 24-hour mean pruritus score on Itch NRS: Pruritus is one of the signs / symptoms of BP; furthermore, pruritus associated with BP can be debilitating. This endpoint will determine whether agamod PH20 SC treatment provides relief from pruritus, which is considered a clinically meaningful disease improvement.

[0486] Select study assessment The basic principle

[0487] The BP disease assessment terms and definitions used in this study were adapted from those established by Murrell et al., J Amer Acad Dermatol. 2012; 66(3): 479-485. These terms and definitions have been internationally accepted by AIBD medical experts and clinicians who treat patients with BP.

[0488] Throughout the study, disease severity and symptoms will be monitored using the IGA-BP scale, BPDAI, and Itch NRS. The IGA-BP was developed in 2021 by medical experts in the field of AIBD, and it is currently being used (along with the BPDAI) in other clinical studies of BP therapy. The IGA-BP scale has specific guidance for equating the extent of skin lesions with disease severity, while the BPDAI score also takes into account the presence of mucosal lesions. Itch symptoms will be measured using the Itch NRS.

[0489] BPDAI and Itch NRS are validated and internationally recognized measures of BP disease severity and itch intensity, respectively. Masmoudi W et al., Br J Dermatol. 2021; 1 84(6): 1106-1112; Phan N et al., Acta Derm Venereol. 2012; 92(5): 502-507; Verweyen E et al., Acta Derm Venereol. 2019; 99(7): 657-663; Storck M et al., J Eur Acad Dermatol Venereol. 2021; 35(5): 1176-1185.

[0490] EQ-5D-5L, DLQI and ABQoL are validated and internationally recognized indicators of patient QoL. Finlay AY et al., Clin Exp Dermatol. 1994; 19(3): 210-216; Sebaratnam DF et al., JAMA Dermatol. 2013; 149(10): 1186-1191.

[0491] Rationale for selecting treatment regimen and dosage

[0492] In ARGX-113-2009, study participants will receive either agamod PH20 SC or PBO PH20 subcutaneously (SC). To date, agamod PH20 SC has been safely administered to healthy volunteers and participants with gMG, primary ITP, CIDP, and pemphigus.

[0493] The SC route of administration provides convenience to patients with BP, their caregivers, and healthcare providers because SC injections are easier to administer than IV injections. In addition, co-formulation of agamod with rHuPH20 allows SC dosing of higher volumes than typical SC injections because rHuPH20 reduces resistance to fluid flow and increases dispersion and absorption of injected drugs and fluids, which allows injection of larger volumes with limited skin swelling or pain.

[0494] In BP, patients usually achieve CDA, PR, or CR only after a few weeks of treatment; sometimes even months of treatment are needed to achieve CR or PR. In addition, patients with BP tend to relapse within a few months of achieving remission. Bernard P et al., Arch Dermatol. 2009; 145(5): 537-542; Wang Y et al., Ann Med. 2018; 50(3): 234-239. Therefore, studies of BP must have sufficient duration to assess the durability of IMP efficacy and the sustainability of remission in patients when OCS therapy is stopped. It is for these reasons that a 36-week treatment period was selected for ARGX-113-2009.

[0495] Initially, clinical development of agamod was based on IV administration. Results from a Phase 1 study in healthy subjects, a Phase 2 / 3 study in participants with gMG, a Phase 2 study in participants with ITP, and PK / PD model analysis showed that once-weekly administration of agamod IV 10 mg / kg achieved nearly maximal reductions in serum IgG levels. Studies in participants with gMG and ITP also showed that once-weekly administration of agamod IV 10 mg / kg produced clinical efficacy while reducing serum pathogenic autoantibody levels while maintaining good safety / tolerability.

[0496] In ARGX-113-2009, participants will be administered agamod PH20 SC at a uniform dose (rather than weekly doses adjusted based on body weight) because this is more convenient for both study participants and site staff. Results from PK / PD modeling analyses indicate that once-weekly administration of agamod PH20 SC 1000 mg will result in reductions in total IgG serum levels equivalent to weekly doses of agamod IV 10 mg / kg. Results from a Phase 1 study (ARGX-113-1907) comparing the PK and PD properties of IV and SC administration of agamod in healthy subjects demonstrated that 4 weekly injections of agamod PH20 SC 1000 mg were non-inferior to 4 weekly infusions of agamod IV 10 mg / kg in reducing total IgG serum levels. Therefore, the sponsor selected once-weekly administration of agamod PH20 SC 1000 mg as the maintenance dose for ARGX-113-2009.

[0497] Nonetheless, given that IgG autoimmune activity is thought to contribute to the pathophysiology of BP, any therapy targeting this activity should be designed to maximally reduce total IgG serum levels as rapidly as possible. Therefore, ARGX-113-2009 participants assigned to the agamod PH20 SC group will receive a dose of 2000 mg at baseline (week 0) and week 1. It is expected that initiation of treatment with 2 weekly doses of agamod PH20 SC 2000 mg will achieve a nearly maximal reduction in total IgG serum levels within 2 weeks, which is similar to the effect of once-weekly injections of agamod PH20 SC 1000 mg at steady state.

[0498] B. Study Population

[0499] Prospective approval of protocol deviations from recruitment and inclusion criteria, also known as protocol waivers or exemptions, is not permitted.

[0500] Inclusion criteria

[0501] Participants were eligible for inclusion in the study only if they met all of the following criteria:

[0502] - Participants are willing and able to: a) understand the requirements of the study; b) provide written informed consent (including consent for the use and disclosure of health information related to the study); and c) comply with study protocol procedures (including required study visits);

[0503] - Participants are male or female and have reached legal age at the time of signing the informed consent form;

[0504] - Participants have clinical signs of BP (i.e., presence of bullae), with or without urticaria / eczematous / erythematous plaques, or pruritus at Screening and Baseline Visits. The diagnosis of BP must be confirmed by positive histopathology and DIF before randomization to treatment and by positive serology (by IIF, CLEIA, or ELISA, depending on local practice) at Screening;

[0505] - Participants have an IGA-BP score of 3 or 4 at screening and baseline;

[0506] - Participant has a Kamofsky performance status of at least 60% at screening;

[0507] - Contraceptive use by men and women should comply with local regulations regarding contraceptive methods for participation in clinical research and:

[0508] a. Male participants must agree to use an acceptable method of contraception from the date of signing the informed consent form until the date of the last dose of IMP.

[0509] b. Females of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test at baseline before study intervention can be administered; and must agree to use at least one method of contraception from the date of signing the informed consent form until the date of the last dose of IMP (females are considered to be of childbearing potential unless they are postmenopausal or surgically sterilized).

[0510] Exclusion criteria Participants were excluded from the study if they met any of the following criteria:

[0511] - Other forms of pemphigoid (including but not limited to pemphigoid gestationis, drug-induced BP that resolves after discontinuation of the causative drug, anti-p200 pemphigoid, mucous membrane pemphigoid, and cicatricial pemphigoid) or other AIBD (including but not limited to epidermolysis bullosa acquisita, pemphigus vulgaris, and exfoliative erythroderma);

[0512] - Receiving any treatment at doses known to cause or worsen unstable BP (e.g., angiotensin-converting enzyme inhibitors, penicillamine, furosemide, phenacetin, dipeptidyl peptidase 4 inhibitors) for at least 4 weeks prior to the baseline visit;

[0513] -BP treatments other than OCS, topical corticosteroids, conventional immunosuppressants (eg, azathioprine, cyclophosphamide, methotrexate, mycophenolate mofetil, or morphine), or dapsone, including the following:

[0514] o Sulfasalazine, IVIg, subcutaneous immunoglobulin (SCig), immunoadsorption, or plasma exchange within 8 weeks of baseline visit;

[0515] o Use of tetracycline (with or without niacinamide) above the recommended daily allowance (RDA) / dietary reference intake (DRI) within 2 weeks of the baseline visit;

[0516] o Any monoclonal antibody (including rituximab or other anti-CD20 biologics) within 6 months of the baseline visit;

[0517] o Complementary therapies—such as traditional Chinese medicine, herbal remedies, or procedures (e.g., acupuncture)—within 4 weeks (or 5 half-lives) of the Baseline Visit if the investigator determines that such therapies may interfere with the efficacy assessments of the study and / or pose a potential risk to the safety of the participants;

[0518] - Known contraindications to OCS therapy;

[0519] - Clinically significant uncontrolled active or chronic bacterial, viral, or fungal infection at screening;

[0520] - Positive COVID-19 test result at screening (testing required based on local requirements);

[0521] - Any other known autoimmune disease that the investigator believes would interfere with the accurate assessment of clinical symptoms of BP or place the participant at undue risk;

[0522] - History of malignancy, unless considered cured by adequate treatment and without evidence of recurrence ≥3 years before first administration of IMP. Participants with the following cancers may be included at any time, provided they are adequately treated prior to study entry: a) basal cell or squamous cell skin cancer; b) carcinoma in situ of the cervix; c) carcinoma in situ of the breast; d) prostate cancer with incidental histologic findings (tumor node metastasis [TNM] stage T1a or T1b);

[0523] - Clinical evidence of other significant serious illness, recent surgery, or any other condition that the investigator believes may confound the study results or place the patient at undue risk;

[0524] - Use of the investigational product within 3 months or 5 half-lives (whichever is longer) before the first dose of IMP;

[0525] - Previously participated in clinical studies of agamod;

[0526] - Known hypersensitivity to any component of the administered treatment;

[0527] - A positive serological test result when screening for active infection with any of the following conditions: a) HBV indicating acute or chronic infection unless associated with a negative HBsAg or negative HBV DNA test; b) HCV based on an HCV antibody assay unless a negative RNA test is available; c) based on a test result associated with an AIDS-defining condition or a CD4 count ≤ 200 cells / mm 3 HIV;

[0528] - Primary or secondary hypogammaglobulinemia with a total serum IgG level <4 g / L at screening. Study candidates with a total IgG serum level of 4-6 g / L at screening may be allowed to participate in the study after discussion and agreement between the investigator and the sponsor.

[0529] - Current alcohol, drug, or substance abuse or a history of alcohol, drug, or substance abuse (i.e., within 12 months of screening);

[0530] - Pregnant or breastfeeding women and women who intend to become pregnant during the study or within 90 days after the last dose of IMP;

[0531] -Prolonged ECG QTcF interval.

[0532] As described above, participants with BP who received any of the following treatments were excluded from study participation: a) sulfasalazine, IVIg, SCIg, immunoadsorption, or plasma exchange within 8 weeks of the baseline visit; b) tetracyclines (with or without nicotinamide [at doses above the RDA / DRI]) within 2 weeks of the baseline visit; c) any monoclonal antibody (including rituximab or other anti-CD20 biologics) within 6 months of the baseline visit.

[0533] However, any potential ARGX-113-2009 candidate who has been treated with any of the above therapies and still wishes to participate in the study must complete a washout period prior to being randomized to the study intervention. The duration of the required washout period must match the duration established above for each class of medication. NOTE: Therapy with topical corticosteroids and / or conventional immunosuppressants (including but not limited to azathioprine, cyclophosphamide, methotrexate, and mycophenolate mofetil) or dapsone does not require a washout period; however, these therapies must be discontinued prior to baseline.

[0534] C. Study Interventions and Concomitant Therapies

[0535] Table S1 lists the list of study interventions (both IMP and non-study medicinal products), while Table S2 describes the characteristics of the 2 treatment groups of ARGX-113-2009. Fixed doses of agamod PH20 SC or PBO PH20 SC will be administered at body sites without any cutaneous BP lesions, with the abdominal region being the preferred site. Optional sites (such as thighs and arms) may be used. PBO PH20 SC will contain the same excipients as agamod PH20 SC, but without the active ingredient agamod. Covered vials and covered syringes will be provided to maintain study blinding.

[0536] Study intervention administered

[0537] Table S1. Study interventions administered

[0538]

[0539]

[0540] BP = bullous pemphigoid; EFG = efagmod; EFG PH20 SC = efagmod and rHuPH20 (coformulation) for SC injection; IMP = investigational medicinal product; OCS = oral corticosteroid (prednisone or equivalent); PBO = placebo; PBO PH20 SC = placebo and rHuPH20 (coformulation) for SC injection; rHuPH20 = recombinant human hyaluronidase PH20; SC = subcutaneous (by subcutaneous route)

[0541] a Refers to oral prednisone or equivalent OCS.

[0542] b The IMP will be administered to a body site that does not have any cutaneous BP lesions; the abdomen is the preferred site. An optional site (such as the thigh or arm) may be chosen.

[0543] Table S2. Characteristics of treatment groups

[0544]

[0545] BP = bullous pemphigoid; EFG = efagmod; EFG PH20 SC = efagmod and rHuPH20 (coformulation) for SC injection; IMP = investigational medicinal product; OCS = oral corticosteroid (prednisone or equivalent); PBO = placebo; PBO PH20 SC = placebo and rHuPH20 (coformulation) for SC injection; rHuPH20 = recombinant human hyaluronidase PH20; SC = subcutaneous (by subcutaneous route)

[0546] Any medications or vaccines that the participant is taking at screening or during the study (including over-the-counter or prescription medications, recreational drugs, vitamins, and / or herbal supplements) must be recorded and include the following information: 1) reason for use; 2) dates of administration, including start and end dates; 3) dosing information, including dose and frequency; and 4) brand name (for vaccines only).

[0547] All available vaccination history should be recorded as part of the participant's prior medication for vaccinations received in the past or as part of the concomitant medication for vaccinations received during the trial. In addition, any vaccination information that the participant, their caregiver, or their legally authorized representative can remember should be recorded (record the brand name of the vaccine and the date of vaccination, if possible).

[0548] If there are any questions regarding concomitant or prior therapy, the medical monitor should be contacted.

[0549] All participants, regardless of study IMP assignment, will also receive concurrent therapy with OCS, i.e., prednisone at a starting dose of 0.5 mg / kg / day at baseline (week 0), or an alternative OCS of equivalent dose strength. Throughout the study, OCS dose will be adjusted based on each participant's BP disease status, with the goal of rapidly reducing systemic corticosteroid exposure and preventing and / or treating relapses. The oral prednisone dose adjustment procedure is further described below.

[0550] If deemed necessary by the investigator, participants may be administered ≤ 0.3 mg / kg / day of prednisone (or equivalent OCS) orally during the Screening and Baseline visits.

[0551] Information on the formulation, unit dosage strength, source, packaging, and labeling of oral prednisone is summarized in Table S1.

[0552] Investigators, site staff, and participants must follow package label instructions for proper storage and handling of oral prednisone.

[0553] During each site visit, site staff will provide participants with a daily oral prednisone dose (or equivalent OCS) sufficient to last until the participant's next site visit. Participants will return all used and unused doses to the site at the next site visit.

[0554] Participants will take oral prednisone (or equivalent OCS) daily at a dose directed by the investigator.

[0555] Participants will be provided with a diary to record their daily intake of each oral prednisone dose. Participants will bring their completed diary to each site visit so staff can review dosing records; participants will share their diary information with site staff during home visits.

[0556] If participants miss one or more doses of oral prednisone, they must contact the investigator. Missed doses may not be “made up”; instead, participants will resume taking the investigator-prescribed daily oral prednisone dose unless there is a change in their BP disease status that requires a dose adjustment.

[0557] The Investigator should not deviate from the recommended concurrent oral prednisone dosing regimen (described below) unless the safety of the participant could be compromised. After appropriate steps have been taken to ensure the safety of the participant, such concerns should be documented and communicated to the Sponsor’s Medical Monitor and designee within 24 hours of the event. Note: In the following list, “oral prednisone” refers to prednisone or an alternative OCS of equivalent dosage strength.

[0558] All participants will begin the study with oral prednisone 0.5 mg / kg / day, starting at baseline (Week 0; Day 1).

[0559] If a participant does not achieve CDA within 1-3 weeks of treatment with oral prednisone 0.5 mg / kg / day, the dose may be increased to 0.75 mg / kg / day for up to an additional 3 weeks. This period may be extended for an additional week (based on clinical judgment) to achieve CDA at oral prednisone doses of 0.75 mg / kg / day or 1 mg / kg / day.

[0560] Participants were considered to have treatment failure if they did not achieve CDA after receiving the above prednisone dosing regimen.

[0561] Participants who experienced treatment failure would permanently discontinue the study intervention, complete the ETD visit (Table S4), could start rescue therapy (described below), and then continue to participate in the study and resume their treatment period visits as scheduled. In this case, the participant would be considered a nonresponder.

[0562] When CDA is achieved, the oral prednisone dosing regimen is adjusted as follows:

[0563] -After CDA has been continued for ≥2 weeks, the dose taper schedule begins at the next lower oral prednisone dose listed in Table S3. Each new dose must be maintained for at least 2 weeks as long as no new lesions (transient or non-transient) develop. The duration of the taper step of the incremental dose (>0.5 mg / kg / day) may be shortened based on clinical judgment.

[0564] - For participants who achieve CDA on oral prednisone 0.5 mg / kg / day, the taper steps are 0.3, 0.2, 0.15, and 0.1 mg / kg / day. For participants who require a dose increase to 0.75 or 1.0 mg / kg / day to achieve CDA, the oral prednisone dose must first be tapered to 0.5 mg / kg / day and then continued to 0.3, 0.2, 0.15, and 0.1

[0565] mg / kg / day, as shown in Table S3.

[0566] - Further taper to below the lowest OCS therapy level may be performed in 2.5 mg / day steps until the participant stops oral prednisone therapy (Table S3). Each new dose step must be maintained for at least 2 weeks as long as no new lesions (transient or non-transient) develop.

[0567] - If a participant develops a new lesion but the investigator determines it is not a relapse, prednisone taper will be delayed.

[0568] In this case, tapering can be resumed when no new lesions have appeared for at least 1 week (Table S3).

[0569] If a participant relapses:

[0570] - Increase oral prednisone dose based on the investigator's clinical judgment, and it is recommended to resume administration of 2 tapered doses before relapse. CDA tapering may be resumed after the dose has been increased for at least 2 weeks.

[0571] - If CDA is not achieved, participants should resume initial oral prednisone dose of 0.5 mg / kg / day.

[0572] - Participants must resume weekly study center visits until CDA is restored.

[0573] Investigators will call participants weekly during home visits between mandatory study center visits to review participants' BP disease status and current oral prednisone dosing regimen.

[0574]

[0575] Prohibited drugs

[0576] Participants were not allowed to use the following medications or treatments while receiving the IMP:

[0577] - Any systemic treatment for BP other than OCS, including but not limited to immunosuppressants, IVIg, SCIg, immunoadsorption, anti-CD20 biologics, tetracycline (with or without nicotinamide), dapsone, and methotrexate;

[0578] -Topical corticosteroids (must be discontinued prior to baseline);

[0579] - Any other biologics or experimental / investigational IMPs;

[0580] - Live vaccines or live attenuated vaccines;

[0581] - Complementary therapies including traditional Chinese medicine, herbal remedies, or procedures (e.g., acupuncture) as assessed by the investigator.

[0582] As described below, some of these treatments may be administered as rescue therapy if a participant stops taking IMP.

[0583] Rescue therapy

[0584] Participants will discontinue IMP and begin rescue therapy if any of the following occur:

[0585] - Participant has failed treatment with IMP ("treatment failure," as defined above);

[0586] - Participant relapsed twice;

[0587] - Participant develops steroid toxicity (or any serious AE deemed by the investigator to be related to OCS therapy).

[0588] Participants who report any of the above events will discontinue study intervention and complete the assessments listed for the ETD visit (Table S4). These participants will continue to attend study visits for the remainder of the 36-week treatment period while receiving rescue BP therapy (defined below). At Week 36, these participants will complete the EoTP visit (Table S4); if these participants meet the extension eligibility requirements, they will be invited to immediately participate in the OLE study ARGX-113-2010. Participants who do not meet the extension eligibility requirements or choose not to participate in the OLE study will participate in a 7-week treatment-free follow-up period.

[0589] Rescue therapy may include OCS, topical corticosteroids, immunosuppressants, tetracyclines (with or without niacinamide), dapsone, or methotrexate. As described above, these treatments are permitted as rescue therapy after IMP interruption.

[0590] D. Research Assessment and Procedures

[0591] Each participant was expected to attend each study visit on the designated date (see Table S4 below, which presents the schedule of visit activities to be performed throughout the study). The visit window allowed during the treatment period was ±2 days, and the visit window allowed during the no-treatment follow-up period was ±3 days.

[0592]

[0593]

[0594]

[0595]

[0596] BP disease status assessment and OCS dose monitoring

[0597] The efficacy of treatment will be assessed by the investigator at the site visit, and the investigator will assess the participant's BP disease status (CDA, PR, CR, relapse, treatment failure) based on the definitions / criteria presented herein. The investigator will also record the daily OCS dose administered to the participant since the last visit, adjust the daily OCS dose (taper, stop, restart, or increase) based on the participant's BP disease status, and record treatment failures during the site visit. For home visits between mandatory site visits, the investigator will call the participant once a week to review the current BP disease status and OCS dosing regimen.

[0598] IGA-BP

[0599] Researchers will use the IGA-BP to assess TBP disease activity and severity. The IGA-BP is a new assessment tool that was developed in 2021 by medical experts in the field of AIBD and is currently being used (along with the BPDAI) in other clinical studies of BP therapy. The IGA classifies the severity of BP on a numerical scale from 0 (clear) to 4 (severe).

[0600] IGA-BP will be administered during all center visits (Table S4).

[0601] BPDAI

[0602] In addition to IGA-BP, investigators will assess BP disease activity using the BPDAI. The BPDAI is an internationally validated tool for objectively measuring disease activity. The BPDAI differentiates scores for skin (erosions / blistering and urticaria / erythema) and mucosal activity at multiple anatomical locations. In addition, separate scores for lesions (e.g., pigmentation) are recorded to account for healing lesions.

[0603] BPDAI will be administered during all center visits (Table S4).

[0604] Itch-NRS

[0605] Pruritus symptoms of BP will be indicated by the participants on the Itch NRS, recording the average and worst score of pruritus experienced in the past 24 hours.

[0606] The Itch NRS will be administered during all mandatory site visits starting at baseline (Week 0) (Table S4).

[0607] Quality of Life (QoL) Assessment

[0608] Participants will complete the following PRO assessments of their QoL at the time points listed in the SoA (Table S4):

[0609] -EuroQol 5-Dimension 5-Level Scale (EQ-5D 5L): EQ-5D 5L is a standardized measure of health status developed by the EuroQoL Group to provide a simple, universal measure of health for clinical and economic assessments. The descriptive system includes 5 dimensions (mobility, self-care, usual activities, pain / discomfort, anxiety / depression). Each dimension now has 5 levels: no problem, slight problem, moderate problem, severe problem, and extreme problem.

[0610] - Dermatology Life Quality Index (DLQI): The DLQI consists of 10 questions concerning participants' perceptions of the impact of skin disease in the last week on different aspects of their health-related QoL. The impact of each aspect on QoL rating is qualitatively rated, ranging from "not at all" to "very much".

[0611] -Autoimmune Bullous Disease Quality of Life Index (ABQoL) Questionnaire: The ABQoL was developed and validated to determine the impact of AIBD and its treatment on patients' daily lives. It is a series of 17 questions that address participants' perceptions of how AIBD affects their daily lives, including comfort, hygiene, diet, appearance, social interactions, sexual activity, and employment.

[0612] Glucocorticoid toxicity index

[0613] As an additional measure of the effect of glucocorticoid morbidity, GTI v2.0 will be assessed at the visits listed in the SoA (Table S4). GTI v2.0 is a supplemental scoring system for the overall reporting of AEs judged by the investigator to be related to glucocorticoids during the intervention study. It can also monitor the long-term tolerability of chronic glucocorticoid use in clinical practice.

[0614] GTI v2.0 consists of the following two tools:

[0615] -The Composite GTI (C-GTI) is a primary tool designed to capture toxicities that may result from glucocorticoid exposure. The C-GTI has 9 functional domains: BMI, glycemic control, blood pressure, lipid metabolism, bone mineral density, muscle strength, skin toxicity, neuropsychiatric effects, and infections. Each domain includes several weighted items that correspond to varying degrees of glucocorticoid toxicity. Note: The bone mineral density domain will not be used in this study because bone densitometry is not reliable enough to measure changes over shorter durations and is therefore generally excluded from studies of duration <1 year. Two analysis scores are generated from the weighted C-GTI items: the Cumulative Worsening Score (CWS) and the AIS. The CWS is designed to assess cumulative glucocorticoid toxicity, while the AIS can be used to assess whether a new therapy is effective in reducing glucocorticoid toxicity over time. Together, the CWS and AIS provide complementary information about the ability of an investigational agent to reduce overall glucocorticoid toxicity.

[0616] The -GTI Specific List (GTI-SL) lists well-known glucocorticoid-associated side effects. This non-weighted tool provides additional information on the areas of a participant's treatment that are most impacted by glucocorticoid use. It contains 11 domains (9 of which are shared with the C-GTI) and 23 items. Note: For the reasons stated above, the GTI SL items covering decreased bone mineral density (part of the Bone Health domain) will not be used in this study.

[0617] The tabular components of the modified GTI applicable to this study are listed in Tables S5-S6.

[0618] Table S5. Revised GTI 2.0 Composite Index

[0619]

[0620]

[0621]

[0622] Source: Adapted from McDowell et al., J Allergy Clin Immunol. 2021;9(1):365-372.

[0623] BMI = body mass index; GTI = glucocorticoid toxicity index; HbA1c = glycosylated hemoglobin; LDL = low-density lipoprotein; NP = neuropsychiatric

[0624] Table S6. Specific list of revised GTI 2.0

[0625]

[0626]

[0627] Source: Adapted from McDowell et al., J Allergy Clin Immunol. 2021;9(1):365-372.

[0628] BMI = body mass index; GTI = glucocorticoid toxici...

Claims

1. A method of treating bullous pemphigoid (BP) in a subject in need thereof, the method comprising administering to the subject an effective amount of a human neonatal Fc receptor (FcRn) antagonist.

2. The method of claim 1, wherein the FcRn antagonist comprises two, three or four FcRn binding regions.

3. The method of claim 1 or 2, wherein the FcRn antagonist comprises or consists of a variant Fc region or an FcRn binding fragment thereof.

4. The method of claim 3, wherein the variant Fc region or FcRn binding fragment thereof binds to FcRn with a higher affinity at pH 6.0 than the corresponding wild-type Fc region.

5. The method of claim 3 or 4, wherein the variant Fc region or FcRn binding fragment thereof binds to FcRn with higher affinity at pH 7.4 compared to the corresponding wild-type Fc region.

6. The method according to any one of claims 3 to 5, wherein the variant Fc region comprises or consists of a first Fc domain and a second Fc domain that form a homodimer or a heterodimer.

7. The method of claim 6, wherein the first Fc domain and / or the second Fc domain comprises amino acids Y, T, E, K and F located at EU positions 252, 254, 256, 433 and 434, respectively.

8. The method of claim 6 or 7, wherein the first Fc domain and / or the second Fc domain comprises amino acids Y, T, E, K, F and Y at EU positions 252, 254, 256, 433, 434 and 436, respectively.

9. The method according to any one of claims 6 to 8, wherein the first Fc domain and / or the second Fc domain comprises an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO:

30.

10. The method of any one of claims 6 to 9, wherein the first Fc domain and the second Fc domain comprise an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO:

30.

11. The method according to any one of claims 1 to 10, wherein the FcRn antagonist is igamod.

12. The method of claim 1, wherein the FcRn antagonist is an anti-FcRn antibody.

13. The method of any one of claims 1 to 12, wherein the FcRn antagonist is administered to the subject at a fixed dose of 200 mg to 20,000 mg or at a dose of 2 mg / kg to 200 mg / kg.

14. The method of any one of claims 1 to 13, wherein the FcRn antagonist is administered subcutaneously once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

15. The method of claim 14, wherein the FcRn antagonist is administered subcutaneously at a fixed dose of 200 mg to 20,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

16. The method of claim 14 or 15, wherein the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg or 2000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

17. The method of claim 16, wherein the FcRn antagonist is first administered subcutaneously twice on the same day at a fixed dose of about 1000 mg.

18. The method of any one of claims 1 to 16, wherein the FcRn antagonist is administered subcutaneously at a fixed dose of about 2000 mg for the first two administrations and is subsequently administered subcutaneously at a fixed dose of about 1000 mg.

19. The method of claim 18, wherein the FcRn antagonist is administered subcutaneously at a fixed dose of 2000 mg for the first two administrations and is subsequently administered subcutaneously at a fixed dose of 1000 mg.

20. The method of any one of claims 1 to 19, wherein the first two administrations of the FcRn antagonist are subcutaneous administrations at a fixed dose of about 1000 mg administered twice on the same day.

21. The method of claim 20, wherein the first two administrations of the FcRn antagonist are subcutaneous administrations at a fixed dose of 1000 mg administered twice on the same day.

22. The method of claim 11, wherein the igamod is administered subcutaneously once a week at a fixed dose of 800 to 1200 mg.

23. The method of claim 11, wherein the igamod is administered subcutaneously once a week at a fixed dose of about 1000 mg.

24. The method of claim 11, wherein the igamod is administered subcutaneously once a week at a fixed dose of 1000 mg.

25. The method of any one of claims 1 to 24, wherein the FcRn antagonist is co-formulated with hyaluronidase and administered subcutaneously.

26. The method of claim 25, wherein the hyaluronidase is recombinant human hyaluronidase PH20 (rHuPH20).

27. The method of claim 26, wherein the rHuPH20 is administered once a week at a dose of 2000 U / mL.

28. The method of claim 26, wherein the rHuPH20 is administered once a week at about 11,000 U or about 22,000 U.

29. The method of any one of claims 1 to 13, wherein the FcRn antagonist is administered intravenously once a week or once every two weeks.

30. The method of claim 29, wherein the FcRn antagonist is administered intravenously at a dose of 2 mg / kg to 200 mg / kg once a week or once every two weeks.

31. The method of claim 29 or 30, wherein the FcRn antagonist is administered intravenously at a dose of 3 mg / kg to 60 mg / kg once a week or once every two weeks.

32. The method of any one of claims 29 to 31, wherein the FcRn antagonist is administered intravenously at a dose of 5 mg / kg once a week or once every two weeks.

33. The method of any one of claims 29 to 31, wherein the FcRn antagonist is administered intravenously at a dose of 10 mg / kg once a week or once every two weeks.

34. The method of any one of claims 29 to 31, wherein the FcRn antagonist is administered intravenously at a dose of 25 mg / kg once a week or once every two weeks.

35. The method of any one of claims 29 to 34, wherein the FcRn antagonist is first administered intravenously and subsequently administered subcutaneously.

36. The method of claim 35, wherein the FcRn antagonist is administered first intravenously and then subcutaneously at a fixed dose of 200 mg to 20,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

37. The method of claim 36, wherein the FcRn antagonist is administered first intravenously and then subcutaneously at a fixed dose of 1000 mg or 2000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

38. The method of any one of claims 1 to 37, wherein the FcRn antagonist is administered for 52 weeks or less.

39. The method of any one of claims 1 to 38, wherein the FcRn antagonist is administered for 36 weeks or less.

40. The method of any one of claims 1 to 39, wherein the FcRn antagonist is administered for at least 26 weeks.

41. The method of any one of claims 1 to 37, wherein the FcRn antagonist is administered for at least 36 weeks.

42. The method of any one of claims 1 to 41, further comprising administering to the subject a dose of a corticosteroid.

43. The method of claim 42, wherein the dose of the corticosteroid is reduced after disease control or complete remission has been achieved.

44. The method of claim 43, wherein the dose of the corticosteroid is reduced after disease control has been sustained for at least two weeks.

45. The method of claim 44, wherein after two weeks of sustained disease control, the dose of the corticosteroid is reduced from 0.5 mg / kg / day prednisone equivalents to 0.3 mg / kg / day prednisone equivalents, from 0.3 mg / kg / day prednisone equivalents to 0.2 mg / kg / day prednisone equivalents, from 0.2 mg / kg / day prednisone equivalents to 0.15 mg / kg / day prednisone equivalents, and from 0.15 mg / kg / day prednisone equivalents to 0.1 mg / kg / day prednisone equivalents.

46. ​​The method of claim 44, wherein after two weeks of sustained disease control, the dose of the corticosteroid is reduced from 0.75 mg / kg / day prednisone equivalents to 0.5 mg / kg / day prednisone equivalents, from 0.5 mg / kg / day prednisone equivalents to 0.3 mg / kg / day prednisone equivalents, from 0.3 mg / kg / day prednisone equivalents to 0.2 mg / kg / day prednisone equivalents, from 0.2 mg / kg / day prednisone equivalents to 0.15 mg / kg / day prednisone equivalents, and from 0.15 mg / kg / day prednisone equivalents to 0.1 mg / kg / day prednisone equivalents.

47. The method of claim 44, wherein after two weeks of sustained disease control, the dose of the corticosteroid is reduced from 1 mg / kg / day prednisone equivalents to 0.75 mg / kg / day prednisone equivalents, from 0.75 mg / kg / day prednisone equivalents to 0.5 mg / kg / day prednisone equivalents, from 0.5 mg / kg / day prednisone equivalents to 0.3 mg / kg / day prednisone equivalents, from 0.3 mg / kg / day prednisone equivalents to 0.2 mg / kg / day prednisone equivalents, from 0.2 mg / kg / day prednisone equivalents to 0.15 mg / kg / day prednisone equivalents, and from 0.15 mg / kg / day prednisone equivalents to 0.1 mg / kg / day prednisone equivalents.

48. The method of any one of claims 45 to 47, wherein each dose of the corticosteroid is maintained for at least two weeks.

49. The method of claim 48, wherein each dose of corticosteroid is maintained for at least two weeks as long as no new lesions appear.

50. The method of any one of claims 45 to 49, further comprising reducing the daily dose of corticosteroid by 2.5 mg prednisone equivalents every two weeks for one or more two-week periods.

51. The method of claim 50, wherein the daily dose of corticosteroid is reduced by 2.5 mg of prednisone equivalents every two weeks for one or more two-week periods until the daily dose of corticosteroid is zero, resulting in discontinuation of corticosteroid therapy.

52. The method of claim 50 or 51, wherein each daily dose is maintained for two weeks as long as no new lesions appear.

53. The method of any one of claims 45 to 49, further comprising reducing the daily dose of the corticosteroid by 1 mg of prednisone equivalent per week for a period of one or more weeks.

54. The method of claim 53, wherein the daily dose of corticosteroid is reduced by 1 mg of prednisone equivalent weekly for one or more one week periods until the daily dose of corticosteroid is zero, resulting in discontinuation of corticosteroid therapy.

55. The method of claim 53 or 54, wherein each daily dose is maintained for one week as long as no new lesions appear.

56. The method of any one of claims 42 to 55, wherein the corticosteroid is prednisone.

57. The method according to any one of claims 1 to 56, wherein the BP is selected from the group consisting of newly diagnosed BP, recurrent BP and refractory BP.

58. The method of any one of claims 1 to 57, wherein the subject is diagnosed with moderate to severe BP, mild BP, moderate BP, or severe BP.

59. The method of any one of claims 1 to 58, wherein the subject has detectable serum levels of anti-BP180 antibodies or anti-BP230 antibodies, or both.

60. The method of claim 59, wherein the subject exhibits a decrease in serum levels of the anti-BP180 antibody or the anti-BP230 antibody after administration of the FcRn antagonist.

61. The method of claim 60, wherein the reduction in the serum level of the anti-BP180 antibody or anti-BP230 antibody after administration of the anti-FcRn antagonist is at least 10%, at least 25%, at least 50%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% of the serum level of the anti-BP180 antibody or anti-BP230 antibody in the subject before administration of the anti-FcRn antagonist.

62. The method of claim 60 or 61, wherein the serum level of the anti-BP180 antibody or anti-BP230 antibody is undetectable following administration of the FcRn antagonist.

63. The method of any one of claims 1 to 62, wherein the FcRn antagonist is administered until disease control, partial remission, or complete remission is achieved.

64. The method of any one of claims 1 to 63, wherein the subject achieves complete remission.

65. The method of any one of claims 1 to 64, wherein the subject's complete remission lasts for at least 2 months.

66. The method of claim 65, wherein the subject's complete remission lasts for at least 6 months.

67. The method of any one of claims 63 to 66, wherein the subject remains in complete remission in the absence of oral corticosteroids.

68. The method of claim 67, wherein the subject remains in complete remission in the absence of oral corticosteroids for at least eight weeks.

69. The method of claim 68, wherein at the end of the 36-week treatment period, the subject remains in complete remission in the absence of corticosteroids for at least eight weeks.

70. The method of any one of claims 1 to 62, wherein BP recurrence is prevented after achieving remission from BP, wherein prevention of BP recurrence persists for at least 36 weeks after initiation of administration of the FcRn antagonist.

71. The method of any one of claims 1 to 70, wherein the subject has an IGA-BP score of 0 or 1 following administration of the FcRn antagonist.

72. The method of claim 71, wherein the subject has an IGA-BP score of 0 or 1 in the absence of oral corticosteroids for at least eight weeks.

73. The method of claim 72, wherein at the end of the 36-week treatment period, the subject has an IGA-BP score of 0 or 1 in the absence of oral corticosteroids for at least eight weeks.

74. The method of any one of claims 63 to 70, wherein the subject has an IGA-BP score of 0 following administration of the FcRn antagonist.

75. The method of claim 74, wherein the subject has an IGA-BP score of 0 in the absence of oral corticosteroids for at least eight weeks.

76. The method of claim 75, wherein at the end of the 36-week treatment period, the subject has an IGA-BP score of 0 in the absence of oral corticosteroids for at least eight weeks.

77. An FcRn antagonist for use in treating BP, wherein the treatment is performed according to the method of any preceding claim.

78. An FcRn antagonist for use in the manufacture of a medicament for the treatment of BP, wherein the treatment is performed according to the method of any preceding claim.

79. A method for monitoring the efficacy of treatment of BP in a subject following treatment with a first FcRn antagonist, the method comprising: a) measuring in vitro the serum level of anti-BP180 antibodies and / or anti-BP230 antibodies in a blood sample taken from the subject; as well as b) comparing said serum level of said anti-BP180 antibody and / or said anti-BP230 antibody with a reference value associated with BP in said subject, wherein if the serum level of the anti-BP180 antibody and / or the anti-BP230 antibody in the sample is greater than or equal to the reference value, the treatment is ineffective, and wherein if the serum level of the anti-BP180 antibody and / or the anti-BP230 antibody is less than the reference value, the treatment is effective.

80. A method of treating BP in a subject who has received a first FcRn antagonist and is receiving a corticosteroid dosing regimen, the method comprising: a) administering to said subject an effective amount of a second FcRn antagonist; b) measuring in vitro the serum level of anti-BP180 antibodies and / or anti-BP230 antibodies in a blood sample taken from the subject; and c) comparing said serum level of said anti-BP180 antibody and / or said anti-BP230 antibody with a reference value associated with BP in said subject, wherein if the serum level of the anti-BP180 antibody and / or the anti-BP230 antibody in the sample is greater than or equal to the reference value, the corticosteroid dosing regimen is maintained, or wherein if the serum level of the anti-BP180 antibody and / or the anti-BP230 antibody is less than the reference value, the corticosteroid dosing regimen is gradually reduced.

81. A method for treating BP in a subject, the method comprising: (a) administering to the subject one or more initial doses of an effective amount of a first FcRn antagonist; as well as (b) administering to the subject one or more additional doses of an effective amount of a second FcRn antagonist if the subject's serum level of anti-BP180 antibodies and / or anti-BP230 antibodies after step (a) is greater than or equal to a reference value associated with the subject's BP, or discontinuing treatment with the first FcRn antagonist if the subject's serum level of anti-BP180 antibodies and / or anti-BP230 antibodies after step (a) is less than a reference value associated with the subject's active disease.

82. A method for treating BP in a subject, the method comprising: administering to the subject an effective amount of a second FcRn antagonist, wherein the BP of the subject has relapsed following prior therapy with a first FcRn antagonist, and wherein the subject has a serum level of anti-BP180 antibody and / or anti-BP230 antibody greater than or equal to a reference value associated with the subject's BP.

83. A method for determining whether a subject who has been previously treated for BP with a first FcRn antagonist requires further treatment with a second FcRn antagonist, the method comprising: a) measuring in vitro the serum level of anti-BP180 antibodies and / or anti-BP230 antibodies in a blood sample taken from the subject; as well as b) comparing said serum level of said anti-BP180 antibody and / or said anti-BP230 antibody with a reference value associated with BP in said subject, Wherein if the serum level of the anti-BP180 antibody and / or the anti-BP230 antibody in the sample is greater than or equal to the reference value, the subject needs further treatment with the second FcRn antagonist.

84. The method of any one of claims 79 to 83, wherein the subject was previously treated with the first FcRn antagonist at a fixed dose of about 200 mg to about 20,000 mg or at a dose of 2 mg / kg to 200 mg / kg.

85. The method of any one of claims 79 to 83, wherein the subject was previously treated with the first FcRn antagonist administered intravenously at a dose of 20 mg / kg to 100 mg / kg.

86. The method of claim 84 or 85, wherein the subject was previously treated with the first FcRn antagonist administered intravenously at a dose of 3 mg / kg to 60 mg / kg.

87. The method of any one of claims 80 to 83, wherein the effective amount of the second FcRn antagonist is a higher dose compared to a previous treatment with the first FcRn antagonist.

88. The method of any one of claims 80 to 83, wherein the effective amount of the second FcRn antagonist is a lower dose compared to a previous treatment with the first FcRn antagonist.

89. The method of any one of claims 80 to 83, wherein the effective amount of the second FcRn antagonist is administered at a fixed dose of about 200 mg to about 20,000 mg or at a dose of 2 mg / kg to 200 mg / kg.

90. The method of claim 89, wherein the effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of about 750 mg to about 3000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

91. The method of claim 90, wherein the effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of about 1000 mg or about 2000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

92. The method of any one of claims 80 to 83, wherein the first FcRn antagonist and the second FcRn antagonist are each the same FcRn antagonist.

93. The method of any one of claims 80 to 83, wherein the first FcRn antagonist and the second FcRn antagonist are each different FcRn antagonists.

94. The method of claim 93, wherein the FcRn antagonist comprises or consists of a variant Fc region or an FcRn binding fragment thereof.

95. The method of claim 94, wherein the first FcRn antagonist or the second FcRn antagonist comprises or consists of a variant Fc region or an FcRn binding fragment thereof.

96. The method of claim 94 or 95, wherein the variant Fc region or FcRn binding fragment thereof binds to FcRn with a higher affinity at pH 6.0 and / or pH 7.4 compared to a corresponding wild-type Fc region.

97. The method of claim 94 or 95, wherein the variant Fc region comprises or consists of two Fc domains that form a homodimer or a heterodimer.

98. The method of any one of claims 92, 94, 96 or 97, wherein the FcRn antagonist is an Fc region comprising amino acids Y, T, E, K, F and Y at EU positions 252, 254, 256, 433, 434 and 436, respectively.

99. The method of any one of claims 93, 95, 96 or 97, wherein the first FcRn antagonist or the second FcRn antagonist is an Fc region comprising amino acids Y, T, E, K, F and Y at EU positions 252, 254, 256, 433, 434 and 436, respectively.

100. The method of claim 98, wherein the FcRn antagonist is igamod.

101. The method of claim 99, wherein the first FcRn antagonist or the second FcRn antagonist is igamod.

102. The method of any one of claims 92, 94, 96 or 97, wherein the amino acid sequence of at least one of the Fc domains is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO:

3.

103. The method of any one of claims 93, 95, 96 or 97, wherein the amino acid sequences of both of the Fc domains are independently selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO:

3.

104. The method of claim 102, wherein the first FcRn antagonist is an anti-FcRn antibody and the second FcRn antagonist is igamod.

105. The method of claim 102, wherein the first FcRn antagonist is an anti-FcRn antibody and the second FcRn antagonist comprises the amino acid sequence of SEQ ID NO: 1, 2 or 3.

106. The method of claim 104 or 105, wherein the patient has not been previously treated with agamod.

107. The method of any one of claims 79 to 106, wherein the subject has one or more physical symptoms of BP following treatment with the first FcRn antagonist.

108. The method of any one of claims 79 to 107, wherein the subject has a serum level of anti-BP180 antibody or anti-BP230 antibody that is associated with recurrence of BP.

109. A method of treating BP in a subject in need thereof, the method comprising administering to the subject an effective amount of a human FcRn antagonist and a corticosteroid, wherein the cumulative oral dose of the corticosteroid administered to the subject does not exceed 100 mg / kg, does not exceed 75 mg / kg, does not exceed 50 mg / kg, or does not exceed 25 mg / kg.

110. A method of treating BP in a subject in need thereof, the method comprising administering to the subject an effective amount of a human FcRn antagonist and a corticosteroid, wherein the oral prednisone equivalent dose of the corticosteroid administered to the subject does not exceed 1 mg / kg / day, does not exceed 0.75 mg / kg / day, does not exceed 0.5 mg / kg / day, does not exceed 0.3 mg / kg / day, does not exceed 0.25 mg / kg / day, does not exceed 0.2 mg / kg / day, does not exceed 0.15 mg / kg / day, or does not exceed 0.1 mg / kg / day.

111. A method of treating BP in a subject in need thereof, the method comprising administering to the subject an effective amount of a human FcRn antagonist and a corticosteroid, wherein the oral prednisone equivalent dose of the corticosteroid administered to the subject does not exceed 12.5 mg / day or does not exceed 10 mg / day.

Images